Consultations in

Infectious Disease
A Case Based Approach to
Diagnosis and Management
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Consultations in
Infectious Disease
A Case Based Approach to
Diagnosis and Management

Daniel Caplivski, MD
Associate Professor of Medicine
Division of Infectious Diseases
Director, Travel Medicine Program
Mount Sinai School of Medicine
New York, NY

W. Michael Scheld, MD
Bayer-Gerald L Mandell Professor of Infectious Diseases
Professor of Medicine
Clinical Professor of Neurosurgery
Director, Pfizer Initiative in International Health
University of Virginia Health System
Charlottesville, VA

1
1
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Library of Congress Cataloging-in-Publication Data

Caplivski, Daniel.
Consultations in infectious disease : a case based approach to diagnosis and management
/ Daniel Caplivski, W. Michael Scheld.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-0-19-973500-6 (pbk. : alk. paper)
1. Communicable diseases—Diagnosis—Case studies. 2. Central nervous system—
Infections—Diagnosis—Case studies. I. Scheld, W. Michael. II. Title.
[DNLM: 1. Communicable Diseases—diagnosis—Case Reports. 2. Communicable
Diseases—therapy—Case Reports. 3. Central Nervous System Infections—diagnosis—
Case Reports. 4. Central Nervous System Infections—therapy—Case Reports. WC 100]
RC113.3.C37 2011
616.07'5—dc22 2011012555

9 8 7 6 5 4 3 2 1
Printed in China
on acid-free paper
 Dedication

v
Joshua Gibson was a beloved member of the Mount Sinai family. He studied
at Bowdoin College and the Yale School of Medicine before completing his
internship and residency at Mount Sinai Hospital. Together with other resi-
dents, he started the Advancing Idealism in Medicine program so that future
generations of residents would reconnect with the humanistic goals that had
first brought them to the field of medicine. He went on to care for patients in
Mount Sinai’s World Trade Center Program before starting his fellowship in
infectious diseases. Those who knew Josh are quick to smile as they remember
his love for the Boston Celtics and Red Sox, his eclectic music collection
(including many Pavement albums and Lee Scratch Perry’s “Dub Chill Out”),
and his endless spirit of adventure. He traveled all over India, worked in refugee
camps in Africa, and researched the epidemiology of AIDS in China. He was a
great basketball player, and used to commute by running from Mount Sinai to
his home in Brooklyn—a mere 10 miles away. Most of all, we remember him as
a dear friend, husband, son, and brother. We hope that throughout your career
you will return to these pages and be inspired by what a great person he was.
 Preface
Foreword

During the writing of this book, we have experienced an operatic range of

emotions as we have relived many of our most interesting infectious disease
consultations. There was the tension of an unresolved set of symptoms, the
joy of a diagnosis confirmed, and sometimes the shock of an unexpected
assailant. There were dramatic moments at the microscope when a key image
on the glass slide would lift the veil from our eyes and finally link all of the
clues together. There were also moments of great sadness, as we recalled
overwhelming infections that claimed the lives of our patients. Names like
Rhizopus and Nocardia stir a visceral reaction when we hear them because
of the devastation that they can cause in an immunocompromised host. In
the many images in this book, we hope to transfer that visceral memory to
physicians and students and to offer a field guide to the limitless territory of
infectious diseases consultations.
Books of this nature are collaborations of a musical sort. We have felt like
conductors working with a world-class ensemble of musicians, and the end
vi

result is a reflection of their hard work and dedication to this project. We

thank all of our contributors for their evocative storytelling and for the illu-
minating discussions they have written. Teaching infectious diseases fellows,
residents, and students is one of the great privileges of a career in academic
medicine, and this book is a written expression of how much we love that
process. We are very grateful to our colleagues at Oxford University Press
for the opportunity to share this work with a wider audience, and to all of our
families and friends who tolerated our reclusiveness as we completed this pro-
ject. Finally, we thank our patients for sharing their stories with us, for helping
us to understand the importance of simple blessings, and for inspiring us to
never stop learning.
Contents

Contributors xv
1. Meningitis 1
Case 1a: A College Student with Altered Mental Status:
Neisseria meningitidis Meninigitis 1
Amy Mathers and W. Michael Scheld
Case 1b: Television Intolerance: Streptococcus
pneumoniae Meningitis 4
Jennifer Jao and Daniel Caplivski
Case 1c: Gait Instability and Slurred Speech in an
Immunosuppressed Patient: Cryptococcus neoformans
Meningitis 8
Sean Pawlowski and W. Michael Scheld

vii
Case 1d: A 38-year-old Woman from Thailand with
Pulmonary Infiltrates and Meningitis: Mycobacterium
tuberculosis Meningitis 13
Najah Doka and W. Michael Scheld
Case 1e: Fever and Confusion after Neurosurgery: Klebsiella
pneumoniae Meningitis 18
Rachel Chasan
2. Encephalitis and Myelopathy 23
Case 2a: Recurrent Meningitis: Herpes simplex virus
Meningoencephalitis 23
Sean Pawlowski and W. Michael Scheld
Case 2b: Confusion and Fever in an Elderly Woman:
Varicella zoster virus Encephalitis 25
Mahesh Swaminathan
Case 2c: A 41-year-old Woodcutter with Progressively
Worsening Mental Status: Acanthamoebã Encephalitis 32
Florence Nana, W. Michael Scheld, and Joshua Dowell
Case 2d: A Renal Transplant Recipient with Weakness
and Gait Instability: Human T-lymphotropic virus-1
Myelopathy 36
Michael Lief and Shirish Huprikar
 3. Focal Central Nervous System Infections
CONTENTS

43
Case 3a: Ataxia, Dizziness, and Altered Mental Status in a
Patient Previously Treated for Pneumonia: Streptococcus
intermedius Brain Abscess 43
Sean Pawlowski and W. Michael Scheld
Case 3b: A 55-Year-Old Man with Back Pain: Staphylococcus
aureus Epidural Abscess 47
Rupa Rajesh Patel and Daniel Caplivski
Case 3c: A Bone Marrow Transplant Recipient with Back
Pain and Weakness: Nocardia farcinica Epidural Abscess 50
Nicole M. Bouvier and Daniel Caplivski
Case 3d: A Construction Worker with Headache and
Visual Loss: Neurocysticercosis 54
Luciano Kapelusznik and Daniel Caplivski
Case 3e: A 42-Year-Old Man with Progressive Cognitive
Decline: Progressive Multifocal Leukoencephalopathy 60
Rupa Rajesh Patel and Daniel Caplivski
4. Ophthalmologic Infections 67
viii

Case 4a: A 23-Year-Old Contact Lens Wearer with Eye

Pain and Decreased Vision: Pseudomonas Keratitis 67
Nancy Sun and Chad Zatezalo
Case 4b: A 46-Year-Old Man with a Painful Red Eye and a
Rash: Treponema pallidum Uveitis 70
Chad Zatezalo and Ronni Lieberman
Case 4c: Cytomegalovirus Retinitis in a Patient with AIDS:
Cytomegalovirus Retinitis 76
Chad Zatezalo and Ronni Lieberman
Case 4d: A 17-Year-Old Female with Peripheral Vision
Loss: Streptococcus bovis Endophthalmitis 84
Rupa Rajesh Patel, Katherine Zamecki, Michael Mullen,
and Shirish Huprikar
Case 4e: Fever, Chills, and Unilateral Vision Loss in a
73-Year-Old Man: Streptococcus bovis Endophthalmitis 90
Daniel Caplivski, Chad Zatezalo, and Robert S. Klein
Case 4f: Decreased Vision and a Painful, Red Eye in
a Patient with Acute Myelogenous Leukemia (AML)
and Prolonged Neutropenia: Aspergillus fumigatus
Endophthalmitis 94
Lindsey Reese, Chad Zatezalo, Stephen Mercer, Robert Phelps, and
Shirish Huprikar
 Case 4g: Blurry Vision in a Patient with AIDS: Immune

CONTENTS
Reconstitution Uveitis 99
Ronni Lieberman
5. Oropharyngeal and Sinus Infections 107
Case 5a: A 43-Year-Old Man with Neck Swelling and
Stridor: Meenakshi Mehrotra Rana 107
Meenakshi Mehrotra Rana
Case 5b: Sore Throat and Neck Swelling in a 48-Year-Old
Man with AIDS :Streptococcus pyogenes 111
Daniel Caplivski
Case 5c: Sore Throat and Shortness of Breath followed
by Septic Shock in a Healthy 18-Year-Old Polo Player:
Lemierre’s Syndrome 116
Joshua C. Eby and W. Michael Scheld
Case 5d: A Renal Transplant Recipient with Facial Pain and
Swelling: Mucormycosis 120
Daniel Caplivski and Shirish Huprikar

ix
6. Pulmonary Infections in Immunocompetent Hosts 127
Case 6a: A 27-Year-Old Woman with a Fever, Cough, and
Pleuritic Chest Pain: Streptococcus pneumoniae 127
Jennifer Jao and Daniel Caplivski
Case 6b: A 31-Year-Old Man with Skin Lesions Following a
Respiratory Illness: Mycoplasma pneumoniae 132
Mahesh Swaminathan
Case 6c: Persistent Cough in a Woman from Mexico:
Mycobacterium tuberculosis 137
Mahesh Swaminathan
Case 6d: Respiratory Distress in 2009: H1N1 Influenza 147
Irini Scordi-Bello and David P. Calfee
Case 6e: Three Men with Severe Pneumonia after Entering
a Mine: Histoplasma capsulatum 153
Daniel Caplivski
7. Pulmonary Infections in Immunocompromised Hosts 161
Case 7a: A 73-Year-Old Man with Nosocomial Pneumonia:
Pseudomonas aeruginosa 161
Keith Sigel, Irini Scordi-Bello, Gopi Patel, and Daniel Caplivski
Case 7b: A 72-Year-Old Woman with Persistent Cough
and Neutropenia: Respiratory Syncytial Virus 167
Daniel Caplivski and Shirish Huprikar
CONTENTS

Case 7c: A 56-Year-Old Woman with Pulmonary Nodules:

Aspergillus fumigatus 170
Daniel Caplivski, Mary Beth Beasley, and Shirish Huprikar
Case 7d: A 47-Year-Old Woman from Thailand with
Worsening Dyspnea: Pneumocystis jiroveci 176
Jennifer Jao
Case 7e: Severe Pneumonia from a Gram-Positive Bacillus:
Nocardia asteroides 180
Meenakshi Mehrotra Rana and Mary Beth Beasley
Case 7f: Fever, Cough, and Shortness of Breath in an
Immunocompromised Host Legionella pneumophila 184
Luciano Kapelusznik
8. Cardiac Infections 191
Case 8a: A 36-Year-Old Man with Homonymous
Hemianopsia: Streptococcus constellatus Endocarditis 191
Meenakshi Mehrotra Rana
Case 8b: Shortness of Breath and Weight Loss in a
Patient with Hypertrophic Obstructive Cardiomyopathy:
x

Cardiobacterium hominis Endocarditis 200

Luciano Kapelusznik and Jeffrey Gumprecht
Case 8c: A 24-Year-Old Man from Botswana with Pleuritic
Chest Pain:Tuberculous Pericarditis 204
Florence Nana and W. Michael Scheld
Case 8d: Skin Lesion in a Patient with Recent Heart
Transplant: Chagas Disease 208
Mahesh Swaminathan and Shirish Huprikar
9. Gastrointestinal Infections 217
Case 9a: Diffuse Colitis and Pseudomembranes: Clostridium
difficile Colitis 217
David P. Calfee
Case 9b: Abdominal Pain, Fever, and Weight Loss in a Patient
with Crohn’s Disease: Gemella morbillorum Liver Abscess 222
Marion-Anna Protano, Luciano Kapelusznik,
and Daniel Caplivski
Case 9c: Fevers and Chills after Travel to India: Typhoid
Fever 226
Jennifer Jao
Case 9d: Enlarging Liver Cysts in a Woman from
Uzbekistan: Hydatid Cysts from Echinococcus granulosus 230
Daniel Seth Fierer and Daniel Caplivski
 Case 9e: A-65 Year-Old Heart Transplant Recipient with

CONTENTS
Abdominal Pain and Altered Mental Status: Strongyloides
stercoralis 233
Gopi Patel, Michael Lief, and Daniel Caplivski
Case 9f: A Liver Transplant Recipient with Fever and
Abdominal Pain: Cytomegalovirus Colitis 239
Meenakshi Mehrotra Rana, and Shirish Huprikar
10. Urinary Tract Infections 247
Case 10a: Methicillin-Susceptible Staphylococccus
aureus (MSSA) Pyelonephritis: Staphylococcus aureus
Pyelonephritis 247
Florence Nana and W. Michael Scheld
Case 10b: A 19-Year-Old Stem Cell Transplant Recipient
with Hematuria: BK Virus Hemorrhagic Cystitis 249
Daniel Caplivski and Shirish Huprikar
Case 10c: Multidrug-Resistant Organisms: KPC-producing
Klebsiella pneumoniae 251
Gopi Patel

xi
Case 10d: An 84-Year-Old Man in Septic Shock: Prostatic
abscess Meenakshi Mehrotra Rana 255
Meenakshi Mehrotra Rana
11. Skin and Soft Tissue Infections 261
Case 11a: A 21-Year-Old Man with Recurrent Abscesses:
Methicillin-Resistant Staphylococcus aureus Infection 261
Rachel Chasan
Case 11b: A 60-Year-Old Woman with Diabetes Mellitus
and Severe Leg Pain: Streptococcus agalactiae Necrotizing
Fasciitis 265
Mahesh Swaminathan, Marco Harmaty, and Daniel Caplivski
Case 11c: Postoperative Dehiscence Following Gastric
Banding Surgery: Mycobacterium fortuitum 271
Meenakshi Mehrotra Rana, Marco Harmaty,
and Daniel Caplivski
Case 11d: A 61-Year-Old Woman from Mexico with
Cutaneous Ulcers: Sporothrix schencki 277
Florence Nana and W. Michael Scheld
Case 11e: Enlarging Skin Lesions in a Kidney–Pancreas
Transplant Recipient: Alternaria 279
Sean Pawlowski and W. Michael Scheld
CONTENTS

Case 11f: Orbital, Ear, and Skin Lesions in a Healthy

Laboratory Research Assistant: Vaccinia Virus
Infection 282
Joshua C. Eby and W. Michael Scheld
Case 11g: A 46-Year-Old Man with Fevers, Rash, and
Malaise: Acute Retroviral Syndrome: Acute Retroviral
Syndrome 286
Meenakshi Mehrotra Rana, Michael Mullen, and Daniel Caplivski
12. Bone and Joint Infections 291
Case 12a: 51-Year-Old Woman with a Painless Foot Ulcer:
Diabetic Foot Infections 291
Keith Sigel
Case 12b: Non-Healing Skin Ulceration with an Associated
Fistulous Tract: Tuberculous Osteomyelitis 293
Sean Pawlowski and W. Michael Scheld
Case 12c: A Painful, Swollen Knee: Prosthetic Joint
Infections 297
Michael M. Gaisa and Michael Mullen
xii

Case 12d: A 68-Year-Old Woman with Fever and Multiple

Inflamed Joints: Neisseria meningitidis 301
Jennifer Jao
13. Vector-Borne Infections 305
Case 13a: A Veterinarian with Multiple Skin Ulcers after
Travel to Costa Rica: Leishmaniasis 305
Daniel Caplivski and Robert Phelps
Case 13b: Fever in a Returned Traveler: Plasmodium vivax
malaria 310
Sean Pawlowski and W. Michael Scheld
Case 13c: A 51-Year-Old Woman with Fever, Rash, and an
Eschar: Rickettsialpox 315
Luciano Kapelusznik
Case 13d: A Call from the Hematology Lab: Babesiosis 320
Meenakshi Mehrotra Rana
Case 13e: Altered Mental Status, Thrombocytopenia
and Leukopenia in a Hiker: Human Granulocytic
Anaplasmosis 325
Rachel Chasan
14. Noninfectious Syndromes that Mimic Infections

CONTENTS
331
Case 14a: Prolonged Postpartum Fever: Septic Pelvic
Thrombophlebitis 331
Lindsey Reese
Case 14b: Worsening Dyspnea and Pulmonary Infiltrates:
Cryptogenic Organizing Pneumonia 334
Michael M. Gaisa, Mary Beth Beasley, and Daniel Caplivski
Case 14c: Fever, Hypotension, and Rash in an
Immunocompromised Patient with Lymphoma: Graft
versus Host Disease 338
Lindsey Reese, Shirish Huprikar, Stephen Mercer, and Robert Phelps
Case 14d: A Renal Transplant Recipient with a Mediastinal
Mass: Post-transplant Lymphoproliferative Disease 343
Daniel Caplivski and Shirish Huprikar
Case 14e: A 23-Year-Old Man with Unexplained Fevers,
Diffuse Pains, and Rash: Still’s Disease 346
Michael M. Gaisa, Stephen Mercer, and Daniel Caplivski
Case 14f: A 45-Year-Old Man with Bullae and Vesicles:

xiii
Vancomycin-associated Linear IgA Bullous Dermatosis 352
Amy Mathers, Stephen Mercer, and William Michael Scheld

Index 357
This page intentionally left blank
 Contributors

Mary Beth Beasley, MD Joshua C. Eby, MD

Associate Professor of Pathology Assistant Professor, Department of
Head, Pulmonary Pathology Internal Medicine
Mount Sinai Medical Center Division of Infectious Disease and
New York, NY International Health
University of Virginia
Nicole Bouvier, MD Charlottesville, VA
Clinical Fellow, Division of Infectious
Diseases Daniel Seth Fierer, MD
Mount Sinai School of Medicine Assistant Professor, Division of
New York, NY Infectious Diseases
Mount Sinai School of Medicine
David P. Calfee, MD, MS New York, NY
Chief Hospital Epidemiologist
Department of Medicine, Weill Michael M. Gaisa, MD, PhD

xv
Cornell Medical College Assistant Professor, Division of
New York-Presbyterian Hospital/ Infectious Diseases
Weill Cornell Mount Sinai School of Medicine
New York, NY New York, NY
Rachel Chasan, MD, MPH Jeffrey Gumprecht, MD
Clinical Fellow, Division of Infectious Assistant Clinical Professor of Medicine
Diseases Division of Infectious Diseases
Mount Sinai School of Medicine Mount Sinai School of Medicine
New York, NY New York, NY
Najah I. Doka, MD, MPH Marco Harmaty MD
Clinical Fellow, Division of Assistant Professor of Surgery
Infectious Diseases and Department of Surgery
International Health Division of Plastic Surgery
Department of Medicine Mount Sinai School of Medicine
University of Virginia New York, NY
Charlottesville, VA
Shirish Huprikar, MD
Joshua D. Dowell, MD, PhD Director, Transplant Infectious
Resident Physician, Department of Diseases Program
Radiology Associate Professor, Department of
University of Virginia Medicine
Health Systems Mount Sinai School of Medicine
Charlottesville, VA New York, NY
CONTRIBUTORS

Jennifer Jao, MD, MPH Michael P. Mullen, MD

Clinical Instructor, Department of Interim Chief, Division of Infectious
Medicine Diseases
Division of Infectious Diseases Associate Professor of Medicine
Mount Sinai School of Medicine Mount Sinai School of Medicine
New York, NY New York, NY

Luciano Kapelusznik, MD Florence Nana, MD

Clinical Fellow, Division of Infectious Clinical Fellow, Division of Infectious
Diseases Diseases and International Health
Mount Sinai School of Medicine Department of Medicine
New York, NY University of Virginia
Charlottesville, VA
Robert S. Klein, MD
Gopi Patel, MD
Professor, Department
of Medicine Assistant Professor, Division of
Division of Infectious Diseases Infectious Diseases
Mount Sinai School of Medicine Mount Sinai School of Medicine
New York, NY New York, NY
Rupa Rajesh Patel, MD
Ronni Lieberman, MD
Adjunct Faculty, Division of
Assistant Clinical Professor,
xvi

Infectious Diseases
Department of Ophthalmology
Mount Sinai School of Medicine
Mount Sinai School of Medicine
New York, NY
New York, NY
Sean Pawlowski, MD
Michael H. Lief, MD
Colorado Infectious Disease
Assistant Professor, Division of Associates
Infectious Diseases Denver, CO
Mount Sinai School of Medicine
New York, NY Robert G. Phelps, MD
Director, Division of
Amy Mathers, MD Dermatopathology
Assistant Professor, Division of Professor, Departments of
Infectious Diseases and International Dermatology and Pathology
Health Mount Sinai School of Medicine
Medical Director Antimicrobial New York, NY
Stewardship
Marion-Anna Protano, MD
University of Virginia School of
Medicine Resident Physician, Department of
Charlottesville, VA Medicine
Mount Sinai School of Medicine
Stephen E. Mercer, MD, PhD New York, NY
Fellow, Division of Meenakshi Mehrotra Rana, MD
Dermatopathology
Clinical Fellow, Division of Infectious
Department of Pathology
Diseases
Mount Sinai School of Medicine
Mount Sinai School of Medicine
New York, NY
New York, NY
Lindsey Reese, MD Mahesh Swaminathan, MD

CONTRIBUTORS
Clinical Fellow, Division of Infectious Adjunct, Instructor of Medicine
Diseases Division of Infectious Diseases
Mount Sinai School of Medicine Department of Internal Medicine
New York, NY Mount Sinai School of Medicine
New York, NY
Keith Sigel, MD
Clinical Fellow, Division of Infectious Katherine Zamecki
Diseases Resident Physician, Department of
Mount Sinai School of Medicine Ophthalmology
New York, NY Mount Sinai School of Medicine
New York, NY
Irini Scordi-Bello, MD, PhD
Assistant Professor, Department of Chad Zatezalo, MD
Pathology Oculoplastics and Facial
Mount Sinai School of Medicine Reconstruction Fellow
New York, NY Bascom Palmer Eye Institute
University of Miami Health System
Nancy Sun, MD Miami, FL
Resident Physician, Department of
Ophthalmology
Mount Sinai School of Medicine

xvii
New York, NY
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 Chapter 1

Meningitis

Ca e 1a:
Case 1a: A C
College
oll
llege SSt
Student
tudentt wit
tud with
ith
h Al
Alt
Altered
tere
red
d Me
Ment
Mental
ntall St
SStatus
tatus
tat
tu

Amy Mathers and W. Michael Scheld

Case Presentation
A 21-year-old male college student presented with the sudden onset of fever
and confusion. He initially had complained of a mild headache and nausea, but

1
six hours later his roommates found him to be noncoherent and agitated. In the
emergency department, the patient was febrile and hypotensive with nuchal
rigidity. He was noncommunicative and lethargic, and was intubated for airway
protection. Blood cultures were drawn immediately, and vancomycin and cef-
triaxone were initiated. Cerebrospinal fluid analysis was notable for numerous
white cells (20,894 WBC/μl, 71% neutrophils 25% bands), hypoglycorrhachia
(glucose < 1 mg/dl), normal protein (41 mg/dl), and intracellular Gram-negative
diplococci on Gram stain (Figure 1a.1).
The patient’s hypotension responded to an intravenous fluid resuscitation,
and he did not require vasopressors. Within 48 hours the patient was extu-
bated, alert, and felt back to his normal state of health. He never developed
a rash, denied further headache, and recovered without focal neurologic defi-
cits. Blood cultures eventually grew Neisseria meningitidis serogroup Y, and the
patient completed a 14-day course of intravenous ceftriaxone. Two years prior
to admission, the patient had received the nonconjugate polysaccharide menin-
gococcal vaccine after a diagnosis of non-typeable N. meningitidis left knee sep-
tic arthritis. Evaluation during that hospitalization revealed a total complement
(CH50) of 8 units/mL (normal range 101–300 U/mL), a C7 complement level of
6 U/mL (normal range of 36–60 U/mL) and normal C3, C4, C6 and C8 levels.
Case 1a Discussion: Neisseria meningitidis Meninigitis
Each year, an estimated 1,400–2,800 cases of meningococcal disease occur in
the United States, a rate of 0.5–1.1/100,000 population.1 N. meningitidis colo-
nizes mucosal surfaces of the nasopharynx of humans, and is transmitted
through direct contact with large-droplet respiratory secretions from patients
Meningitis
CHAPTER 1

Figure 1a.1. Gram stain of cerebrospinal fluid showing intracellular Gram-negative

diplococci.

or asymptomatic carriers. The case–fatality ratio for meningococcal disease is

10%–14% in the United States, despite little drug resistance and access to effec-
2

tive antibacterials and supportive care.1 Patients who survive often have serious
neurologic sequelae or loss of limbs. During 1991–2002, the highest rate of
meningococcal disease (9.2/100,000) occurred among infants aged <1 year; the
rate for persons aged 11–19 years (1.2/100,000) also was higher than that for
the general population. The rate in college students is similar to age-matched
persons in the general population; however, living in a dormitory increases the
risk for college students compared to students living off campus.1
In the United States, more than 98% of cases of meningococcal disease are
sporadic, but there may be a trend toward more outbreak cases.1 Serogroups
B, C, and Y are the major causes of meningococcal disease in the United States,
each being responsible for approximately one-third of cases.1 Serogroup B pre-
dominately affects infants, whereas 75% of patients 11 years of age and older
have serogroup C, Y, or W-135.1 This epidemiology is dynamic, and newer vac-
cines may have an impact on the incidence of nonvaccine types.
Disease in Complement-Deficient Patients
Patients with late complement (C5–9) deficiency are at substantially increased
risk of invasive N. meningitidis infections (57% vs. 0.0072 % in normal hosts).2 It
has also been demonstrated that 5%–10% of individuals with invasive menin-
gococcal disease have a complement deficiency, but this rate varies and is
dependent on the extent of endemic meningococcal disease.2 N. meningitidis is
the most common pathogen in late complement-deficient patients and, unlike
patients with early complement deficiencies, they are not at increased risk of
Haemophilus influenzae or Streptococcus pneumoniae infections.2 Compared to
normal hosts, late complement-deficient individuals on average present later

Meningitis
in life with meningococcal infections, and tend not to have as severe a course
of disease.2 This was seen in the rapid and full recovery of this patient, which
is somewhat atypical for meningococcal meningitis. One study of 276 patients

CHAPTER 1
demonstrated 1.5% mortality in patients with a late complement deficiency
and N. meningitidis infection, compared to 19% in the general population.2 C7
complement deficiency tends to occur more frequently in Caucasians, although
this patient was African-American.2 As was demonstrated in this case, patients
with late complement deficiencies are also at risk for developing recurrent
meningococcal infections (41% recurrence rate vs. a 0.34% recurrence rate in
normal individuals).2
Vaccination Interval for Late Complement-Deficient (LCCD) Patients
The high risk and rate of recurrence of invasive N. meningitidis in LCCD indi-
viduals warrants vaccination against meningococcal disease in this group.3
Until recently there was data available only for LCCD patients with the poly-
saccharide vaccine (serogroup A, C, Y and W-135). In a study from Russia,
six new episodes of meningococcal infection developed in four patients in
the group of 31 vaccinees (19%); six episodes in six patients developed in the
same time frame, in the group of 14 nonvaccinated LCCD persons (42%).4
Although there are no large studies of patients with late complement defi-
ciency receiving the more recently developed conjugate vaccine (polysac-

3
charide diphtheria toxoid conjugae, Menactra, Groups A, C, Y and W-135),
serum bactericidal antibodies are higher when compared to the polysaccha-
ride vaccine.3 Based on expert opinion and the antibody response data, the
Advisory Committee on Immunization Practices (ACIP) recommends con-
jugate vaccine in all patients with late complement deficiency.1 The current
recommendation in LCCD patients is revaccination with conjugate vaccine
every five years.3 There is no conclusive data regarding antibiotic prophylaxis
in LCCD patients.

References
1. Centers for Disease Control and Prevention. Prevention and control of meningo-
coccal disease. Recommendations of the Advisory Committee on Immunization
Practices (ACIP). MMWR. 2005;54(RR07);1–21.
2. Figueroa JE, Densen P. Infectious diseases associated with complement deficien-
cies. Clin Microbiol Rev. 1991; 4:359–395.
3. Centers for Disease Control and Prevention. Updated recommendation from
the Advisory Committee on Immunization Practices (ACIP) for revaccination
of persons at prolonged increased risk for meningococcal disease. MMWR.
2009;58(37);1042–1043.
4. Platonov AE, Vershinina IV, Kuijper EJ, Borrow R, Kayhty H. Long term effects of
vaccination of patients deficient in a late complement component with a tetrava-
lent meningococcal polysaccharide vaccine. Vaccine. 2003;21:4437–4447.
Meningitis

Ca e 11b:
Case b: T
b: Television
elevi
l isiion Int
IIntolerance
ntollerance

Jennifer Jao and Daniel Caplivski

CHAPTER 1

Case Presentation
A 35-year-old man with a history of asthma and glomerulonephritis with mild
renal insufficiency presented with two days of sinus congestion and pain. He
attended his office Christmas party, but left early because he developed a severe
headache. That night he felt myalgias, rigors, fever to 101º Fahrenheit, and
drenching sweats. By the next day he experienced nausea, vomiting, and photo-
phobia, recalling that he found even the light of the television intolerable.
Upon initial examination in the emergency department he was alert and ori-
ented, and his temperature was 37.9º Celsius, his heart rate 128 beats per min-
ute, and his blood pressure 121/78. He had no neck stiffness or other meningeal
signs and the initial evaluation focused on fever and vomiting, possibly from viral
gastroenteritis. His laboratory values were remarkable for a leukocytosis of
11,300 WBC/μl and a creatinine of 2.1 mg/dl. Several hours into his evaluation
he became increasingly confused, answering questions inappropriately and hav-
ing visual hallucinations of caterpillars on the walls. On repeat physical examina-
tion, he was unable to touch his chin to his chest. Ceftriaxone, vancomycin, and
dexamethasone were initiated, and a head CT scan and lumbar puncture were
4

performed. Cerebrospinal fluid analysis revealed protein 424 mg/dl, glucose

<20 mg/dl, and 370 WBC/μl (74% polymorphonuclear cells). Gram stain of the
cerebrospinal fluid revealed sheets of lancet-shaped Gram positive diplococci
(Figures 1b.1 and 1b.2).
Streptococcus pneumoniae with a penicillin minimal inhibitory concentra-
tion of <0.03 μg/ml was recovered from the cerebrospinal fluid culture. The

Figure 1b.1. Gram stain of cerebrospinal fluid showing many white blood cells and
innumerable Gram-positive cocci in pairs and chains. Many of the elongated forms had a
classic lancet-shaped appearance.
patient’s mental status returned to normal with intravenous antibiotics and

Meningitis
corticosteroids, but after several days of improvement his fevers recurred. A
CT scan of the sinuses revealed a concha bullosa, nasal septal deviation, and a
subtotal opacification of the left sphenoid sinus (Figures 1b.3 and 1b.4). The

CHAPTER 1
patient underwent surgical removal of the concha bullosa, septoplasty, and
debridement of the left sphenoid sinus, from which copious purulent material
was released. Gram stain of this material revealed many polymorphonuclear

5
Figure 1b.2. Gram stain of cerebrospinal fluid showing lancet-shaped diplococci and a
clearing around one pair that highlights its polysaccharide capsule.

Figure 1b.3. CT scan of the sinuses, coronal view revealed subtotal opacification of the
left sphenoid sinus.
Meningitis
CHAPTER 1

Figure 1b.4. CT scan of the sinuses, axial view revealed a concha bullosa, nasal septal
deviation, and a subtotal opacification of the left sphenoid sinus.
6

cells, but no organisms were seen or recovered in culture. The patient’s fevers
resolved and he made a full recovery after treatment with intravenous ceftri-
axone for 28 days. An immunologic evaluation did not reveal any acquired or
inherited deficiencies.
Case 1b Discussion: Streptococcus pneumoniae Meningitis
Clinical Features and Diagnosis
Streptococcus pneumoniae is one of the most common causes of bacterial
meningitis in both adults and children worldwide. Also known as pneumo-
coccus, it is a Gram-positive alpha-hemolytic Streptococcus, which can be
identified in the laboratory by its susceptibility to Optochin, catalase negativ-
ity, as well as its lysis in bile salts. Although less commonly used in the clini-
cal microbiology laboratory, the Quellung reaction highlights the bacterium’s
polysaccharide capsule by causing it to be more refractile and visible. Major
virulence factors associated with S. pneumoniae include its antiphagocytic
capsule, its capacity to adhere to pharyngeal cells, and its production of
toxins such as pneumolysin, a specific factor resulting in neuronal loss in
meningitis.1
Meningitis occurs when pneumococcal organisms invade the nasopharyngeal
mucosa, cross the blood–brain barrier, and replicate in the cerebrospinal fluid
(CSF). Because pneumococcus commonly colonizes the naropharynx, it is often
encountered as the etiologic organism in sinusitis, otitis media, and pneumonia.
Pneumococcal meningitis can occur via direct extension from a sinusitis, or
from a basilar skull fracture causing a CSF leak. In the case described above, the
concha bullosa (an air-filled nasal turbinate which may occlude the sinus ostia

Meningitis
and cause recurrent sinusitis) likely played an important role in the persistence
of the infection. Clinical features of pneumococcal meningitis include fever,
headache, confusion, nuchal rigidity, and in severe cases, coma. The course of

CHAPTER 1
the disease is rapid, and mortality rates have been reported to be as high as
40%. Those at greatest risk for morbidity and mortality from invasive pneumo-
coccal disease include asplenic patients, patients with complement deficiencies,
and those with other acquired and congenital immunodeficiencies.2
Diagnosis is usually made by the identification of typical Gram positive
lancet-shaped cocci in pairs on Gram stain of the CSF. An elevated protein,
decreased glucose, and an elevated WBC count with a predominance of neu-
trophils in the CSF, all suggest bacterial meningitis. CSF and blood should be
sent for culture and antimicrobial susceptibility testing, although, as in this
case, blood cultures may be sterile despite positive CSF culture. Detection
of pneumococcal antigens in CSF may aid in the diagnosis of pneumococcal
disease in patients in whom antibiotics may inhibit recovery of the organisms
in cultures; however, these assays have yet to show superiority over conven-
tional Gram stain.1
Treatment and Prevention
In 1990, few pneumococcal isolates in the United States showed high level
(>2ug/ml) penicillin resistance, and only 5% showed moderate resistance, but

7
rates of invasive disease due to penicillin-resistant pneumococci have been
increasing. The current standard of care in treating pneumococcal meningitis
before susceptibility testing is to use both a third-generation cephalosporin and
high dose vancomycin intravenously. Selected third-generation cephalosporins,
such as ceftriaxone and cefotaxime, are bactericidal agents with excellent CSF
penetration. Vancomycin is not rapidly bactericidal, but penetrates the CSF
adequately in the setting of meningeal inflammation. The antimicrobial regimen
may be adjusted once susceptibilities are known. Surgical intervention may be
required in cases of pneumococcal meningitis from anatomic problems, such as
obstructive sinusitis or CSF leak.
Much of the pathogenesis of bacterial meningitis is linked to destructive
effects of the intense inflammatory response of the immune system. Therapeutic
interventions to lessen this damage have led to several trials of corticoster-
oids in bacterial meningitis, but this topic remains controversial. One large
Scandinavian study showed that the early administration of dexamethasone in
patients with pneumococcal meningitis decreased the overall mortality, as well
as the rate of neurologic sequelae such as hearing loss.3 Two other large stud-
ies in patients from Vietnam and Africa failed to replicate this benefit, though
rates of tuberculosis and HIV in these populations may have played a role in the
different outcomes.4,5
The heptavalent pneumococcal conjugate vaccine (PCV-7) and the 23-valent
pneumococcal polysaccharide vaccine are the two vaccines effective against
pneumococcus currently. PCV-7 contains the 7 capsular polysaccharide anti-
gens from the strains most commonly involved in pediatric infections; it is used
 in infants and children particularly, because the protein conjugation enables
Meningitis

a more protective antibody response. The 23-valent polysaccharide vaccine

provides protection against a much larger number of invasive pneumococcal
serotypes, and is recommended for many categories of patients at risk for
CHAPTER 1

pneumococcal disease. These include adults over 65, patients with chronic pul-
monary disease, and patients with immunocompromising conditions such as
HIV infection, diabetes, asplenia, and chronic renal insufficiency. Repeat vac-
cination at 5–7 year intervals is recommended for maintenance of protective
immunity.6

References
1. Mahon, Connie. Textbook of Diagnostic Microbiology, 3rd edition. St. Louis: Saunders,
Elsevier; 2007:393–404.
2. Tuomanen EI, Austrian R, Masure HR. Pathogenesis of pneumococcal infection.
N Engl J Med. 1995;332:1280–1284.
3. de Gans J, van de Beek D. Dexamethasone in adults with bacterial meningitis.
N Engl J Med. 2002;347:1549–1556.
4. Nguyen TH, Tran TH, Thwaites G, et al. Dexamethasone in Vietnamese adoles-
cents and adults with bacterial meningitis. N Engl J Med. 2007;357(24):2431–1240.
5. Scarborough M, et al. Corticosteroids for bacterial meningitis in adults in sub-
Saharan Africa. N Engl J Med. 2007;357(24):2441–2450.
8

6. Pletz, M et al. Pneumococcal vaccines: mechanism of action, impact on epidemiol-

ogy and adaption of the species. Int J Antimicro Ag. 2008;32:199–206.

Case
C a e 11c:
c: G
Gait
ait
it IInstability
nsttabi
bil
ilit
ilit
ity and
d Slurred
Sll d Speech
Sp ch iin
n an
Immunosuppressed
Immu
Im munosuppresssed Patie Patient
i nt

Sean Pawlowski and W. Michael Scheld

Case Presentation
A 58-year-old man with a history of rheumatoid arthritis and myasthenia gravis
presented with a 2-week history of fever, nausea, vomiting, and diarrhea. He
also had an acute onset of slurred speech, worsening gait instability, inability to
stand, confusion, and loss of bowel and bladder function. His immunosuppres-
sive medications included azathioprine 50mg/day and prednisone 40 mg/day.
On presentation the patient was febrile (102.9º Fahrenheit) and unarous-
able, but moved all extremities in response to painful stimuli. He has scattered
2–3mm maculopapular, nonblanching lesions from his bilateral knees to the
dorsum of his feet (sparing the soles) and on the bilateral elbows (Figure 1c.1).
Due to his altered consciousness, signs of meningeal irritation could not be
reliably assessed, and he was intubated for airway protection.
Laboratory values were significant for hyponatremia (130 mmol/L), but
were otherwise unremarkable. Lumbar puncture (LP) revealed an opening
pressure of 380 mm Hg, 72 RBC/μl, 36 WBC per μl (41% neutrophils, 37%
lymphocytes, 21% monocytes, 1% eosinophils), protein 50 g/dl, and glucose
 Meningitis
CHAPTER 1
Figure 1c.1. The rash on the lower extremities consisted of 2–3mm maculopapular,
non-blanching lesions from his bilateral knees to the dorsum of his feet (sparing the
soles).

18 mg/dl. Gram stain revealed numerous polymorphonuclear cells, no bac-

teria, and budding yeast cells (Figure 1c.2). A CSF cryptococcal antigen titer

9
was greater than 1:2048. CT scan revealed numerous acute cerebral infarcts,
and brain MRI confirmed leptomeningeal enhancement, along with numerous
bihemispheric acute infarcts involving the grey and white matter (Figure1c.3
and 1c.4).
Blood and CSF cultures were positive for Cryptococcus neoformans, and the
patient was treated with liposomal amphotericin and every-other-day lumbar
punctures. Because of persistently positive CSF fungal cultures, high dose flu-
conazole (800mg/d) was added for induction therapy. The patient’s opening
pressure eventually decreased to less than 250 mm Hg, CSF cultures were
sterilized, and he was continued on oral fluconazole. The patient’s clinical status
improved, but he was left with chronic neurologic sequelae.
Case 1c Discussion: Cryptococcus neoformans Meningitis
Cryptococcus neoformans, which causes the vast majority of human cryptococcal
infections, has evolved into three distinct varieties (var gattii, grubii, and neofor-
mans). C. neoformans var neoformans is the most common causative pathogen in
both immunocompetent and immunocompromised hosts.1 While Cryptococcus
accounts for 45% of meningoencephalitis cases in AIDS patients in sub-Saharan
Africa, it is a rare cause of CNS disease in HIV-negative patients. In the pre-
AIDS era, it was estimated that there was an overall incidence of 0.2–0.8 cases
per 100,000 person years in the United States.1 The development of aggres-
sive surgeries, organ transplantation, and immunosuppressive therapies has led
to an increase in the overall prevalence of invasive fungal diseases, including
cryptococcosis, in HIV-negative individuals. Additionally, some reports indicate
Meningitis
CHAPTER 1

Figure 1c.2. Gram stain of the cerebrospinal fluid showing numerous polymorphonu-
clear cells and budding yeast cells (original magnification 100x).
10

Figure 1c.3. CT scan brain, axial view showing numerous acute cerebral infarcts.
 Meningitis
CHAPTER 1
11
Figure 1c.4. Brain MRI, axial view showing leptomeningeal enhancement as well as
numerous bihemispheric acute infarcts involving the grey and white matter.

immunocompetent patients with cryptococcosis may have increased mortal-

ity and chronic neurological sequelae as compared to immunocompromised
patients. The worse prognosis in this group is hypothesized to be secondary to
a more inflammatory immune response, as well as delay in recognition.2
Clinical Features of CNS Cryptococcosis
The most common sites of cryptococcal infection include the lungs (the most
common portal to infection), followed by the central nervous system and the
skin. Clinical manifestations and site of infection are determined by the level of
immunosuppression and by the infecting variety. A study by Mitchell and col-
leagues indicated that C. neoformans var gatii was more likely than C. neoformans
var neoformans to cause disease in immunocompetent hosts. Patients infected
with gatii varieties tended to have more invasive parenchymal disease, cryp-
tococcomas, and hydrocephalus.2 Immunosuppressed patients may also mani-
fest an immune reconstitution syndrome, leading to worse clinical symptoms
despite having negative cultures and antigen assays. This phenomenon is seen
when antiretroviral therapy leads to a recovery of cell mediated immunity, or
when immunosuppressive medication effects wane.1
Patients with CNS cryptococcosis may present with symptoms of acute,
subacute, or chronic meningitis or meningoencephalitis, including headaches,
 fever, cranial nerve abnormalities, altered mental status, memory loss, or
Meningitis

coma.1–3 A presenting semicomatose state in both immunocompetent and

immunosuppressed patients has been shown to be a poor prognostic factor.3
Studies in immunocompetent patients indicate that presenting symptoms
CHAPTER 1

are often chronic, and include headaches, weakness, and fevers.2,3 They are
less likely to present with extraneural cryptococcosis (pulmonary, crypto-
coccemia, cutaneous) as compared to immunocompromised individuals.
Immunocompetent hosts are more likely to present with parenchymal disease,
higher levels of CSF inflammatory cells and protein, but lower levels of cryp-
tococcal antigen.1
A lumbar puncture (LP) is indicated in all patients suspected of CNS disease
and all immunosuppressed patients with pulmonary disease or cryptococcemia.
Lumbar puncture should be performed in the lateral decubitus position, and
evaluated for opening pressure, protein, glucose, cell profile, and cryptococcal
antigen with fungal culture. India ink stains, which detect yeast between 102 and
104 CFU/ml, are no longer routinely performed by many laboratories, but high-
light the antiphagocytic polysaccharide capsule. CT scans of the head should
be performed in immunocompromised patients suspected of cryptococcosis,
to rule out space-occupying lesions. Patients will often demonstrate elevated
opening pressure (>200 mm Hg), elevated protein, hypoglycorrhachia, and lym-
phocytic pleocytosis. In a study by Shih and colleagues, initial CSF antigen levels
of greater than 1: 512 were an independent predictor of mortality.3 Positive
12

CSF cultures may be seen in patients in whom antigen is not detected (possibly
due to acapsular invasive strains); therefore, culture is recommended even with
a negative antigen test.
Treatment
Prior to 1950, CNS infection with Cryptococcus was uniformly fatal, but with
the advent of polyene antimicrobials such as amphotericin, treatment is
successful 60%–70% of the time.4 In 2000, the Infectious Disease Society of
America (IDSA) published its CNS cryptococcosis treatment goals: to resolve
infection through the use of antimicrobials, and to reduce long-term neuro-
logic sequelae by controlling elevated intracranial pressure.4 In HIV-negative
patients, the guidelines recommend a 2-week induction course of amphot-
ericin B (0.7–1 mg/kg/d) or liposomal amphotericin B (3–5 mg/kg/d) in those
with renal impairment, plus flucytosine (100 mg/kg/d divided into 4 doses)
for two weeks, followed by consolidation therapy with fluconazole (400mg/d)
for a minimum of 10 weeks.4 In immunocompromised HIV-negative patients,
similar to HIV-positive patients, higher dose fluconazole consolidation therapy
(400–800 mg/d) may be used followed by 6–12 months of suppressive flucon-
azole (200mg/d).4 Additional therapies include an extended combination of
amphotericin B plus flucytosine for 6–10 weeks.4 Therapies studied in HIV-
positive patients that have not yet been validated in HIV-negative patients
include induction amphotericin with high dose fluconazole (800mg/kg/d) fol-
lowed by consolidation fluconazole therapy.5
Elevated cranial pressures can be seen in up to 50% of non-HIV-infected
patients and, therefore, follow-up lumbar punctures are an important adjunctive
therapy to monitor infection and relieve elevated intracranial pressure. The

Meningitis
goal pressure is d200 mm Hg or 50% of the initial opening pressure.5 Lumbar
punctures with culture should be performed daily until the pressures have nor-
malized, but lumbar drains or ventriculoperitoneal shunts may be necessary for

CHAPTER 1
patients with refractory disease. In patients who have normal initial opening
pressure, subsequent lumbar puncture with culture should be performed after
2 weeks to confirm CSF sterilization. Patients with nonclearing cryptococco-
mas may require surgical excision.1

References
1. Chayakulkeeree M, Perfect JR. Cryptococcosis. Infect Dis Clin North Am.
2006;20(3):507–544.
2. Mitchell DH, Sorrell TC, Allworth AM, et al. Cryptococcal disease of the CNS in
immunocompetent hosts: influence of cryptococcal variety on clinical manifesta-
tions and outcome. Clin Infect Dis. 1995;20(3):611–616.
3. Shih CC, Chen YC, Chang SC, Luh KT, Hsieh WC. Cryptococcal meningitis in
non-HIV-infected patients. QJM. 2000;93(4):245–251.
4. Perfect JR, Dismukes WE, Dromer F,et al.. Clinical practice guidelines for the
management of cryptococcal disease: 2010 update by the Infectious Diseases
Society of America. Clin Infect Dis. 2010;50(3):291–322.
5. Pappas PG, Chetchotisakd P, Larsen RA, et al. A phase II randomized trial of

13
amphotericin B alone or combined with fluconazole in the treatment of HIV-
associated cryptococcal meningitis. Clin Infect Dis. 2009;48(12):1775–1783.

Case
C a e 1d:
1d: A 338
38-year-old
8-year-oold Woman
W ffrom ThThailand
ail
iland
nd wit
with
ith
ith
Pulmonary
Pu lmonary Infiltra
Pulm ltrates
rate and
tes an Meningitis
nd Mening git
itis

Najah Doka and W. Michael Scheld

Case Presentation
A 38-year-old woman from Thailand, who had immigrated to the United
States 10 years prior to presentation, was admitted with several days of
fever, headache, nausea, and vomiting. Three days prior to admission, she
also developed confusion. On physical examination she was very cachectic,
confused, febrile (temperature 38.8 o Celsius), and tachycardic (heart rate
111 beats per minute). Her pulmonary exam was significant for crackles
in the upper fields bilaterally, but the rest of the physical examination was
unremarkable.
Laboratory examinations were notable for peripheral leukocytosis (13.5 x 10³
WBC/μl, 79.4% neutrophils, 13.4% monocytes), anemia (Hgb of 11.5gm/dl),
and hyponatremia (sodium 125 meq/l). Head CT showed no mass-occupying
lesions, and lumbar puncture revealed 1010 WBC/μl (63% neutrophils, 10%
monocytes, and 27% lymphocytes), elevated protein (340mg/dL), 3 RBCs/μl,
and hypoglycorrhachia (glucose < 20 mg/dL). Gram stain, calcofluor white
 stain, and smears for acid fast bacilli on the cerebrospinal fluid were nega-
Meningitis

tive. Given the concern for bacterial meningitis, the patient was started on
cefepime, vancomycin and ampicillin, with no clinical improvement. Her HIV
test was positive and her CD4 count (44 cells/μl) and viral load (9,742 copies/
CHAPTER 1

ml) were consistent with advanced AIDS. Chest radiography showed bilateral
upper lobe infiltrates (Figure 1d.1) and neurologic imaging showed multiple
infarcts of the thalami, cerebellum, frontal, and occipital lobes (Figures 1d.1
and 1d.2a–c).
Mycobacterium tuberculosis PCR on CSF was positive, and mycobacterial
culture eventually grew Mycobacterium tuberculosis. Antibacterial antibiotics
were discontinued, and isoniazid, rifampin, ethambutol, and pyrazinamide
were initiated. Four days later, tenofovir, emtricitabine, and efavirenz were
added, but the patient’s worsening nausea, vomiting, and elevated liver
enzymes prompted discontinuation of all medications. Liver function tests
improved three days later, and isoniazid, rifampin, ethambutol, and pyrazin-
amide were restarted with the addition of moxifloxacin, given concern for
resistant tuberculosis. One week later, with only mild improvement in the
patient’s neurologic status, susceptibility testing of the isolate first showed
isoniazid resistance, so isoniazid was replaced with amikacin and cyclos-
erine. Further testing revealed the isolate to be also resistant to rifampin,
ethionamide, and streptomycin—but by the time full resistance testing was
available, the patient’s clinical status had declined and she died several days
14

later.

Figure 1d.1. Portable anterior-posterior chest radiograph revealing bilateral interstitial

infiltrates most prominent in the upper lobes.
 Meningitis
CHAPTER 1
Figure 1d.2a. Brain MRI, axial view, revealing cerebellar infarcts.

15

Figure 1d.2b. Brain MRI, axial view, revealing occipital lobe infarcts.
Meningitis
CHAPTER 1

Figure 1d.2c. Brain MRI, axial view, revealing frontal lobe infarcts.
16

Case 1d Discussion: Mycobacterium tuberculosis Meningitis

Clinical Features and Diagnosis
The presentation of tuberculous meningitis mimics bacterial meningitis, with
complaints of fever (68%–91%), headache (83%–100%), vomiting (77%–81%),
nuchal rigidity, (68%–100%), and altered mental status (55%–72%), but the
onset of symptoms is generally more subacute.1 Other findings on physical
examination may include cranial nerve abnormalities, such as facial nerve palsy
(15%–45%). Depending on the symptoms, patients presenting with TB men-
ingitis can be divided into Stage I – lucid with nonfocal neurological signs or
evidence of hydrocephalus; Stage II – lethargic, confused, with mild focal signs
(cranial palsy or hemiparesis); or Stage III – with delirium, stupor, coma, seizures,
multiple cranial nerve palsies, and/or dense hemiplegia.1 Typical cerebrospinal
fluid findings include opening pressure of 10–20cm H2O, many white blood
cells (100–500 cells/μl with lymphocytic predominance in 70%–90% of cases),
elevated protein (100–500mg/dL), and hypoglycorrhachia (glucose < 45mg/
dL). Acid fast bacilli smear is positive in CSF only 13%–20% of the time and
only 10%–30% of cases are found to have positive CSF cultures. Mycobacterium
tuberculosis PCR may be a useful adjunctive test, but its sensitivity and speci-
ficity is higher in smear-positive specimens. Chest radiography is abnormal in
50%–75% of cases with 9%–34% of patients presenting with a miliary pattern.
Less than 50% of patients with tuberculous meningitis are PPD positive, but
neurologic imaging may reveal hydrocephalus, basilar meningitis, focal brain
lesions (tuberculoma), edema, or infarction, in 68%–94% of cases.1
Treatment

Meningitis
Mortality due to TB meningitis is high, ranging from 19% (Stage I) to 65% (Stage
III). A worse prognosis is associated with HIV infection and in patients present-
ing with CSF glucose < 40, protein > 1500mg/dL, and those who have other foci

CHAPTER 1
of TB besides the meninges.1 Treatment of drug-susceptible TB includes 9–12
months of isoniazid, rifampin, pyrazinamide, and ethambutol (see Chapter 6 for full
discussion).2 Corticosteroids are often added to regimens for meningeal tubercu-
losis, particularly for patients presenting in more advanced stages of the disease.3
Treatment of MDR tuberculosis should be undertaken with the guidance of
tuberculosis experts; a detailed discussion is beyond the scope of this book.
As a general guideline, isolates resistant to isoniazid alone may be treated with
rifampin, pyrazinamide, ethambutol, and a fluoroquinolone such as moxifloxa-
cin for 6 months following a negative AFB smear. In patients with isoniazid
and rifampin resistant TB, a fluoroquinolone, pyrazinamide, ethambutol, and an
injectable agent ( aminoglycosides like streptomycin, amikacin, or kanamycin),
with or without another, second agent (cycloserine, clarithromycin, amoxicil-
lin/clavulanate, ethionamide, p-aminosaliclyic acid), should be used for 18–24
months post a negative AFB smear.4
TB and HIV Coinfection
In patients already taking antiretroviral medications, TB medications should
be added to the antiretroviral regimen continued. In patients with CD4+ cell

17
counts less than 100cells/μl, the benefits of treating both HIV and TB concur-
rently generally outweigh the associated problems of drug interactions, side
effects, and possible inflammatory responses. Particular consideration should
be given to interactions that arise from p450 inhibition by protease inhibitors.
Both HIV and Mycobacterium tuberculosis exert a suppressive effect on the
immune system, and treatment of either or both may lead to exacerbations
of symptoms. In the case of HIV, the immune reconstitution inflammatory syn-
drome may require corticosteroids to lessen the inflammation. Similarly para-
doxical reactions may be seen several weeks into treatment of tuberculosis.
This worsening of symptoms may prompt concerns for resistant tuberculosis,
but if cultures of repeat specimens are sterile, these exacerbations of symp-
toms may also be managed with corticosteroids.2,5

References
1. Jacob JT, Mehta AK, Leonard MK. Acute forms of tuberculosis in adults. Am J Med.
2009;122(1):12–17.
2. Horsburgh CR,Jr, Feldman S, Ridzon R, Infectious Diseases Society of
America. Practice guidelines for the treatment of tuberculosis. Clin Infect Dis.
2000;31(3):633–639.
3. Prasad K, Singh MB. Corticosteroids for managing tuberculous meningitis.
Cochrane Database Syst Rev. 2008 Jan 23;(1):CD002244.
4. Yew WW, Leung CC. Management of multidrug-resistant tuberculosis: Update
2007. Respirology. 2008;13(1):21–46.
5. Dean GL, Edwards SG, Ives NJ, et al. Treatment of tuberculosis in HIV-infected
persons in the era of highly active antiretroviral therapy. AIDS. 2002;16(1):75.
Meningitis

Ca e 11e:
Case e: FFever aand
nd
dCConfusion
onffusion
i afafter
ft N
fter Neurosurgery
eurosu
urg
r ery

Rachel Chasan
CHAPTER 1

Clinical Presentation and History

A 63-year-old man with a history of hypertension, hyperlipidemia, and glau-
coma was seen by a neurologist for progressive hearing loss in the left ear over
the prior two years. He had also recently developed left-sided facial weakness
and numbness, and MRI demonstrated a mass at the left cerebellopontine angle
with extension into the left auditory canal, consistent with a vestibular schwan-
noma (Figure 1e.1). The patient underwent left suboccipital craniectomy with
tumor resection several days later, and he was discharged home after an
uncomplicated postoperative course.
Two days following discharge, the patient was readmitted with weakness,
unsteady gait, and a headache. He was initially afebrile and answering questions
slowly but appropriately, but on his second hospital day he was febrile (38.1°
Celsius) and he became progressively confused. On physical examination, he
had a left-sided facial droop, unchanged since surgery, and the incision on his
scalp was clean with no exudate or erythema. He was lethargic, had difficulty
following commands, and had nuchal rigidity. His speech was slow and slurred,
but the rest of his physical examination was unremarkable.
18

Laboratory values were remarkable for leukocytosis (15.5 x 10³ WBC/μl)

and thrombocytopenia (82 x 10³ platelets/μl). CT scan of the brain showed
no hemorrhage, infarct, or mass, and CSF analysis revealed: 3540 white blood
cells/μl (93% neutrophils); protein 112 mg/dl; glucose < 20 mg/dl; and many
Gram negative bacilli (Figure 1e.2). The culture from the lumbar puncture grew
heavy-growth Klebsiella pneumoniae, susceptible to ceftriaxone (Figure 1e.3).

Figure 1e.1. Brain MRI, axial view, demonstrating a mass at the left cerebellopon-
tine angle with extension into the left auditory canal, consistent with a vestibular
schwannoma.
 Meningitis
CHAPTER 1
Figure 1e.2. Gram stain of cerebrospinal fluid revealing numerous Gram-negative
bacilli.

19

Figure 1e.3. Cultures of cerebrospinal fluid culture on MacConkey agar and sheep’s
blood agar revealed a lactose fermenting organism with mucoid colonies.

The patient was initially treated with IV cefepime 2 grams every eight hours
while awaiting culture results, and he eventually completed a 14-day course of
intravenous ceftriaxone. His mental status returned to his baseline, and he was
transferred to inpatient rehabilitation following completion of his antibiotics
with no further complications.
 Case 1e Discussion: Klebsiella pneumoniae Meningitis
Meningitis

Clinical Presentation and Diagnosis

Spontaneous aerobic Gram-negative bacillary meningitis is relatively uncom-
mon in the United States, contributing only a small proportion to commu-
CHAPTER 1

nity-acquired bacterial meningitis (<5%).1 Most patients in whom aerobic

Gram-negative bacillary meningitis develops spontaneously suffer from an
underlying predisposing condition, such as alcoholism, liver cirrhosis, or dia-
betes.1 Disseminated strongyloidiasis is a rare cause of meningitis with enteric
pathogens, discussed in further detail in Chapter 9. Gram-negative bacil-
lary CNS infections are more common, however, following neurosurgery or
head trauma.2 Diagnosis can be difficult in patients post-neurosurgery or head
trauma, as they often cannot provide a history, and interpretation of CSF stud-
ies is complicated by postoperative inflammation.2 Mortality in patients with
Gram-negative bacillary meningitis is high (ranging from 15%–70%), as is the rate
of postinfection neurologic sequelae.1,2,3
Retrospective reviews have demonstrated a range of neurosurgical proce-
dures leading to the development of Gram-negative meningitis, including the
insertion or revision of an external ventricular drain or shunt, excision or deb-
ulking of a tumor, aneurysm clipping, and repair of a CSF leak.2 The risk of
development of infection following a neurosurgical procedure is highly vari-
able, ranging from < 1% to 8%, with most series involving a limited number
20

of patients. A recent review4 of over 2000 patients who underwent a range

of neurosurgical procedures demonstrated an incidence of postsurgical bacte-
rial meningitis of only 0.3%, though other series4 have found an incidence of
1.4%–1.9%.
Diagnosis of postsurgical bacterial meningitis is difficult, given the frequent
development of noninfectious meningitis postsurgery, and the shared clinical
presentation of chemical and bacterial meningitis. Most patients diagnosed with
Gram-negative bacillary meningitis are febrile, with meningismus and altered
mental status.3 The diagnosis of bacterial meningitis is generally based on CSF
studies; patients with bacterial meningitis usually have a markedly elevated CSF
protein level, hypoglycorrhachia, elevated white blood cell count (with pre-
dominantly neutrophils) and, frequently, positive CSF Gram stain and culture.2
Elevated lactate levels in the CSF have been shown to support the diagnosis of
bacterial meningitis.5
The majority of Gram-negative bacilli isolated from the CSF are
Enterobacteriaceae, particularly Klebsiella pneumoniae and Escherichia coli, but
a range of other organisms have been recovered as well, including Pseudomonas
aeruginosa, Proteus mirabilis, and Acinetobacter haemolyticus.1 In addition to Gram-
negative pathogens, Staphylococcus aureus, coagulase-negative Staphylococci, and
Propionibacterium acnes are important considerations in postsurgical patients and
those with shunts in place.4
Treatment

Meningitis
Antibiotic choice must be based on both an understanding of the resistance
patterns of nosocomial pathogens, as well as CSF penetration of antimicrobial
therapy. The Infectious Disease Society of America Practice Guidelines rec-

CHAPTER 1
ommend the use of vancomycin plus cefepime, ceftazidime, or meropenem
in patients with meningitis post-neurosurgery, or with a shunt in place, while
awaiting culture results.5 Although aminoglycosides played a significant role
historically, this class of drugs has poor CSF penetration and thus is generally
inadequate when administered parenterally to treat Gram-negative bacillary
meningitis. There is limited data to guide the use of antibiotic therapy intrath-
ecally or intraventricularly; however, agents with poor CNS penetration are
sometimes administered via this route to treat patients with very resistant bac-
terial pathogens.5

References
1. Bouadma L, Schortgen F, Thomas R, et al.; Gram-Negative Meningitis Collaborative
Study Group. Adults with spontaneous aerobic Gram-negative bacillary meningi-
tis admitted to the intensive care unit. Clin Microbiol Infect. 2006;12:287–289.
2. Briggs S, Ellis-Pegler R, Raymond N, Thomas M, Wilkinson L. Gram-negative
bacillary meningitis after cranial surgery or trauma in adults. Scan J Infect Dis.
2004;36:165–173.

21
3. Mancebo J, Domingo P, Blanch L, Coll P, Net A, Nolla J. Post-neurosurgical
and spontaneous gram-negative bacillary meningitis in adults. Scan J Infect Dis.
1986;18:533–538.
4. McClelland S, Hall WA. Postoperative central nervous system infection: inci-
dence and associated factors in 2111 neurosurgical procedures. Clin Infect Dis.
2007;45:55–59.
5. Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management
of bacterial meningitis, Infectious Disease Society of America guidelines. Clin Infect
Dis. 2004;39:1267–1284.
This page intentionally left blank
 Chapter 2

Encephalitis and
Myelopathy

Ca e 2a:
Case 2a: Recurre
R
Recurrent
ntt M
Meningitis
eniingiti
itis

Sean Pawlowski and W. Michael Scheld

Case Presentation
A 69-year-old man, with a history of head trauma 10 years prior to admission,
presented to the emergency department with a two-day history of headaches,
photophobia, nausea, and vomiting. The pain was band-like, 10 out of 10, and

23
not related to position. The patient also had a history of hypertension, hyperlip-
idemia, and coronary artery disease, and his medications included simvastatin,
atenolol, lisinopril, and aspirin. He denied any other over-the-counter medica-
tions including nonsteroidal anti-inflammatory agents. He had had three prior
episodes similar to this, in 1995, 2000, and 2004.
On physical examination, he had a mild fever (100.3° Fahrenheit), was diffi-
cult to arouse, and was not able to follow commands. He had meningismus and
photophobia, but the remainder of his physical examination was unremarkable.
CT and MRI of the head showed no evidence of masses, or temporal lobe or
meningeal enhancement. Cerebrospinal fluid analysis revealed a lymphocytic
pleocytosis (189 WBC/μl, 67% lymphocytes, 10% monocytes, 12% atypical
lymphocytes, 7% neutrophils, and 3% basophils), 11 RBC/μl, elevated protein
(209 mg/dl), glucose 40 mg/dl, and no organisms on Gram stain. The patient
was empirically treated with vancomycin, ceftriaxone, and acyclovir until sev-
eral days later, when the CSF HSV PCR was reported as positive for HSV-2.
Vancomycin and ceftriaxone were discontinued, and the acyclovir was con-
tinued. A review of the patient’s prior hospitalization at another institution
revealed that in 2004 his CSF PCR had also been positive for HSV-2.
Case 2a Discussion: Herpes Simplex Virus Meningoencephalitis
Recurrent benign lymphocytic meningitis (RBLM) was first described in 1944
by the French neurologist, Pierre Mollaret. RBLM is not a chronic meningitis,
but is a syndrome in which patients have recurrent episodes of aseptic menin-
gitis.1 When first described, Mollaret noted an increased level of “endothelial
cells” in the CSF early in the disease, which he dubbed Mollaret cells. These
 large, granular cells have a monocytic/macrophage lineage.1 They can appear
Encephalitis and Myelopathy

early in the disease, or not at all, but eventually the predominant cells in the
CSF become lymphocytes. Studies have shown a probable link between HSV
(most commonly HSV-2) and RBLM—but other viruses, such as Epstein-Barr
virus, coxsackievirus, and echoviruses, have been implicated as causes of recur-
rent meningitis. There is, however, limited data on these other viruses.1–3
Rheumatological diseases have also been implicated.
Clinical Manifestations and Diagnosis
Approximately one-half of patients have transient neurological symptoms,
including seizures, hallucinations, diplopia, cranial nerve palsies, or altered lev-
CHAPTER 2

els of consciousness.1 These symptoms are transient and, if they persist, a diag-
nosis of RBLM should be excluded. Most symptoms resolve within 2–5 days,
with recurrences seen weeks, months, or years later.1
The diagnosis of RBLM is a diagnosis of exclusion. In 1962, Bruyn proposed
the clinical diagnostic criteria of: (1) recurrent episodes of severe headache,
meningismus, and fever; (2) CSF pleocytosis with large “endothelial” cells, neu-
trophils, and lymphocytes; (3) attacks separated by symptom-free periods of
weeks to months to years; (4) spontaneous remission of symptoms and signs;
and (5) no causative etiologic agent detected. 4 Since the diagnostic criteria
were proposed, studies have shown that patients can present without fever,
without the typical Mollaret cells, and are often PCR positive for HSV.
24

HSV Type 1 and Type 2 establish latent infections in the peripheral nervous
system of humans. Reactivation of latent HSV infection from sensory ganglia
results in a broad range of clinical manifestations, depending on the site of
latency, virus type, and immune competency of the host. HSV-2 latency occurs
primarily in sensory neurons of sacral dorsal root ganglia. It is postulated that
HSV-1 in trigeminal ganglia may spread to brain parenchyma, producing enceph-
alitis, whereas HSV-2 in sacral dorsal root ganglia may seed the cerebrospinal
fluid and produce meningitis.1,2 Even when meningitis results from the reactiva-
tion of latent HSV-2 infection in patients with known genital herpes, coincident
herpetic skin lesions are documented in less than 50% of cases; similarly, in
HSV-1 encephalitis, mucocutaneous manifestations are seldom seen.2,3
In the largest study to date of patients who met the criteria for RBLM, they
averaged 4.6 attacks of meningitis over 2–21 years, with attacks lasting 3–14
days. 2 CSF white blood cell counts ranged from 48–1600 cells/μl, with a lym-
phocytic predominance, normal glucose, and protein ranging from 41–240 mg/
dl.2 HSV was detected by PCR in 11/13 (84.6%), and 10/11 (91%) specimens
were HSV-2. 2 Only 3 of 11 patients with HSV DNA and antibody in their cere-
brospinal fluid had a history of recurrent genital HSV infection.2
Treatment
Because of the rarity of this syndrome, there are no large clinical trials compar-
ing one therapy against another. Administration of intravenous acyclovir (10–15
mg/kg every 8 h for 7–10 days) has putatively resulted in rapid resolution of
infection.1 Valacyclovir and famciclovir have been used, as well. Steroids, colchi-
cine, antihistamines, and phenylbutazone have been administered to patients
with RBLM without reported benefit.1 Other experts have advocated for no

Encephalitis and Myelopathy

treatment, since the symptoms are often self-limiting. In cases of HSV encepha-
litis, a 21-day course of acyclovir (10–15 mg/kg every 8 h) is recommended.
There is little data regarding the use of prophylaxis to prevent recurrence. In
one instance, a 52-year-old woman who experienced 21 episodes of recur-
rent aseptic meningitis over 20 years began suppressive therapy with acyclo-
vir; no other outbreaks were reported after treatment.1 Prophylaxis should be
weighed based on the frequency of recurrences.

References

CHAPTER 2
1. Shalabi M, Whitley RJ. Recurrent benign lymphocytic meningitis. Clin Infect Dis.
2006;43(9):1194–1197.
2. Tedder DG, Ashley R, Tyler KL, Levin MJ. Herpes simplex virus infection as a cause
of benign recurrent lymphocytic meningitis. Ann Intern Med. 1994;121:334–338.
3. Kupila L, Vainionpaa R, Vuorinen T, Marttila RJ, Kotilainen P. Recurrent lympho-
cytic meningitis: the role of herpesviruses. Arch Neurol. 2004;61:1553–1557.
4. Bruyn GW, Straathof LJ, Raymakers GM. Mollaret’s meningitis. Differential diag-
nosis and diagnostic pitfalls. Neurology. 1962 Nov;12:745–753.

Ca e 2b:
Case 2b:
b: Conf
C
Confusion
fusion
i aand
nd
d Fever
F iin an E
Elderly
lderlly Woman
ld W n

25
Mahesh Swaminathan
Presentation and Case History
An 80-year-old woman with no known past medical history was brought to the
emergency department because of confusion and bizarre behavior. Two days
prior to admission, the doorman of the patient’s building noticed the patient
wandering the halls of the building in a confused, agitated state; according to the
doorman, the patient is normally highly functional and manages her own affairs.
On initial assessment, the patient was confused and unable to give a coherent
history, stating, “I am fine. Who are you? Why am I here?” She denied any and
all complaints and sick contacts, had no pets, and had not traveled outside of
New York City in the last year.
On physical examination, the patient’s temperature was 38.9º Celsius, heart
rate was 92 beats per minute, blood pressure was 115/77, and respiratory rate
was 18 breaths per minute; oxygen saturation on pulse oxymetry was 100%
on ambient air. In general, she was a well-developed, well-nourished elderly
woman in no apparent distress. She was delirious and confused and oriented
to person only, but had no other focal neurological deficits. Her neck was soft
and supple, mucous membranes were moist and oropharynx was clear, and the
remainder of her physical examination was unremarkable.
Laboratory studies were notable for leukocytosis (12.5 x 10³cells/μl), but all
other studies including serum electrolytes, TSH, RPR, hemoglobin, and urinaly-
sis were within normal limits. A chest X-ray and computed tomography (CT) of
 the head without intravenous contrast were unremarkable. A lumbar puncture
Encephalitis and Myelopathy

was performed; CSF analysis showed a lymphocytic pleocytosis (65 WBC/μl,

1% neutrophils, 87% lymphocytes), protein 29 mg/dl, and glucose 71 mg/dl. CSF
Gram stain, VDRL, and fungal stain were negative. A presumptive diagnosis
of HSV meningitis was made, and IV acyclovir started. The patient’s mental
status improved and her fever resolved. On the third day of her hospitaliza-
tion, the patient noted the appearance of a rash on the left side of her chest.
The patient remembered that she had some itching in the area of the rash
several days before her hospitalization. Examination revealed an erythematous,
vesicular rash in a dermatomal distribution (Figure 2b.1). The patient denied
pain at the site of the rash, but complained of mild pruritus. The CSF PCR for
CHAPTER 2

varicella zoster virus (VZV) was reported as positive, giving a diagnosis of VZV
encephalitis. The patient continued to improve and was discharged home in
stable condition after receiving 7 days of intravenous acyclovir.
Case 2b Discussion: Varicella Zoster Virus Encephalitis
Virology and Epidemiology
Varicella zoster virus is a member of the Herpesviridae family, and is the etio-
logical agent of primary varicella infection (chicken pox) and herpes zoster.
VZV infects sensory nerve fibers during primary infection, and establishes per-
manent latency in neuronal bodies located in regional sensory ganglia. Herpes
zoster is the manifestation caused by the reactivation of latent VZV, which
26

Figure 2b.1. Left thorax with an erythematous, vesicular rash in a dermatomal

distribution
leads to dermatomally restricted cutaneous disease (“shingles”) or, less com-

Encephalitis and Myelopathy

monly, disseminated or visceral disease.
VZV is transmitted via the respiratory route, where it replicates in the
nasopharynx or upper respiratory airways.1 Patients with herpes zoster are
infectious from the onset of the rash until the lesions crust; susceptible patients
who are infected develop primary varicella infection. Transmission can be
greatly reduced by covering the affected area. Patients should be asked to avoid
contact with susceptible persons, particularly those at risk for complications
(e.g., pregnant women, prematurely born infants, immunocompromised per-
sons) until all of their lesions have crusted over.2 Hospitalized persons who
have disseminated zoster, or lesions that are difficult to cover, should be iso-

CHAPTER 2
lated using airborne and contact precautions. The use of masks and type of
masks (e.g., surgical mask versus N95 respirator) used by either immune or sus-
ceptible healthcare workers is a subject of some debate, and should be decided
in each institution by local infection control specialists.3
The main risk factor for herpes zoster is a history of primary varicella.
Approximately 99.5% of the adult population over the age of 40 has serologi-
cal evidence of prior infection, despite the fact that many will not remember a
history of the chickenpox rash3; therefore, nearly all older adults are at risk for
zoster. Age is an important risk factor, with significant increases occurring dur-
ing the sixth decade of life (Figure 2b.2). Approximately 50% of persons living to
the age of 85 will experience at least one episode of herpes zoster.

27
The risk of reactivation is dramatically increased in immunocompromised
hosts, especially those with deficits in T-cell mediated immunity (e.g., HIV,
lymphoproliferative diseases, solid organ or bone marrow transplantation).
Inflammatory diseases, such as systemic lupus erythematosis, rheumatoid

11
10 Zoster
9 PHN
8
7
6
Rate

5
4
3
2
1
0
20 30 40 50 60 70 80
Age (yrs)

Figure 2b.2. Rate of zoster and postherpetic neuralgia (PHN) by age—United States.
Source: Centers for Disease Control and Prevention. Harpaz R, Ortega-Sanchez IR,
Seward JF. Prevention of Herpes Zoster. MMWR. May 15, 2008: 57;1–30.
 arthritis, Wegener’s granulomatosis, Crohn’s disease, and ulcerative colitis,
Encephalitis and Myelopathy

have also been associated with an increased risk of herpes zoster. It is unclear
if this increased risk is related to the actual disease process, or to immunosup-
pressive medications that are used for treatment.2
Most complications of herpes zoster are related to the specific area of
involvement. The most frequent complication is post-herpetic neuralgia (PHN),
defined as the persistence of pain after resolution of skin lesions. The inci-
dence of PHN in the pre-vaccine era was 18%, 13%, and 10% at 30, 60, and 90
days, respectively, after resolution of the rash. The incidence of PHN increases
with age, and approximately 20% of patients over the age of 80 experience
PHN three months after resolution of rash.4 PHN can be debilitating, leading to
CHAPTER 2

loss of employment, depression, social isolation, and increased medical costs.

Bacterial superinfection of the vesicular lesions, typically with normal skin flora,
can also occur.
Herpes zoster ophthalmicus can affect almost all structures of the ipsilat-
eral eye and requires immediate evaluation by an ophthalmologist, as well as
prompt antiviral therapy to prevent loss of vision. Involvement of the mucocu-
taneous division of cranial nerve VII and/or VIII can lead to the Ramsey-Hunt
syndrome, characterized by facial paralysis, associated hearing and vestibulatory
symptoms, and vesicular lesions in the external auditory canal. Facial nerve
involvement can occur without the presence of vesicular lesions. Other serious
complications, such as encephalitis, meningitis, retinitis, myelitis, or death, are
28

uncommon. They usually occur in immunocompromised hosts, but can affect

persons with no obvious predisposing condition or medication-related deficit
in cell-mediated immunity.
Clinical Features
Herpes zoster is characterized by a painful vesicular rash in a unilateral, der-
matomal distribution, with occasional involvement of two or three adjacent
dermatomes. The pain is classically described as burning, throbbing, or stabbing,
and is often associated with tactile hyperesthesia, though occasionally pruritus
is the dominant complaint. Pain generally precedes the appearance of the rash
by several days and, depending on the sensory dermatome involved, can be
confused with other acute medical conditions, such as unstable angina, chole-
cystitis, or renal colic.
Although virtually any peripheral sensory nerve can be a source of reactiva-
tion, the most common sites in immunocompetent hosts are the thoracic sen-
sory nerves, followed by the ophthalmic division of the trigeminal nerve (herpes
zoster ophthalmicus). Herpes zoster rarely presents in atypical or severe forms,
especially in patients with deficits in cell-mediated immunity. Examples include
disseminated cutaneous disease (vesicles appearing at a distance or contralat-
erally from the original dermatome), meningoencephalitis, or visceral disease
(e.g., pneumonitis, hepatitis, pancreatitis, etc.).5,6
VZV meningoencephalitis presents similarly to other causes of viral infec-
tions of the brain (e.g., headache, fever, photophobia, nausea, vomiting, and
confusion).1 The characteristic rash of herpes zoster often appears after
the onset of CNS symptoms, though in some cases it can be the presenting
symptom.7,8 The rash can help distinguish the disease from other viral causes of

Encephalitis and Myelopathy

meningoencephalitis, such as herpes simplex virus or West Nile virus.
Diagnosis
Herpes zoster is typically a clinical diagnosis based on the characteristic appear-
ance and distribution of the rash, associated symptoms, and time course of
disease (Figure 2b.3). In patients who present with an atypical rash or dissemi-
nated disease, VZV direct fluorescent antigen (DFA) testing of skin scrapings
can provide a rapid diagnosis. Real-time polymerase chain reaction (PCR) can
be performed on a variety of clinical samples, including CSF. The utility of viral
culture is limited by a longer turnaround time.

CHAPTER 2
Since patients with uncomplicated cutaneous herpes zoster will frequently
have a headache, it is important that other symptoms associated with viral
CNS infection, or risk factors for invasive disease, be present before aggres-
sively pursuing the diagnosis of VZV meningoencephalitis. Some patients with
uncomplicated herpes zoster may have a lymphocytic pleocytosis, even in the
absence of overt encephalitis.9 CSF sampling is critical for diagnosis of VZV
meningoencephalitis, and for distinguishing this disease from other causes of
invasive CNS disease. CSF analysis will reveal abnormalities consistent with
other causes of viral meningoencephalitis: a lymphocytic pleocytosis, elevated
protein, and occasionally decreased glucose. PCR for VZV can be performed
on CSF samples; a positive result confirms the diagnosis.

29
Treatment
Systemic antiviral therapy, specifically with acyclovir, famciclovir, or valacyclo-
vir, is the mainstay of treatment and has been shown to reduce viral shedding,
duration of rash, and PHN (see Table 2b.1).6

Figure 2b.3. Dermatomal rash with lesions in various stages: crops of vessicles with an
erythematous base and other lesions that have crusted over.
 30 CHAPTER 2 Encephalitis and Myelopathy

Table 2b.1 Oral Antiviral Medications for Herpes Zoster

Medication Dosage Duration of treatment, Most common Precautions and contraindications
days adverse effects
Acyclovir 800 mg 5 times daily (every 4–5 h) 7–10 Nausea, headache Dosage adjustment required for patients with renal
insufficiency
Brivudina 125 mg once daily 7 Nausea, headache Contraindicated for patients treated with
5-fluorouracil or other 5-fluoropyrimidines, because
of drug interaction associated with severe and
potentially fatal bone marrow suppression
Famciclovir 500 mg 3 times daily (approved 7 Nausea, headache Dosage adjustment required for patients with renal
dosage in United States; in some insufficiency
other countries, 250 mg 3 times
daily is approved)
Valacyclovir 1000 mg 3 times daily 7 Nausea, headache Dosage adjustment required for patients with renal
insufficiency; thrombotic thrombocytopenic purpura/
hemolytic uremic syndrome reported at dosages of
8000 mg daily in immunocompromised patients
a
Not available in the United States.
Reprinted with permission from The University of Chicago Press. Dworkin RH, Johnson RW, Breuer J, et al. Recommendations for the Management of Herpes Zoster. Clinical Infectious
Diseases. 2007;44:S1–S26.
 The duration of treatment is usually seven days, and valacyclovir is generally

Encephalitis and Myelopathy

preferred because of its convenient dosing schedule. The most common side
effects of these medications are nausea and headache. Dose adjustments are
needed in patients with impaired renal function. Antiviral therapy is strongly rec-
ommended in immunocompetent patients with any of the following criteria:6
1. Age > 50
2. Non-truncal involvement
3. Moderate to severe pain and/or rash
4. Presentation within 72 hours of the onset of symptoms

CHAPTER 2
Given their benign side-effect profile, many experts recommend consider-
ing the use of antivirals in all patients with herpes zoster, even those at low
risk for severe complications or who present greater than 72 hours after the
onset of symptoms.6 Oral therapy is appropriate in most cases of herpes zoster.
Intravenous acyclovir is recommended in patients with serious or disseminated
disease, depressed cell-mediated immunity, or herpes zoster ophthalmicus.
Meningoencephalitis is a serious complication of herpes zoster and should
be treated aggressively with intravenous therapy; therapy should be instituted
immediately, as soon as this diagnosis is suspected, and not delayed while wait-
ing for the results of confirmatory diagnostic tests (e.g., PCR). There are no
good data evaluating oral therapy (e.g., with valacyclovir), but it may not be

31
unreasonable to switch to oral therapy if the patient has a rapid therapeutic
response to intravenous therapy after a few days. In both mild and serious
cases of herpes zoster, there is little data to support a duration of therapy
greater than 7 days. Herpes zoster can be prevented with administration of a
live, attenuated vaccine. This vaccine has been shown to decrease the incidence
of herpes zoster by 50% and to lower the risk of post-herpetic neuralgia by 67%.
It is recommended for all patients over the age of 60, including patients who
have had an episode of herpes zoster prior to vaccination.2

References
1. Whitley RJ. Varicella-zoster virus. In: Mandell GL, Bennett JE, Dolin R, eds.
Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases.
7th ed. Philadelphia, PA: Churchill, Livingston, Elsevier; 2009:1963–1968.
2. Harpaz R, Ortega-Sanchez IR, Seward JF. Prevention of herpes zoster: recom-
mendations of the Advisory Committee on Immunization Practices (ACIP).
MMWR Recomm Rep. 2008;57(RR-5):1–30.
3. Siegel JD, Rhinehart E, Jackson M, Chiarello L, Healthcare Infection Control
Practices Advisory Committee. 2007 Guideline for isolation precautions: prevent-
ing transmission of infectious agents in healthcare settings. Available at: http://
www.cdc.gov/hicpac/2007ip/2007isolationprecautions.html.
4. Yawn BP, Saddier P, Wollan PC, St. Sauver JL, Kurland MJ, Sy LS. A population-
based study of the incidence and complication rates of herpes zoster before
zoster vaccine introduction. Mayo Clin Proc. 2007;82(11):1341–1349.
5. Wareham DW, Breuer J. Herpes zoster. BMJ. 2007;334(7605):1211–1215.
 6. Dworkin RH, Johnson RW, Breuer J, et al., Recommendations for the manage-
Encephalitis and Myelopathy

ment of herpes zoster. Clin Infect Dis. 2007;44(Suppl):S1–26.

7. Ihekwaba UK, Kudesia G, McKendrick MW. Clinical features of viral meningi-
tis in adults: significant differences in cerebrospinal fluid findings among herpes
simplex virus, varicella zoster virus, and enterovirus infections. Clin Infect Dis.
2008;47:783–789.
8. Kupila L, Vuorinen T, Vainionpää R, Hukkanen V, Marttila RJ, P. Kotilainen P.
Etiology of aseptic meningitis and encephalitis in an adult population. Neurology.
2006;66:75–80.
9. Elliott KJ. Other neurologic complications of herpes zoster and their manage-
ment. Ann Neurol. 1994;35(Suppl):S57–S61.
CHAPTER 2

Case
C a e 22c:
c A 441
c: 41-year-old
1-year-oold W
Wood
Woodcutter
dcutt
tter wi
with
ith P
Pro
Progressively
ogressive
ivelly
Wors
Wo rsening Mental
Worsening al St
SStatus
tatu
us

Florence Nana, W. Michael Scheld, and Joshua Dowell

Case Presentation
A 41-year-old woodcutter presented to an outside facility with a 3-month his-
tory of generalized malaise, weakness, dyspnea, and productive cough that
started one week prior to his presentation to another institution. The patient
32

reported no history of hemoptysis or chest pain, but he had been having night
sweats and rigors for three months. He was febrile on admission and was noted
to have a scaly dry lesion on the right eyebrow. His mental status worsened
at the initial hospital to the point that he required mechanical ventilation. The
patient was discovered to have advanced AIDS when his HIV serology was
reported as positive, and his CD4+ cell count was 4 cells/μl; his most likely risk
factor was a remote history of drug abuse.
CT scan of the head revealed multiple brain lesions in the right cerebel-
lum. A brain MRI revealed multiple T2 and FLAIR hyperintense lesions, the
largest in the cerebellum with patchy T1 shortening, moderate mass-effect,
and significant surrounding edema. Additional lesions were present in the left
anterior frontal subcortical white matter and in the left medial temporal lobe.
Diffuse leptomeningeal enhancement within the cerebellum and surrounding
the brainstem was also evident (Figures 2c.1a through 2c.1d). PET scan revealed
markedly elevated FDG activity within both medial temporal bones, differential
FDG activity in the cortex, and deep gray nuclei with a relatively increased
FDG uptake in the deep gray nuclei and decreased FDG uptake in the cortex
(Figure 2c.2).
Multiple laboratory studies, including urine Histoplasma antigen, CMV viral
load, RPR, and cryptococcal serum antigen were all negative. CSF analysis
revealed 10 WBC/μl with 1% neutrophils, 95% lymphocytes, protein 79 mg/dl,
and glucose 72 mg/dl. JCV, EBV, HSV, and Toxoplasma were all negative on CSF
analysis. Brain biopsy revealed cerebellar tissue with numerous macrophages
engulfing intracytoplasmic amebas with prominent nuclei and karyosomes
(Figures 2c.3a through 2c.3d).
 Encephalitis and Myelopathy
A B

CHAPTER 2
C D

33
Figure 2c.1a through 2c.1d. Non-contrast head CT demonstrating the right cer-
ebellar hemisphere hypodense lesion with mild mass effect upon the fourth ventricle. T2
(B), T1 (C), and T1 postcontrast (D) axial head MR images demonstrating T2 and FLAIR
hyperintense lesion in the right cerebellum with patchy T1 shortening, moderate mass-
effect, and significant surrounding edema.

The differential diagnosis included infection with Acanthamoeba spp.,

Balamuthia mandrillaris, and Naegleria fowleri. Given the presence of a double-
contoured cyst wall and the appearance of the nuclei and karyosomes, the
pathologist in our institution favored Balamuthia as the etiologic agent.
Naegleria fowleri was thought to be unlikely, given that the encysted form is not
usually identified in histologic sections. With the pathology results suggestive
of Balamuthia mandrillaris infection multiple antimicrobials with in vitro activity
against free-free living amebas were initiated. The patient remained unrespon-
sive when not sedated and ventilator-dependent despite multiple antimicrobi-
als that have been found to have in vitro activity against free living amebas. It
was decided to pursue only palliative measures. He died soon thereafter.
The indirect immunofluorescence on brain tissue performed at the CDC
was later found to be positive for Acanthamoeba sp (Figures 2c.3 c,d). Real-
time PCR on CSF was also positive for Acantamoeba, negative for Balamuthia
mandrillaris and Naegleria fowleri. Serologic testing using indirect immuno-
fluorescence antibody was negative for both Acanthamoeba and Balamuthia
mandrillaris. Postmortem examination confirmed amoebic encephalitis involv-
ing the parenchyma of the cerebellum and cerebrum with dissemination
through the ventricles and cerebrospinal fluid, and brain PCR was positive for
Acanthamoeba sp.
Encephalitis and Myelopathy
34 CHAPTER 2

Figure 2c.2. Positron Emission Tomography (PET) scan of brain showing hypometa-
bolic lesion within the right hemisphere of the cerebellum.

Case 2c Discussion: Acanthamoeba Encephalitis

Diagnosis and Clinical Features
Free living ameba of the genus Acanthamoeba are found in the environ-
ment worldwide, and are responsible for disease mainly in immunocom-
promised patients, but cases of amebic infection due to Acanthamoeba
have been described in adults and children with no underlying conditions.1–4
Acanthamoeba spp with Balamuthia mandrillaris are the causative agents of
granulomatous amebic encephalitis (GAE), a subacute CNS infection char-
acterized by insidious onset of symptoms over a period of time that varies
from weeks to months. Patients may present with headache, confusion, nau-
sea, vomiting, low-grade fever, lethargy, focal neurologic deficits, or signs of
increased intracranial pressure.2,4 The prognosis of GAE is very poor; death
usually occurs from brain herniation due to increased intracranial pressure.
Humans are presumably infected by direct inoculation via nasal passages, pul-
monary inhalation, or introduction through skin lesion and dissemination to
the brain, possibly via hematogenous spread.4
 Encephalitis and Myelopathy
Charlottesville, U. VA –CDC# 2009012248 (S09-6388)-Acanthamoeba

A B

X100 X1000

CHAPTER 2
troph

Empty cyst

X1000 D
X1000 C

A. CNS section Showing A canthamoeba cysts (at arrows)

35
B. A high power view showing an encysted Acanthamoeba
C. The cyst as in B reacting with the anti-Acanthamoeba IgG in
the imunofluorescence(IIF) test.
D. An excysted Acanthamoeba trophozoiteleaving behind an
empty cyst (IIF test)

Figure 2c.3a through 2c.3d. (A) Brain biopsy showing Acanthamoeba cysts, hema-
toxylin and eosin stain; (B) Brain biopsy with encysted Acanthamoeba, hematoxylin and
eosin stain; (C) Brain biopsy with encysted Acanthamoeba, immunofl uorescence stain;
and (D) Brain biopsy with Acanthamoeba trophozoite and cyst, immunofl uorescence
stain.

The clinical diagnosis is difficult and the definitive diagnosis is usually achieved
by brain biopsy, often not until postmortem exam. The pathogenesis of the infec-
tion is poorly understood; severe hemorrhagic necrosis, fibrin thrombi, and sub-
acute granulomatous encephalitis are found on pathology. Tissue examination
may reveal numerous trophozoites and cysts, and granulomas may be scarce
or absent in immunocompromized hosts.4 CSF analysis is not pathognomic
and can reveal lymphocytic pleocytosis, slight increased protein, and normal or
mildly decreased glucose.1 In case of high index of suspicion, trophozoites may
be observed on Wright-Giemsa stain and wet mount preparation of CSF.5 The
organism can be detected by immunofluorescence staining, and PCR can detect
Acanthamoeba DNA; serology can be done by indirect immunofluorescence.2,5
CT scans in different cases have shown enhancing lesions and multifocal lesions,
edema; multiple ring enhancing lesions may be observed on MRI.2,6
 Treatment
Encephalitis and Myelopathy

Treatment of GAE is challenging, because diagnosis is often delayed and because

the organism is generally poorly responsive to therapy once there is CNS
involvement. Many combinations of different agents have been tried based on
in vitro activity. These have included trimethoprim-sulfamethoxazole, rifampin,
miltefosine, amphotericin, pentamidine, etc., but none have been demonstrated
to have satisfactory outcome in late-stage disease.

References
1. Visvesvara GS, Moura H, Schuster FL. Pathogenic and opportunistic free-living
CHAPTER 2

amoebae: Acanthamoeba spp., Balamuthia mandrillaris, Naegleria fowleri, and

Sappinia diploidea. FEMS Immunol Med Microbiol. 2007 June;50(1):1–26.
2. Da Rocha-Azevedo B, Tanowitz HB, Marciano-Cabral F. Diagnosis of infec-
tions caused by pathogenic free-living amoebae. Interdiscip Perspect Infect Dis.
2009;2009:251406
3. Petry F, Torzewski M, Bohl J, et al. Early diagnosis of Acanthamoeba infection
during routine cytological examination of cerebrospinal fluid. J Clin Microbiol.
2006;44:1903–1904.
4. Martinez AJ, Visvesvara GS. Free-living, amphizoic and opportunistic amebas.
Brain Pathol. 1997;7:583–598.
5. Schuster FL, Visvesvara GS. Opportunistic amoebae: challenges in prophylaxis
36

and treatment. Drug Resist Updat. 2004;7(1):41–51.

6. Perez MT, Bush LM. Fatal amebic encephalitis caused by Balamuthia mandrillaris
in an immunocompetent host: a clinicopathological review of pathogenic free-
living amebae in human hosts. Ann Diagn Pathol. 2007;11(6):440–447

Case
C a e 22d:
d: A R
d: Ren
Renal
all T
Tra
Transplant
ansplant
l tR Recipient
eciipien
i nt with
ith W
Weakness
eak
kness
knes
and
an Gait
d Ga
G Instability
it Instabili
lity
ty

Michael Lief and Shirish Huprikar

Clinical Presentation
A 38-year-old man from Romania was admitted with numbness and tingling in
both legs, as well as unsteady gait. One day prior to admission he noted dif-
ficulty getting up from a chair, and eventually he had difficulty ambulating and
walking up stairs. He also began experiencing numbness and tingling in both
legs. Upon further questioning, he admitted that over the past six months he
had noticed feeling a bit more “clumsy,” but attributed this to lack of exercise.
He denied any fevers or chills, visual changes, cough, dyspnea, abdominal pain,
diarrhea, or rash.
He had undergone renal transplantation for glomerulonephritis, in Romania,
25 years earlier. He underwent a second renal transplant for chronic rejection
in Oregon, seven years prior to presentation. His immunosuppressive medica-
tions included cyclosporine, mycophenolate mofetil, and prednisone. He was
born in Romania but had lived in the United States for 20 years, and had not

Encephalitis and Myelopathy

recently traveled. He had no pets or sick contacts.
On physical examination, the patient had no fever, photophobia, or nuchal
rigidity. His neurologic exam was significant for decreased lower extremity
strength (4/5), hypertonicity, and hyperreflexia in both legs and sustained ankle
clonus on the right. He had decreased sensation to light touch pinprick and
vibration in both legs, as well as a spastic gait and a positive Romberg sign. In
addition, he had a right foot drop and a positive plantar reflex on the right. The
remainder of the physical examination was unrevealing. His admission labora-
tory values, including tests for HIV and syphilis, were nondiagnostic. MRI of the
brain with gadolinium was normal, but MRI of the spine revealed cord atrophy

CHAPTER 2
at T4–11 (Figure 2d.1). Cerebrospinal fluid analysis revealed 27 white blood
cells (88% lymphs, 12% mono), increased protein (78 mg/dl), and normal glu-
cose (82 mg/dl). No organisms were found on Gram stain, acid fast stain, or
fungal stains of the CSF. Cerebrospinal fluid tests for CMV, HSV-1/2, VZV, EBV,
HHV-6, West Nile virus, Toxoplasma, Lyme, lymphochoriomeningitis virus, and
Cryptococcus were all negative. HTLV-1 (human T-lymphotropic virus) DNA
was detected by PCR of the CSF, however, and the patient was diagnosed with
HTLV-1 associated myelopathy. Upon further investigation, it was discovered
that the second donor kidney had been harvested from a cadaveric donor who
was originally from the Caribbean.

37
Case 2d Discussion: Human T-lymphotropic virus-1 Myelopathy
Epidemiology
It is estimated that between 10 and 20 million people worldwide are infected
with HTLV-1. Certain geographic areas are endemic for infection, such as
southern Japan and the Caribbean. Rates of seropositivity in Jamaica, Trinidad
and Tobago, Barbados, Haiti, and the Dominican Republic range between 5%

Figure 2d.1. MRI spine (sagittal view) showing mild spinal cord atrophy at T4–11.
 and 14%. HTLV-1 is also present in South and Central America, including Brazil
Encephalitis and Myelopathy

(especially Bahia and the northeast), Colombia, Venezuela, Guyana, Surinam,

Panama, and Honduras.
In the United States, large-scale blood supply screening has documented
rates of HTLV-I/II of 0.3 to 0.4 per 1000, of which one-third to half of these are
HTLV-1.1 Evidence suggests that most of these donors had links to an endemic
area, or an exposure risk such as blood transfusion or multiple sexual partners.
Seroprevalence tends to increase with age, and women are nearly twice as
likely as men to be infected, a phenomenon likely related to higher efficiency of
sexual transmission from male to female.2,3 As HTLV-1 infection is more preva-
lent in women, the incidence of HAM/TSP is also more common. It affects less
CHAPTER 2

than 2% of HTLV-1 carriers, and the onset ranges from 4 months to 30 years,
with a median of about 3 years after infection.
The primary mode of transmission of HTLV-1 is breastfeeding. Virus is found
in breast milk, and animal studies have confirmed transmission.4 Human epide-
miologic studies have shown that breastfed infants have a fourfold increased
risk of infection versus bottle-fed infants, and the longer a mother breastfeeds,
the higher the risk of transmission.5 There is likely a transient protective effect
of maternal antibodies transferred in utero.6 While breast milk is the principal
mode of HTLV-1 transmission, it can also be spread via sexual intercourse,
blood transfusion, and shared needles, as well as vertically during birth.
38

Donor-Derived HTLV-1 in Organ Transplantation

Finally, an area that deserves special attention due to our case is donor-de-
rived infections during solid organ transplantation. It is not known whether
HTLV infection contributes to significant morbidity in solid organ recipients.
Obviously, donor-derived transmission and infection can simply lead to sero-
conversion in the organ recipient, as in nontransplant hosts, without evidence
of the patient ever developing clinical disease. However, seroconversion and
evolution of disease years later has been reported, with HTLV-1-associated
myelopathy being reported in a previously seronegative recipient 4 years after
cadaveric renal transplantation.7 In another series, three recipients of solid
organ transplants (one liver, two kidney) developed a subacute myelopathy
within 2 years after becoming infected with HTLV-I from a single asymptomatic
HTLV-I donor.8 Despite these case reports, UNOS (United Network for Organ
Sharing) data suggests that transmission of virus leading to morbidity is rare, and
that HTLV-positive donors should be considered. In 25 seropositive donors
found from 1988–2000, with 22 organs transplanted, there were no cases of
HTLV-related disease reported in recipients, with a median nearly 12 months
of follow-up.9
Clinical Presentation
HTLV-1 infection has a broad range of manifestations. The vast majority of
patients who are HTLV-1 seropositive are asymptomatic. The virus infects
T cells and can lead to smoldering or aggressive adult T-cell lymphoma/leu-
kemia. Defects in cellular immunity can lead to increased risk for relapsing
strongyloidiasis and infective dermatitis. HTLV-1-associated myelopathy is

Encephalitis and Myelopathy

a disease of insidious onset, in which patients experience slowly progressive
weakness and spasticity of one or both legs. Other manifestations include
hyperreflexia, ankle clonus, extensor plantar responses, and lumbar pain.
The upper extremities are spared, but genitourinary symptoms are common,
including detrusor instability leading to nocturia, urinary frequency, and incon-
tinence. There are also minor sensory changes, especially paresthesias and loss
of vibration sense, but cognitive function is unaffected. HTLV-1 infection can
also lead to a spectrum of other neurologic abnormalities besides myelopathy,
including generalized leg weakness, impaired tandem gait, urinary incontinence,
and impaired vibration sense.

CHAPTER 2
Diagnosis
Diagnostic criteria were agreed upon by a World Health Organization (WHO)
panel in 1989 (See Table 2d.1).10
MRI of the brain and spinal cord can be normal, but may reveal atrophy of
the cervical or thoracic cord and/or white matter lesions in the subcortical and
periventricular regions. Neurophysiologic studies may reveal evidence of pos-
terior column dysfunction, as well as a peripheral neuropathy.

39
Table 2d.1 WHO Diagnostic Criteria for TSP/HAM
I. Clinical criteria
The florid clinical picture of chronic spastic paraparesis is not always seen when
the patient first presents. A single symptom or physical sign may be the only
evidence of early HAM/TSP.
A. Age and sex incidence
Mostly sporadic and adult, but sometimes familial; occasionally seen in
childhood; females predominant.
B. Onset
This is usually insidious but may be sudden.
C. Main neurological manifestations
1. Chronic spastic paraparesis, which usually progresses slowly, sometimes
remains static after initial progression.
2. Weakness of the lower limbs, more marked proximally.
3. Bladder disturbance usually an early feature. Constipation usually occurs
later; impotence or decreased libido is common.
4. Sensory symptoms such as tingling, pins and needles, burning, etc. are more
prominent than objective physical signs.
5. Low lumbar pain with radiation to the legs is common.
6. Vibration sense is frequently impaired; proprioception is less often affected.
7. Hyperreflexia of the lower limbs, often with clonus and Babinski’s sign.
8. Hyperreflexia of upper limbs; positive Hoffmann’s and Tromner signs
frequent; weakness may be absent.
9. Exaggerated jaw jerk in some patients.
Encephalitis and Myelopathy

Table 2d.1 Continued

D. Less frequent neurological findings
Cerebellar signs, optic atrophy, deafness, nystagmus, other cranial nerve
deficits, hand tremor, absent or depressed ankle jerk.
Convulsions, cognitive impairment, dementia, or impaired consciousness
are rare.
E. Other neurological manifestations that may be associated with HAM/TSP
Muscular atrophy, fasciculations (rare), polymyositis, peripheral neuropathy,
polyradiculopathy, cranial neuropathy, meningitis, encephalopathy.
F. Systemic nonneurological manifestations that may be associated with HAM/TSP
CHAPTER 2

Pulmonary alveolitis, uveitis, Sjögren’s syndrome, arthropathy, vasculitis,

ichthyosis, cryoglobulinemia, monoclonal gammopathy, adult T-cell leukemia/
lymphoma.
II. Laboratory diagnosis
A. Presence of HTLV-1 antibodies or antigens in blood and cerebrospinal fluid (CSF).
B. CSF may show mild lymphocyte pleocytosis.
C. Lobulated lymphocytes may be present in blood and/or CSF.
D. Mild to moderate increase of protein may be present in CSF.
E. Viral isolation when possible from blood and/or CSF.
Reprinted with permission from WHO. Virus Diseases: Human T lymphotropic virus type I,
HTLV-I. Wkly Epidemiol Rec 1989; 64:377–384.
40

Management and Prognosis

There is no effective antiviral therapy for the treatment of HAM/TSP. Case
series suggest that immunosuppressant medications such as corticosteroids
may help to slow progression of disease and reduce neurologic disability. There
are, however, no randomized clinical trials evaluating this, and so this therapy
remains controversial. Combination therapy with the nucleoside analogs, zido-
vudine and lamivudine, was evaluated in a randomized double-blind, placebo-
controlled study, which included 16 patients with HAP/TSP, but no significant
clinical improvement was noted after 12 months of follow-up.1 The prognosis
for patients affected by HAP/TSP is poor. One series of 123 affected patients
demonstrated progression of disease from onset to wheelchair confinement
occurring over a median of 21 years.2

References
1. Lee HH, Swanson P, Rosenblatt JD, et al. Relative prevalence and risk fac-
tors of HTLV-I and HTLV-II infection in US blood donors. Lancet. 1991;
337(8755):1435–1439.
2. Mueller N, Okayama A, Stuver S, Tachibana N. Findings from the Miyazaki
Cohort.
3. Study. J Acquir Immune Defic Syndr Hum Retrovirol. 1996;13(Suppl):S2–S7.
 4. Murphy EL, Figueroa JP, Gibbs WN, et al.. Sexual transmission of human

Encephalitis and Myelopathy

T-lymphotropic virus type I (HTLV-I). Ann Intern Med. 1989;111(7):555–560.
5. Kinoshita K, Hino S, Amagaski T, et al. Demonstration of adult T-cell leu-
kemia virusantigen in milk from three sero-positive mothers. Gann. 1984;
75(2):103–105.
6. Takahashi K, Takezaki T, Oki T, et al.; The Mother-to-Child Transmission Study
Group. Inhibitory effect of maternal antibody on mother-to-child transmission
of human T-lymphotropic virus type I. Int J Cancer. 1991 Nov 11;49(5):673–677.
7. Nakatsuji Y, Sugai F, Watanabe S, et al. HTLV-I-associated myelopathy mani-
fested after renal transplantation. J Neurol Sci. 2000;177(2):154–156.
8. Toro C, Rodés B, Poveda E, Soriano V. Rapid development of subacute myelop-

CHAPTER 2
athy in three organ transplant recipients after transmission of human T-cell lym-
photropic virus type I from a single donor. Transplantation. 2003;75(1):102–104.
9. Shames BD, D’Alessandro AM, Sollinger HW. Human T-cell lymphotropic
virus infection in organ donors: a need to reassess policy? Am J Transplant.
2002;2(7):658–663.
10. World Health Organization (WHO). Virus diseases: human T lymphotropic
virus type I, HTLV-I. Wkly Epidemiol Rec. 1989;64:382.
11. Taylor GP, Goon P, Furukawa Y, et al. Zidovudine plus lamivudine in human
T-lymphotropic virus type-I-associated myelopathy: a randomised trial.
Retrovirology. 2006;3:63.
12. Olindo S, Cabre P, Lézin A, et al. Natural history of human T-lymphotropic

41
virus 1-associated myelopathy: a 14-year follow-up study. Arch Neurol.
2006;63(11):1560–1566.
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 Chapter 3

Focal Central Nervous

System Infections

Case
C a e 3a:
3a: At
A
Ataxia,
taxia,
i D Di
Dizziness,
izzi
ziness,
i and
d Al
Alt
Altered
tereed M
Mental
ent
ntall SSt
Status
tattus
tus
i aP
in Patient Previviou
oussly Tr
Previously T eated forr Pneu
Treated umo
monia
Pneumonia

Sean Pawlowski and W. Michael Scheld

Case Presentation
A 70-year-old man with a history of hypertension, atrial fibrillation, and hyper-

43
lipidemia presented with a 4-day history of dizziness and falls to his left side.
Three weeks prior to presentation, he was evaluated at an outside hospital for
fever, chills, productive cough, and dyspnea. He was treated with levofloxacin
for possible pneumonia and his cough had since resolved.
On physical examination, he was febrile (101.8º F), confused, and unable to
cooperate with a full neurologic evaluation. There was a 2/6 systolic ejection
murmur heard along the left sternal border, and rales at the lung bases bilaterally.
The remainder of his physical examination was unrevealing. Laboratory analyses
were notable for elevated erythrocyte sedimentation rate (86 mm/h) and normal
C-reactive protein (0.5 mg/dl) with normal complete blood count and electrolytes.
CT of the head demonstrated a mass in the right occipital and temporal
lobes, with adjacent edema leading to mass-effect of the right lateral ventricle.
Brain MRI further clarified the lesion as multilobulated with an additional infe-
rior satellite lesion (Figures 3a.1a and 3a.1b, and Figure 3a.2). Purulent material
(10 cc) was drained through a burr hole approach, and cultures were positive
for Streptococcus intermedius. His initial antibiotics (cefepime, vancomycin, and
metronidazole) were narrowed to ceftriaxone and metronidazole when cul-
tures returned Streptococcus intermedius. A CT of the chest was performed,
which demonstrated a small pulmonary lesion, suspicious for an abscess.
Case 3a Discussion: Streptococcus intermedius Brain Abscess
Clinical Presentation and Diagnosis
Brain abscesses are focal, space-occupying, purulent infections of brain paren-
chyma. Patients with brain abscess usually present with headache, confusion,
and focal neurologic signs (e.g., weakness, aphasia, ataxia), but fever is reported
Focal Central Nervous System Infections

A
CHAPTER 3

B
44

Figure 3a.1a and 3a.1b Brain MRI (axial view) showing a right occipitotemporal lobe
complex cerebral abscess due to S. intermedius with associated edema on T1 (A) and T2
(B) weighted imaging.

in d50% of cases.1,2 Patients with known brain abscesses who experience a sud-
den worsening of headache may have abscess rupture with associated ventricu-
litis. Elevated, normal, or decreased peripheral white blood cell counts may
be present. Lumbar puncture is not necessary with suspected brain abscess,
and poses a risk of brain herniation, but on CSF analysis approximately 60% of
 Focal Central Nervous System Infections
CHAPTER 3
Figure 3a.2 Brain MRI (axial view) showing multiple cerebral abscesses with sur-
rounding edema on T2 weighted imaging in a different patient with S. intermedius
bacteremia.

45
patients have pleocytosis, increased protein, and/or hypoglycorrhachia.3 Low
Glasgow Coma Scale (GCS), immunodeficiency, and presence of an underlying
malignancy are poor prognostic factors.3
Advances in the antimicrobial and surgical treatment of sinonasal and oro-
facial infections, along with improvements in radiography (e.g., CT/MRI) for
earlier detection, have decreased the mortality rate of cerebral abscesses
from 60% during the 1970s to 10%–32%.3 The predisposing condition leading
to abscess formation predicts the focus of cerebral infection and presenting
signs. Otogenic spread more often affects the temporal lobes (seizures) and
cerebellum (ataxia), whereas sinonasal disease more often affects the frontal
lobes (headache, personality changes, inattention). Trauma or surgery can lead
to infection at the site of cranial defect.2 Hematogenous spread can lead to mul-
tiple brain abscesses in varying locations. Endogenous infection most commonly
arises from pyogenic sources within the thoracic or intra-abdominal cavities,
particularly in patients with endocarditis or congenital cyanotic heart disease. In
up to 40% of cases, no source is identified.3
Most bacterial cerebral abscesses are due to aerobic, anaerobic, and
microaerophilic streptococci (up to 70%). The Streptococcus anginosus group
(S. anginosus, S. constellatus, and S. intermedius) is particularly associated
with brain abscess, and S. intermedius is the most frequently identified spe-
cies.1 Animal models demonstrate that members of this group grow better
in an acidic abscess environment, and that anaerobic organisms promote the
growth of streptococci. Clinical studies in both immunocompetent and immu-
nocompromised patients indicate that 45%–60% of S. anginosus infections are
 mixed.4,5 Staphylococcus aureus and Staphylococcus epidermidis, enterobacteri-
Focal Central Nervous System Infections

aceae, Pseudomonas, anaerobic bacteria (e.g., Peptostreptococcus, Bacteroides,

Prevotella), Mycobacterium tuberculosis, and higher order bacteria (Actinomyces
and Nocardia ) are well-recognized causes of bacterial abscesses. S. aureus
causes 10%–20% of all cerebral abscess cases, and is the most common cause
of trauma and postsurgical cases.1 Diagnosis relies on radiographic findings, as
well as tissue for culture and pathology. Computed tomography with contrast
localizes cerebral areas of enhancement, as well as sinus and mastoid origins,
but MRI has a higher sensitivity and can identify cerebral abscesses during early
stages of infection.1 Stereotactic or open drainage for culture provides valuable
diagnostic information as well as therapeutic advantage, when compared to
empiric antimicrobial therapy without drainage.
Treatment
Successful treatment depends on a combined surgical and medical approach,
CHAPTER 3

with culture results guiding antimicrobial choice; medical therapy without surgi-
cal intervention is associated with a poor outcome.3 It is ideal for drainage and
culture to be performed prior to the initiation of antibiotics, but this is often
not possible due to concomitant sepsis or risk of herniation. Initial empiric
regimens for community-acquired, traumatic, or nosocomial-acquired brain
abscesses can include a third- or fourth-generation cephalosporin combined
with metronidazole. The addition of vancomycin is particularly advisable in
46

post-neurosurgical and post-trauma cases. Since anaerobic cultures have low

sensitivity, a negative anaerobic culture does not exclude their involvement,
and antimicrobial activity against them should be continued.
Intravenous therapy is recommended for 6–8 weeks followed by 2–6 months
of an appropriate oral antibiotic that achieves adequate CNS levels.1 In cases of
nocardiosis, sulfonamides are the drug of choice, but combination therapy with
an aminoglycoside, fluoroquinolone, carbapenem, or cephalosporin is recom-
mend in immunocompromised patients and those with progressive disease.2
Therapy for Nocardia abscesses requires at least 3–12 months of treatment,
and possibly longer in immunocompromised patients (see case 3c). Adjunctive
corticosteroid use is controversial, but recommended for patients with signifi-
cant edema, increased intracranial pressure, or a predisposition to herniation.
Antiepileptic medications should be used for patients who have experienced
seizures, and antibiotics that predispose patients to seizures should be avoided.
MRI after surgical and medical therapy may be used for assessment of therapeu-
tic success, but abscess resolution may lag behind clinical improvement.

References
1. Tunkel A. Brain abscess. In: Mandell GL, Dolin R, and Bennett JE, eds. Principles and
Practice of Infectious Diseases. 7th ed. Philadelphia: Elsevier Churchill Livingstone;
2010:1265–1278.
2. Mathisen GE, Johnson JP. Brain abscess. Clin Infect Dis. 1997;25:763–781.
3. Xiao F, Tseng M, Teng L, Tseng H, Tsai J. Brain abscess: clinical experience and
analysis of prognostic factors. Surg Neurology. 2005;63(5):442–449.
4. Singh KP, Morris A, Lang SD, MacCulloch DM, Bremner DA. Clinically significant

Focal Central Nervous System Infections

Streptococcus anginosus. NZ Med J. 1988;101(859):813–816.
5. Stelzmueller I, Berger N, Wiesmayr S, Eller M, Tabarelli W, et al. Group mil-
leri streptococci: significant pathogens in solid organ recipients. Transpl Int.
2007;20(1):51–56.

Ca e 3b:
Case 3b:
b: A 555
55-Year-Old
5-Y
Year-O
Old Man
M wit
with
ith
hBBack
ack
kPPain
ain
in

Rupa Rajesh Patel and Daniel Caplivski

Case Presentation
A 55-year-old man with a history of diabetes, hypertension, and coronary
artery disease presented to an outside facility with low back pain. He had an

CHAPTER 3
extensive history of disseminated MRSA infections that began 6 months prior
to presentation with osteomyelitis of the right foot. He required amputation
of the right hallux, and blood cultures and wound cultures from the operating
room were positive for MRSA. Despite treatment with intravenous vancomy-
cin he returned with lower back pain radiating to the right leg. He denied any
weight loss, night sweats, or fever, and did not note any numbness or tingling
in the lower extremities. His back pain was unremitting, however, and he was
found to have an L4–5 discitis, epidural collection, and psoas abscess on lum-

47
bar spine MRI (figure 3b.1). In addition to ongoing vancomycin therapy using
appropriate weight-based dosing (15 mg/kg intravenously with trough goals of

Figure 3b.1 MRI lumbar spine, sagittal view showing L4–5 osteomyelitis and discitis.
 15–20 μg/ml), the patient was also treated with rifampin given the progressive
Focal Central Nervous System Infections

nature of his infection.

On physical examination, he was afebrile and had no focal neurologic defi-
cits, but did have a positive straight leg test on the right. His laboratory find-
ings were significant for the elevated erythrocyte sedimentation rate (132 mm/
hour) and C-reactive protein (44). He underwent surgical debridement of the
abscesses, L4-L5 anterior decompression, partial corpectomy, and allograft
reconstruction. Culture of the abscess was sterile, but he was treated again
with 6 weeks of intravenous vancomycin.
Case 3b Discussion: Staphylococcus aureus Epidural Abscess
Clinical Presentation and Diagnosis
Spinal epidural abscesses are infections of the space between the dura and
vertebral column. They are usually the result of hematogenous spreading from
other infected sites, or direct local invasion. Sources of bacteremia include
CHAPTER 3

skin infections, urinary tract infections, endocarditis, pneumonia, periodontal

abscesses, intravenous drug use, and indwelling venous catheters. Infections
from local space invasion occur through procedures, including epidural anes-
thesia, lumbar puncture, and back surgery, or local infections, such as sacral
decubitus ulcers and vertebral osteomyelitis. In 20%-40% of cases, the exact
source cannot be identified. A major risk factor for disease is an immunocom-
promised state, including diabetes mellitus.1 The organisms most frequently
48

recovered include Staphylococcus aureus in 50%–90% of cases, streptococci in

8%–17% of cases, and Gram negative bacilli in 12%–17% of cases. The differ-
ential diagnosis for spinal lesions also includes Nocardia spp., dimorphic fungi,
Mycobacterium tuberculosis, and fungi.
The clinical presentation of spinal epidural abscesses includes back pain that
may be acute or chronic. Acute presentation occurs over hours to days, and
is typically associated with hematogenous seeding. Chronic symptoms develop
over weeks to months, and are more common in the setting of contiguous
foci of infection (i.e., vertebral osteomyelitis). Fever is reported in 30%–60% of
cases, but may be notoriously absent. Clinical symptoms may evolve from focal
back pain to sensory and/or motor deficits, and ultimately complete paralysis.
Prompt recognition is vital, since neurologic deficits are potentially reversible
with treatment before paralysis develops.
Physical examination is often notable for focal spinal tenderness and neu-
rologic deficits of involved spinal cord levels. Pertinent laboratory studies
reveal an elevated C-reactive protein (CRP) and erythrocyte sedimentation
rate (ESR). The diagnosis of epidural abscesses is confirmed with spine imag-
ing. Magnetic Resonance Imaging (MRI) with gadolinium-contrast enhancement
yields higher resolution images than computed topography (CT) scanning. MRI
is superior at detecting associated osteomyelitis and discitis, and the presence
of hyperintense signal on T2-weighted images may allow for differentiation of
infected versus sterile collections. MRI may also be used to assess treatment
response; however, radiologic changes often lag behind clinical cure.1
 Cranial epidural abscesses are usually the result of an extension of infection

Focal Central Nervous System Infections

from sinus, mastoid, and/or middle ear infections. Infection may also result from
procedures such as craniotomy, and trauma can be a direct mechanism of infec-
tion. Cranial epidural abscesses present with headache in the absence of other
symptoms, but a delay in diagnosis can lead to enlargement of the abscess with
resulting focal neurologic symptoms and seizures. Physical examination may
reveal neurologic deficits and signs associated with increased intracranial pres-
sure, such as papilledema. Complications of a cranial epidural abscess include
subdural empyema, brain abscess, and meningitis.
Management
Epidural abscesses, both spinal and cranial, require a combination of medical
and surgical therapy. Cranial epidural abscess requires a minimum of 3–6 weeks
after surgical drainage, with a minimum of 6 weeks duration if osteomyelitis
is evident. For surgical evacuation, craniectomy is preferred over burr hole

CHAPTER 3
placement. Spinal epidural abscess is treated for a minimum of 6–8 weeks after
surgical debridement; the risk of relapse is decreased with 8 weeks of therapy.1
Empiric antimicrobials such as vancomycin and third-generation cephalosporins
are directed against Staphylococcus aureus and the Gram-negative organisms
most frequently isolated in this disease. Newer anti-Staphylococcal agents such
as daptomycin have been used for epidural abscess treatment, though large
scale trials are lacking.2 In post-neurosurgical infections, empiric therapy should

49
account for local hospital epidemiology and antimicrobial resistance. Dorsal
lesions are more likely than ventral lesions (30% versus 7%) to present with
quadriplegia or paraplegia.3 Patients with neurologic deficits require emergent
surgical decompression with stabilization to prevent permanent damage. The
mortality rate of epidural abscesses is 5%–23%, and neurologic presentation
before surgical intervention is a major predictor of permanent neurologic
sequelae.4,5

References
1. Tunkel A. Subdural empyema, epidural abscess, and suppurative intracranial
thrombophlebitis. In Mandell GL, Bennet JE, Dolan R, eds. Mandell, Douglas, and
Bennett’s Principles and Practices of Infectious Diseases, Vol. 1. 6th ed. Philadelphia,
PA: Churchill Livingstone; 2004:1165–1168.
2. Burdette, SD. Daptomycin for methicillin-resistant Staphylococcus aureus infec-
tions of the spine. Spine J. 2009;9(6):e5–e8.
3. Karikari IO, Powers CJ, Reynolds RM, et al. Management of a spontane-
ous spinal epidural abscess: a single-center 10-year experience. Neurosurgery.
2009;65(5):919–923.
4. Darouiche RO. Spinal epidural abscess and subdural empyema. Handb Clin
Neurol. 2010;96:91–99.
5. González-López JJ, Górgolas M, Muñiz J, et al. Spontaneous epidural abscess:
analysis of 15 cases with emphasis on diagnostic and prognostic factors. Eur J
Intern Med. 2009;20(5):514–517.
Focal Central Nervous System Infections

Case
C a e 33c:
c: A B
Bone Marrow
Marr
rrow Transplant
Transplant
T l t Re
R
Recipient
eciipien
ientt with
ith
Back
Ba ck Pain and We
Weak
aknesss
Weakness

Nicole M. Bouvier and Daniel Caplivski

Case Presentation
A 39-year-old man with a history of allogeneic bone marrow transplantation
for acute myelogenous leukemia presented with several months of worsening
lower extremity weakness, back pain, and dry cough. He received the bone
marrow transplant from a closely matched sibling donor two years prior to pre-
sentation; however, his leukemia had subsequently relapsed. He was originally a
farmer from rural Mexico, but had been working as a cook in New York for five
years. Previous evaluations of his symptoms had revealed a lumbar paraspinal
CHAPTER 3

mass, and several left lower lobe pulmonary nodules. Biopsies of the paraspinal
mass had revealed only acute inflammation, necrotic tissue, and sterile cultures.
His medications included prednisone, voriconazole, ciprofloxacin, atovaquone,
and valacyclovir.
On physical examination, he was febrile to 103º Fahrenheit, and had
decreased strength and diminished reflexes in bilateral lower extremities. His
pulmonary examination was unremarkable. Laboratory findings were significant
50

for leukopenia (2.6x10³ WBC/μl, 24% neutrophils, 4% blasts), anemia (hemo-

globin 8.4 grams/dl), and thrombocytopenia (23x10³ platelets/μl). A dense
left lower lobe consolidation with areas of necrosis was seen on chest CT
(Figure 3c.1). Lumbar spine MRI revealed a worsening epidural abscess at the
level of L3-L4, with collapse of the vertebrae and increasing compression of the

Figure 3c.1 CT lungs, axial view showing left lower lobe nodular consolidation.
thecal sac and cauda equina. There were also paraspinal components of the

Focal Central Nervous System Infections

abscess involving the psoas and paraspinal muscles (Figure 3c.2). Brain imaging
did not reveal any focal abnormalities
Neurosurgical drainage of the abscess was performed, and cultures eventu-
ally yielded a Gram-positive, filamentous, branching rod with dry colonies that
was identified as Nocardia farcinica (Figures 3c.3, 3c.4, 3c.5).

Figure 3c.2 MRI spine, sagittal view showing epidural abscess at the level of L3-L4 with 51 CHAPTER 3
collapse of the vertebrae and increasing compression of the thecal sac and cauda equina.
There were also paraspinal components of the abscess involving the psoas and paraspinal
muscles.

Figure 3c.3 Gram stain of lung biopsied material showing filamentous, beaded,
branching Gram-positive bacilli.
Focal Central Nervous System Infections
CHAPTER 3

Figure 3c.4 Modified acid fast stain of biopsied material showing filamentous bacilli.
52

Figure 3c.5 Dry, pigmented colonies of Nocardia farcinica on Sabaroud’s dextrose agar.

The patient was treated with high doses of trimethoprim/sulfamethoxazole

and imipenem for 6 weeks, followed by several months of trimethoprim/
sulfamethoxazole; however, he died 6 months later due to refractory acute
myelogenous leukemia and Pseudomonas sepsis.
Case 3c Discussion: Nocardia farcinica Epidural Abscess
Clinical Features and Diagnosis
Nocardia are aerobic, Gram-positive bacilli in the order Actinomycetales. They
are ubiquitous, soil-dwelling bacteria, yet they are an uncommon etiology of
localized and systemic suppurative infections in immunosuppressed and, to a
lesser extent, immunocompetent human hosts. More than 50 species comprise

Focal Central Nervous System Infections

the genus Nocardia; human disease is most often caused by the Nocardia aster-
oides complex, including N. asteroides sensu stricto, N. farcinica, N. nova, and
N. cyriacigeorgica. Other species causing human infections include N. brasiliensis,
N. pseudobrasiliensis, and N. otitidiscavarium (formerly N. caviae). Species have
varying geographic distributions, which influences the most common species
identified in single-center case series.1,2
Risk factors for nocardiosis include solid organ and bone marrow transplan-
tation, the acquired immune deficiency syndrome (AIDS), glucocorticoid use,
malignancy, and pulmonary disease.1 The lungs are the most common site of
infection with Nocardia spp., followed by skin and soft tissues, the central ner-
vous system (CNS), and other sites, including bones, kidneys, bloodstream,
lymphatics, and lymph nodes.1,2
In disseminated infection, Nocardia spp. have an observed tendency toward

CHAPTER 3
invasion of the CNS, where they can persist for months or even years prior to
diagnosis, long after the primary focus of infection is no longer evident. Brain
abscess is the most common finding; however, diffuse cerebral inflammation,
meningitis, and epidural abscess have also been reported, as well as vertebral
osteomyelitis, discitis, and psoas abscess.3 The presentation depends on the
CNS site involved; clinically, findings can range from silent infections discov-
ered incidentally on brain imaging or at autopsy, to acute, rapidly evolving
mass lesions associated with a localizing constellation of neurological findings.

53
Signs of systemic infection, like fever and leukocytosis, may be present or
absent.4
Management
Despite a lack of controlled clinical trials, sulfonamides like trimethoprim-
sulfamethoxazole (TMP-SMX) have traditionally been the treatment of choice
for Nocardia infections, based on retrospective data.5 Other intravenous anti-
biotics used against nocardia include imipenem, amikacin, and third-generation
cephalosporins (ceftriaxone and cefotaxime). Minocycline, dapsone, and
extended-spectrum fluoroquinolones are also known to have in vitro and/or in
vivo activity against Nocardia.6
Because antibiotic susceptibility among Nocardia species and isolates var-
ies, severe infections, including CNS disease, are generally treated with
TMP-SMX, plus one or occasionally two additional intravenous antibiotics.
Isolate sensitivities should be obtained, and antibiotics tailored accordingly.
Intravenous therapy should continue until clinical improvement occurs, usually
for a minimum of 6 weeks in immunocompromised hosts. After intravenous
induction, the patient may be switched to an oral maintenance regimen with
TMP-SMX, minocycline, or amoxicillin-clavulanate, again depending on isolate
susceptibilities.
The duration of therapy has not been rigorously studied; however, the
relapsing nature of Nocardia infections has led most experts to conclude that
CNS disease in an immunosuppressed host requires a minimum of one year of
treatment,3 and lifelong suppressive therapy may be considered.
 References
Focal Central Nervous System Infections

1. Lederman ER, Crum NF. A case series and focused review of nocardiosis: clinical
and microbiological aspects. Medicine. 2004;83(5): 300–313.
2. Valerio Minero M, Marin M, Cercenado E, Martin Rabadan P, Bouza E, Munoz P.
Nocardiosis at the turn of the century. Medicine. 2009;88(4):250–261.
3. Lerner PI. Nocardiosis. Clin Infect Dis, 1996;22(6):891–903.
4. Atalkay B, Azap O, Cekinmez M, Caner H, Haberal, M. Nocardial epidural
abscess of the thoracic spinal cord and review of the literature. J Infect Chemother.
2005;11:169–171.
5. Wallace RJ, Septimus EJ, Williams TW, et al. use of trimethoprim-
sulfamethoxazole for treatment of infections due to Nocardia. Rev Infect Dis.
1982;4(2):315–325.
6. Fihman V, Bercot B, Mateo J, et al. First successful treatment of Nocardia farci-
nica brain abscess with moxifloxacin. J Infect. 2006;52:e99–e102.
CHAPTER 3

Case
C a e 33d:
d: A C
d: Con
Construction
stru
t cttion W
Worker
orker
k wit
with
ith
hHHeadache
eada
dach
he aand
nd
d
V
Vi suaal Loss
su
Visual

Luciano Kapelusznik and Daniel Caplivski

54

Case Presentation
A 34-year-old man presented to an ophthalmologist with progressive visual
blurring and headache over the month prior to evaluation. He was originally
from rural Ecuador, and had been working in construction in New York for
ten years. His friends noted that he had been having spells during which he
would be unresponsive for several seconds. On physical examination, the
patient was found to have bilateral papilledema (Figure 3d.1), and his visual
acuity was only light perception bilaterally. He was referred emergently to
the emergency department for evaluation of increased intracranial pressure.
Imaging of the brain revealed dilated ventricles, multiple calcified lesions, and
multiple fluid-filled cysts in the brain parenchyma. At the base of the brain,
clusters of cysts (racemose disease) were obstructing the fourth ventricle
(Figures 3d.2–3d.4).
An external ventricular drain was placed emergently to reduce the
increased intracranial pressure. Some of the ventricular cysts were so closely
adherent to the midbrain that they could not be removed, and a ventricu-
loperitoneal shunt was placed. The patient was treated with steroids and
prolonged courses of high-dose albendazole, but the racemose disease was
unrelenting. He was subsequently admitted with multiple ventriculoperito-
neal shunt malfunctions and infections, and died within 12 months of his initial
presentation.
 Focal Central Nervous System Infections
CHAPTER 3
Figure 3d.1 Fundoscopic examination revealing papilledema.

55

Figure 3d.2 Head CT, axial view revealing hydrocephalus, viable cysts, and
calcifications.
Focal Central Nervous System Infections
CHAPTER 3

Figure 3d.3 Brain MRI, sagittal view showing hydrocephalus and viable cysts in the
frontal cortex and at the base of the brain.
56

Figure 3d.4 Brain MRI, axial view revealing racemose lesions at the base of the brain
obstructing CSF flow through the fourth ventricle.
Case 3d Discussion: Neurocysticercosis

Focal Central Nervous System Infections

Epidemiology and Clinical Presentation
Neurocysticercosis is an important disease mainly endemic to developing
nations where pigs and humans live in close contact. It is the leading cause
of adult-onset seizures in the developing world, and in some rural commu-
nities in South America, 20% of the population have asymptomatic cysts on
neuroimaging.1 The etiologic agent of neurocysticercosis is the larval form of
the tapeworm Taenia solium. This helminth is responsible for two very dis-
tinct clinical syndromes. The most benign of these syndromes, intestinal human
taeniasis, develops after the ingestion of live cysticerci (tissue cysts) in under-
cooked pork, followed by attachment of the scolex (anterior end of the worm)
to the human intestinal wall. The intestinal tapeworm then slowly elongates
over time, as proglottid segments are added in a process called strobilization.
Adult tapeworms are visible to the naked eye, and can reach several meters in

CHAPTER 3
length. The egg-filled proglottid segments are shed in human stool; when the
segments are ingested by pigs, oncospheres penetrate the intestinal wall, dis-
seminate throughout the pig’s tissues and become encysted, and the lifecycle
continues (Figure 3d.5).
In contrast, neurocysticercosis develops when humans accidentally ingest
eggs via contamination of food or water with stool shed by a human infected
with the adult worm. The oncospheres penetrate the human intestinal wall,

57
disseminating throughout human tissue and becoming encysted. The most
dreaded complications of this event are when the organisms reach the central
nervous system. Dozens of cysts may lodge in the brain or ventricles and
evade immune detection for years. Once the parasites are lodged in the brain
parenchyma, they form cysticerci that undergo four stages of involution. The
vesicular stage is characterized by a cyst with translucent vesicular wall, trans-
parent fluid, and a viable invaginated scolex. The cyst then develops a thick
vesicular wall, the fluid becomes turbid, and the scolex degenerates during
the next stage, which is termed the colloidal stage. An intense inflammatory
host response is seen, and is reflected histologically by varying degrees of
acute and chronic inflammation. The cyst continues to degenerate as it moves
into the granular stage, which is characterized by a thick vesicular wall, degen-
erated scolex, gliosis, and little inflammatory host response. Ultimately, the
parasite transforms into coarse calcified nodules—the calcific stage. As they
degenerate, an inflammatory response is elicited that may cause headaches,
nausea, and seizures. The intraventricular and subarachnoid (cisternal) forms
of neurocysticercosis are seen in 15% to 54% of patients, and present clini-
cally in a more aggressive manner as compared to the parenchymatous form.
Patients commonly present with raised intracranial pressure caused by large
cyst size or load, occlusion of CSF pathways, associated ependymitis, and basal
arachnoiditis. The racemose form of neurocysticercosis is characterized by
the presence of a cluster of large cisternal cysts that resemble a “bunch of
grapes.”1
Focal Central Nervous System Infections

Oncospheres hatch, Cysticerci may develop in

penetrate intestinal any organ, being more
wall, and circulate to common in subcutaneous
musculature 8 tissues as well as in the
brain and eyes
9
Embryonated eggs i
ingested by human host
Cysticercosis
7

4 Humans infected by
ingesting raw or i
undercooked infected meat
3 Oncospheres hatch,
penetrate intestinal
CHAPTER 3

Oncospheres develop
wall, and circulate to into cysticerci in pig muscle
musculature

2 Embryonated eggs
58

and/or gravid proglottids 5

ingested by pigs Scolex attaches
to intestine

i d
6
Adults in small intestine
1

i = Infective Stage Eggs or gravid proglottids in feces

d = Diagnostic Stage and passed into environment

Figure 3d.5 Lifecycle of Taenia solium. Source: Centers for Disease Control and
Prevention http://www.dpd.cdc.gov/dpdx

Diagnosis
Diagnosis of the presence of an intestinal tapeworm may be achieved by
examination of the stool for the presence of T. solium eggs or proglottids,
but stool studies are usually not useful in the diagnosis of neurocysticercosis.
Neuroimaging is the most common diagnostic modality for the larval form of
the disease. Early in the infection, a vesicular cyst appears as a spherical lesion
on computerized tomography (CT) and as a CSF-like signal on magnetic reso-
nance imaging (MRI); both modalities may reveal the invaginated scolex. In the
degenerative phase, the cyst has a ring-like appearance, or nodular contrast
enhancement, with or without perilesional edema. The final stage is observed
when the cyst dies and a process of mineralization and resorption takes place,

Focal Central Nervous System Infections

resulting in a calcified nodule. While CT is generally adequate to detect the
presence of most cysts, MRI may reveal cysts not seen on CT, particularly in
the anatomic structures of the posterior fossa. Serologic testing via enzyme-
linked immunoelectrotransfer blot assay (ETIB) has a sensitivity and specificity
approaching 100% for patients with two or more cystic or enhancing lesions.
The test performance declines for patients with single intracranial lesions or
calcified lesions, in which a sensitivity as low as 50% has been reported. In cases
in which the cyst is surgically removed, microscopic examination may reveal the
typical undulating membrane pattern of Cysticercus cellulosae, the pathologic
description of the larval form of Taenia solium (Figure 3d.6).
Management
Treatment of neurocysticercosis is controversial, in part because the natural
history of the disease is for the cysts to slowly involute over time. Many patients

CHAPTER 3
with less than five cysts can be managed with antiepileptic medications alone.
In the presence of 5–100 cysts, consensus guidelines support the use of anti-
parasitic medications in order to decrease the likelihood of further seizures.
Praziquantel is effective against the adult tapeworm; however, albendazole
achieves superior levels in the central nervous system (particularly when given
concomitantly with corticosteroids), and is therefore considered the first-line
agent. In patients with numerous cysts, antiparasitic therapy is often combined

59
with corticosteroids in order to prevent the sudden encephalitis that may result
from the inflammatory response to the parasitic antigens.2 Antiparasitic treat-
ment is not currently recommended for patients with nonviable lesions; how-
ever, patients with calcified lesions might have intermittent perilesional edema
and present with seizures, requiring antiepileptic medications.

Figure 3d.6 Brain biopsy revealing undulating membrane of Cysticercus cellulosae.

Original magnification 40x. Image courtesy of George Kleinman.
 Intraventricular cysts may not respond to medical management, and
Focal Central Nervous System Infections

often require surgical removal if they are obstructing the flow of CSF.
Neuroendoscopic removal is a preferred method, since it is less invasive than
open neurosurgery. Unfortunately, patients may have cysts that cannot be
removed surgically, and may require ventriculoperitoneal shunt placement to
relieve increased intracranial pressure. These shunts are prone to malfunction
and bacterial infection due to the accumulation of parasite antigens and inflam-
matory proteins. Racemose neurocysticercosis is a form that is often refractory
to therapies, though some investigators have had success with higher doses of
albendazole and steroids for prolonged periods of time.3
Prevention of the disease requires improved sanitation in developing coun-
tries, but public health campaigns have employed multiple strategies for control
of the disease. Education campaigns have highlighted proper cooking of pork, as
well as recognition of infected tissue by butchers and food handlers. Mass treat-
CHAPTER 3

ment campaigns focusing on both pigs and humans have also been employed in
efforts to eradicate the disease in communities with high endemicity. A porcine
vaccine is currently available, but current strategies have only been successful in
partially limiting transmission of the infection.4

References
1. Garcia HH, Del Brutto OH, Nash TE, White AC Jr, Tsang VC, Gilman RH. New
60

concepts in the diagnosis and management of neurocysticercosis (Taenia solium).

Am J Trop Med Hyg. 2005;72(1):3–9.
2. Garcia HH, Evans CA, Nash TE, et al: Current consensus guidelines for treatment
of neurocysticercosis. Clin Microbiol Rev. 2002;15:747–756.
3. Proaño JV, Madrazo I, Avelar F, López-Félix B, Díaz G, Grijalva I. Medical treat-
ment for neurocysticercosis characterized by giant subarachnoid cysts. N Engl J
Med. 2001;345(12):879–885.
4. Garcia HH, Gonzalez AE, Del Brutto OH, et al: Strategies for the elimination of
taeniasis/cysticercosis. J Neurol Sci. 2007;262:153–157.

Case
C a e 33e:
e: A 442
42-Year-Old
2-Y
Year-O
Old Man
M wit
with
ith
hPProgressive
rog
ogressiv
ive C
Cognitive
ognit
itiive
it
Decline
Decl
De cliine

Rupa Rajesh Patel and Daniel Caplivski

Presentation and Case History
A 42-year-old man with a history of sarcoidosis was admitted for elective hip
arthroplasty due to osteoarthritis. In the postoperative period he was found to
be confused and agitated, and further investigation revealed that he had been
having cognitive problems for several months. His roommate noted that he
was having memory lapses, as well as personality changes. He had been work-
ing as an actor and dancer, but was finding it increasingly difficult to perform
even the basic activities of daily living. The patient had been diagnosed with
severe pulmonary sarcoidosis three years prior to presentation, but had not

Focal Central Nervous System Infections

been receiving any immunosuppressive medications.
On physical examination, he was afebrile and his other vitals signs were
unremarkable. His neurological exam was notable for disorientation to the
time of year, left-sided neglect, horizontal nystagmus, and abnormal cerebel-
lar function with dysmetria on the left. Further examination revealed bilateral
lower extremity weakness and hyporeflexia. MRI of the brain revealed scat-
tered white matter lesions in both cerebral hemispheres, the largest of which
were in the left frontal parietal lobe and the left frontal lobe. No contrast
enhancement or mass effect was noted (Figures 3e.1 and 3e.2).
His laboratory evaluation included normal erythrocyte sedimentation rate
and C-reactive protein, and negative human immunodeficiency virus ELISA,
tuberculosis skin test, rapid plasma reagin, Lyme antibody, Toxoplasma antibod-
ies, and autoimmune studies. Brain biopsy revealed multiple areas of selective

CHAPTER 3
demyelination at various stages of evolution within the cerebral white matter.
The oligodendrocytes (i.e., myelin-producing cells) had large nuclei and intra-
nuclear basophilic material, and the astrocytes were enlarged and had irregular
nuclei (Figures 3e.3 and 3e.4). The patient’s cerebrospinal fluid JC virus PCR
was positive. Based on the history, brain biopsy, and laboratory evidence, the
patient was diagnosed with progressive multifocal leukoencephalopathy (PML),
and was treated with supportive management including physical therapy.

61

Figure 3e.1 Brain MRI, axial view revealing scattered white matter lesions in both
cerebral hemispheres, the largest of which were in the left frontal parietal lobe and the
left frontal lobe.
Focal Central Nervous System Infections
CHAPTER 3

Figure 3e.2 Brain MRI, axial view revealing scattered white matter lesions in both
cerebral hemispheres, the largest of which were in the left frontal parietal lobe and the
62

left frontal lobe.

Case 3e Discussion: Progressive Multifocal Leukoencephalopathy

Clinical Presentation and Diagnosis
Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease
associated with reactivation or primary infection of JC virus in the central ner-
vous system of immunosuppressed individuals. PML was first described as a
clinical entity in 1958, in patients with hematologic malignancies, but the epi-
demiology of PML changed with the emergence of AIDS. Prior to the 1980s,
PML was described in patients mainly with lymphoproliferative and myelopro-
liferative diseases, but was also observed in patients with cell-mediated immune
defects, those treated with corticosteroids and, rarely, in patients without
apparent immunocompromise. During the onset of the AIDS epidemic, 1%–4%
of HIV-positive patients had PML, and half of the deaths from PML occurred
in patients with AIDS. PML has also emerged as an important complication
in patients taking immunosuppressant medications for organ transplantation,
or monoclonal antibody anti-inflammatory medications such as natalizumab,
rituximab, and efalizumab.1 Cases of PML in pulmonary sarcoidosis are rare, but
severe cases have been described even in the absence of immunosuppressive
medications.2
JC virus is a polyomavirus that was first isolated from brain tissue in a patient
with PML in 1971. Asymptomatic infection with the JC virus likely occurs dur-
ing childhood and persists for years without clinical consequences in most
 Focal Central Nervous System Infections
CHAPTER 3
Figure 3e.3 Brain biopsy revealed multiple areas of selective demyelination at various
stages of evolution within the cerebral white matter. The oligodendrocytes had large
nuclei and intranuclear basophilic material and the astrocytes were enlarged and had
irregular nuclei. Image courtesy of George Kleinman.

63

Figure 3e.4 Brain biopsy with immunohistochemical stain for SV40 (which cross reacts
with JC virus) revealed multiple infected cells. Image courtesy of George Kleinman.

immunocompetent patients. Viral transmission is thought to occur through

inhalation or close contact, and viral reservoirs for latent disease include the
kidneys, central nervous system, and tonsils. In PML, JC virus infects astrocytes
and oligodendrocytes and leads to decreased myelin production. The role of
the 5HT2a serotonin receptor as a cellular receptor for JC virus has led to
investigation of potential therapeutic benefits of serotonin receptor antagonists,
 such as mirtazapine. It remains unknown whether PML results primarily from
Focal Central Nervous System Infections

primary infection, reactivation of a latent infection of the brain, or a secondary

infection of the brain due to viremia originating from a latent infection of the
kidney. Latent infections of both brain and kidney have been demonstrated by
JC virus polymerase chain reaction (PCR) of renal and cerebral tissue, as well as
urine and cerebrospinal fluid (CSF) PCR of asymptomatic individuals.
PML presents with subacute to rapidly progressing neurological deficits,
including hemiparesis, cognitive deficits, ataxia, visual field deficits, cranial nerve
involvement, and seizures. Severe manifestations and symptoms late in the
course of disease include quadriplegia, blindness, dementia, and coma. Clinical
deterioration and death usually take place within 6 months of diagnosis, and the
median survival is 3 months. Disease typically involves cerebral white matter,
but it can include the cerebellum and brainstem. Remyelination of damaged
areas does not usually occur in HIV-positive PML patients treated with anti-
CHAPTER 3

retroviral therapy (ARVs), and over 80% of those who survive this fatal disease
have severe neurologic deficits.3
The differential diagnosis for PML includes HIV encephalopathy, primary
central nervous system lymphoma, stroke, and brain tumor. The gold stan-
dard for diagnosis for PML is a brain biopsy demonstrating features of JC
virus infection. Pathologic characteristics of PML include cerebral white mat-
ter with asymmetrical foci of demyelination, and different stages of evo-
lution of demyelination. Electron microscopy may reveal polyomavirus in
64

enlarged oligodendrocytes. A positive JC virus CSF PCR supports a diagnosis

of PML when the patient is presenting with consistent clinical and radio-
logic features, but a negative PCR does not exclude disease. Sensitivities
of CSF PCR range from 72%–92%, and specificity ranges from 92%–100%.1
There is inconclusive evidence regarding the use of quantification of JC viral
DNA PCR as a prognostic marker. CSF cell count, glucose, and protein are
typically normal. Brain imaging reveals symmetric or asymmetric multifocal
areas of white matter demyelination. On computed topography (CT) scans,
PML lesions are hypodense and scattered throughout the parenchyma, and
are not characterized by edema or contrast enhancement. On magnetic
resonance imaging (MRI), lesions have an increased signal on T2-weighted
images. Electroencephalography (EEG) can reveal focal slowing, but may be
normal.1
Management
Most patients in whom JC virus is detected are asymptomatic, and treatment is
not necessary. There is currently no proven treatment regimen for non-HIV-
associated PML, and existing studies largely involve HIV-positive patients. The
Aids Clinical Trials Group (ACTG) performed a multicenter, randomized study
comparing the efficacy of antiretroviral treatment alone versus antiretroviral
treatment with the addition of intravenous or intrathecal cytarabine in biopsy-
proven, HIV-infected PML patients. There was no efficacy or survival benefit in
the intervention group, and those treated with cytarabine developed throm-
bocytopenia and anemia more often than the control arm.4 Other medications
that have been studied include interleukin-2, cidofovir, and interferon alpha-2,
but no convincing data exists to support their use. In HIV-positive patients

Focal Central Nervous System Infections

there is a definite role for antiretroviral (ARV) therapy, and median survival is
now 1.8 years versus 0.4 years during the pre-ARV era.3 Immune reconstitution
inflammatory syndrome (IRIS) may occur after treatment initiation.
In the case of organ transplantation, possible benefit with reduction in immu-
nosuppression has been documented through case reports.5 One study with
HIV-negative PML patients with hematologic malignancies, rheumatologic dis-
eases, and transplantation showed a benefit of intravenous cytarabine, 2 mg/kg
every 12 hours for 5 days, in stabilizing neurologic function in 7 out of 19 (36%)
patients on 2.5 year follow-up; however, patients experienced bone marrow
toxicity.6 Cidofovir is not recommended for PML as per the American guide-
lines for the treatment of AIDS-associated PML. In vitro studies have demon-
strated effectiveness of mirtazapine; it is postulated that JC virus uses serotonin
receptors for cell entry. A case report describes a woman with polycythemia

CHAPTER 3
vera and PML to have radiographic and clinical improvement within a month of
treatment with mirtazipine.7 Mefloquine has in vitro effects on JC virus, and is
currently under investigation.

References
1. Demeter L. JC, BK, and other polyomaviruses; progressive multifocal leukoen-
cephalopathy. In Mandell GL, Bennet JE, Dolan R, eds. Mandell, Douglas, and

65
Bennett’s Principles and Practices of Infectious Diseases, Vol. 2. 6th ed. Philadelphia,
PA: Churchill Livingstone; 2004:1856–1863.
2. De Raedt S, Lacor P, Michotte A, Flamez A, Ebinger G. Progressive multifocal
leukoencephalopathy as first manifestation of sarcoidosis. Clin Neurol Neurosurg.
2008;110(2):186–189.
3. Engsig FN, Hansen AB, Omland LH, et al. Incidence, clinical presentation, and
outcome of progressive multifocal leukoencephalopathy in HIV-infected patients
during the highly active antiretroviral therapy era: A nationwide cohort study.
J Infect Dis. 2009;199(1):77–83
4. Hall CD, DAfni U, Simpson D, et al. Failure of cytarabine in progressive multifocal
leukoencephalopathy associated with human immunodeficiency virus infection.
N Engl J Med. 1998;338:1345–1351.
5. Crowder CD, Gyure KA, Drachenberg CB, et al. Successful outcome of progres-
sive multifocal leukoencephalopathy in a renal transplant patient. Am J Transplant.
2005;5(5):1151–1158.
6. Aksamit AJ. Treatment of non-AIDS progressive multifocal leukoencephalopa-
thy: a monocenter observational study with clinical and JC virus load monitoring.
J Neurovirol. 2001; 7(4):386–390..
7. Verma S, Cikurel K, Koralnik IJ, et al. Mirtazapine in a progressive multifo-
cal leukoencephalopathy associated with polycythemia vera. J Infect Dis.
2007;196:709–711.
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 Chapter 4

Ophthalmologic Infections

Case
C a e 4a:
4a: A 223
23-Year-Old
3-Y
Year-O
Old Cont
C
Contact
tactt LLens Wearer
We er wi
with
ith Eye
ith Ey
Pain
Pa in and Decreased
Decreassed Vision
Visio
on

Nancy Sun and Chad Zatezalo

Case Presentation
A 23-year-old woman presented with a 2-day history of right eye pain, redness,

67
and decreased vision. At presentation, the patient was wearing 2-week dispos-
able soft lenses for myopic correction. The patient wore her contact lenses
daily, averaging 12 to 14 hours per day, and occasionally slept in her lenses.
Prior to the onset of symptoms, the patient had worn her contacts continu-
ously for 48 hours. The patient occasionally showered without removing her
lenses, but denied wearing the lenses in hot tubs or swimming pools. She stored
her contact lenses with over-the-counter multipurpose contact lens solution.
On examination, uncorrected visual acuity was 20/400 in the right eye, no
improvement with pinhole, and 20/40 in the left eye improving to 20/20 with
pinhole. There was moderate edema of the right eyelids with visible epiphora.
Slit-lamp examination of the right eye showed diffuse conjunctival injection,
chemosis, and a paracentral corneal ulcer with epithelial staining measuring
2.5mm x 2.0mm (Figure 4a.1). The ulcer showed severe dense suppurative
stromal infiltrate, approximately one-third of the corneal thickness. Uninvolved
portions of the cornea had a diffuse ground-glass appearance secondary to
edema. Anterior chamber reaction of 1+ cell was noted with no hypopyon
present. Examination of the left eye was unremarkable.
The contact lens case and corneal scrapings were taken for Gram stain
and culture. Treatment was initiated with broad-spectrum fortified antibiotics
consisting of tobramycin (15mg/ml) and cefazolin (50mg/ml) every one hour
while awake, along with cyclopentolate hydrochloride 1% three times daily
for patient comfort. Contact lens use was discontinued. After initiating treat-
ment, the patient was followed closely as an outpatient on a daily basis. The
size of the epithelial defect decreased over the first 24–48 hours of treatment,
Ophthalmologic Infections
CHAPTER 4

Figure 4a.1 Paracentral corneal ulcer with dense suppurative stromal infiltrate and
surrounding edema.

and completely healed in approximately one week. The stromal infiltrate was
68

slower to resolve, fading over the course of 3 to 4 weeks.

The cultures returned positive for Pseudomonas aeruginosa, susceptible to
tobramycin. Cefazolin was discontinued and the patient was maintained on for-
tified tobramycin, with reduction in the frequency of administration as corre-
lated with clinical improvement. Final uncorrected visual outcome was 20/60 in
the right eye, improving to 20/30 with pinhole, and unchanged in the left eye.
Case 4a Discussion: Pseudomonas Keratitis
Clinical Features and Diagnosis
Bacterial keratitis is a common sight-threatening ophthalmic infection. These
infections are generally rapid in both onset and progression, and if left
untreated can lead to corneal destruction with perforation and potential loss
of the eye. Disruption of corneal epithelial integrity, secondary to multiple eti-
ologies, is a common risk factor for infectious keratitis. In developed countries,
the most common risk factor is contact lens wear.1 Other risk factors include
trauma, history of keratopathy, contaminated ocular medication or contact
lens solution, and impaired host defense secondary to malnutrition, alcohol-
ism, diabetes, or HIV.
Among contact lens wearers, increased risk for infectious keratitis is most
commonly due to noncompliance with proper lens-care protocol.2 Deviations
from protocol include overnight lens use, which conveys greater risk with
increased number of nights, poor hygiene, and improper cleaning and storage of
lenses. Important questions to ask a contact lens wearer include type of contact
lens (soft, hard, rigid gas permeable), schedule of wear (daily, extended, hours
per day, overnight wear), disposable interval, cleaning and storage routine (type

Ophthalmologic Infections
of cleaning solution, tap water use), and activities while wearing lenses (swim-
ming, showering, use of hot tub).
The ocular surface has a number of natural defenses against infection. The
eyelids and lashes act as a physical barrier to foreign material. Each blink pumps
tears from the lacrimal gland and distributes the tear film across the cornea,
while sweeping away microorganisms. The tear film itself contains many fea-
tures, such as lysozyme, lactoferrin, ceruloplasmin, immunoglobulins, and com-
plement factors that inhibit microbial growth.1 An intact corneal epithelium
not only acts as a mechanical barrier against microbial entry, but also actively

CHAPTER 4
phagocytizes microbes for removal.
Contact lenses increase the risk of infectious keratitis by adversely affect-
ing these natural defenses.3 The lenses act as a scaffold for microbial growth,
while interfering with the sweep of the eyelids and tear flow across the cor-
nea. Insertion and removal of the lenses, as well as lens defects, may cause
trauma with epithelial damage allowing microbial entry. The normal cornea
receives its oxygen by diffusion from the air. Contact lenses interfere with
this process and induce corneal hypoxia, which leads to reduced epithelial
turnover and compromised cellular junctional integrity, and greater epithelial
fragility.
Most patients with infectious keratitis will present with acute onset of
eye pain, conjunctival injection, and decreased visual acuity.4 The history in

69
a person suspected of bacterial keratitis should include the ocular symptoms
(visual acuity changes, pain, characteristics of discharge, photophobia, onset,
duration), past ocular history (trauma, prior eye surgery, past infections, use
of contact lenses), current use of any ocular medication, and other systemic
medical problems. Baseline visual acuity and slit lamp examinations are also
essential. The eyelids are examined for any ulcerations, glandular dysfunctions,
or eyelash abnormalities. The conjunctiva is inspected for any injection or
chemosis, follicular or papillary changes, and discharge. The cornea may show
an epithelial defect with fluorescein staining, a stromal infiltrate, ulceration,
thinning, or frank perforation. The size, depth, margin, and location of any infil-
trate are important in the diagnosis and management of the patient. Patients
with infiltrates suspected of being vision-threatening may require hospitaliza-
tion for treatment. Keratitis may also be associated with anterior chamber
inflammation and hypopyon.
Pseudomonas keratitis is noted for being rapidly progressive, and is frequently
associated with a dense ring-like stromal infiltrate and marked suppuration that
may very quickly lead to corneal necrosis and perforation. However, although
a careful history and exam may provide clues to the final diagnosis, there
are no specific signs or symptoms that are pathognomonic for the causative
agent. Cultures are necessary for definitive diagnosis of the infectious etiology.
The most common organisms in bacterial keratitis are those normally part
of the ocular flora.3 These include Staphylococcus aureus, Staphylococcus epi-
dermidis, Streptococcus species, and Pseudomonas aeruginosa. Among patients
with contact lenses, the most common causative organism is Pseudomonas
 aeruginosa. In addition, though the most common type of infectious keratitis
Ophthalmologic Infections

in contact lens wearers are bacterial, other etiologies such as fungal keratitis
and Acanthamoeba keratitis must be included in the differential for this high-risk
group.
Treatment
Treatment is usually initiated with intensive broad-spectrum topical antibiot-
ics applied frequently (every 30–60 min) around the clock, targeting the most
common causative organisms.4 Patients who cannot comply with the dosing
regimen or have vision-threatening infections may require hospitalization for
CHAPTER 4

treatment. The initial choice of antibiotics may include a fluoroquinolone, such

as ciprofloxacin, possibly combined with other fortified antibiotics (tobramy-
cin, gentamicin, cefazolin, vancomycin, etc.). Those patients treated on an out-
patient basis must be followed closely with daily exams until the condition
clinically improves. The antibiotics are modified according to the culture and
susceptibility results, while the frequency of dosing may be tapered with clini-
cal improvement. A worsening clinical picture despite appropriate treatment
should prompt reculturing and consideration of other, less common causative
agents.3 Additional therapy for other sources of infection, such as fungus or
Acanthamoeba, should be considered. The prognosis and ultimate visual out-
come varies markedly, depending on the causative organism in addition to the
size and location of the lesion.
70

References
1. Krachmer J, Mannis M, Holland E. Cornea. St. Louis, MO: Mosby; 2004.
2. Liesegang TJ. Contact lens-related microbial keratitis: Part I: epidemiology.
Cornea. 1997;16(2):125–131.
3. Liesegang TJ. Contact lens-related microbial keratitis: Part II: pathophysiology.
Cornea. 1997;16(3):265–273.
4. Tasman W, Jaeger E. Duane’s Ophthalmology. Philadelphia, PA: Lippincott Williams
& Wilkins; 2007.

Case
C a e 44b:
b: A 446
b: 46-Year-Old
6-Y
Year-O
Old M
Man wit
with
ith
haP
Painful
ainffull Re
R
Red
d Eye
Eye
and
an d a Rash

Chad Zatezalo and Ronni Lieberman

Case Presentation
A 46-year-old Hispanic man presented with a 2-day history of a red, painful right
eye associated with a decrease in vision. The patient also complained of floaters
and a nonpruritic facial rash that he had noticed two weeks before presenta-
tion. He had no known past medical history and was taking no medications. On
physical examination, he was afebrile but had a maculopapular rash on the face,
palms, and soles. Ophthalmic examination revealed a vision of counting fingers
in the right eye, and 20/20 in the left. The right eye had conjunctival injection

Ophthalmologic Infections
and on slit lamp examination, both anterior chamber inflammation and poste-
rior synechiae were seen (Figure 4b.1). Dilated fundoscopic examination was
significant for a 3+ vitritis (Figure 4b.2), associated with multiple active placoid
chorioretinal lesions in the mid-periphery (Figure 4b.3).

71 CHAPTER 4
Figure 4b.1 Right eye with conjunctival injection. On slit-lamp examination both ante-
rior chamber inflammation and posterior synechiae were seen.

Figure 4b.2 Dilated fundoscopic examination was significant for a 3+ vitritis.

Ophthalmologic Infections
CHAPTER 4

Figure 4b.3 Dilated fundoscopic examination with multiple active placoid chorioretinal
lesions in the mid-periphery.

The patient was diagnosed with a panuveitis, and additional testing included
72

chest radiography, tuberculin skin testing, and serologic testing for syphilis
(RPR-FTA). The differential diagnosis for this patient included tuberculosis,
syphilis, viral retinitis (CMV, acute retinal necrosis), sarcoidosis, toxoplasmosis,
and lymphoma; however, the constellation of both systemic and ocular signs
and symptoms was highly suggestive of syphilis. Syphilis RPR and IgG were both
reactive, and the serum titer was found to be 1:4096. A lumbar puncture was
performed, and the cerebrospinal fluid RPR was 1:512. The patient was diag-
nosed with neurosyphilis and admitted for treatment with 14 days of intrave-
nous penicillin, as well as topical corticosteroids and cycloplegics. At this time,
the patient was found to have advanced AIDS with positive HIV serology and a
CD4+ lymphocyte count of 46 cells/μl.
Clinically, the patient’s condition improved rapidly: within two weeks,
the vision in the right eye had improved to 20/100, with partial resolution of
anterior and vitreous inflammation (Figure 4b.4). Over time, the lesions were
slowly resolving, decreasing in both size and activity (Figure 4b.5) until they left
a hyperpigmented chorioretinal scar (Figure 4b.6). At six months, serologies
continued to be positive at 1:256, and one year after diagnosis, the ratio was
1:128. Repeat lumbar punctures were declined by the patient, but after resolu-
tion of the panuveitis, the patient initiated antiretroviral medications.
Case 4b Discussion: Treponema pallidum Uveitis
Uvea Anatomy
The uvea is the middle coat of the eye that begins anteriorly as the iris and
ciliary body, and extends posteriorly to include the choroid. Inflammation
of the anterior uveal tract is called anterior uveitis (i.e., iritis, iridocyclitis).
 Ophthalmologic Infections
CHAPTER 4
Figure 4b.4 Dilated fundoscopic examination showing partial resolution of anterior and
vitreous inflammation.

73

Figure 4b.5 Dilated fundoscopic examination showing lesions were slowly resolving,
decreasing in both size and activity.

Inflammation of the posterior segment is differentiated based on the site of

active inflammation (e.g., choroiditis, vitritis, pars planitis, retinitis, chorioretini-
tis). The presentation of a patient with uveitis depends on the portion of the
uveal tract that is involved. Anterior uveitis usually produces photosensitivity
and redness. Patients presenting with posterior or intermediate uveitis (vitritis)
Ophthalmologic Infections
CHAPTER 4

Figure 4b.6 Dilated fundoscopic examination showing a hyperpigmented chorioretinal

scar.

are less likely to experience pain, but may experience visual changes such as
74

floaters or reduced visual acuity.

Clinical Features
Syphilis is a sexually transmitted, chronic, systemic infection caused by the spi-
rochete Treponema pallidum. If left untreated, the disease progresses though
four stages and may cause significant pathology in any major organ of the body.
From 2000 to 2004, the number of cases of primary and secondary syphilis in
the US increased from 5,979 to 7,980, and the rate increased from 2.1 to 2.7
cases per 100,000. The increase was seen primarily as a result of rising rates
among men who have sex with men.1
Syphilis is known as the “great masquerader.” Involvement of the eye
may be the presenting manifestation of syphilis, and is often associated with
delayed diagnosis and delayed treatment, which may result in irreversible
visual loss and structural damage. The eyes are affected in approximately
10% of cases, and the most common presentation of syphilis in the eye is
uveitis.2 Other ocular manifestations include interstitial keratitis, scleritis, reti-
nal vasculitis, neuroretinitis, and cranial and optic neuropathies. The Argyll
Robertson pupil is most commonly seen late in the disease, although it can
present early.3 The pupils are unequal, irregular, and miotic, with a light-near
dissociation.
The characteristics of syphilitic iridocyclitis and chorioretinitis are not
pathognomonic of the disease, and other etiologies should be entertained.
Typically, chorioretinitis manifests as multiple elevated creamy white lesions
with an associated vitritis. Placoid chorioretinitis (geographic flat creamy
white lesions) of the macula are characteristic in patients with concurrent HIV
infection.4 Syphilitic uveitis can occur as soon as 6 weeks after primary infec-

Ophthalmologic Infections
tion, but may not manifest for many years. HIV and syphilis are defined as
coinfections, often acquired simultaneously, and a diagnosis of syphilitic uveitis
should prompt HIV testing. Ocular syphilis is not an ophthalmic opportunistic
infection; however, when diagnosed concurrently, treatment of the syphilis is
indicated before initiation of antiretroviral therapy, to decrease the likelihood
of the immune reconstitution syndrome.
Diagnosis
Uveitis can be divided into two broad categories: infectious and noninfectious.

CHAPTER 4
The differential diagnosis of syphilitic uveitis includes tuberculosis, Lyme dis-
ease, herpetic disease, toxoplasmosis, sarcoidosis, Vogt-Koyanagi-Harada dis-
ease, white dot syndromes, and Wegner’s granulomatosis among others. Since
it is nearly impossible to rule out syphilis as a cause of uveitis based solely
on clinical presentation, the evaluation of any unexplained ocular inflammation
should include testing for syphilis.2 Diagnosis demands a high level of clinical
suspicion, and includes both treponemal-specific and nontreponemal serologic
tests.
There are two general categories of serologic tests: (1) nontreponemal tests,
such as the Venereal Disease Research Laboratory (VDRL) and rapid plasma
reagin (RPR), and (2) treponemal tests, such as the fluorescent treponemal
antibody absorbed (FTA-ABS).5 There are several shortcomings to these sero-

75
logic tests, as several comorbidities can lead to false negative and false positive
testing. For example, HIV infection can lead to a false negative result in both the
nontreponemal and treponemal tests,5 and highlights the need for a high clinical
suspicion when diagnosing syphilitic uveitis.
When serological test results are positive, the possibility of neurosyphilis
should be investigated by means of lumbar puncture and study of the relevant
antibody markers in cerebrospinal fluid (CSF). A positive CSF VDRL is consid-
ered diagnostic for neurosyphilis; however, VDRL may be nonreactive in some
cases of active neurosyphilis. CSF FTA-ABS is less specific, but is highly sensitive
and is used to exclude neurosyphilis, though some clinicians consider syphilitic
uveitis to be equivalent to the diagnosis of neurosyphilis for the purposes of
treatment.5
Treatment
Conventional syphilis staging is of little use in understanding ocular syphilis;6
once diagnosed with syphilitic uveitis, patients should be treated with intrave-
nous penicillin for 10–14 days. Topical, periocular, and systemic corticosteroids
also have roles in the management of the ocular sequelae of syphilis. Topical
corticosteroids can minimize the inflammatory damage of interstitial keratitis
and anterior uveitis. Oral and IV corticosteroids can be used for posterior
uveitis, scleritis, and optic neuritis; however, only timely treatment with sys-
temic penicillin can lead to resolution of ocular inflammation.
There are no proven alternatives to penicillin in the treatment of neuro-
syphilis. The CDC also recommends that penicillin be used for the treatment
of all stages of syphilis in patients coinfected with HIV. Therefore, penicillin-
 allergic patients in those categories should be desensitized and treated with
Ophthalmologic Infections

penicillin.1 Early treatment is the key to reducing ophthalmic structural dam-

age from a syphilitic infection. These anatomic complications include posterior
synechiae, secondary glaucoma, cataract, retinal scarring, macular edema, and
retinal detachment that may ultimately compromise vision.

References
1. Centers for Disease Control and Prevention: Sexually transmitted diseases treat-
ment guidelines 2002. MMWR 2002;51(No. RR-6).
CHAPTER 4

2. Samson CM, Foster CS. Diagnosis and Treatment of Uveitis. Philadelphia, PA: WB
Saunders; 2002:237–244
3. Marra CM. Neurosyphilis. Curr Neurol Neurosci Rep 2004;4(6):435–440.
4. Gass JD, Braunstein RA, Chenoweth RG. Acute syphilitic placoid chorioretinitis.
Ophthalmology. 1990;97:1288–1297.
5. Kiss S, D’Amico FM, Young L. Ocular manifestations and treatment of syphilis.
Semin Ophthalmol. 2005;20(3):161–167.
6. Browning DJ. Posterior segment manifestations of active ocular syphilis,
the response to a neurosyphilis regimen of penicillin therapy, and influ-
ence of human immunodeficiency virus status on response. Ophthalmology.
2000;107:2015–2023.
76

Case
C a e 44c:
c: C
Cytomegalovirus
ytomeg
t alov
loviirus R
Retinitis
eti
tiniiti
itis iin
naP
Patient
ati
tien
e t
with
wi th AIDS

Chad Zatezalo and Ronni Lieberman

Case Presentation
A 41-year-old Hispanic female with a history of HIV and cytomegalovirus
retinitis (CMVR) was referred to an ophthalmology service for manage-
ment. The patient was diagnosed with bilateral CMVR one year prior, and
had been treated successfully with induction and maintenance ganciclovir.
Although she was prescribed antiretrovirals, the patient’s CD4+ cell count
remained low (<50 cells/μl), and she developed a recurrence of the CMVR
sixth months later. She was again treated with induction dose intravenous
ganciclovir, but her disease continued to progress and ganciclovir resistance
was suspected. CMV resistance testing revealed mutations at both UL-97
and UL-54 loci, implying an absolute resistance to ganciclovir, and the patient
was treated with induction dose foscarnet. Although the CMVR responded,
the patient developed acute renal failure from the foscarnet, and the medi-
cation was discontinued. The patient was then referred to our service for
consultation.
On examination, the vision was measured at 20/70 in the right eye and 20/40
in the left eye. Slit lamp examination was noteworthy for fine pigmented ker-
atic precipitates on the corneal endothelium in both eyes. Dilated fundoscopic
examination revealed areas of active CMVR in both eyes (Figures 4c.1 to 4c.5).
 Ophthalmologic Infections
77 CHAPTER 4

Figure 4c.1 through 4c.5 Dilated fundoscopic examination revealed areas of active
CMVR in both eyes.
Ophthalmologic Infections
78 CHAPTER 4

Figure 4c.1 through 4c.5 Continued

Given the ganciclovir resistance and adverse effects of foscarnet (implying

intolerance to cidofovir as well), the patient was treated with intravitreal injec-
tions of foscarnet, first on a biweekly basis as induction. The patient was noted
to clinically improve (Figures 4c.6 to 4c.9), and after the CMVR became inactive
(Figures 4c.10 to 4c.12), the intravitreal treatment continued at a weekly inter-
val for maintenance therapy. After 6 months of this regimen, and a change to
the antiretroviral medications, the patient’s CD4+ cell count increased to 348
cells/μL over several months. At this point, intravitreal therapy was terminated
and the CMVR has remained quiescent.
 Ophthalmologic Infections
79 CHAPTER 4

Figure 4c.6 through 4c.9 Dilated fundoscopic examination with clinically improved
CMVR.
Ophthalmologic Infections
CHAPTER 4

Figure 4c.6 through 4c.9 Continued

80

Figure 4c.10 through 4c.12 Dilated fundoscopic examination revealed

inactive CMVR.
 Ophthalmologic Infections
81 CHAPTER 4

Figure 4c.10 through 4c.12 Continued

Case 4c Discussion: Cytomegalovirus Retinitis

Clinical Features and Diagnosis
CMVR is caused by a ubiquitous DNA virus, found in up to 80% of the adult
population. A member of the herpes family, it remains quiescent in the host
until the host becomes immunocompromised, allowing for the reactivation
and subsequent proliferation of the virus. The etiologies for an immune-
compromised state include HIV/ AIDS, transplant (both solid organ and bone
marrow), and chemotherapy.1 Although most commonly manifesting as a
retinitis, CMV has been shown to cause meningitis, cerebritis, pneumonitis,
and gastrointestinal disease including esophagitis, colitis, and hepatitis.
 In patients with HIV/AIDS, CMVR is found mostly in patients with CD-4+
Ophthalmologic Infections

cell counts below 50cells/μl. With the advent of highly active antiretroviral
therapy (HAART), there has been a 75%–80% decline in the incidence of CMV.
In addition, rates of retinitis progression have decreased from 3.0 cases/patient
year (PY) to 1.0 cases/PY in the HAART era.2 Most new cases of CMVR appear
to be in patients who are either HAART naïve, have HIV viruses with multiple
resistance mutations, or are intolerant of their medications.2,3 HAART has also
resulted in an improvement in the ability to control the retinitis and, subse-
quently, in the rates of complications. There is still a need for ongoing screening
of patients with CD-4+ cell counts below 50cell/μl, and for ongoing monitoring
CHAPTER 4

of patients with inactive disease, as the disease can progress even in patients
who have experienced immune recovery (CD-4+ >100). In addition, immune
reconstituted patients may still experience significant visual loss, either second-
ary to factors such as foveal or optic nerve involvement, or chronic problems
such as sequelae of immune reconstitution syndrome or cataract.
Patients with CMVR may present with either a decrease in vision or a
complaint of floaters; however, some patients are entirely asymptomatic. On
examination, the patient may have a slightly injected conjunctiva, fine keratic
precipitates on the corneal endothelium, and a minimal anterior chamber reac-
tion. There may also be cells in the vitreous. Fundus examination may reveal
either single or multiple areas of infected retina adjacent to inactive, necrotic
areas. This may be accompanied by blot hemorrhages and cotton wool spots
82

(HIV retinopathy). Diagnosis is made on clinical examination by an experienced

ophthalmologist.
Treatment
Treatment consists of both systemic and local therapies. Systemic options
include ganciclovir, valganciclovir, foscarnet, and cidafovir. All of these medica-
tions are virustatic, not virucidal, and are therefore administered as an induc-
tion dose until the disease is completely quiescent. The patient is then treated
with chronic maintenance therapy. Ganciclovir, a nucleoside analogue of
2-deoxyguanosine, inhibits the replication of herpes viruses. Intravenous induc-
tion dose is 5mg/kg given twice daily, and maintenance is 5mg/kg daily (adjust-
ment for renal function is necessary). The most common toxicity is bone
marrow suppression. Resistance may develop when a mutation occurs at either
the UL-97 or UL-54 loci of the CMV strain. Valganciclovir (Valcyte®) is an orally
administered ganciclovir analogue, with similar bioavailability to ganciclovir. The
induction dose is 900mg twice daily and maintenance is 900mg daily. Foscarnet
is a pyrophosphate analogue, administered intravenously at 90mg/kg/bid during
induction, with maintenance therapy at 90mg/kg/day. Foscarnet’s most com-
mon toxicities include renal insufficiency and electrolyte imbalances. Cidofovir
is a nucleotide analogue, and is dosed at 5mg/kg on a weekly basis as induction,
and then given on an every 2–3 week maintenance schedule. Cidofovir can lead
to severe, irreversible renal failure, and must be administered with probenecid
both prior to, during, and after the infusion.
Local therapies have the advantage of delivering a high dose of medication
directly to the affected area, with no systemic ramifications. Local therapies
include intravitreal injections of either ganciclovir or foscarnet, in addition to

Ophthalmologic Infections
a ganciclovir implant. Although an off label use, intravitreal administration of
ganciclovir and foscarnet are considered standard of care in vision-threatening
CMVR. Complications from an intravitreal injection include endophthalmitis,
hemorrhage, retinal detachment and cataract. The ganciclovir implant is a
sustained release device that is placed in the vitreous cavity, and allows for
a high-dose steady state of drug release over 7–8 months. Note that CMVR
is associated with an increased mortality risk, and this risk is decreased when
the patient is placed on systemic therapy.4 It is therefore recommended that
all patients with active CMVR be placed on systemic therapy, in addition to the

CHAPTER 4
possible adjuvant use of local treatment.
Treatment algorithms are based upon location of disease, the patients’
experience with HAART, and the resistance or sensitivity of the CMVR to the
available medications. In addition, medication can be administered systemically,
locally, or in combination. Patients with Zone I disease (CMVR within the vas-
cular arcades) should be treated with intravitreal injections (to be followed
by an implant) in combination with systemic antiviral medications. Patients
who are HAART-experienced and have persistently low CD4+ cell counts
may need reevaluation of their regimen. Any patient with Zone II or III dis-
ease (outside the vascular arcades) should be treated with oral valgancyclovir,
although patients who are HAART-experienced may benefit from an implant.5
If the patient does not respond appropriately, ganciclovir resistance testing is

83
warranted.
After resolution of active disease, patients are placed on a follow-up sched-
ule according to their CD-4+ counts. If the lymphocyte count is below 50 cells/
μl, patients should be seen on a monthly basis, although the intervals may be
increased accordingly as the CD-4+ cell count improves. Termination of ther-
apy may be considered if immune reconstitution takes place, which is defined
as a rise of CD-4+ of at least 50 cell/μl to over 100cell/μl. This elevation must
be sustained for at least 6 months, with some clinicians waiting one year before
discontinuing therapy for CMVR.

References
1. Chakrabarti S, Mackinnon S, Chopra R, et al. High incidence of cytomegalovi-
rus infection after nonmyeloablative stem cell transplantation: potential role of
Campath-1H in delaying immune reconstitution. Blood. 2002;99:4357– 4363.
2. Jabs DA, Van Natta ML, Kempen JH, et al. Characteristics of patients with
cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Am J
Ophthalmol. 2002;133(1):48–61.
3. Holland GN, Vaudaux JD, Shiramizu KM, et al. Characteristics of untreated
AIDS related cytomegalovirus retinitis, II: findings in the era of highly active anti-
retroviral therapy (1997 to 2000). Am J Ophthalmol. 2008;145(1):12–22.
4. Jabs DA, Holbrook JT, Van Natta ML, et al. Risk for mortality in patients
with AIDS in the era of highly active antiretroviral therapy. Ophthalmology.
2005;112(5):771–779.
5. Jabs D. AIDS and ophthalmology. Arch Ophthamal. 2008;126(8):1143–1146.
Ophthalmologic Infections

Case
C a e 44d:
d: A 117
d: 17-Year-Old
7-Y
Year-O
Old FFem
Female
ale
l with
ith P
Peripheral
eriiphe
herall Vi
Vision
sio
si
ion
Loss
Lo ss

Rupa Rajesh Patel, Katherine Zamecki, Michael Mullen,

and Shirish Huprikar
Presentation and Case History
A 16-year-old female from New York City presented with one day of distorted
CHAPTER 4

central vision in her left eye. Three weeks prior, she had noticed a non-tender,
one-centimeter left neck mass, which resolved after two weeks. She reported
no symptoms affecting the right eye, and the left eye was without redness, pain,
or discharge. She denied fever, chills, headache, or other neurological symptoms.
On physical examination, she was afebrile and her other vital signs were unre-
markable. Visual acuity in the left eye was 20/50, and dilated fundus examination
revealed a retinochoroiditis with active lesions near the fovea (Figures 4d.1 to
4d.6). There was no evidence of anterior segment inflammation.
Several laboratory studies, including erythrocyte sedimentation rate,
C-reactive protein, human immunodeficiency virus ELISA, tuberculin skin test,
reactive plasma reagin, Lyme antibody, Toxoplasma antibodies, and autoim-
mune studies were unremarkable; however, serologic studies were positive for
84

Bartonella henselae (IgM 1:40, IgG positive, no titer available).

On further questioning, the patient reported spending time with her neigh-
bor’s kitten and having been scratched multiple times. Her neighbor had expe-
rienced fevers, neck and axillary masses, and visual changes three months prior
to her presentation. Based on the history, ophthalmologic examination, and
serologic evidence, our patient was diagnosed with ocular bartonellosis. She
was treated with oral corticosteroids for 2 weeks, but continued doxycycline
and rifampin for a total of 6 weeks. Retinal examination of the left eye after
therapy showed near resolution of lesions, and visual acuity returned to 20/20
(Figure 4d.7).
Case 4d Discussion: Bartonella henselae Retinitis
Clinical Presentation and Diagnosis
The genus Bartonella was first described as an erythrocyte-adherent organ-
ism in 1909 by Alberto Barton Thompson, a Peruvian microbiologist of English
descent. Bartonella is a slow-growing, Gram-negative bacillus, and has three
main pathogenic species in humans: B. bacilliformis, B. henselae, and B. quintana.
Bartonella bacilliformis is transmitted by sandfly vectors, and causes Oroya fever
and verruga peruana in the Andes mountains. Oroya fever is an acute febrile
hemolytic illness, whereas verruga peruana is chronic dermal manifestation that
presents months after acute illness. Verruga peruana lesions include miliary,
nodular, and mulaire (i.e., blood-filled ulcerative lesions). Bartonella quintana
is transmitted by the louse tick, and is the cause of trench fever. Additionally,
it may cause bacillary angiomatosis (BA), bacillary peliosis (BP), and culture-
negative endocarditis in both HIV-infected and uninfected patients. BA is a
 Ophthalmologic Infections
85 CHAPTER 4

Figure 4d.1 through 4d.7 Dilated funduscopic examination revealed a retinochor-

oiditis with active lesions near the fovea.
 86 CHAPTER 4 Ophthalmologic Infections

Figure 4d.1 through 4d.7 Continued

 Ophthalmologic Infections
CHAPTER 4
Figure 4d.1 through 4d.7 Continued. Retinal examination of the left eye after therapy
with near complete resolution of the lesions.

neovascular proliferative skin and lymphatic disorder, and BP is a disease of

hepatic and splenic blood-filled cystic structures. Bartonella henselae can cause

87
BA, BP, fever of unknown origin (FUO) in children and the immunocompro-
mised, and cat scratch disease (CSD).6
CSD was first described as a syndrome in 1950 as la maladie des griffes du
chat. There are 22,000 cases of CSD per year in the United States. It gener-
ally occurs in immunocompetent individuals, and more commonly in children,
adolescents, and young adults.1 CSD typically manifests as a self-limited regional
lymphadenopathy. Patients may initially develop a pustule at the inoculation
site, followed by fever and unilateral regional lymphadenopathy within seven
weeks of infection; other complaints include anorexia, fatigue, malaise, and
headache. Lymphadenopathy usually spontaneously regresses within 2 to 4
months. Disseminated disease occurs in 5%–14% of patients, and presents with
atypical manifestations including pneumonitis, splenitis, hepatitis, encephalopa-
thy, cardiac disease, and ocular disease. Prior to the development of effective
laboratory techniques, the diagnosis of typical CSD was based on clinical and
epidemiologic criteria. With modern PCR and serologic assays, the criteria
have evolved to include:
1. History of cat or flea exposure
2. Laboratory (i.e., polymerase chain reaction assay positive) or radiologic
(computed topography [CT] scan with liver and/or spleen abscesses)
evidence of disease
3. Positive serology tests >1:64 for B. henselae or B. quintana (i.e., enzyme
immunoassay [EIA] or indirect fluorescent antibody assay [IFA])
4. Tissue biopsy with evidence of granulomatous inflammation compat-
ible with CSD or pleomorphic bacilli found on Warthin-Starry silver
stain2
 Serology with EIA or IFA for B. henselae with an antibody titer ratio of >1:256
Ophthalmologic Infections

is usually indicative of active infection, whereas a titer >1:64 indicates possible

infection. Sensitivity of serologic tests is 90% in immunocompetent patients and
70% in immunodeficient patients. The prevalence of Bartonella IgG positivity
within the general population is 4%–6%, and lifelong immunity is conferred with
one attack of CSD.2 The differential diagnosis of CSD includes lymphogranu-
loma venereum, tuberculosis, other mycobacterial infections, bacterial adeni-
tis, tularemia, brucellosis, histoplasmosis, coccidioidomycosis, sarcoidosis,
toxoplasmosis, infectious mononucleosis, and benign or malignant tumors (i.e.,
lymphoma).
CHAPTER 4

Transmission of Bartonella henselae from cats to humans has been estab-

lished by epidemiologic, microbiologic, and PCR studies; the exact role of the
flea vector in cat-to -human transmission is still being defined. People are fif-
teen times more likely to contract CSD when owning more than one kitten
younger than 12 months of age, when compared to those who owned older
cats. Those scratched by a kitten were 27 times more likely to develop disease.
Those having more than one kitten with fleas were 29 times more likely to
become infected with B. henselae than those owning kittens without fleas.2
There are three forms of ocular bartonellosis: (1) Parinaud’s oculoglandular
syndrome (POS); (2) neuroretinitis: and (3) focal retinochoroiditis.3 Parinaud’s
oculoglandular syndrome has been described in up to 5% of patients with CSD,
and includes a granulomatous conjunctivitis and ipsilateral preauricular lymph-
88

adenitis. POS presents as unilateral eye pain, foreign body sensation, unilateral
eye redness, mild eyelid swelling, and possible eye ulceration. Transmission to
the eye in ocular bartonellosis is postulated to result from direct inoculation of
cat flea feces from hand-to-eye contact. The differential diagnosis of unilateral
granulomatous conjunctivitis and POS includes tuberculosis, syphilis, tularemia,
sporotrichosis, tularemia, mononucleosis, coccidioidomycosis, and Chlamydia
trachomatis infection.3
Neuroretinitis develops in 1%–2% of patients with CSD, and presents with
a sudden loss of visual acuity. It is associated with papilledema and stellate
macular exudates, arranged in a star formation known as the “macular star.”
It is a form of optic neuropathy that involves optic disk swelling. Other signs
from residual macular lesions include diminished contrast sensitivity and altered
color vision. Disease is usually self-limited with mild residual visual deficits. The
differential diagnosis for optic disk swelling with a macular exudate star for-
mation includes pseudotumor cerebri, diabetes mellitus, sarcoidosis, syphilis,
tuberculosis, toxoplasmosis, toxocariasis, Lyme disease, malignant hyperten-
sion, vascular disorders, viral infection, and leptospirosis.
Focal retinochoroiditis can occur with or without macular exudates and
optic disk edema. Multifocal lesions usually cause optic disk swelling, and symp-
toms are similar to those seen in neuroretinitis. Complications involve retinal
artery and vein occlusions, along with retinal detachment. Other ocular disease
includes optic neuritis and uveitis. The diagnosis of ocular bartonellosis is made
by a combination of clinical ophthalmologic findings, blood culture, serologic
testing, and PCR of ocular tissue.3,4
Management

Ophthalmologic Infections
Treatment for typical, localized CSD in immunocompetent patients is generally
not indicated, since disease is self-limited. Bartonella henselae, in general, is
susceptible to beta-lactams, tetracyclines, macrolides, aminoglycosides, fluo-
roquinolones, vancomycin, rifampin, chloramphenicol, and co-trimoxazole. A
five-day treatment with a macrolide antibiotic in immunocompetent patients
with CSD has been shown to shorten the duration of symptoms (i.e., measured
by lymph node size) in a randomized prospective, placebo-controlled trial.5
Other 5- to 14-day single antibiotic regimens for CSD include ciprofloxacin,
trimethoprim-sulfamethoxazole, and rifampin.

CHAPTER 4
The treatment for ocular bartonellosis is not well defined, and is based on
case reports and case series. Given the risk of permanent neurologic deficits,
corticosteroids and doxycycline with rifampin are often given for an extended
course (i.e., usually 4–6 weeks) based on clinical improvement. In a retrospective
case series of seven patients with Bartonella neuroretinitis treated with both
doxycycline 100 mg and rifampin 300 mg oral tablets every 12 hours, all but
one patient regained baseline vision within 4 weeks. All patients were treated
with less than 2 weeks of oral corticosteroids, and were treated with antibiotics
for 4–6 weeks. Rifampin is advantageous in this setting because of its adequate
penetration of the blood–brain barrier. The authors concluded that a prompt
initiation of antibiotic treatment may shorten the course of ocular disease.4

89
Recommendations extrapolated from case reports suggest a longer duration
of treatment with antibiotics (i.e., up to 4 months) in the immunocompromised
patient, and a shorter duration (2 weeks) in immunocompetent patients.3
In order to prevent disease, declawing and routine nail clipping of kittens
is recommended. In addition, cat flea control, regular care of the litter box,
proper hand hygiene after close contact with kittens and cats, and clean-
ing scratches and bites with soap and water may decrease the likelihood of
Bartonella transmission.2

References
1. Jackson LA, Perkins BA, Wenger JD. Cat scratch disease in the United States: an
analysis of three national databases. Am J Public Health. 1993;83:1707–1711.
2. Margileth AM. Recent advances in diagnosis and treatment of cat scratch diseases.
Curr Infect Dis Rep. 2000:2(2):141–146.
3. Cunningham ET, Koehler J. Ocular bartonellosis. Am J Ophthalmol. 2000;
130:340–349.
4. Reed JB, Scales JK, Wong MT, et al. Bartonella henselae neuroretinitis in cat
scratch disease. Ophthalmology. 1998;105:456–466.
5. Bass JW, Freitas AD, Freitas AD. Prospective randomized double-blind placebo-
controlled evaluation of azithromycin for treatment of cat-scratch disease. Pediatr
Infect Dis J. 1998;17:447–452
6. Slater, LN, Welch, DF. Bartonella, including cat-scratch disease. In Mandell GL,
Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett’s Principles and Practice
of Infectious Diseases. 7th ed. Philadelphia, PA: Churchill, Livingston, Elsevier;
2009:2995–3009.
Ophthalmologic Infections

Case
C a e 44e:
e: FFever, Chills,
Chil
Chillls,
il ls and
dUUnilateral
nil
illater
t all V
Vision
isiion
n LLoss
oss iin
na
73-Y
73 -Yeear-Old Man
73-Year-Old n

Daniel Caplivski, Chad Zatezalo, and Robert S. Klein

Case Presentation
A 73-year-old man with a history of benign prostatic hypertrophy presented
with sudden loss of vision of the right eye on the day of admission. He also
noted pain and tearing of the eye, but denied exacerbation of the pain when
CHAPTER 4

moving the eye. He had not had any trauma to the eye and did not wear con-
tact lenses. For 12 days prior to presentation he felt fatigue, mild dyspnea, and
fevers up to 38.5˚ Celsius. He also had been having night sweats and weight loss
that he estimated to be 10 pounds over the preceding few weeks.
On physical examination, his temperature was 37.3ºC and his blood pressure
was as low as 88/63 before hydration. The right eye had conjunctival erythema
and tearing with a visible hypopyon (Figure 4e.1). His visual acuity on the right
eye was limited to hand movements, while on the left eye it was 20/60. The reti-
nal exam on the left was normal, but the degree of vitreous clouding in the right
eye did not allow for visualization of the retina. No conjunctival petechiae or
other stigmata of infectious endocarditis were noted, but the patient was found
90

to have a III/VI holosystolic murmur heard loudest at the apex. The patient’s
laboratory values were significant for a mild anemia (hemoglobin, 13 gm/dl) and
leukocytosis (11.3 x103 WBC/μl).
Multiple blood cultures and cultures of the anterior chamber fluid were
positive for gram positive cocci in pairs (Figure 4e.2). The organism was identi-
fied as Streptococcus bovis with negative PYR testing, absence of growth in 6.5%
saline, and hydrolysis of starch. A transesophageal echocardiogram revealed
a ruptured P2 scallop of the posterior mitral valve leaflet, with long mobile
components consistent with vegetation or destroyed mitral valve resulting in
moderate mitral regurgitation (Figure 4e.3). The patient underwent mitral valve

Figure 4e.1 Right eye examination revealing injected conjunctiva and hypopyon.
 Ophthalmologic Infections
CHAPTER 4
Figure 4e.2 Gram stain of blood culture revealing small Gram-positive cocci in pairs
(original magnification 100x).

91

Figure 4e.3 Transesophageal echocardiogram revealing ruptured P2 scallop of the

posterior mitral valve leaflet with long mobile components consistent with vegetation or
destroyed mitral valve resulting in moderate mitral regurgitation.

replacement, vitrectomy, and installation of intravitreous vancomycin. He was

discharged with 4 weeks of intravenous penicillin and subsequently returned to
his home in Venezuela, where he was to have a colonoscopy for further evalu-
ation for gastrointestinal pathology.
 Case 4e Discussion: Streptococcus bovis Endophthalmitis
Ophthalmologic Infections

Clinical Features and Diagnosis

Endophthalmitis represents infection of the vitreous or aqueous humor,
or both. It may be classified by the route of infection: either endogenous
endophthalmitis or exogenous endophthalmitis. Exogenous endophthalmitis
may be caused by surgical procedures, trauma to the eye, or by keratitis that
progresses posteriorly. Endogenous endophthalmitis is the result of hematoge-
nous spread of organisms from endovascular sites, such as infected heart valves.
Bacteria (including viridans group streptococci, beta-hemolytic streptococci,
CHAPTER 4

and staphylococcal species) represent the majority of cases of endogenous

endophthalmitis, but fungi may also cause this vision-threatening infection (see
Case 4f).1 A mucoid strain of Klebsiella pneumoniae that has been noted to
cause a syndrome of liver abscess, pulmonary abscess, and endophthalmitis, has
been described in Taiwan.1
Clinical signs of endophthalmitis may include eye pain, redness, and sudden
visual loss. Most patients with exogenous endophthalmitis do not have fever
or other systemic signs and symptoms of infection, but those with endogenous
endophthalmitis are likely to have positive blood cultures and systemic signs
of inflammation.1 The diagnosis may be supported by positive blood cultures
in the case of endogenous endophthalmitis, but vitreous cultures are often
needed for confirmation. Gram stain of the vitreous fluid may indicate the most
92

likely pathogen, even before cultures are positive.1

Streptococcus bovis was first associated with gastrointestinal malignancies in
the late 1970s, and the association was subsequently confirmed in several stud-
ies. In a study of 278 patients, S. bovis fecal carriers were more likely to have
carcinoma of the colon than controls with other nonenterococcal bacteria.2 A
subsequent study of 29 patients also confirmed the link between S. bovis septi-
cemia and carcinoma of the colon, and emphasized the need for colonoscopy
in patients from whom the organism is isolated.3 Recent taxonomic reclassifica-
tion of the Streptococcus bovis group has led to some confusion. The new name
Streptococcus gallolyticus has replaced S. bovis, and three subspecies (gallolyticus,
pasteurianus, macedonicus) replaced the biotypes of S. bovis.4 For the purposes
of this discussion, the two species names will be used interchangeably. The
organisms are part of the nonenterococcal group of Group D streptococci
that are characterized microbiologically by their growth in the presence of 40%
bile, hydrolysis of esculin, and inability to grow in 6.5% sodium chloride.2 S. bovis
is responsible for approximately 17% of infectious endocarditis cases, and it
is not associated with increased morbidity or mortality when compared to
other streptococcal causes of endocarditis, beyond the association with colonic
malignancy.5
Two case reports describing Streptococcus bovis endogenous bacterial
endophthalmitis highlight the rarity of this organism as a cause of eye infec-
tions. In one of the cases, the eye findings were the initial presentation of colon
cancer. In the second case, the patient was an elderly man known to have liver
cancer.6,7 In both cases, the diagnosis was confirmed by positive cultures of
the blood and the vitreous fluid. In one case, the patient was managed with a

Ophthalmologic Infections
combination of vitrectomy, intravitreous antibiotics, and intravenous antibiot-
ics, while in the second, the patient had signs of severe sepsis and required
enucleation.6,7
Management
Exogenous endophthalmitis is usually managed with intravitreous antibiotics,
along with vitrectomy in severe cases. Endogenous endophthalmitis requires
a combination of systemic and intravitreal antibiotics. Vitrectomy is generally
reserved for fulminant cases, as well as those that fail to respond to 24 hours

CHAPTER 4
of intravitreous vancomycin and amikacin.1 Most Streptococcus bovis isolates are
susceptible to penicillin (MIC <0.1 mg/l) but, due to variations in minimal inhibi-
tory concentrations, susceptibility testing should guide therapy.
Endocarditis can be managed, in some cases with several weeks of systemic
antibiotics alone, but, in some cases surgical intervention may be required.
Indications for surgery include patients with ring abscess, refractory bacteremia,
multiple embolic events, and heart failure. In this case, the valve was replaced
because of valve perforation and concern for further embolic events. Given the
strong association between gastrointestinal pathology and Streptococcus bovis
bacteremia, patients who are found to have positive cultures with this organism
should be evaluated with colonoscopy.

93
References
1. Durand M. Endophthalmitis. In Madell, Douglas, & Bennett, eds. Principles
and Practice of Infectious Diseases, 7th ed. Philadelphia, PA: Elsevier; 2010:
1553–1559.
2. Klein RS, Recco RA, Catalano MT, Edberg SC, Casey JI, Steigbigel NH.
Association of Streptococcus bovis with carcinoma of the colon. N Engl J Med.
1977;297(15):800–802.
3. Klein RS, Catalano MT, Edberg SC, Casey JI, Steigbigel NH. Streptococcus bovis
septicemia and carcinoma of the colon. Ann Intern Med. 1979;91(4):560–562.
4. Schlegel L, Grimont F, Ageron E, Grimont PA, Bouvet A. Reappraisal of the tax-
onomy of the Streptococcus bovis/Streptococcus equinus complex and related
species: description of Streptococcus gallolyticus subsp. gallolyticus subsp. nov.,
S. gallolyticus subsp. macedonicus subsp. nov. and S. gallolyticus subsp. pasteur-
ianus subsp. nov. Int J Syst Evol Microbiol. 2003;53(Pt 3):631–645.
5. González-Juanatey C, González-Gay MA, Llorca J, et al. Infective endocarditis
due to Streptococcus bovis in a series of nonaddict patients: clinical and mor-
phological characteristics of 20 cases and review of the literature. Can J Cardiol.
2003;19(10):1139–1145.
6. Bleibel W, D’Silva K, Elhorr A, Bleibel S, Dhanjal U. Streptococcus bovis
endophthalmitis: a unique presentation of colon cancer. Dig Dis Sci. 2007;
52(9):2336–2339.
7. Hayasaka K, Nakamura H, Hayakawa K, Gaja T. A case of endogenous bac-
terial endophthalmitis caused by Streptococcus bovis. Int Ophthalmol.
2008;28(1):55–57.
Ophthalmologic Infections

Case
C a e 44f:
f: Decreas
f: D
Decreased
ed
dVVision
ision
isi
io anddaP Painful,
aiinfful
ful, Red
Redd Eye
E iinna
Pati
Pa tieent with Acute
Patient te Myelo
M l genous LLeukemia
Myelogenous eukemi miaa ((AML)
AML) an
and
Prolonged
P Neutropenia
rolonged Neutro ropenia

Lindsey Reese, Chad Zatezalo, Stephen Mercer, Robert

Phelps, and Shirish Huprikar
Presentation and Case History
CHAPTER 4

A 46-year-old male with refractory AML was admitted for chemotherapy.

He had previously received an allogeneic stem cell transplant from an HLA-
identical sister, but subsequently relapsed. His treatment course was previously
complicated by severe graft-versus-host disease involving skin, liver, and gas-
trointestinal tract that required high-dose corticosteroid therapy. The patient’s
medications included tacrolimus and prednisone, as well as prophylactic valacy-
clovir, levofloxacin, and voriconazole.
On physical examination, the patient was afebrile with oral thrush and mild,
diffuse wheezing. The remainder of his examination was unremarkable. His
admission laboratory values were significant for pancytopenia (hemoglobin
11.3 g/dl; white blood cell count 3.9 x 103/μl, absolute neutrophil count 400
cells/μl; platelets 54 x 103/μl) and elevated liver enzymes (aspartate amino-
94

transferase 58 units/l; alanine aminotransferase 120 units/l). Voriconazole was

discontinued due to the liver function abnormalities, and caspofungin was
initiated for antifungal prophylaxis.
After starting reinduction chemotherapy, the patient developed prolonged
neutropenic fever. He was treated with broad-spectrum antibiotics, and liposo-
mal amphotericin B was substituted for caspofungin due to a worsening nodular
infiltrate on chest CT (Figure 4f.1). The antibiotics and amphotericin B were
continued and, in approximately one month, fevers resolved. He subsequently

Figure 4f.1 Chest CT, axial view revealing worsening right lower lobe nodular
consolidation.
developed tender, subcutaneous nodules on his lower extremities, and a skin

Ophthalmologic Infections
biopsy was performed (Figures 4f.2, 4f.3, and 4f.4). Based on the presence of
fungal hyphae consistent with Aspergillus, his antifungal therapy was changed
to voriconazole; however, two days later he developed pain, redness, and
decreased vision in his right eye (Figure 4f.5).

95 CHAPTER 4
Figure 4f.2 Leg with tender, subcutaneous nodules and non-blanching macules.

Figure 4f.3 Skin biopsy. Periodic acid-Schiff stain revealing septated hyphae (original
magnification 100x).
Ophthalmologic Infections
CHAPTER 4

Figure 4f.4 Skin biopsy. Gomori methenamine silver stain revealing branching, septated
hyphae (original magnification 100x).
96

Figure 4f.5 Eye examination revealing injected conjunctiva of right eye.

Ophthalmologic exam revealed marked vitreal infiltrates, and aspiration

of vitreous fluid was performed for culture. Intravitreal amphotericin B was
administered for presumed fungal endophthalmitis. His vision continued to
worsen to light perception only. At this time, intravitreal voriconazole was
administered based on the vitreal cultures, and a vitrectomy was performed.
Unfortunately, the patient failed extubation after the procedure and subse-
quently expired. The cultures from both the skin and the vitreal cavity grew
Aspergillus fumigatus (Figures 4f.6 and 4f.7).
 Ophthalmologic Infections
CHAPTER 4
Figure 4f.6 Vitreous culture, macroscopic colony appearance on Sabaroud’s
dextrose agar.

97

Figure 4f.7 Vitreous culture, microscopic appearance of fruiting head stained with
lactophenol blue (original magnification 40x).

Case 4f Discussion: Aspergillus fumigatus Endophthalmitis

Clinical Features and Diagnosis
Endogenous Fungal Endophthalmitis (EFE) is predominantly due to Candida
albicans (56%) and Aspergillus species (24%).1 A. fumigatus and A. flavus
comprise the majority of Aspergillus infections. The major risk factors for
Aspergillus EFE are primary pulmonary infection or disseminated disease in an
 immunocompromised host, corticosteroid use, broad-spectrum antibiotics,
Ophthalmologic Infections

and intravenous drug use. Aspergillus EFE has faster progression from symptoms
to visual loss (5 days) compared to Candida EFE (61 days) and has a much worse
visual prognosis.1 One case series by Essman et al. reported that 76% of patients
with Candida endophthalmitis responded to standard treatment, consisting of
systemic and intravitreal amphotericin B and vitrectomy, with a visual acuity of
20/400 or better compared to 0% of patients with Aspergillus EFE.2
Patients with EFE present most commonly with decreased or blurry vision,
redness, and pain in the affected eye. Ophthalmologic exam of the anterior
chamber often reveals significant injection and a corresponding hypopyon.
CHAPTER 4

Evidence of vitritis in the posterior chamber is also common, particularly in

Aspergillus EFE. In addition, a pseudo-hypopyon (gravitational layering of
subretinal inflammatory cells) is considered by some as pathognomonic for
Aspergillus EFE, although it is found in only 11% of patients with this infection.3
Retinal findings including cotton wool spots, Roth spots, and hemorrhages,
and choroidal and vitreal infiltrates are found in 40% of patients with EFE.3 In
Aspergillus EFE, the central macula is often involved and accounts for the poor
visual prognosis.
Diagnosis requires clinical suspicion and immediate ophthalmologic exami-
nation to obtain cultures. Cultures from the anterior chamber are diagnostic
only one-third of the time. Therefore, it is frequently necessary to culture the
vitreous fluid or vitrectomy fluid, which are diagnostic in up to 90% of patients
98

with EFE.3 Although Aspergillus EFE often develops from disseminated disease,
blood cultures are diagnostic in only 20% of cases.1 As in this case, cultures
from other sites, such as skin or from bronchoscopy, can also be helpful. The
use of polymerase chain reaction (PCR) has been shown to be more sensitive
than traditional methods in detecting fungal infections. However, since many
labs do not support PCR analysis, and PCR does not provide susceptibility data,
traditional methods must still be applied.1
Treatment
Treatment of EFE has consisted of a combination of systemic antifungal medica-
tions, intravitreal amphotericin B, and vitrectomy. Intravenous amphotericin B,
traditionally used in disseminated fungal infections, has poor penetration into
the vitreous cavity, and although intraocular levels may be higher when using
the liposomal formulation, the data is inconclusive in humans.4 The treatment
of EFE, therefore, also requires intravitreal administration of amphotericin B in
doses of 5–10 μg.1 Since intravitreal amphotericin B has been reported to have
retinal toxicity in animal studies, there has been interest in discovering alter-
native antifungal agents that maintain a broad spectrum of coverage. Systemic
fluconazole and flucytosine have adequate intraocular penetration but are lim-
ited by resistance, especially with Aspergillus species.1 Voriconazole given orally
or intravenously has been found to have intravitreal concentrations well above
minimal inhibitory concentrations for most Candida and Aspergillus species. In
addition, it appears to be safe for intraocular use, without evidence of retinal
toxicity even at high concentrations in the eye. There are now multiple case
reports citing the efficacy of systemic and intravitreal voriconazole in treating
Aspergillus EFE that has failed prior conventional antifungal therapy.5
 Surgical treatment with vitrectomy is often necessary, especially in cases

Ophthalmologic Infections
with marked vitreal involvement, which is typical in Aspergillus EFE.6 Prompt
vitrectomy in these cases is not only diagnostic but also necessary to deb-
ulk the vitreal cavity and remove the infecting organism. Vitrectomy has been
associated with improved visual acuity and resolution of infection in cases of
Aspergillus EFE, and is recommended along with systemic antifungal therapy
with liposomal amphotericin B or voriconazole in cases of disseminated
infection.1,3 If an Aspergillus species is confirmed as the pathogen via vitrectomy
culture, a second injection of intravitreal amphotericin B should be given, as
the half-life of amphotericin B post-vitrectomy is shortened from 7–10 days

CHAPTER 4
to only 2 days.3 Repeat vitrectomy and injections may be needed depending
on the resolution of infiltrates in the posterior chamber. Systemic antifungal
therapy should be continued for at least 4 weeks and until the disseminated
infection has resolved.3

References
1. Smith SR, Kroll AJ, Lou PL, Ryan EA. Endogenous bacterial and fungal endophthal-
mitis. Int Ophthalmol Clin. 2007;47(2):173–183.
2. Essman TF, Flynn HW, Jr., Smiddy WE, et al. Treatment outcomes in a
10-year study of endogenous fungal endophthalmitis. Ophthalmic Surg Lasers.
1997;28(3):185–194.

99
3. Riddell Iv J, McNeil SA, Johnson TM, Bradley SF, Kazanjian PH, Kauffman CA.
Endogenous Aspergillus endophthalmitis: report of 3 cases and review of the
literature. Medicine (Baltimore). 2002;81(4):311–320.
4. Goldblum D, Rohrer K, Frueh BE, Theurillat R, Thormann W, Zimmerli S. Ocular
distribution of intravenously administered lipid formulations of amphotericin B in
a rabbit model. Antimicrob Agents Chemotherapy. 2002;46(12):3719–3723.
5. Hariprasad SM, Mieler WF, Lin TK, Sponsel WE, Graybill JR. Voriconazole in the
treatment of fungal eye infections: a review of current literature. Br J Ophthalmol.
2008;92(7):871–878.
6. Weishaar PD, Flynn HW, Jr., Murray TG, et al. Endogenous Aspergillus
endophthalmitis. Clinical features and treatment outcomes. Ophthalmology.
1998;105(1):57–65.

Ca e 4g:
Case 4g: Bl
B
Blurry
lurry Vision
Vision
ion in
i aP
Patient
ati
tient
i t with
wiith AID
AIDS
AIDSS

Ronni Lieberman
Clinical Presentation
A 56-year-old woman with HIV/AIDS was referred to ophthalmology for
distorted vision in the left eye. She had been diagnosed with HIV/AIDS eight
months prior to her presentation, and her CD4+ cell count had increased while
taking atazanavir, ritonavir, and tenofovir-emtricitabine from 4 cells/μl at the
time of diagnosis to 102 cells/μl at the time of presentation. She had a his-
tory of HIV-associated neuropathy and Candida esophagitis, but had never been
treated for an ocular opportunistic infection.
 On examination, her vision was 20/50 with some metamorphopsia. The
Ophthalmologic Infections

examination of the right eye was unremarkable, but the left eye was noted
to have 1+ anterior chamber inflammation, in addition to 1+ vitreous cells.
She was found to have a large chorioretinal scar, originating at the optic
nerve and following the course of the superior temporal arcade. The involved
area extended within one-half disc diameter of the fovea, but did not involve
the fovea. The lesion was consistent with inactive CMV retinitis (CMVR)
(Figure 4g.1). There was no evidence of active disease at this time; vitreous
cells were noted to overlie the lesion.
Ocular coherence tomography (OCT) was performed, and showed cystoid
CHAPTER 4

macular edema (Figure 4g.2), which was also demonstrated on fluorescein

angiography (Figure 4g.3). Her CD4+ cell count had been steadily trending
upward since diagnosis. In the context of an inactive lesion of CMVR, associated
with both anterior and vitreous inflammatory cells, structural retinal changes,
and an increasing CD-4+ count now over 100 cells/μl, the diagnosis of immune
reconstitution syndrome was made.
100

Figure 4g.1 Fundoscopic examination of left eye revealed sharp optic nerve margins,
sheathed vessel along superior arcade, chorioretinitis scar, and retinal pigment epithe-
lium mottling in posterior pole.

Figure 4g.2 Ocular coherence tomography (OCT) showing cystoid macular edema.
 Ophthalmologic Infections
(a)

CHAPTER 4
(b)

101

Figure 4g.3a and 3b Fluorescien angiography showing large CR scar along superior-
temporal arcade, with late staining along areas of scarring, no leakage, window defects in
macula that stain late and correspond to retinal pigment epithelium mottling, associated
cystoids macular edema, and no leakage from disc.

The patient was treated with topical prednisolone acetate; however, on

repeat examination one month later, the patient was noted to have a decrease
of vision to 20/80, with a subsequent increase of both intraretinal edema and
cystoid changes on clinical and OCT examination (Figure 4g.4). Her CD-4+
count had risen to 136cells/ml. These changes persisted for 4 weeks and, at that
time, an intravitreal injection of triamcinolone acetate, 40mg/0.1ml was per-
formed. Vision improved to 20/40, anterior and vitreous inflammation resolved,
and cystoid changes and retinal edema decreased significantly, both clinically
and on OCT (Figure 4g.5).
Ophthalmologic Infections
CHAPTER 4

Figure 4g.4 Ocular coherence tomography (OCT) showing increase in cystoid macular
edema.
102

Figure 4g.5 Fundoscopic examination showing increase in cystoid macular

edema (CME).

The patient’s vision remained stable over the course of a year, with topical
steroids being tailored to the clinical status until she was ultimately tapered off
all ocular medications.
Case 4g Discussion: Immune Reconstitution Uveitis
Clinical Features and Diagnosis
Immune reconstitution uveitis (IRU) is a syndrome characterized by increased
ocular inflammation, both anterior and in the vitreous, in patients with a now-
quiescent intraocular infection, who have experienced immune recovery.1 It is

Ophthalmologic Infections
sometimes considered a subset of immune reconstitution syndrome, seen in a
number of HAART-treated patients, who exhibit a paradoxical deterioration in
their clinical status as their immune status improves. Although most commonly
seen in patients with inactive CMV retinitis, it has been noted in patients with
ocular toxoplasmosis, tuberculosis, cryptococcosis and leishmaniasis. IRU is
thought to occur as a response to intraocular antigens; therefore, patients with
unilateral inactive CMVR are only at risk in that eye. IRU occurs in the early
stages of immune recovery2 and has been noted to occur between 2 and 26
weeks after initiation of antiretroviral therapy, with the median at 4 weeks.3

CHAPTER 4
IRU is not uncommon; it was found in 9.6% of 259 patients with inactive CMV
retinitis and immune recovery, in an Longitudinal Study of Ocular Complications
of AIDS (LSOCA) study.4 It is seen in the context of immune recovery, unde-
tectable CMV DNA or HIV RNA levels in blood, history of intraocular infec-
tion with no currently active disease, and often in patients taking antiretroviral
medications to treat previously active lesions. Large lesions are thought to
predispose the patient to IRU, as the larger the area of infected retina is, the
larger the subsequent antigen load will be, thereby increasing the odds of an
inflammatory reaction.1 These patients are also less likely to be on anti-CMVR
treatment.1 IRU is associated with moderate to severe vision loss, with these
patients having over a 20-fold higher risk of cystoid macular edema, in addition
to an increased risk of epiretinal membrane (ERM) formation and cataract.1

103
Early signs and symptoms of IRU include anterior and/or vitreous inflamma-
tory cells, floaters, posterior synechiae and optic disc edema, all of which can
cause decreased vision. This must be recognized promptly and treated aggres-
sively to prevent late complications. The mainstay of therapy is steroids, given
either topically, intravitreally or systemically, which have an approximate 50%
success rate. If there is only mild to moderate anterior and vitreous inflamma-
tion with no structural changes, topical steroids (prednisolone acetate 1%) are
recommended; however, the patient must be monitored closely, as any early
structural or anatomic change (CME, ERM, etc.), must be addressed immedi-
ately. This warrants treatment with either systemic steroids (1mg/kg initially)
or intravitreal injection (triamcinolone acetate 40mg/0.1ml). These therapies
all have potentially significant complications, and the patient must be moni-
tored appropriately. There is some evidence to suggest that the institution of
anti-CMVR therapy may be of use, as it decreases antigen load and thus may
facilitate control of inflammation.5
Late manifestations leading to moderate vision loss include cystoid macular
edema (CME; Figures 4g.2 and 4g.3), ERM (Figure 4g.6), vitreoretinal traction
(VRT) (Figure 4g.7), and neovascular membrane formation (NVE), in addition
to cataract. CME, ERM, and NVE can all be treated with steroids, either intra-
vitreal or systemic. Surgical intervention may be necessary to treat ERM, VRT,
and cataract.
IRU is an entity that may be difficult to diagnose and treat, but is of utmost
importance in the evaluation of HIV/AIDS patients with intraocular inflamma-
tion. The distinction between active disease and IRU is further complicated
Ophthalmologic Infections

Figure 4g.6 Ocular coherence tomography (OCT) showing resolution of cystoids

changes.
104 CHAPTER 4

Figure 4g.7 Fundoscopic examination showing resolution of cystoid changes.

by evidence demonstrating that patients with untreated ocular disease at the

inception of immune reconstitution are predisposed to the development of
IRU. It is, therefore, recommended that all patients with AIDS be seen by
an ophthalmologist prior to starting antiretroviral therapy. If active disease
(CMVR, for example) is found, it is recommended that it be treated before
the patient initiates antiretrovirals.5 In addition, the treatment of retinal lesions
with HAART may indeed result in inactive disease at some point, but at the risk
of a larger retinal lesion, which in turn puts the patient at higher risk for the
development of IRU.5 Patients may need multiple courses of therapy for IRU,
and careful monitoring over time with attention to even minimal changes in
intraocular inflammation, as these can lead to structural and anatomic changes
in the eye and, ultimately, decreased vision.
References

Ophthalmologic Infections
1. Kempen, et al. Risk of immune recovery uveitis in patients with cytomegalovirus
retinitis. Ophthalmology. 2006;113:684–694.
2. Holland GN. AIDS and ophthalmology: the first quarter century. Am J Ophthalmol.
2008;145(3):397–408.
3. Karavellas MP, Lowder CY, Macdonald C, et al. Immune recovery vitritis associ-
ated with inactive cytomegalovirus retinitis: a new syndrome. Arch Ophthalmol.
1998;116:169–175.
4. Jabs DA, van Natta ML, Holbrook JT, et al. Longitudinal study of the ocular com-

CHAPTER 4
plications of AIDS: 2 Ocular examination results at enrollment. Ophthalmology.
2007;114:787–793.
5. Ortega-Larrocea G. Lower incidence and severity of cytomegalovirus-associated
immune recovery uveitis in HIV-infected patients with delayed highly active anti-
retroviral therapy. AIDS. 2005;19(7):735–738.

105
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 Chapter 5

Oropharyngeal and Sinus

Infections

Case
C a e 5a:
5a: A 443
43-Year-Old
3-Y
Year-O
Old Man
M wit
with
ith
hNNeck
eck
k SSwell
Swelling
lli
ling and
d
SStridor
St rido
ridor

Meenakshi Mehrotra Rana

Case Presentation
A 43-year-old man presented to an outside hospital with a 2-day history of

107
tooth pain, and subsequent left-sided neck swelling and difficulty swallowing
(Figure 5a.1). He had a past medical history of alcoholic cirrhosis and chronic
renal insufficiency, but was taking no medications. He had recently moved to the
United States from Turkey, one year prior to presentation. In the emergency
department, a computed tomography scan of the neck showed necrotizing cel-
lulitis consistent with Ludwig’s angina (Figure 5a.2). Surgery was recommended,
but the patient left against medical advice. He returned several hours later
for a second opinion, and at this time he was noted to have stridor and voice
changes.
On physical examination, he was afebrile with temperature of 36°C., with
normal heart rate and blood pressure; room air saturation was 100% on pulse
oximetry. He was noted to have scleral icterus, poor dentition, and trismus
with elevation of the tongue and “woody” edema of the floor of the mouth.
He had bilateral brawny edema of the neck, but no crepitus was palpated. The
patient was intubated under fiberoptic guidance and taken to the operating
room by ENT for incision and drainage of a submandibular abscess. In addition,
oral maxillofacial surgery extracted four teeth with gross caries.
The patient was treated with ampicillin-sulbactam, but remained persistently
febrile, and the antibiotics were changed to vancomycin, imipenem, and clin-
damycin. Microscopic examination of the purulent drainage from the abscess
revealed a mixed flora consisting of many Gram-positive cocci in pairs and
chains, and many Gram-negative rods (Figure 5a.3). Aerobic and anaerobic cul-
tures from the operating room grew Streptococcus constellatus, group F beta-
hemolytic Streptococcus, and Prevotella buccae. He eventually defervesced after
a repeated bedside washout of wound, and was eventually transitioned to oral
amoxicillin-clavulanate for completion of several weeks of antibiotic treatment.
Oropharyngeal and Sinus Infections
CHAPTER 5

Figure 5a.1 Physical examination revealed marked neck swelling.

108

Figure 5a.2 CT scan neck, axial view showing emphysematous changes in the soft
tissues consistent with a necrotizing infection.
 Oropharyngeal and Sinus Infections
CHAPTER 5
Figure 5a.3 Gram stain of purulent drainage from the abscess revealed a mixed flora
consisting of many Gram-positive cocci in pairs and chains and many Gram-negative rods
(original magnification 1000x).

Case 5a Discussion: Ludwig’s Angina

109
Head and Neck Infections
While infections of the head and neck are relatively uncommon in the post-
antibiotic era, infections of three particular spaces in the head and neck are of pri-
mary importance, as they can be life-threatening in certain circumstances. These
“space infections” are categorized by three locations—submandibular, lateral
pharyngeal, and the retropharyngeal/danger/prevertebral spaces. Understanding
the anatomy of these particular spaces provides insight into the clinical manifes-
tations and management of these infections. The submandibular space is bor-
dered anteriorly and laterally by the mandible, and inferiorly by the deep cervical
fascia. The mylohyoid muscle separates the submandibular space into the sublin-
gual and submylohyoid space. Infections in this space are typically odontogenic in
nature, and include Ludwig’s angina as described in the patient above.1
The other two spaces include the lateral pharyngeal space, which is a
2.5 cm long inverted cone extending from the hyoid to the sphenoid bone. It
is bordered laterally by the parotid gland, mandible, and the attached internal
pterygoid muscle. Its medial wall is contiguous with the carotid sheath, which
contains the vital structures of the internal carotid artery, the internal jugular
vein, and the vagus nerve. Infection of the lateral pharyngeal space may result
from pharyngitis, tonsillitis, parotitis, otitis, or mastoiditis, as well as from
ondontogenic infection.1
Lastly, the retropharyngeal/prevertebral/danger space is located between the
posterior aspect of the pharynx/esophagus and the anterior portion of the spine.
The retropharyngeal space is most anterior and extends from the base of the
skull to the C7/T1 region. Infections in the retropharyngeal space can spread to
the superior anterior mediastinum, resulting in pleural and pericardial infections.
 The danger space is located posterior to the alar fascia, and is bounded poste-
Oropharyngeal and Sinus Infections

riorly by the prevertebral fascia. The prevertebral space is bound posteriorly

by the vertebral bodies, and anteriorly by the prevertebral fascia. It extends
from the base of the skull down to the coccyx, and infections in this space usu-
ally develop after cervical spine infections from hematogenous seeding, or from
contiguous spread from vertebral osteomyelitis. Unlike other infections in the
head and neck, which are primarily mixed infections of oropharyngeal origin, in
prevertebral infections Staphylococcus aureus can play a prominent role.1
Ludwig’s Angina
Ludwig’s angina refers to the rapidly spreading cellulitis and potentially lethal
infection involving the submandibular and sublingual space. It was first described
in 1836 by Wilhelm Friedrich von Ludwig, who observed five patients develop
CHAPTER 5

“gangrenous induration of the connective tissues of the neck which advances

to involve the tissues which cover the small muscles between the larynx and
the floor of the mouth.” He described a rapidly spreading cellulitis with subse-
quent airway obstruction, resulting in a 60% mortality rate. The term “Ludwig’s
angina” was coined one year later, and is derived from the Latin term angina to
describe the terrible suffocation observed in these patients.2
In the pre-antibiotic era, mortality was extremely high and therapy consisted
of emergent surgery in order to avoid airway obstruction; despite this, mortal-
ity rates of 40%–80% were described. Since then, the combination of systemic
110

antibiotic therapy and aggressive surgical intervention with airway protection has
reduced the mortality to 0%–4%. Odontogenic infection is the source of infection
in Ludwig’s angina in the majority of cases, and usually derives from the second or
third molar teeth. Although most infections occur in healthy individuals, certain
predisposing factors have been described, including diabetes mellitus, neutrope-
nia, aplastic anemia, glomerulonephritis, and certain immunodeficiencies. Ludwig’s
angina can also follow after post-traumatic infection from fracture of the mandible,
penetrating injury to the floor of the mouth, or even trauma from intubation.3
Patients classically present with tooth pain and describe poor dental hygiene
or recent dental work. Symptoms include progressive upper bilateral neck pain
and swelling resulting in trismus, dysphagia and dysphonia with the classic “hot
potato” voice. Patients often have systemic signs and symptoms, including fever
and tachycardia, and appear toxic. On exam, there is brawny swelling of the
submandibular space that is not pitting. In addition, there is classically “woody
edema” of the base of the mouth that results in protrusion of the tongue.
Examination of the neck may reveal crepitus, but fluctuation and lymphade-
nopathy are usually absent. Frequently, tachypnea, stridor and cyanosis usually
signal impending airway obstruction and need for emergent airway access.4
Diagnosis is usually made clinically, but imaging may be helpful in providing
localization of an abscess or finding an odontogenic focus. Plain radiographs
may demonstrate the extent of the swelling, as well as reveal gas indicating an
anaerobic infection. CT or MRI will confirm airway edema and help localize any
fluid collection.
Management in Ludwig’s angina most importantly involves securing a stable
airway. Blind endotracheal intubation is usually not advised because of compli-
cations secondary to trismus, pooled secretions, and altered airway anatomy.
Intubation under fiberoptic guidance, while the patient is awake, allows for

Oropharyngeal and Sinus Infections

intubation under visualization. Otherwise, tracheostomy can also be performed
with the use of local anesthetic; use of paralytics is generally avoided because
it may precipitate occlusion of the airway secondary to loss of tone of the
pharyngeal musculature.4
Antibiotic therapy is an important component of management, and should
cover mixed aerobic and anaerobic organisms associated with oral flora. Initial
regimens should cover beta-lactamase-producing aerobic organisms, as well as
anaerobic Gram-positive cocci and Gram-negative bacilli; therefore, a penicillin-
derivative/beta lactamase inhibitor combination such as ampicillin/sulbactam
or piperacillin/tazobactam, would be appropriate. There have been reports of
Klebsiella pneumoniae in patients with diabetes mellitus from the Asian litera-
ture; therefore, carbapenems may also be an appropriate initial choice. Other

CHAPTER 5
initial recommended antibiotic regimens include clindamycin with Gram-
negative coverage or third- or fourth-generation cephalosporins with metroni-
dazole. In addition, if methicillin-resistant Staphylococcus aureus is a concern in
a colonized individual, it may be reasonable to add vancomycin as well. Candida
and Aspergillus species have also been reported in a small number of patients.3
Lastly, surgical incision and drainage of any purulent collections is a necessary
part of the management of these infections. Drains are often left in place to
allow for continued drainage of purulent material. In addition, extraction of any
teeth with gross caries should be carried out, as this serves as a likely nidus for

111
these infections. With a combination of surgical intervention, antibiotic therapy
and airway management, many patients with Ludwig’s angina can make a suc-
cessful recovery.

References
1. Chow AK. In: Infections of the oral cavity, neck and head. In Mandell GL, Bennett
JE, Dolin R. eds. Mandell, Douglas and Bennett’s Principles and Practice of Infectious
Diseases. 7th ed. Philadelphia: Elsevier Churchill Livingston; 2009:855–871
2. Barakate M, Jensen M, Hemli JM, Graham AR. Ludwig’s angina: report of a case
and review of management issues. Ann Otol Rhinol Laryngol. May 2001:453–456
3. Reynolds SC, Chow, A. Life-threatening infections of the peripharyngeal and deep
fascial spaces of the head and neck. Infect Dis Clin N Am. 2007;21:557–576
4. Patterson HC, Kelly JH, Strome M. Ludwig’s angina: an update. Laryngoscope,
April 1982: 370–78.

Case
C a e 5b:
5b: Sore
S Throat
Th att aand
Thro
Th nd
dN Neck
k Swelling
Swelli
lli
lin
ng in
i a
48-Y
48 -Yeear-Old Man
48-Year-Old n wi
witth A
with IDS
AIDS

Daniel Caplivski
Case Presentation
A 48-year-old man with AIDS developed worsening sore throat, fever, chills,
and neck swelling over the course of three weeks. His lowest CD4+ cell count
Oropharyngeal and Sinus Infections

had been 194 x103 cells/μl, but his most recent count several weeks earlier
had been 452 x 103 cells/μl. His symptoms had improved slightly when he took
several doses of his wife’s penicillin, but then dramatically worsened when he
ran out of the antibiotic. He was originally from Puerto Rico, but he had not
traveled recently and had no known history of tuberculosis.
On evaluation in the emergency department, he was noted to have a large
left-sided neck mass and an overlying cellulitis (Figures 5b.1 and 5b.2). He was
febrile (temperature, 39.5ºC) and tachycardic (heart rate 136), but no stridor
was noted. His laboratory examinations were notable for a leukocytosis of
31x103 WBC/μl (89% polymorphonuclear cells). Computed tomography of
the neck revealed multiple enhancing lymph node abscesses with surrounding
edema. The abscesses were as large as 3.4 cm and were displacing the carotid
CHAPTER 5

artery and internal jugular vein on the left (Figure 5b.3). Ampicillin/sulbactam
and intravenous vancomycin were initiated, and the patient underwent surgical
drainage of the abscesses.
112

Figure 5b.1 and 5b.2 Physical examination revealed a large left-sided neck mass with
overlying cellulitis.
 Oropharyngeal and Sinus Infections
CHAPTER 5
Figure 5b.3 CT scan of the neck, axial view revealed multiple enhancing lymph node
abscesses with surrounding edema. The abscesses were as large as 3.4 cm and were
displacing the carotid artery and internal jugular vein on the left.

113

Figure 5b.4 Gram stain of fluid from abscess revealed Gram-positive cocci in short
chains.

Operative drainage of the abscesses revealed several milliliters of pus from

each abscess. Gram-positive cocci in short chains were noted on Gram stain of
the material (Figure 5b.4), and Streptococcus pyogenes (beta-hemolytic Group A
streptococcus) was recovered in cultures (Figures 5b.5 and 5b.6). The patient
required a second debridement procedure to further drain the abscesses, but
eventually recovered after the two surgeries and intravenous ampicillin/sulbac-
tam, followed by oral amoxicillin/clavulanate for 4 weeks.
Oropharyngeal and Sinus Infections
CHAPTER 5

Figure 5b.5 Sheep’s blood agar plate with beta-hemolytic colonies.

114

Figure 5b.6 Gram stain of cultured material with Gram-positive cocci in long chains.

Case 5b Discussion: Streptococcus pyogenes

Clinical Features and Diagnosis
Streptococcus pyogenes (Group A beta-hemolytic streptococcus) is an organ-
ism capable of producing human disease both directly as an invasive pathogen
and indirectly via the immune-mediated responses to its antigens. As a directly
invading pathogen, it is the most common bacterial cause of pharyngitis, and
rarely can become life-threatening when airway is compromised. It is also the
causative agent of soft tissue infections that range from simple cellulitis, ery-
sipelas, and impetigo, to necrotizing fasciitis. In the case of necrotizing fascii-
tis, the organism rapidly spreads through subcutaneous tissues, and it secretes
superantigens that nonspecifically activate T-cells resulting in massive tissue

Oropharyngeal and Sinus Infections

inflammation and necrosis.1
Toxic shock syndrome is closely related to necrotizing fasciitis, in that a
nonspecific activation of the immune system results from the release of strep-
tococcal exotoxins that act as superantigens. This syndrome is characterized by
hypotension, tachycardia, fever, a diffuse rash with subsequent desquamation,
and end organ damage. The evidence of end organ inflammation may be seen
with acute kidney injury, elevated liver enzymes, vomiting and diarrhea, altered
mental status, or thrombocytopenia.1
The nonsuppurative complications of Streptococcus pyogenes infec-
tion include post-streptococcal glomerulonephritis and rheumatic fever.
Glomerulonephritis is an active inflammation of the kidneys that results
from the deposition of immune complexes in the basement membrane fol-

CHAPTER 5
lowing an episode of streptococcal pharyngitis or skin infection. Rheumatic
fever occurs only after streptococcal pharyngitis. The signs and symptoms
that make up this syndrome are categorized between major and minor cri-
teria (carditis, migratory arthritis, serologic assays, fever, etc.). The dam-
age caused to endocardial tissue (in particular, the chronic scarring of heart
valves) remains a major cause of morbidity worldwide, and is thought to
result from molecular mimicry between the antigens of S. pyogenes and heart
valve tissue.1
The definitive diagnosis of the invasive manifestations of S. pyogenes relies on

115
culture of the organism from sterile sites. Throat cultures have traditionally been
the gold standard in the diagnosis of pharyngitis, but the delay in obtaining defini-
tive results has led to the development of rapid antigen detection tests (RADT)
that provide more immediate information.2 This advent is particularly important
when trying to differentiate streptococcal infections from viral upper respiratory
infections that do not require antibiotics. When the organism is isolated from a
lymph node abscess (as in this case), it is characterized on Gram stain as a Gram-
positive coccus in short chains. When cultured on sheep’s blood agar, it exhib-
its complete hemolysis and will produce elongated chains. Using the Lancefield
classification system, it can be differentiated from other beta-hemolytic strepto-
cocci such as Streptococcus agalactiae (Group B streptococcus).2–4
Management
S. pyogenes remains universally susceptible to penicillin, but rates of resistance
to macrolides have emerged as a cause of concern, given the widespread use
of these antimicrobials.5 The pyogenic nature of the organism may lead to peri-
tonsillar or lymph node abscess formation, a condition that may require surgical
drainage to prevent occlusion of the airway. Necrotizing fasciitis is another
manifestation that requires emergent surgical debridement in order to stop the
massive destruction of tissues, as well as the massive cytokine release caused
by nonspecific T-cell activation.3 Nonsuppurative complications of S. pyogenes,
such as glomerulonephritis, may be self-limiting; however, children with this
syndrome should be treated with antibiotics to prevent spread of nephrito-
genic strains. The inflammation induced by acute rheumatic fever is treated
with salicylates and corticosteroids, but continuous monthly injections of peni-
cillin are used to prevent relapses.1
 References
Oropharyngeal and Sinus Infections

1. Bisno A, Stevens D. Streptococcus pyogenes and nonsuppurative poststreptococ-

cal sequelae: rheumatic fever and glomerulonephritis. In Mandel GL, Bennett JE,
Dolin R. eds. Principles and Practices of Infectious Diseases, Volume 2. 7th Edition.
2009:2593–2621.
2. Gieseker KE, Mackenzie T, Roe MH, Todd JK. Comparison of two rapid
Streptococcus pyogenes diagnostic tests with a rigorous culture standard. Pediatr
Infect Dis J. 2002;21(10):922–927.
3. Bisno AL, Gerber MA, Gwaltney JM Jr, Kaplan EL, Schwartz RH; Infectious
Diseases Society of America. Practice guidelines for the diagnosis and manage-
ment of group A streptococcal pharyngitis. Clin Infect Dis. 2002;35(2):113–125.
4. Lancefield RC. A serological differentiation of human and other groups of hemo-
lytic streptococci. J Exp Med. 1933;57(4):571–595.
CHAPTER 5

5. Robinson DA, Sutcliffe JA, Tewodros W, Manoharan A, Bessen DE. Evolution

and global dissemination of macrolide-resistant group A streptococci. Antimicrob
Agents Chemother. 2006;50(9):2903–2911.

Case
C a e 55c:
c: SSore Th
Thro
Throatatt aand
nd
d Sh
SShortness
hortness
t o
off B
Breath
reaath
t ffollowed
oll
llowe
lowed d
by SSe
Septic
eptic Shock in a Healthy 18-Year-Old
Heaalthy 18-Yeear-Old dP Polo Player
Playyer
e
116

Joshua C. Eby and W. Michael Scheld

Case Presentation
An 18-year-old female college student with no past medical history presented
to the emergency department in April with fever and shortness of breath.
She played on the university polo team, and had been performing well in her
classes. Seven days prior to admission, she reported to her friend and her
sister that she had a sore throat and felt ill. She developed subjective fevers
and shaking chills. A rapid streptococcal test was negative, and she received
azithromycin from her student health facility without improvement. Over the
36 hours prior to admission, she experienced progressive shortness of breath
and was admitted to her local community hospital with a chest radiograph
showing bilateral pulmonary infiltrates, elevated bands (30%), and hypoten-
sion requiring vasopressor support. Blood cultures were drawn and she was
started subsequently on vancomycin and cefepime. Her respiratory status
deteriorated, requiring endotracheal intubation, and she was then transferred
to our facility. Per the patient’s family, she had no potential exposures other
than cleaning horse stalls. She was not sexually active and had never used
illicit drugs.
On transfer, rectal temperature was 38.6°C, blood pressure was supported
on norepinephrine, and her respiratory function was supported on assist con-
trol ventilation with a fractional inspired oxygen concentration of 50%. She was
responsive to voice but sedated. There was no cervical edema or lymphade-
nopathy, but she had a jugular venous wave 3cm above the sternal angle. There
was no organomegaly, but trace lower extremity edema was present.
 Her laboratory findings included anemia (hematocrit 26.7), and throm-

Oropharyngeal and Sinus Infections

bocytopenia (platelets 55,000/mm3, decreased from 122,000 on the day of
admission), with normal white blood cell count (5000/μl). Other laboratory
test findings were normal, including coagulation profile, HIV serology, urine
Legionella antigen, and influenza PCR and transthoracic echocardiography.
Ciprofloxacin and doxycycline were added to her antimicrobial regimen.
On the day after transfer, blood cultures from the outside facility were grow-
ing a Gram-negative rod in the anaerobic samples that was later identified as
Fusobacterium necrophorum (Figures 5c.1a and b). Computed tomography
showed a left, nonocclusive, internal jugular vein thrombus (Figures 5c.2a and b).

117 CHAPTER 5
Figure 5c.1a Blood agar plate revealing growth only under anaerobic conditions.

Figure 5c.1b Gram stain of colonies with elongated Gram-negative bacilli.

Oropharyngeal and Sinus Infections

(a) (b)

Figure 5c.2 (a) CT neck, transverse view revealing nonocculsive left internal jugular
vein thrombosis; and (b) CT neck, coronal view revealing nonocculsive left internal
jugular vein thrombosis.
CHAPTER 5

On further questioning of the family, she had been complaining of left-sided neck
pain prior to her respiratory decompensation. She was treated with metron-
idazole for 6 weeks, with complete resolution of symptoms and no long-term
sequelae.
Case 5c Discussion: Lemierre’s Syndrome
Clinical Features
118

Lemierre’s syndrome was first described in 1936 as “suppurative thrombophle-

bitis of the internal jugular vein with metastatic infection.” The syndrome is
a complication of oropharyngeal infections, and since the initial description,
the incidence has decreased due to the use of antibiotics for treatment of
pharyngitis. The syndrome occurs almost exclusively in adolescents and young
adults, with an estimated annual incidence of 14 cases per million adolescents.1,2
Fusobacterium necrophorum is the etiologic agent in 81% of cases, and growth
of this organism in blood cultures is nearly pathognomonic for this disease.
Anaerobic streptococci, Bacteroides, and Peptostreptococcus have also been iso-
lated in the setting of Lemierre’s syndrome.
The diagnosis is often not considered due to the nonspecific initial clinical
presentation. In an estimated 87% of cases, the syndrome occurs in associa-
tion with pharyngitis,3 but infection may originate from other sources in the
head and neck. A patient may report symptoms of pharyngitis, upper respira-
tory tract symptoms, dysphagia, or dysphonia. Approximately 3–7 days after
oropharyngeal symptoms start, there may be a slight improvement followed
by the development of shaking chills and fever.4 Swelling or pain in the neck
can occur ipsilateral to the thrombosis and should suggest the diagnosis.
Embolic or disseminated infection is often considered part of the definition of
Lemierre’s syndrome, and is present in up to 97% of patients with septic jugular
thrombophlebitis. The lung is the most common site of metastatic infection
(Figures 5c.3a and b) and septic arthritis has been frequently reported. Severe
sepsis, as in the case above, can occur. Although mortality has decreased since
the initial description of the syndrome, 10% of patients exhibit persistent defi-
cits after treatment.
 Oropharyngeal and Sinus Infections
(a)

CHAPTER 5
(b)

119

Figure 5c.3a and 3b CT lungs axial view with bilateral upper lobe nodules. The right
upper lobe nodule shows early cavitation consistent with septic pulmonary emboli.

Diagnosis and Treatment

Diagnosis is made by radiologic identification—by computed tomography,
ultrasound or MRI5—of jugular venous thrombus in conjunction with clinical
and microbiologic data. Imaging often identifies pulmonary emboli with cavi-
tation and pleural effusions. Parapharyngeal infection may not be evident on
imaging, but edema surrounding the affected vein is common. The associated
organism is generally identified through blood culture, and a sample taken from
seeded tissue may also assist in the diagnosis.
Even in cases of multiorgan involvement, medical management with 3–6
weeks of antibiotics is generally effective. If Lemierre’s syndrome is suspected,
empiric antibiotic therapy should include a E-lactam antibiotic with an agent
active against oral anaerobic bacteria. Ampicillin/sulbactam or ceftriaxone with
clindamycin would be appropriate empiric regimens. Because some Fusobacteria
Oropharyngeal and Sinus Infections

produce a E-lactamase,6 these regimens could also be used in the case of

F. necrophorum infection until the presence of a E-lactamase has been excluded.
Intravenous penicillin G should be used for treatment of E-lactamase negative
F. necorphorum, and metronidazole is probably equally effective. Macrolides and
azithromycin are not clinically effective. The therapeutic benefit of anticoagula-
tion and venous ligation is not well defined.

References
1. Centor RM. Expand the pharyngitis paradigm for adolescents and young adults.
Ann Intern Med. 2009;151(11):812–815.
2. Hagelskjaer KL and Prag J. Lemierre’s syndrome and other disseminated
Fusobacterium necrophorum infections in Denmark: a prospective epidemiologi-
CHAPTER 5

cal and clinical survey. Eur J Clin Microbiol Infect Dis. 2008;27(9):779–789.
3. Chirinos JA, Lichtstein DM, Garcia J, Tamariz LJ. The evolution of Lemierre
syndrome: report of 2 cases and review of the literature. Medicine (Baltimore).
2002;81(6):458–465.
4. Sinave CP, Hardy GJ, Fardy PW. The Lemierre syndrome: suppurative throm-
bophlebitis of the internal jugular vein secondary to oropharyngeal infection.
Medicine (Baltimore). 1989;68(2):85–94.
5. Screaton NJ, Ravenel JG, Lehner PJ, Heitzman ER, Flower CD. Lemierre syn-
drome: forgotten but not extinct--report of four cases. Radiology. 1999;
120

213(2):369–374.
6. Appelbaum PC, Spangler SK, Jacobs MR. Beta-lactamase production and sus-
ceptibilities to amoxicillin, amoxicillin-clavulanate, ticarcillin, ticarcillin-clavu-
lanate, cefoxitin, imipenem, and metronidazole of 320 non-Bacteroides fragilis
Bacteroides isolates and 129 fusobacteria from 28 U.S. centers. Antimicrob Agents
Chemother. 1990;34(8):1546–1550.

Case
C a e 55d:
d: A R
d: Ren
Renal
all T
Tra
Transplant
ansplant
l tR Recipient
eciipien
i nt with
ith FFacial
aciiall Pai
P
Pain
ain
and
an SSwelling
d Sw elling

Daniel Caplivski and Shirish Huprikar

Case Presentation
A 77-year-old man with a history of an uncomplicated cadaveric kidney trans-
plantation 5 months earlier for diabetic nephropathy presented with left-sided
facial pain and swelling. He had previously consulted a dentist for dental pain
and was prescribed penicillin without relief. The pain was severe over the left
frontal, maxillary, and nasal sinuses, and radiated to the left temporal area.
Immunosuppressive medications included tacrolimus, prednisone, and myco-
phenolate mofetil.
The patient was initially evaluated at an outside hospital, and was found to
have a new facial nerve palsy. He was afebrile and normotensive, but viola-
ceous, echymotic areas on his face were noted to be spreading (Figure 5d.1).
Initial laboratory values were significant for hyponatremia (sodium, 128 meq/L),
 Oropharyngeal and Sinus Infections
CHAPTER 5
Figure 5d.1 Physical examination with marked facial swelling and violaceous and echy-
motic skin changes on the left side of the face.

acidosis (C02 19 meq/L) and hyperglycemia (glucose 161 mg/dl). His men-

121
tal status progressively declined and he was intubated for airway protection
shortly after transfer to our hospital. The patient’s ophthalmologic examination
was significant for proptosis, anisocoria with a fixed and dilated left pupil, and
papilledema.
Computed tomography scans of the sinuses revealed mucosal inflammation
of the sinuses on the left (Figure 5d.2), and imaging of the brain also revealed
left temporal lobe cerebritis (Figure 5d.3).
Surgical debridement revealed that the mucosa of the nasal sinus cavity was
boggy, edematous, and hemorrhagic. On the floor of the nasal cavity, filamen-
tous material consistent with a fungus was seen by the surgeon. On pathologic
examination, broad, ribbon-like fungal hyphae were seen on permanent sec-
tions stained with hemotoxylin-eosin (Figure 5d.4) and Gomori methanmine
silver stain (Figure 5d.5). The hyphal elements were aseptate, branching at right
angles, and invading blood vessels.
After several days of incubation, cultures of the nasal biopsied material
began growing a mold that was subsequently identified as a Rhizomucor species
(Figures 5d.6 and 5d.7). The patient’s course was further complicated by intrac-
erebral extension of the infection, and infarction into the left middle cerebral
artery territory. A decision to pursue only palliative measures was made, and
the patient died shortly thereafter.
Case 5d Discussion: Mucormycosis
Epidemiology
Rhinocerebral mucormycosis is a devastating fungal infection that is often fatal in
immunocompromised patients. The infection is caused by a group of molds that
are characterized by broad, ribbon-like, aseptate or poorly-septated hyphae.
Oropharyngeal and Sinus Infections
CHAPTER 5

Figure 5d.2 CT scan sinuses, axial view with marked facial edema and left sided sinus-
itis with mucosal edema and air fluid levels.
122

Figure 5d.3 Brain MRI axial view with left temporal lobe cerebritis.
 Oropharyngeal and Sinus Infections
CHAPTER 5
Figure 5d.4 Biopsy of sinus contents, hemotoxylin-eosin stain showing ribbon-like
aseptate fungal hyphae invading blood vessels.

123

Figure 5d.5 Biopsy of sinus contents, Gomori methanmine silver stain with aseptate
hyphae branching at right angles and invading blood vessels.
Oropharyngeal and Sinus Infections
CHAPTER 5

Figure 5d.6 Cultures of sinus contents on blood agar and Sabaroud’s dextrose agar
growing a mold identified as a a Rhizomucor species.
124

Figure 5d.7 Lactophenol stain of cultured material identified as a Rhizomucor species

with large round sporangia.

Multiple genera and species were included in the class Zygomycetes, but this
class has subsequently been renamed Glomeromycetes.1 Due to this taxonomic
reorganization, and the diversity of molds that can cause this invasive infection,
the group is now referred to as the agents of mucormycosis.1 Among the agents
of mucormycosis, Rhizopus and Rhizomucor are among the most frequently iso-
lated genera. These molds are environmental saprophytes and are widely found
in environmental sources. They become invasive pathogens principally in immu-
nocompromised hosts, particularly diabetics, neutropenic patients, organ trans-
plant recipients, and patients receiving chronic corticosteroid therapy.1
 Patients with diabetes mellitus are at increased risk for this infection due to

Oropharyngeal and Sinus Infections

a combination of factors: hyperglycemia leads to neutrophil dysfunction, and
metabolic acidosis from diabetic ketoacidosis increases the availability of free
iron, an important fungal growth factor. Iron overload in patients with hemo-
chromatosis also increases their risk for invasive mucormycosis. Paradoxically,
iron chelation therapy with deferoxamine also increases their risk, because it
is used by the mold as a siderophore to increase intracellular iron uptake.2
Modern iron chelators, such as deferasirox, are not associated with this prop-
erty and have been shown to be protective in animal models of mucormycosis.1
Prolonged neutropenia in the setting of cancer chemotherapy and hemato-
poietic stem cell transplantation has steadily increased in importance as a risk
factor. Antifungal prophylaxis with voriconazole (which has activity against
Aspergillus, but not against the agents of mucormycosis) has led to improved

CHAPTER 5
survival of patients with neutropenia, but the rate of non-Aspergillus mold infec-
tions has also been climbing.3
Clinical Features and Diagnosis
Inhalation of fungal spores from the environment is the most common route
of acquisition of the agents of mucormycosis. In the immunocompromised host
with inadequate macrophage and neutrophil function, the spread of the organ-
ism is rapid and is not limited by soft tissues or bones. The angioinvasive nature
of these molds leads to hemorrhage, thrombosis, and necrosis of local tissues.

125
Sinus pain and swelling may be initially indistinguishable from bacterial causes
of sinusitis, and radiographic findings are similarly nonspecific, showing inflam-
mation of the sinus cavities with air-fluid levels and bony erosion. On physical
examination, skin lesions may initially appear red or violaceous.1 Later-stage
angioinvasive infection may be detected by the presence of black, necrotic
lesions that are visible in the nares, periorbital skin, or oral cavity. In immuno-
compromised patients, infections may progress from the nasal and sinus spaces
to the brain in the course of a few days.2
Pulmonary infections with the agents of mucormycosis are difficult to distin-
guish radiographically from other invasive mold infections, and tissue biopsy and
culture is generally required to confirm the diagnosis. Symptoms may include
dyspnea, nonproductive cough, pleuritic chest pain, and fever. Computed
tomography findings range from isolated cavitary nodules to diffuse bilateral
infiltrates and wedge infarcts.1 Gastrointestinal infection from ingested spores,
and skin and soft tissue infections from direct inoculation, are manifestations
of mucormycosis that may be seen in immunocompetent patients. Nonsterile
bandages or dressings applied to surgical sites or traumatic wounds are a well-
described source of cutaneous mucormycosis.4
The microscopic appearance of these molds in tissue often allows for their
differentiation from other fungal organisms such as Aspergillus. The hyphae of
the agents of mucormycosis are typically broad, ribbon-like, and lack septations,
while those of Aspergillus species are thinner and divided by septations. The
right-angle branching of the hyphae of the agents of mucormycosis also helps
to differentiate them from the acute-angle branching of Aspergillus hyphae. Both
molds may be visible on hematoxylin and eosin stained tissue, but Gomori
methenamine silver stain enhances the visibility of the hyphae. Cultures of
 biopsied tissue allow for species identification, but they are rarely recovered
Oropharyngeal and Sinus Infections

from blood culture.1,2 Agents of mucormycosis such as Rhizopus species grow

well on standard blood agar and Sabouraud dextrose agar. They tend to grow
more rapidly on culture media than Aspergillus species, and structures such as
sporangia, columellae, and rhizoids allow for their differentiation.2
Management
Due to its rapidly progressive nature in immunocompromised hosts, rhinoc-
erebral mucormycosis represents a surgical and medical emergency. The
importance of surgical debridement in upper airway disease is especially critical
due to the anatomic proximity of the brain and the angioinvasive nature of
the mold.1 The primary antifungal medication used in conjunction with sur-
gical debridement is amphotericin (deoxycholate and lipid preparations).3,5
CHAPTER 5

Lipid formulations of amphotericin are less likely to cause nephrotoxicity than

nonlipid formulations, an attribute that is especially important in treating dia-
betic patients who may have underlying renal dysfunction.1 While voriconazole
has excellent activity against Aspergillus species, it lacks activity against the
agents of mucormycosis. Therefore, rapid differentiation between Aspergillus
and the agents of mucormycosis in pathologic tissues is essential in patients
being treated empirically with voriconazole. With increasing use of voricon-
azole and echinocandins as routine prophylactic or presumptive therapy
of neutropenic fever, the incidence of mucormycosis has increased in some
126

cancer centers.3

References
1. Kontoyiannis, D. Lewis, R. Agents of mucormycosis and entomophthoramycosis.
In Mandell GL, Bennett JE, Dolin R. eds Principles and Practice of Infectious Diseases,
7th ed. 2009:3257–3269.
2. Ribes JA , Vanover-Sams CL, Baker DJ. Zygomycetes in human disease.
Clin Microbiol Rev. 2000 Apr;13(2):236–301.
3. Perfect JR. Treatment of non-Aspergillus moulds in immunocompromised patients,
with amphotericin B lipid complex. Clin Infect Dis. 2005;40(Suppl 6):S401–408.
4. Gartenberg G, Bottone EJ, Keusch GT, et al: Hospital-acquired mucormyco-
sis (Rhizopus rhizopodiformis) of skin and subcutaneous tissue: epidemiology,
mycology and treatment. N Engl J Med. 1978;299:1115–1118.
 Chapter 6

Pulmonary Infections in
Immunocompetent Hosts

Case
C a e 6a:
6a: A 227
27-Year-Old
7-Y
Year-OOld Woman
W with
wit
ith
h a FFever,
ever,
r Cou
C
Cough,
gh,
gh
h
and
an d Pleuritic
Pleuritic Ches
estt P
Chest ain
Painn

Jennifer Jao and Daniel Caplivski

Case Presentation
A 27-year-old woman with a history of scoliosis was admitted to the hospital

127
with fever, worsening dyspnea, and nonproductive cough. Her initial symp-
toms began 4 days prior to admission with fever (eventually as high as 105º
Fahrenheit), dry cough, left-sided pleuritic chest pain, and worsening dyspnea.
In addition, she noted myalgias, headache, and diarrhea. She had been evaluated
at a local pharmacy 2 days prior, where she had a negative rapid influenza test
and had been told she most likely had a viral upper respiratory infection.
In the emergency department, she was in respiratory distress and spoke in
short sentences. She was initially afebrile but tachycardic (pulse 144 beats per
minute), extremely tachypneic (respiratory rate 37–54 breaths per minute), and
hypoxic (oxygen saturation 84% on ambient air). The lowest blood pressure
recorded was 114/65, and markedly decreased breath sounds were noted on
auscultation of the left hemithorax. Her respiratory status rapidly declined, and
she required endotracheal intubation and mechanical ventilatory support.
Her laboratory values were significant for leukocytosis (white blood cell
count 22,700 per cubic milliliter) with a predominance of immature neutrophils
(45% bands, 53% segmented neutrophils). Chest radiography revealed exten-
sive bilateral infiltrates much worse on the left than the right (Figure 6a.1).
Computed tomography of the lungs confirmed the extensive bilateral infiltrates
with air bronchograms (Figure 6a.2).
Blood cultures became positive after 13 hours of incubation. The Gram
stain from the aerobic bottle revealed Gram-positive cocci in pairs and chains
(Figure 6a.3). The Gram stain of anaerobic bottle was reported as Gram-
positive cocci in pairs and Gram-negative rods (Figure 6a.4).
The patient was treated with ceftriaxone and azithromycin, as well as with
metronidazole, given the apparent polymicrobial bacteremia with Gram-positive
Pulmonary Infections in Immunocompetent Hosts
CHAPTER 6

Figure 6a.1 Chest radiography revealed extensive bilateral infiltrates much worse on
the left than the right.
128

Figure 6a.2 CT lungs with dense bilateral consolidations with air bronchograms.

cocci and anaerobic Gram negative-bacilli. A pleural fluid sample revealed tur-
bid fluid with 10,430 white blood cells per microliter (52% polymorphonuclear
cells, 32% macrophages), 3200 red blood cells, pH 7.7, lactate dehydrogenase
2549, and protein < 2gm/dl. A chest tube was placed both for the empyema
and for the pneumothorax that resulted from the thoracentesis. Cultures of the
pleural fluid remained sterile.
 Pulmonary Infections in Immunocompetent Hosts
Figure 6a.3 Blood culture Gram stain from the aerobic bottle revealed Gram-positive
cocci in pairs and chains.

129 CHAPTER 6

Figure 6a.4 Blood culture Gram stain of anaerobic bottle was reported as Gram posi-
tive cocci in pairs and Gram-negative bacilli. The elongated Gram-negative appearance of
the organism was an artefact likely caused by autolysis.

Eventually, the only organism identified from the blood cultures was pen-
icillin-susceptible Streptococcus pneumoniae (minimal inhibitory concentration
< 0.03 micrograms/ml) (Figure 6a.5). The gram negative appearance of the
organisms was an artefact most likely caused by pneumococcal autolysis. The
patient was soon extubated and eventually discharged from the hospital with
a full recovery after a total of 4 weeks of anti-pneumococcal antibiotics (cef-
triaxone and then amoxicillin). She was subsequently evaluated for possible
immunodeficiency, given the severity of her illness, but none was found.
Pulmonary Infections in Immunocompetent Hosts

Figure 6a.5 Blood agar plate showing alpha hemolytic colonies of Streptococcus
pneumoniae.
CHAPTER 6

Case 6a Discussion: Streptococcus pneumoniae

Diagnosis and Clinical Features
Streptococcus pneumoniae, or pneumococcus, is the leading cause of commu-
130

nity-acquired pneumonia (CAP) worldwide. The overall rate of CAP ranges

from 8–15 per 1000 persons per year. In the United States, common serotypes
associated with invasive disease include 4, 6B, 19, 18C, 23 and 9V as well as 3.
Clinical features of pneumococcal pneumonia include acute fever, chills, pro-
ductive cough, dyspnea, and leukocytosis with predominance of neutrophils.
Definitive diagnosis is sometimes difficult, as the organism is only isolated in
blood culture in 5%–18% of cases.1 Attempts to culture blood, sputum, deep
tracheal aspirates, and pleural fluid—particularly in the case of a parapneu-
monic effusion or empyema—should be made. Once Streptococcus pneumoniae
is identified by culture, it can be separated from other streptococcal species
by its pattern of hemolysis, its sensitivity to optochin, and its lysis by bile salts.2
Gram staining of the organism usually reveals Gram-positive lancet-shaped
diplococci; however, autolysis may cause the organism to appear elongated and
Gram-negative, as in the above case.2 The initial finding of “polymicrobial” bac-
teremia prompted concern for the possibility of aspiration pneumonia or acute
respiratory distress syndrome (ARDS) in response to a perforated esophagus.
Other, more rapid tests for the identification of pneumococcus include the
detection of pneumococcal antigen, particularly in urine and CSF, as well as
real-time polymerase chain reaction (PCR) to detect pneumolysin and hemo-
lysin. The sensitivity of the urine pneumococcal antigen has been reported
to be about 80% with a specificity close to 98%; however, other studies have
shown healthy asymptomatic carriers of pneumococcus to be positive with the
urine antigen as well, raising issues of its overall utility in clinical practice.3,4
The pneumonia severity index (PSI) is one of the most widely used and
validated scoring systems for predicting mortality risk and aiding clinicians in the
decision to admit a patient with CAP. Because it is composed of 20 variables,

Pulmonary Infections in Immunocompetent Hosts

it may be cumbersome as a practical clinical tool. As a result, other, simpler
scoring systems have been developed, such as the CURB-65 and the severity
community-acquired pneumonia (SCAP) score. The former is calculated based
on 5 variables, and the latter on 2 major and 6 minor criteria.5–7
Treatment and Prevention
Because of emerging penicillin resistance in pneumococcal isolates worldwide,
empiric treatment for CAP consists of a third-generation cephalosporin such as
ceftriaxone, plus a macrolide antibiotic. Patients with pneumococcal pneumo-
nia susceptible to penicillin may be treated with penicillin, once susceptibility
is confirmed. Those with high level penicillin resistance may be treated with a
third-generation cephalosporin (if susceptible), or with vancomycin, and should
be treated at least 5 days beyond clinical resolution.8
Three vaccines currently exist for the prevention of S. pneumoniae: two
conjugate vaccines and one unconjugated polysaccharide vaccine. The hep-
tavalent pneumococcal conjugate vaccine (PCV-7), which contains the 7
capsular polysaccharides most commonly involved in pediatric infections is

CHAPTER 6
being superseded by the 13-valent conjugate vaccine (PCV-13), which con-
tains protection against an additional 6 strains. The 23-valent pneumococ-
cal polysaccharide vaccine is used in adults and older children with specific
conditions that increase their risk of invasive pneumococcal disease. The

131
conjugate vaccines (PCV-7 and PCV-13) induce a mucosal immune response
in immunized individuals which results in eradication of colonizing pneumo-
cocci of the vaccine serotypes.8–10

References
1. Pesola G, Charles A. Pneumococcal bacteremia with pneumonia: mortality in
AIDS. Chest. 1992;101(1):150–155.
2. Mahon, Connie. Textbook of Diagnostic Microbiology, 3rd edition. St. Louis: Saunders,
Elsevier; 2007:393–404.
3. Dominguez, J, Gali, N, Blanco, S, et al: Detection of Streptococcus pneumo-
niae antigen by a rapid immunochromatographic assay in urine samples. Chest.
2001;119:243–249.
4. Hamer, DH, Egas, J, Estrella, B, et al: Assessment of the Binax NOW Streptococcus
pneumoniae urinary antigen test in children with nasopharyngeal pneumococcal
carriage. Clin Infect. Dis. 2002;34:1025–1028.
5. Fine, MJ, Auble, TE, Yealy, DM et al. A prediction rule to identify low-risk patients
with community-acquired pneumonia. N Engl J Med. 1997;336:243.
6. Lim WS, van der Eerden MM, Laing R, et al. Defining community acquired pneu-
monia severity on presentation to the hospital: an international derivation and
validation study.” Thorax. 2003;58:377.
7. Espana, PP, Capelastegui, A, Gorordo, I, et al. Development and validation of a
clinical prediction rule for severe community-acquired pneumonia. Am J Respir
Crit Care Med. 2006;174:1249.
8. Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Disease Society of
America/American Thoracic Society consensus guidelines on the management
of community acquired pneumonia in adults. Clin Infect Dis. 2007;44(Suppl 2):
S27–S72.
 9. Pletz M, Maus U, Krug N, et al. Pneumococcal vaccines: mechanism of action,
Pulmonary Infections in Immunocompetent Hosts

impact on epidemiology and adaption of the species.” Int J Antimicrob Ag.

2008;32:199–206.
10. Nuorti JP, Whitney CG; Centers for Disease Control and Prevention (CDC).
Prevention of pneumococcal disease among infants and children—use
of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococ-
cal polysaccharide vaccine—recommendations of the Advisory Committee
on Immunization Practices (ACIP). MMWR Recomm Rep. 2010 Dec 10;
59(RR-11):1–18.

Case
C a e 66b:
b: A 331
b: 31-Year-Old
1-Y
Year-OOld M
Man wit
with
ith
h Sk
Ski
Skin
in Lesio
LLesions
ions
n
Foll
Fo llow
owing a Resp
Following pir
irat
atory Illness
Respiratory

Mahesh Swaminathan
Case Presentation
A 31-year-old man with a past history of genital herpes presented with pain-
CHAPTER 6

ful oral ulcers and vesicles on his lips, extremities, and genitals. He had taken
valacyclovir when he first noted the genital lesions, but in the past he had never
had oral lesions. Two weeks prior to presentation he had experienced fevers,
night sweats, and cough productive of bloody sputum that had resolved after
132

taking azithromycin for 5 days.

On physical examination he appeared uncomfortable but in no acute distress.
He was febrile to 100.3°F. and had numerous vesicles on the lips, extremities,
and genitalia (Figures 6b.1 and 6b.2). His conjunctivae had no abnormalities, but
there were ulcerated lesions on his hard palate. Other than the dermatologic
and mucosal findings, the rest of his physical examination was unremark-
able. Chest radiography revealed prominent hila, but no focal consolidations
(Figure 6b.3). Scraping of the ulcers and unroofed vesicles were negative for
HSV, and VZV antigens were negative by direct fluorescent antibody and viral

Figure 6b.1 Vesicular lesions on the lips.

 Pulmonary Infections in Immunocompetent Hosts
Figure 6b.2 Vesicular lesions on the lower extremities.

133 CHAPTER 6

Figure 6b.3 Chest radiograph, anterior-posterior view with prominent hila but no focal
consolidations.

culture. A skin biopsy revealed necrotic keratinocytes at all levels of the dermis,
as well as a perivascular mononuclear infiltrate, confirming the diagnosis of ery-
thema multiforme major. The patient’s Mycoplasma pneumoniae IgM and IgG
(282 units) were both positive. Because of the severity of the mucosal involve-
ment, the patient was treated with oral prednisone, and the lesions resolved
after 10 days.
 Case 6b Discussion: Mycoplasma pneumoniae
Pulmonary Infections in Immunocompetent Hosts

Microbiology and Epidemiology

M. pneumoniae is a small (about 10 x 200 nm) prokaryote, with an organelle
at one end containing major adhesion proteins that allow attachment to cell
membranes and give the organism an affinity for respiratory epithelium. It lacks
a cell wall, instead possessing a sterol-containing outer trilaminar membrane.
The lack of a peptidoglycan cell wall makes the organism invisible on Gram stain
and inherently resistant to beta-lactam antibiotics. M. pneumoniae is a fastidious
organism that reproduces by binary fission with a doubling time of more than
six hours.1
M. pneumoniae is an extracellular parasite that initiates infection by attaching
to ciliated respiratory epithelium with the aforementioned terminal organelle.
Upon infection, ciliary action ceases and is followed by loss of cilia and desqua-
mation of the effected epithelial cells—a likely cause of the intractable cough
that is a frequent symptom of the disease. Hydrogen peroxide, which is elabo-
rated by the organism, may cause in vivo cellular damage, and is the cause of the
hemolysis exhibited by colonies growing on blood agar plates.2 M. pneumoniae
CHAPTER 6

actively stimulates the immune system, resulting in the production of numerous

proinflammatory and anti-inflammatory cytokines. It also cause the production
of numerous antibodies, some of which appear to have some neutralizing abil-
ity, but others appearing to be autoantibodies, with the best studied being the
134

cold agglutinins.3
M. pneumoniae is spread by respiratory droplets produced by coughing; typi-
cally close contact with the index is required for transmission. Infection usually
occurs singly or as family outbreaks (the index case frequently being a child),
though mini-epidemics can occur in closed populations (e.g., military barracks,
boarding schools).4 The annual incidence of mycoplasma pneumonia in the
United States is estimated to be one case per 1000 persons (approximately 2
million cases annually), though the incidence of non-pneumonic Mycoplasma
respiratory disease is thought to be much higher.5 Disease can occur at any
age, but the highest attack rates occur in those between the ages of 5 and 20.
M. pneumoniae has a worldwide distribution, and most studies do not show
a seasonal pattern to infection, though many outbreaks tend to occur during
the fall months when other causes of community-acquired pneumonia are less
common.3
Clinical Features
Most episodes of infection affect the upper respiratory tract and result in
clinically apparent disease. The incubation period is between 2 and 3 weeks,
and is followed by the insidious onset of fever, malaise, headache, and cough
(Figure 6b.4). The cough, which is usually nonproductive but can be associ-
ated with white or blood-flecked sputum, tends to increase in intensity and
frequency over the course of 1–2 weeks and can become debilitating. The
disease may progress to tracheobronchitis or pneumonia in a small percent-
age of patients, in which case the cough can become more severe and associ-
ated with chest pain or soreness from muscle strain; true pleuritic chest pain is
 Pulmonary Infections in Immunocompetent Hosts
Headache
and malaise
104
Temp. 102 With proper
100 RX

Cough
Chest
soreness
Chest
radiograph
Cold Rapid Test +
agglutinins 1:8 1:32 1:64 1:256 1:16
+ + + + + ±
Culture Remains even
with proper RX
ELISA and
complement – ± + + + +
fixation tests
5 10 15 20 25 40
Days of Illness

CHAPTER 6
Figure 6b.4 Major clinical and laboratory manifestations of mycoplasmal pneumonia.
ELISA, enzyme-linked immunosorbent assay. This figure was published in Baum SG.
Mycoplasma pneumoniae and Atypical Pneumonia. In: Mandell GL, Bennett JE, Dolin R
eds. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, 7th ed.

135
p.2481–2489. Copyright Elsevier 2009.

uncommon. Fever can be present, but shaking chills or rigors are uncommon.
In contrast to viruses that can cause an atypical pneumonia, such as influenza or
adenoviruses, infection with M. pneumoniae is rarely associated with gastroin-
testinal complaints or myalgias.3
On physical examination, pharyngeal erythema may be present but is usually
not associated with extensive cervical lymphadenopathy, as is frequently the
case with Group A streptococcal pharyngitis.3 Bullous myringitis is occasionally
seen, but can be associated with viral infections as well; its presence or absence
is not sufficient to establish or exclude infection.3 Chest examination is fre-
quently unrevealing, and rarely will patients have significant rales or percussive
findings, although wheezing can occur. Patients’ radiographic findings are gen-
erally more impressive than the patient’s appearance or objective findings on
physical exam; hence the term, “walking pneumonia.”
Infection with M. pneumoniae tends to be mild and self-limited, though
severe manifestations and even death have been reported in patients with
sickle cell disease or other sickle cell related hemaglobinopathies. The effect
of other types of immune deficiencies, in particular, HIV infection, on disease
severity is unclear. Extrapulmonary findings in a wide variety of organ system
have been reported, including cardiac (congestive heart failure, conduction
abnormalities, arrhythmias), musculoskeletal (polyarthralgias), and neurologic
(encephalitis, meningoencephalitis, aseptic meningitis, Guillain-Barré syndrome)
 manifestations. Dermatologic manifestations, however, are the most common
Pulmonary Infections in Immunocompetent Hosts

extrapulmonary site of disease.

Erythema multiforme (EM) or Steven-Johnson syndrome occurs in approxi-
mately 7% of cases with the majority of cases occurring in young males. The
classic appearance of EM lesions are erythematous circular lesions with central
clearing (target lesions) distributed mainly on the extremities. Severe mucosal
inflammation occurs with erythema multiforme major. The underlying patho-
genesis of EM is poorly understood, but may be secondary to deposition of
immune complexes in the superficial microvasculature of the skin. Management
of erythema multiforme major with corticosteroids has been advocated, though
evidence for this approach from controlled trials is lacking and most cases are
self-limited.5

Diagnosis
While isolation of M. pneumoniae is the gold standard for diagnosis, culturing
the organism is an intricate and lengthy process requiring specialized media,
and is rarely performed in most hospital and commercial laboratories. Instead,
a diagnosis is usually made based on clinical features and serological tests. The
CHAPTER 6

cold agglutinin assay, once the mainstay of diagnosis, is neither sensitive nor
specific and should not be used except as an adjunct to clinical judgment and
other tests. A chest radiograph may reveal extensive pulmonary infiltrates that
are out of proportion to objective physical findings and the patient’s reported
136

symptoms, though in practice, patients will often have a normal radiograph.

The most frequently used tests are enzyme-linked immunoassays for M. pneu-
moniae specific IgM and IgG, with IgM being the most useful in detecting acute
infection.1 These assays are both sensitive and specific, but are frequently neg-
ative early in the course of infection and thus are not always useful in guiding
initial therapy (see Figure 6b.4). Ideally, acute and convalescent titers collected
2–3 weeks apart should be compared, with a fourfold increase in titers indica-
tive of infection. Polymerase-chain reaction (PCR) assays have been shown to
be both sensitive and specific, but are not widely available because of a lack of
standardization of both the probe and the assay.1

Treatment
Infection with M. pneumoniae is generally self-limited though treatment can
shorten the duration and severity of symptoms. Macrolides, tetracyclines and
respiratory flouroquinolones (e.g. levofloxacin and moxifloxacin) are effective
against this intracellular pathogen, but cell wall acting agents (such as beta-
lactam antibiotics) are ineffective since it lacks a cell wall. The macrolides, tet-
racycline and flouroquinolones are all effective against other bacterial causes
of atypical pneumonia (e.g. Legionella spp., Chlamydia pneumoniae).2

References
1. Baum SG. Mycoplasma pneumoniae and atypical pneumonia. In Mandell GL,
Bennett JE, Dolin R eds. Mandell, Douglas, and Bennett’s Principles and Practice of
Infectious Diseases. 7th ed. Philadelphia, PA: Churchill, Livingston, Elsevier; 2009:
2481–2489.
2. Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Disease Society of

Pulmonary Infections in Immunocompetent Hosts

America/American Thoracic Society Consensus guidelines on the management
of community acquired pneumonia in adults. Clin Infect Dis. 2007;44 (Suppl 2):
S27–S72.
3. Clyde, WA Jr. Clinical Overview of typical Mycoplasma pneumoniae infections.
Clin Infect Dis. 1993;17(Suppl 1): S32–S36.
4. Waits KB, Talkington DF. Mycoplasma pneumoniae and its role as a pathogen. Clin
Microbiol Rev. 2004;17(4):697–728.
5. Rasmussen JE. Erythema multiforme in children. Response to treatment with
systemic corticosteroids. Br J Dermatol. 1976;95(2):181–186.

Ca e 6c:
Case 6c: Per
P
Persistent
siistent
t t Cough
Co h iin
naW
Woman
an from
f mM Mexico
exico
i o

Mahesh Swaminathan
Case Presentation

CHAPTER 6
A 29-year-old woman from Mexico presented to the emergency department
on three occasions for persistent cough for several weeks. She was discharged
on the first two visits with a diagnosis of atypical pneumonia, and treated ini-
tially with azithromycin. On the third visit, a Spanish interpreter better eluci-

137
dated her symptoms, which included drenching night sweats, weight loss (13
pounds), and hemoptysis. The hemoptysis had initially been small amounts, but
on the previous day she had been coughing much greater volumes of bright
red blood and clots (Figure 6c.1). She had been living in the United States for
12 years, and 5 years prior to admission her husband had been treated for
pulmonary tuberculosis.
On physical examination, she was afebrile, with an oxygen saturation
of 97% on ambient air, and crackles were present in the right upper lobe.
A complete blood count revealed anemia (hemoglobin of 12.1 mg/dl) but
normal white blood cell (10.1 x10³ cells/μl) and platelet counts (356x10³
cells/μl). Chest radiography revealed a right upper lobe infiltrate, and CT
scan confirmed the presence of several upper lobe cavities as well as miliary
nodules and hilar lymphadenopathy (Figures 6c.2, 6c.3, and 6c.4). The first
four sputum samples were negative for acid-fast bacilli, but a fifth speci-
men showed several organisms with a typical beaded, clumped appearance
(Figure 6c.5).
Treatment with rifampin, isoniazid, pyrazinamide, and ethambutol was initi-
ated, but the patient had an episode of massive hemoptysis and was intubated
with a bifurcated endotracheal tube. The patient underwent embolization of
a bronchial artery that was in direct communication with the largest cavity in
the right upper lobe. The next day the endotracheal tube was removed, and
smears of her sputum samples became negative for acid fast bacilli. Ten days
later, sputum cultures collected on the day of admission grew Mycobacterium
tuberculosis complex that was susceptible to all four medications. The patient
Pulmonary Infections in Immunocompetent Hosts

Figure 6c.1 Massive hemoptysis.

138 CHAPTER 6

Figure 6c.2 Posterior-anterior chest radiograph showing right upper lobe cavity and
increased interstitial markings.
 Pulmonary Infections in Immunocompetent Hosts
Figure 6c.3 CT chest, axial view with multiple cavities and small nodules in the right

CHAPTER 6
upper lobe.

139

Figure 6c.4 CT chest, axial view with diffuse miliary nodules throughout the right
hemithorax.
Pulmonary Infections in Immunocompetent Hosts

Figure 6c.5 Acid-fast stain of sputum sample showing clumps of beaded acid-fast bacilli.
CHAPTER 6

was discharged with plans for a 6-month course of anti-TB medications under
directly observed therapy (DOT).
140

Case 6c Discussion: Mycobacterium tuberculosis

Microbiology and Epidemiology
The Mycobacterium tuberculosis complex comprises seven species in the genus
Mycobacterium, family Mycobacteriaceae, and order Actinomycetales, which
are causes of human tuberculosis and zoonotic disease, with M. tuberculosis
causing the vast majority of human infections. Mycobacterium bovis, a cause of
disease in cattle, can be transmitted to humans via close contact with infected
livestock or ingestion of unpasteurized dairy products; human-to-human trans-
mission has been reported as well. Mycobacterium africanum and Mycobacterium
canetti are both rare etiologies of tuberculosis in Africa. Mycobacterium caprae,
Mycobacterium microti, and Mycobacterium pinnipedii—pathogens of cattle,
rodents, and seals, respectively—have been reported to cause zoonotic tuber-
culosis (TB) in humans.1
TB is typically spread by aerosolized droplets containing tubercle bacilli,
expectorated by patients with active pulmonary TB; rarely, primary inoculation
occurs in non-pulmonary sites, such as abraded skin, the intestine, the orophar-
ynx, or the genitalia (see Figure 6c.6). These droplets are inhaled by susceptible
individuals into the terminal alveoli, where an initial focus is formed and mul-
tiplication begins. The initial focus is frequently subpleural, and located in the
midlung zone where airflow is greatest. Bacilli are subsequently carried by
infected macrophages via the lymphatic system to regional lymph nodes
or (particularly in non-immune persons) are transmitted hematogenously
throughout the body. Certain sites, including the lymph nodes, kidneys,
epiphyses of the long bones, vertebral bodies, juxtaependymal meningeal
 Pulmonary Infections in Immunocompetent Hosts
Transmission Primary Latent “Reactivation”
tuberculosis tuberculosis tuberculosis
Progression
after 2 years,
5%

Skin test Spontaneous Progression

conversion in healing in within 2
6 to 8 weeks 6 months years, 5%

Progression with
concurrent HIV infection,
10% each year

CHAPTER 6
Figure 6c.6 Tuberculosis natural history and transmission. Reprinted with permission
from Small PM, Fujiwara PI. Management of tuberculosis in the United States.
New England Journal of Medicine 2001;345(3):192–200.

141
areas adjacent to the subarachnoid space, and (most importantly) the apical-
posterior areas of the lungs, favor bacillary multiplications; these sites can
serve as a nidus of progressive infection, either immediately or after a variable
period of latency.1,2
In approximately 90% of hosts with intact cell-mediated immunity (antibod-
ies are produced in response to infection but appear to play little role in the
host defenses) the primary infection is controlled and latent infection is estab-
lished, the clinical hallmark of which is a positive tuberculin skin test. Infection
can reactivate months or years later (secondary or reactivated TB), manifest-
ing in the areas of the body where latent infection has been established (see
above)—most frequently, the apices of the lungs—and is most likely in the
year following primary infection. Reactivation can occur spontaneously or as
a result of weakening in the cell-mediated immunity of the host, associated
with certain risk factors (Table 6c.1). In immunocompetent patients with latent
TB, 5% will experience secondary tuberculosis within 2 years of primary infec-
tion and an additional 5% will have active disease at some later point in their
lives. In patients with HIV infection, the rate of reactivated TB in those with
latent infection is 10% per year; hence, tuberculosis is a major cause of mor-
bidity and mortality in HIV infected patients from TB-endemic areas.2 In the
10% of hosts who are unable to control the initial primary infection, replication
continues, resulting in disseminated (miliary TB), extrapulmonary, or primary
progressive disease. Those with deficits in cell-mediated immunity, particularly
Pulmonary Infections in Immunocompetent Hosts

Table 6c1 Immunosuppressive conditions associated with

reactivation of tuberculosis. While not an exhaustive list, these
are the most frequent risk factors likely to be encountered by
clinicians in practice
Diabetes Mellitus
End Stage Renal Disease
Old Age
Immunosuppressive Drugs: (Particularly Corticosteroids, TNF alpha inhibitors)
Malignant Lymphoma
HIV Infection/AIDS

persons infected with HIV, are frequently unable to control the initial primary
infection and will often present with primary progressive, extra-pulmonary or
disseminated disease.1
A total of 12,898 cases of TB were reported in the United States in 2008.
This represents a decline of 3.8% from 2007 to 4.2 cases per 100,000 population,
CHAPTER 6

the lowest rate recorded since national reporting began in 1953 (Figure 6c.7).
A majority of cases were among foreign-born persons: among persons whose
country of origin was known, approximately 95% of Asians, 76% of Hispanics,
32% of blacks, and 18% of whites were foreign born. In the U.S.-born, the great-
142

est racial/ethnic disparity was in blacks, who had a rate seven times that of U.S.-
born whites.3 Worldwide, 9.27 million new cases of TB occurred in 2007 with
an incidence of 139 per 100,000 persons.4
Clinical Features
Given its tendency to cause disease in virtually any organ system, TB infec-
tion frequently has a protean presentation, particularly in extra-pulmonary TB,
where symptoms are often related to the organ system affected (see Chapters
1, 8, and 12). The signs and symptoms of TB are frequently subtle and nonspe-
cific; a high level of clinical suspicion based on knowledge of risk factors and
local epidemiology is necessary to diagnose this disease.
Pulmonary TB, particularly secondary TB, presents insidiously. Fever, often
accompanied by night sweats, weight loss, and fatigue, are the most common
symptoms; in many cases, constitutional complaints are the sole presenting
symptoms. Cough is more frequent in secondary TB compared to primary TB,
and is often mild and nonproductive initially, but as the disease progresses the
cough can become more severe and productive of mucus, particularly in the
morning when secretions are at their greatest. Hemoptysis can manifest later
in the course of the disease, and is usually a result of endobronchial disease or
cavitation/necrosis; hemoptysis is not necessarily indicative of active disease,
and its presence or absence is not particularly helpful in the diagnosis of pul-
monary TB. Life-threatening hemoptysis may occur when cavities communicate
with bronchial or pulmonary arteries (Rasmussen’s aneurysm), and may require
embolization or surgical resection in severe cases. Dyspnea may also be present
when there is extensive lung involvement, pleural effusion, or pneumothorax.
 Pulmonary Infections in Immunocompetent Hosts
22 45
20 No. of TB cases among U.S.-born persons
No. of TB cases among foreign-born persons 40
18
Number (in thousands)

TB rate among foreign-born persons 35

16 TB rate among U.S.-born persons
30
14
12 25

Rate
10 20
8 15
6
10
4
2 5
0 0
1993 1995 1997 1999 2001 2003 2005 2007
Year
*Per 100,000 population.

Figure 6c.7 Tuberculosis epidemiology. Source: Centers for Disease Control and
Prevention. Trends in Tuberculosis – United States 2008. MMWR 2009;58:252.

CHAPTER 6
Pleuritic chest pain is uncommon, but when present may indicate pleural or
pericardial involvement.
Physical findings are subtle and frequently absent unless the patient presents

143
with advanced or severe disease. Amphora or absent breath sounds may be
heard over areas of cavitation. Rales may be present through inspiration or
after a cough (post-tussive rales). Dullness to percussion or decreased tac-
tile fremitus are present in cases of pleural thickening or effusion.1 Persons
with HIV frequently have atypical or more acute presentations of TB than non-
HIV-infected patients; the diagnosis of TB should be considered in any patient
infected with HIV who presents with pulmonary complaints.
Diagnosis
The diagnosis of TB is primarily based on isolating the organism whenever pos-
sible. Not only does this confirm the diagnosis, but it also allows for drug-
susceptibility testing—an important issue in an era of rising drug resistance. In
cases of suspected extrapulmonary tuberculosis, isolation of the organism from
otherwise sterile sites or tissue samples is critical, given the often nonspecific
signs and symptoms of extrapulmonary TB and the broad differential diagnosis.
Invasive procedures to collect adequate tissue specimens may be necessary in
these cases.
Staining for acid-fast bacilli (AFB) on expectorated sputum is the initial diag-
nostic test for pulmonary TB. A minimum of three sputum samples should be
collected, with at least one collected in the early morning when the yield is
highest. Patients who cannot provide sputum should undergo sputum induc-
tion. A positive smear provides strong support for the diagnosis of TB, but
should be confirmed via cultures or nucleic acid amplification assays (NAAT).
Bronchoscopy is not recommended unless other methods for acquiring spu-
tum are ineffective, sputum testing is inconclusive, or another diagnosis is being
 entertained. In most studies, bronchoscopy does not appear to have diagnostic
Pulmonary Infections in Immunocompetent Hosts

superiority when compared to sputum induction, and carries a higher risk of

nosocomial transmission to healthcare workers.1
Sputum smears may be negative in patients with active pulmonary TB, par-
ticularly in patients with HIV or those without cavitary disease. In these cases,
sputum culture is sensitive and specific, underscoring the importance of col-
lecting samples for culture in all patients suspected of having TB. All patients
suspected of having TB should undergo HIV testing as soon as the diagnosis is
entertained.
Treatment
The treatment of TB benefits the patient by curing a life-threatening disease,
and the community benefits by preventing the transmission of a contagious,
deadly infection. As such, physicians take on a public health role which carries
the responsibility of appropriately prescribing an effective antimicrobial regi-
men and ensuring patient adherence to treatment. Management of TB should
be performed in conjunction with local departments of health under DOT.
An adherence plan, based on an assessment of medical, social, and economic
CHAPTER 6

barriers to adherence, should be implemented at the same time treatment is

started.
While there are clear guidelines on the treatment of drug-susceptible TB, cli-
nicians with little experience in the management of TB should consider referring
144

these patients to more knowledgeable practitioners. There are serious public

health implications if treatment fails, or drug-resistant isolates are selected for
by incorrectly prescribed regimens or patient nonadherence. The management
of drug-resistant TB is beyond the scope of this discussion, and should only
be performed with the help of experts with firsthand experience in the man-
agement of drug-resistant tuberculosis. Treatment should be initiated when
the diagnosis of tuberculosis is confirmed microbiologically in patients who are
smear negative, but where there is a strong clinical suspicion for TB and no
other likely diagnosis, or in patients who are severely immunosuppressed and
the diagnosis of TB is seriously considered.
The medications of choice for the treatment of TB are isoniazid, rifampin,
pyrazinamide, and ethambutol. In most cases, initial treatment requires use of
all four drugs for at least 2 months (intensive phase) followed by 4 months
of treatment with rifampin and isoniazid (Table 6c.2). Ethambutol can be dis-
continued before the end of the intensive phase if susceptibility to all first-line
drugs is confirmed. Streptomycin, an injectable drug that has been shown to be
highly efficacious, is currently not recommended as initial treatment because of
increasing global resistance to this drug, but it can be used in patients intolerant
of ethambutol with documented streptomycin-susceptible isolates. Rifapentine,
a long-acting rifamycin which can be given once weekly, can be used in lieu
of rifampin during the continuation phase in HIV-negative patients with non-
cavitary disease and negative AFB sputum smears after 2 months of treatment.
Data is lacking supporting the use of rifapentine during the intensive phase or
in patients with cavitary disease, and it should not be used for these purposes.
Rifapentine is contraindicated in persons infected with HIV.1
Table 6c.2 Treatment of Pulmonary Tuberculosis
Initial phase Continuation phase Rating* (evidence)‡
Regimen Drugs Interval and doses‡ Regimen Drugs Interval and doses § Range of total doses HIV– HIV+
(minimal duration) (minimal duration) (minimal duration)
1 INH Seven days per week for 56 1a INF/RIF Seven days per week for 126 182–130 (26 wk) A (I) A (II)
RIF doses (8 wk) or 5 d/wk for 40 1b INH/RIF doses (18 wk) or 5 d/wk for 92–76 (26 wk) A (I) A (II)#
doses (8 wk)¶ 90 doses (18 wk)¶
PZA 1c** INH/RPT 74–58 (26 wk) B (I) E (I)
Twice weekly for 36 doses
EMB
(18 wk)
Once weekly for 18 doses
(18 wk)
2 INH Seven days per week for 2a INH/RIF Twice weekly for 36 doses 62–58 (26 wk) A (II) B (II)#
RIF 14 doses (2 wk), then twice 2b** INH/RPT (18 wk) 44–40 (26 wk) B (I) E (I)
weekly for 12 doses (6 wk) or Once weekly for 18 doses
PZA
5 d/wk for 10 doses (2 wk),¶ (18 wk)
EMB then twice weekly for 12 doses
(6 wk)
3 INH Three times weekly for 24 3a INH/RIF Three times weekly for 54 78 (26 wk) B (I) B (II)
RIF doses (8 wk) doses (18 wk)
PZA
EMB
4 INH Seven days per week for 56 4a INH/RIF Seven days per week for 217 273–195 (39 wk) C (I) C (II)
RIF doses (8 wk) or 5 d/wk for 40 4b INH/RIF doses (31 wk) or 5 d/wk for 118–102 (39 wk) C (I) C (II)
doses (8 wk)¶ 155 doses (31 wk)¶
EMB
Twice weekly for 62 doses
(31 wk)
(continued)

145 CHAPTER 6 Pulmonary Infections in Immunocompetent Hosts

 146 CHAPTER 6 Pulmonary Infections in Immunocompetent Hosts

Table 6c.2 Continued

Definition of abbreviations: EMB = Ethambutol; INH = isoniazid; PZA = pyrazinamide; RIF = rifampin; RPT = rifapentine.
* Ratings guide:
A – Preferred (should generally be offered). B – Alternative (acceptable to offer). C – Offer when preferred or alternative regimens cannot be given.
D – Should generally not be offered. E – Should never be offered.
Quality of evidence supporting the recommendation:
I – At least one properly randomized trial with clinical end points.
II – Clinical trials that either are not randomized or were conducted in other populations.
III – Expert opinion.
‡
When DOT is used, drugs may be given 5 days/week and the necessary number of doses adjusted accordingly. Although there are no studies that compare five with seven daily doses, extensive
experience indicates this would be in effective practice.
§
Patients with cavitation on initial chest radiograph and positive cultures at completion of 2 months of therapy should receive a 7-month (31 week; either 217 doses [daily] or 62 doses [twice
weekly]) continuation phase.
¶
Five-day-a-week administration is always given by DOT. Rating for 5 day/week regimens is AIII.
#
Not recommended for HIV-infected patients with CD4+ cell counts <100 cells/μl.
** Options 1c and 2b should be used only in HIV-negative patients who have negative sputum smears at the time of completion of 2 months of therapy and who do not have cavitation on initial
chest radiograph (see text). For patients started on this regimen and found to have a positive culture from the 2-month specimen, treatment should be extended an extra 3 months.
Source: Centers for Disease Control and Prevention. Treatment of Tuberculosis, American Thoracic Society, CDC, and Infectious Diseases Society of America. MMWR. June 20,2003; 52(No.
RR11): 1–77.
 The continuation phase, in patients with drug-susceptible disease, should be

Pulmonary Infections in Immunocompetent Hosts

extended to 7 months in three situations: (1) patients with cavitary disease with
a positive sputum culture collected at 2 months of treatment; (2) those who
did not receive pyrazinamide during the intensive phase; and (3) those receiving
once weekly isoniazid and rifapentine during the intensive phase, who have a
positive sputum culture collected at 2 months.
Sputum must be collected at a minimum of once a month until two con-
secutive specimens have negative cultures. Patients should also undergo clinical
examination at least monthly, and questioned carefully for medication-related
adverse events. Baseline laboratory testing of hepatic and renal function and
platelet count should be collected prior to the initiation of treatment; routine
laboratory monitoring of hepatic and renal function or platelet count is unnec-
essary after treatment is initiated, except in those with baseline abnormalities
or risk factors for hepatotoxicity (e.g., viral hepatitis, alcoholism).5 Patients who
are culture-positive after 2 months of therapy should be carefully evaluated for
reasons to explain poor response. Such reasons may include poor adherence,
drug resistance, extensive cavitary disease, laboratory error, or malabsorption

CHAPTER 6
of medications.

References
1. Centers for Disease Control and Prevention. Trends in tuberculosis – United

147
States 2008. MMWR. 2009;58:249–253.
2. World Health Organization. Global tuberculosis control 2009: surveillance, plan-
ning, financing. Geneva, Switzerland: World Health Organization; 2009. Available
at http://www.who.int/tb/publications/global_report/2009/pdf/full_report.pdf.
3. Fitzgerald DW, Sterling TR, Haas DW. Mycobacterium tuberculosis. In: Mandell
GL, Bennett JE, Dolin R eds. Mandell, Douglas, and Bennett’s Principles and Practice
of Infectious Diseases. 7th ed. Philadelphia, PA: Churchill, Livingston, Elsevier;
2009:3129–3163.
4. Small PM, Fujiwara PI. Management of tuberculosis in the United States. New
Engl J Med. 2001;345(3):189–200.
5. Centers for Disease Control and Prevention. Treatment of tuberculosis,
American Thoracic Society, CDC, and Infectious Diseases Society of America.
MMWR. 2003;52(No. RR-11):1–77.

Ca e 6d:
Case 6d:
d: Res
R
Respiratory
pirat
i toryy Di
D
Distress
isttress iin
n 2200
2009
0099

Irini Scordi-Bello and David P. Calfee

Case Presentation
A 47-year-old female with a past medical history of anxiety, depression, and
hypertension, presented to the emergency department in May 2009 with a 6-day
history of malaise, cough, chills, and subjective fever. These symptoms had pro-
gressively worsened over the 3 days prior to presentation, during which there
was also development of pleuritic chest pain and one episode of hemoptysis.
 Her daughter had encouraged her to seek medical attention sooner but she
Pulmonary Infections in Immunocompetent Hosts

had declined. She reported that her grade-school-aged son had been sick with
a sore throat, fever, rhinorrhea, and cough, the week before the onset of her
symptoms.
Within a few hours of presentation to the ED, she developed increasing
dyspnea, hypoxia (oxygen saturation 88% on room air), and hemodynamic
instability (BP 60/45 mm Hg, HR 133 beats per minute) requiring intubation.
On exam, coarse rales were present bilaterally. Notable laboratory findings
included leucopenia (0.8 x 10³ WBC per μl), thrombocytopenia (103 x 10³
platelets per μl), acute kidney injury (creatinine 2.9 mg/dl), and combined meta-
bolic and respiratory acidosis (pH 7.02, pCO2 60 mm Hg, and lactic acid 13.2
mmol/L). Chest radiograph revealed a right upper lobe consolidation with air
bronchograms (Figure 6d.1).
The patient was treated with vancomycin, cefepime, levofloxacin, oseltami-
vir, and vasopressors, and transferred to the ICU. She remained critically ill,
experienced four cardiac arrests, and expired within 36 hours of arrival to the
emergency department. Nasopharyngeal and bronchoalveolar washings were
CHAPTER 6

negative for influenza A and B by rapid test and DFA. Tests for RSV, adenovi-
rus, parainfluenza virus, and Legionella were negative. Subsequently, 2009 H1N1
influenza A virus was detected in the nasopharyngeal wash specimen by real-
time RT-PCR. Bacterial culture of respiratory tract specimens showed moder-
ate growth of Streptococcus pyogenes.
148

Figure 6d.1 Chest radiograph, posterior-anterior view revealed a right upper lobe
consolidation with air bronchograms.
Case 6d Discussion: 2009 H1N1 Influenza

Pulmonary Infections in Immunocompetent Hosts

Epidemiology and Clinical Presentation
Since the first identification of a novel influenza virus causing human infections
in the spring of 2009, the 2009 H1N1 influenza A virus rapidly spread across
the world. On June 11, 2009, less than three months after the first cases were
recognized, the World Health Organization (WHO) increased the pandemic
alert level to 6, indicating that a global pandemic was underway. The pandemic
was classified by WHO as “moderate” in its severity, based on the findings that
most people recovered from infection without the need for hospitalization or
medical care, levels of severe illness appeared similar to levels seen during local
seasonal influenza periods, and hospitals and healthcare systems were generally
able to cope with the numbers of people seeking care.
The Centers for Disease Control and Prevention (CDC) estimate that
between April and November 2009 there were 34–67 million cases of 2009
H1N1 infection in the United States, with approximately 213,000 hospitaliza-
tions and 9,820 deaths (http://www.cdc.gov/h1n1flu/estimates_2009_h1n1.htm).
Unlike seasonal influenza, the great majority of these cases, hospitalizations, and

CHAPTER 6
deaths have occurred among persons younger than 65 years of age. Factors that
have been associated with severe and/or complicated disease include age less
than 2 years or greater than 65 years, pregnancy, and the presence of underly-
ing medical conditions that have previously been associated with a higher risk of

149
influenza complications (e.g., asthma, diabetes, immunosuppression).
The clinical manifestations of 2009 H1N1 influenza A infection are largely
indistinguishable from those of seasonal influenza, with most patients experienc-
ing fever and cough, and many experiencing other typical influenza symptoms
such as malaise, myalgias, and headache. GI symptoms such as nausea, vomiting,
and diarrhea have been reported in approximately 25%–30% of cases, more
common than has typically been reported with seasonal influenza infection.
Causes of mortality associated with 2009 H1N1 influenza include viral pneu-
monia, acute respiratory distress syndrome, multiorgan system failure, and
bacterial superinfection. Concurrent bacterial pulmonary infection has been
identified in 29%–55% of fatal cases.1,2 Identified bacterial pathogens have
included S. pneumoniae, S. aureus (including MRSA), Group A Streptococcus, and
Streptococcus mitis.
Diagnosis
In many cases, specific testing for influenza is not necessary, and the diagnosis
can be made clinically based on a patient’s symptoms and signs. Studies per-
formed in the setting of seasonal influenza have shown that the accuracy of a
clinical diagnosis may equal or surpass that of some laboratory tests in patients
with typical influenza-like illness, when influenza is known to be circulating in
the community.
A number of laboratory tests are available for the detection of influenza
viruses in respiratory tract specimens. These tests include rapid tests, direct
fluorescent antigen (DFA) tests, viral culture, and polymerase chain reaction
(PCR). Most tests can distinguish influenza A viruses from influenza B viruses;
 however, only PCR-based testing is currently able to distinguish among influ-
Pulmonary Infections in Immunocompetent Hosts

enza A viruses. In terms of the performance characteristics of the various test-

ing methods, studies during the first wave of the pandemic demonstrated that
the sensitivity and negative predictive values of rapid tests and DFA tests for
the detection of the 2009 H1N1 virus were relatively low.3,4 Based on these
findings, a negative result should not be considered to rule out a diagnosis of
2009 H1N1 influenza infection. Viral culture and PCR-based testing have been
demonstrated to have much greater sensitivity and negative predictive values.
Pathology
H1N1 influenza virus, similar to all other influenza viruses, targets the ciliated
epithelium of the tracheobronchial tree, producing a spectrum of changes
depending on the stage of the disease and the presence or absence of super-
imposed bacterial pneumonia. Two recent reports from the United States and
Brazil describe in detail the pathologic changes of fatal novel H1N1 influenza
infection.2,5 Macroscopically, the lungs are always heavy, edematous with areas
of consolidation and variable degrees of hemorrhage. At the microscopic level,
the pathologic changes include necrotizing tracheobronchitis and bronchiolitis,
CHAPTER 6

diffuse alveolar damage (DAD) ranging from focal to diffuse (Figure 6d.2), as well
as variable pulmonary edema and alveolar hemorrhage. DAD is usually of the
exudative type with alveolar and interstitial edema, fibrinous exudate, reactive
150

Figure 6d.2 Lung parenchyma from post mortem examination showing necrotizing
tracheobronchitis and bronchiolitis, diffuse alveolar damage ranging from focal to diffuse
as well as variable pulmonary edema and alveolar hemorrhage.
pneumocytes, and hyaline membranes. Pulmonary thrombi with evidence of

Pulmonary Infections in Immunocompetent Hosts

infarction are sometimes seen as part of the spectrum of DAD (Figure 6d.3).
The large cartilaginous airways typically exhibit epithelial necrosis and squa-
mous metaplasia, while smaller airways show necrotizing bronchiolitis with
extensive necrosis of the bronchiolar wall and dense neutrophilic infiltrates
within the bronchiolar lumen. Epithelial damage to the airway provides a portal
for bacteria such as streptococci and staphylococci, which can lead to acute
bronchopneumonia ranging from focal to diffuse and necrotizing. Since the
viruses produce no characteristic cellular inclusions, identification requires
antigen detection by immunohistochemistry, or immunofluorescence with pos-
itivity predominantly in the epithelium of the tracheobronchial tree and sub-
mucosal glands and, to a lesser extent, in the bronchiolar epithelium, alveolar
epithelial cells, and macrophages.
Treatment
Most patients with influenza infection, including 2009 H1N1 influenza, recover
from the illness without specific treatment. Symptomatic treatment typically
consists of fever suppressants, analgesics, cough suppressants, and adequate

CHAPTER 6
hydration. Antiviral therapy is recommended for persons with confirmed or sus-
pected influenza who have underlying conditions that place them at increased
risk of complicated or severe disease, and for those who require hospitalization.
In these patients, empiric antibacterial therapy should also be initiated if there is

151
clinical suspicion of bacterial coinfection. Decisions to initiate antiviral treatment
of other persons should be made on a case by case basis. In these lower-risk
persons, treatment is most likely to provide benefit (i.e., reduction in duration of
symptoms) if provided within 48 hours of the onset of symptoms.
A neuraminidase inhibitor, oseltamivir or zanamivir, is currently considered
to be the treatment of choice for 2009 H1N1 influenza A viruses because these
viruses are resistant to the adamantanes (i.e., amantadine and rimantadine). For

Figure 6d.3 Lung parenchyma from post mortem examination showing pulmonary
thrombi with evidence of infarction as part of the spectrum of diffuse alveolar damage.
 hospitalized patients who are failing treatment with oral or inhaled neuramin-
Pulmonary Infections in Immunocompetent Hosts

idase inhibitor therapy, or in whom oral or inhaled therapy is not possible, a

treatment alternative is the intravenously administered neuraminidase inhibi-
tor, peramivir. Although not FDA approved, the FDA has issued an Emergency
Use Authorization for this agent. It should be noted, however, that the muta-
tion (H275Y) that has been associated with oseltamivir resistance also results
in resistance to peramivir. An intravenous formulation of zanamivir is currently
available from the manufacturer for compassionate use. Isolates with the H275Y
mutation retain susceptibility to zanamivir.6
Prevention
Several general infection control measures may be helpful in preventing trans-
mission of influenza. These measures include hand hygiene, respiratory eti-
quette (e.g., using tissues, covering one’s mouth and nose when coughing and
sneezing), avoiding contact with sick persons, and staying home when ill. Within
healthcare facilities, the risk of transmission can be reduced through early rec-
ognition of possible cases of influenza, provision of surgical masks and tissues
to patients with influenza-like illness, physical and spatial separation of symp-
CHAPTER 6

tomatic patients from others, and implementation of appropriate transmission-

based precautions.
Vaccination is considered to be the one of the most important components
of an influenza prevention program. In response to the 2009 pandemic, which
152

occurred after production of the 2009–2010 trivalent seasonal influenza vaccine

had already begun, a monovalent 2009 H1N1 influenza A vaccine was devel-
oped. In clinical studies, the vaccine has been shown to be highly immunogenic
in children and adults.7,8

References
1. Centers for Disease Control and Prevention. Bacterial coinfections in lung tissue
specimens from fatal cases of 2009 pandemic influenza A (H1N1)–United States,
May–August 2009. Morbid Mortal Wkly Rpt. 2009;58(38):1071–1074.
2. Gill JR, Sheng ZM, Ely SF, Guinee DG, Beasley MB, et al. Pulmonary pathologic
findings of fatal 2009 pandemic influenza A/H1N1 viral infections. Arch Pathol Lab
Med. 2010;134:E1–E9.
3. Centers for Disease Control and Prevention. Evaluation of rapid influenza diag-
nostic tests for detection of novel influenza A (H1N1) virus–United States, 2009.
Morbid Mortal Wkly Rpt. 2009;58(30):826–829.
4. Ginocchio CC, Zhang F, Manji R, Arora S, Bornfreund M, et al. Evaluation of
multiple test methods for the detection of the novel 2009 influenza A (H1N1)
during the New York City outbreak. J Clin Virol. 2009;45:191–195.
5. Maud T, Hajjar LA, Callegari GD, da Silva FF, Schout D, et al. Lung pathology
in fatal novel human influenza A (H1N1) infection. Am J Respir Crit Care Med.
2010;181:72–79.
6. Fiore AE, Fry A, Shay D, Gubareva L, Bresee JS, Uyeki TM; Antiviral agents for
the treatment and chemoprophylaxis of influenza—recommendations of the
Advisory Committee on Immunization Practices (ACIP). Centers for Disease
Control and Prevention (CDC). MMWR Recomm Rep. 2011 Jan 21;60(1):1–24.
7. Nolan T, McVernon J, Skeljo M, Richmond P, Wadia U, et al. Immunogenicity of a

Pulmonary Infections in Immunocompetent Hosts

monovalent 2009 influenza A (H1N1) vaccine in infants and children: a random-
ized trial. JAMA. 2010; 303(1):37–46.
8. Plennevaux E, Sheldon E, Blatter M, Reeves-Hoché MK, Denis M. Immune
response after a single vaccination against 2009 influenza A H1N1 in USA: a
preliminary report of two randomized controlled phase 2 trials. Lancet. 2010;
375:41–48.

Case
C a e 6e:
6e:
e Th
T
Three
hree Men
M w with
ith
ith SSevere
evere P
Pneum
Pneumonia
umonia
ia aafter
fter
ft
Ente
En terring a Mine
Entering

Daniel Caplivski
Case Presentation
A 65-year-old man from Germany entered a mine in Mexico that had been
out of operation for nearly thirty years. He and his coworkers from Mexico
and Sweden noted the presence of numerous bats and bat droppings when

CHAPTER 6
the doors were opened. Two weeks later, he and his colleagues were in their
respective countries when they each developed decreased appetite, dry cough,
dyspnea, drenching sweats, and fevers to 40º C.
The German patient was evaluated by a physician in Berlin and hospital-

153
ized with respiratory distress. On physical examination he was tachypneic (25
breaths per minute), febrile to 38.5º C, and hypoxic (oxygen saturation, 90%
on ambient air). Pulmonary auscultation was significant for decreased breath
sounds in bilateral bases. His laboratory examinations were mainly notable for
mild elevation of the hepatic enzymes ALT 191, AST 132, LDH 360, and GGT
98. Thoracic imaging revealed bilateral nodular infiltrates, dense consolidations,
and pleural effusions (Figures 6e.1 and 6e.2). A transthoracic echocardiogram
revealed trace pulmonary hypertension, and abdominal ultrasound revealed
the presence of mild hepatic enlargement.
The patient underwent bronchoscopy with transbronchial biopsy, but no
organisms were seen on Gram stain, acid-fast stain, or Gomori methenamine
silver stains. He was presumptively treated for pulmonary histoplasmosis with
liposomal amphotericin B followed by itraconazole. Four weeks later (upon
evaluation in the United States) the patient’s urine Histoplasma antigen was
moderately positive (5.23 ng/ml) and the CT scan revealed diffuse miliary nod-
ules (6e-3). The urine Histoplasma antigen eventually declined to undetectable
levels with completion of antifungal treatment. The two patients in Mexico and
Sweden were also confirmed to have pulmonary histoplasmosis, and responded
well to similar therapies in their respective countries.
Case 6e Discussion: Histoplasma capsulatum
Diagnosis and Clinical Features
Histoplasma capsulatum is a dimorphic fungus found in all areas of the world
where warm moist soil is present and promotes the growth of the mycelial
phase of the organism. In the United States, the areas of highest endemicity
Pulmonary Infections in Immunocompetent Hosts
CHAPTER 6

Figure 6e.1 Chest radiograph, posterior-anterior view with bilateral pleural effusions
and diffuse bilateral nodular infiltrates.
154

Figure 6e.2a CT scan lungs, axial view with bilateral pleural effusion and diffuse bilat-
eral miliary nodules.
 Pulmonary Infections in Immunocompetent Hosts
Figure 6e.2b CT scan lungs, axial view after therapy with resolution of bilateral pleural
effusion and persistence of diffuse bilateral miliary nodules.

CHAPTER 6
are in the Midwest states, along the banks of the Ohio River. The organism is
commonly found throughout Central and South America, and it was originally
described in Panama by the pathologist Samuel Darling, who believed it to be
a protozoan parasite similar to Leishmania. The organism is associated with

155
cave and mine exploration because of the presence in bat guano that enhances
fungal sporulation.1
The clinical manifestations of histoplasmosis vary greatly depending on the
immune status of the host. Initial inhalation of the infectious particles can lead
to severe disease in immunocompetent hosts if the inoculum is large enough,
but many individuals are asymptomatically infected. Patients may present with
nonproductive cough, dyspnea, fevers, and sweats. Progressive disseminated
disease is also characterized by pancytopenia, hepatic and splenic enlargement,
and profound weight loss. Liver enzyme elevation with markedly elevated lac-
tate dehydrogenase levels may be important diagnostic clues in patients with
AIDS and disseminated histoplasmosis. Unrecognized cases may progress to
respiratory failure and septic shock.2
In immunocompetent hosts, chronic inflammatory conditions such as medi-
astinal fibrosis may occur. This complication is characterized by chronic scar-
ring of the mediastinal lymph nodes that are in close proximity to the great
vessels and airways of the mediastinum. It is poorly responsive to antifungal
therapy or steroids, and in a minority of cases can be fatal. Mechanical stenting
of the great vessels is a therapeutic option for this condition.1
Disseminated histoplasmosis is most frequently seen in immunocompro-
mised patients, such as those with advanced AIDS, organ transplant recipients,
and patients with inflammatory conditions treated with other immunosuppres-
sive therapies. Recent cases of disseminated histoplasmosis in patients taking
biologic agents such as infliximab and etanercept highlight the importance
of immune control in preventing reactivation illness.3 Infliximab, an antitu-
mor necrosis factor monoclonal antibody, appears to impart a greater risk of
 reactivation of granulomatous disease than etanercept, a soluble tumor necro-
Pulmonary Infections in Immunocompetent Hosts

sis factor receptor, but both can pose a risk to patients with previous exposure
to Histoplasma capsulatum.3 Figure 6e.3 is a biopsy of a large pulmonary nodule
that developed in a patient who was taking etanercept for severe rheumatoid
arthritis. She had previously lived in Tennessee 4 years prior to moving to New
York. AIDS patients with disseminated histoplasmosis may present with severe
sepsis, acute respiratory distress syndrome, and signs of adrenal insufficiency.
The diagnosis of histoplasmosis can be established by visualization of
the organism in biopsied tissue (Figure 6e.3), bronchoalveolar lavage fluid
(Figure 6e.4), or the peripheral blood smear (Figure 6e.5) of severely
156 CHAPTER 6

Figure 6e.3 Lymph node biopsy, Gomori methenamine silver stain. Innumerable small
(2–4 microns) budding yeast cells consistent with Histoplasma capsulatum.

Figure 6e.4 Bronchoalveolar lavage specimen, Gomori methenamine silver stain with
budding yeast cells of Histoplasma capsulatum.
 Pulmonary Infections in Immunocompetent Hosts
Figure 6e.5 Peripheral blood smear (Wright-Giemsa stain) with intracellular budding
yeast in a patient with disseminated histoplasmosis.

157 CHAPTER 6

Figure 6e.6 Lactophenol blue stain of culture of Histoplasma capsulatum showing the
tuberculate macroconidia of the mycelial phase when grown at 24°C.

immunosuppressed patients. The organism can also be recovered in cultures

where the mycelial phase of the organism can be appreciated (Figures 6e.6 and
6e.7). The Histoplasma urine antigen test is rapid and highly accurate in the
setting of immunosuppressed patients with disseminated disease.2 For patients
with no underlying immune deficiency and low inoculums, the urine antigen
test may be falsely negative, though in some settings this diagnostic problem
may be overcome using concentration methods.4 The usefulness of serology
Pulmonary Infections in Immunocompetent Hosts
158 CHAPTER 6

Figure 6e.7 Macroscopic appearance of mycelial colonies of Histoplasma capsulatum

when grown at 24°C on Sabaroud’s dextrose agar.

is limited in the diagnosis of acute histoplasmosis, particularly in areas in which

asymptomatic exposure is common.2
The radiologic appearance of the CT scan in this case with diffuse nodular
infiltrates was representative of the typical appearance of pulmonary histoplas-
mosis on radiographic imaging. Many of the radiologic findings of pulmonary
histoplasmosis (hilar lymph node enlargement, miliary infiltrates, pleural or
pericardial effusions) mimic tuberculosis, and the clinical symptoms of fevers,
night sweats, weight loss, and dyspnea also overlap. The histologic appearance
of granulomas may also prompt suspicions of tuberculosis, but staining with
Gomori methenamine silver (GMS) stain reveals the 2–4-micron ovoid, bud-
ding yeast cells demonstrated in Figure 6e.4.2
Laboratory studies are often helpful in the diagnosis of disseminated his-
toplasmosis in patients with AIDS or other forms of immunosuppression.
Pancytopenia and elevated liver enzymes are often hallmarks of the disease.
Extremely elevated lactate dehydrogenase (LDH) levels are also a differentiat-
ing laboratory finding. Histoplasma serology is of little practical use in separat-
ing prior exposure from acute infection in patients who live in endemic areas.
The urine Histoplasma antigen has proven itself to be the most reliable diagnos-
tic test in patients with disseminated forms of the disease. Immunocompetent
patients who have mild, self-limited histoplasmosis may have false negative

Pulmonary Infections in Immunocompetent Hosts

urine antigen testing.1
Management
Many patients with mild forms of pulmonary histoplasmosis will have a self-
limited illness that does not require treatment. Immunocompromised patients
with disseminated disease and immunocompetent patients with moderate to
severe pulmonary disease may be managed with antifungals, such as amphoter-
icin and itraconazole. Lipid formulations of amphotericin have shown superior-
ity over conventional amphotericin deoxycholate in adults with histoplasmosis.1
Induction treatment regimens with intravenous amphotericin for 7–14 days are
followed by maintenance treatment with oral itraconazole for several months
in immunosuppressed patients. Echinocandins do not demonstrate in vitro
activity against Histoplasma, and therefore are not recommended. Newer triaz-
ole antifungals have demonstrated in vitro efficacy, and are especially useful for
patients who do not tolerate itraconazole. Echinocandins do not demonstrate
in vitro activity against Histoplasma, and therefore are not recommended.1

CHAPTER 6
References
1. Wheat LJ, Freifeld AG, Kleiman MB, Baddley JW, McKinsey DS, Loyd JE, Kauffman
CA; Infectious Diseases Society of America. Clinical practice guidelines for the
management of patients with histoplasmosis: 2007 update by the Infectious

159
Diseases Society of America. Clin Infect Dis. 2007;45(7):807–825.
2. Caplivski D, Salama C, Huprikar S, Bottone EJ. Disseminated histoplasmosis in
five immunosuppressed patients: clinical, diagnostic, and therapeutic perspec-
tives. Rev Med Microbiol. 2005;16(1)1–7
3. Wallis RS, Broder M, Wong J, Lee A, Hoq L. Reactivation of latent granulomatous
infections by infliximab. Clin Infect Dis. 2005;41(Suppl 3):S194-S198.
4. Srinivasan A, Kleiman MB, Debelenko L, Stokes DC, De Vincenzo J, Wheat JL.
False-negative Histoplasma antigen in acute pulmonary histoplasmosis: the value
of urinary concentration by ultrafiltration and heat denaturation of serum pro-
teins in detection of Histoplasma antigen. Pediatr Infect Dis J. 2009;28(5):447–449.
This page intentionally left blank
 Chapter 7

Pulmonary Infections in
Immunocompromised Hosts

Case
C a e 7a:
7a: A 773
73-Year-Old
3-Y
Year-O
Old Man
M wit
with
ith
hNNosocomial
oso
socomial
ial
Pneu
Pn eumonia
Pneumonia

Keith Sigel, Irini Scordi-Bello, Gopi Patel, and

Daniel Caplivski
Case Presentation

161
A 73-year-old man with a history of benign prostatic hypertrophy, hyperten-
sion, and chronic obstructive pulmonary disease was admitted for surgical
management of a 5.7 cm thoracoabdominal aortic aneurysm (Figure 7a.1). He
underwent aneurysm resection and graft replacement of the aorta from the
midthoracic to the infrarenal portion.
The patient’s perioperative course was complicated by difficult ventilation
and reintubation for hypoxia and atrial fibrillation on the first postopera-
tive day. Over the next several days, he developed agitation, fever (38.5 ºC),
hypotension requiring vasopressors, and peripheral cyanosis in bilateral lower
extremities. His laboratory studies showed progressively worsening leukocyto-
sis (peak 34.5 x103 WBC/ul, 40% bands), thrombocytopenia (34x103 platelets/
ul), acute kidney injury (creatinine 2.8 mg/dl), and hepatic failure (AST 2847
U/L, ALT 712 U/L, bilirubin 8.8 mg/dl). Chest imaging showed dense bilateral
consolidations that worsened over the course of a week (Figures 7a.2 and 7a.3),
and both blood and sputum cultures grew Pseudomonas aeruginosa susceptible
to ciprofloxacin and imipenem (Figure 7a.4).
A rising serum lactate (7.7 mmol/L) caused concern for concomitant intesti-
nal ischemia; however, an exploratory laparotomy showed no signs of ischemia
or aortic graft defect. Despite broad spectrum antibiotics including imipenem,
the patient died on the tenth postoperative day.
Pathology
At autopsy, the lungs were markedly edematous and consolidated, with bilat-
eral necrotizing abscesses and areas of parenchymal hemorrhage (Figure 7a.5).
The pulmonary parenchyma exhibited severe emphysematous changes with
subpleural blebs. Histologically, the alveolar spaces were filled with acute
Infections in Immunocompromised Hosts
CHAPTER 7 Pulmonary

Figure 7a.1 CT reconstruction of thoracoabdominal aortic aneurysm.

162

Figure 7a.2 Chest radiograph, anterior-posterior view showing bilateral pulmonary

consolidations.
 Infections in Immunocompromised Hosts
CHAPTER 7 Pulmonary
Figure 7a.3 CT lungs, axial view showing dense bilateral consolidations.

163

Figure 7a.4 Endotracheal secretions, Gram stain showing innumerable Gram-negative

bacilli and polymorphonuclear cells.
Infections in Immunocompromised Hosts
CHAPTER 7 Pulmonary

Figure 7a.5 Lungs on postmortem examination were markedly edematous and con-
solidated with bilateral necrotizing abscesses and areas of parenchymal hemorrhage. The
pulmonary parenchyma exhibited severe emphysematous changes with subpleural blebs.

inflammatory infiltrates, predominantly neutrophils, with fibrin deposition and

coagulative necrosis (Figure 7a.6). Foci of aspirated vegetable matter and large
164

bacterial colonies were observed. Gram stain revealed Gram-negative rods,

and postmortem lung tissue cultures grew Pseudomonas aeruginosa.
Case 7a Discussion: Pseudomonas aeruginosa
Clinical Presentation and Diagnosis
Pneumonia is the second most common healthcare-associated infection, and
is a significant contributor to healthcare-associated morbidity and mortality.1
Hospital acquired pneumonia (HAP) should be suspected in a hospitalized
patient with a radiographic infiltrate that is new or progressive, along with clinical
findings suggesting infection, including new onset of fever, purulent sputum, leu-
kocytosis, or worsening oxygenation. Ventilator-associated pneumonia (VAP),
a subset of HAP, is an important complication in patients requiring mechanical
ventilation. The diagnosis of suspected HAP may be supported by chest radi-
ography with posterior-anterior and lateral views, two sets of blood cultures,
sputum Gram stain and culture, complete blood count and chemistry, and urine
Legionella antigen testing. Urine pneumococcal antigen testing may also be useful
in guiding antimicrobial therapy; however, its role is controversial.2
Hospital acquired pneumonia can be caused by a diverse range of pathogens;
bacteria are most common, and can include organisms traditionally associated
with community-acquired pneumonia (CAP) such as Streptococcus pneumoniae,
Haemophilus influenzae, and Moraxella catarrhalis. An increasing percentage of
cases, however, are due to Gram-negative organisms, as well as methicillin-
resistant Staphylococcus aureus (MRSA).1,3 Pseudomonas aeruginosa has been
implicated in up to 18% of HAP cases, and is seen much more frequently in
nosocomial pulmonary infections than in those acquired in the community
(Table 7a.1).2
 Infections in Immunocompromised Hosts
CHAPTER 7 Pulmonary
Figure 7a.6 Histologic section of lungs on postmortem examination showing alveolar
spaces filled with acute inflammatory infiltrates, predominantly neutrophils, with fibrin
deposition and coagulative necrosis.

Table 7a.1 Important Pathogens in Nosocomial Pneumonia

165
by Prevalence
Methicillin-resistant Staphylococcus aureus
Streptococcus pneumoniae
Pseudomonas aeruginosa
Methicillin-sensitive Staphylococcus Aureus
Haemophilus species
Other Gram-negative rods
Enterobacteriaceae
Klebsiella Species
Escherichia coli
Legionella Species
Source: Micek et al. Healthcare-associated pneumonia and community-acquired pneumonia:
a single-center experience. Antimicrob Agents Chemother. 2007; 51:3568–3573.

Pseudomonas aeruginosa is the most common multidrug-resistant (MDR)

Gram-negative pathogen causing pneumonia in hospitalized patients.4 It elabo-
rates several virulence factors that are important in its pathogenesis, includ-
ing pili, proteases, lipopolysaccharide, exotoxins, and biofilms. Patients with
structural lung disease or extensive smoking history are at greater risk of
pseudomonal pneumonia because of ineffective clearance of the organism.
Pseudomonas aeruginosa thrives in hospital water sources, such as mechani-
cal ventilator tubing. Microbiologic confirmation should be pursued in patients
with enhanced risk of Pseudomonas aeruginosa pneumonia to aid in determina-
tion of appropriate antimicrobial therapy.5
 Management
Infections in Immunocompromised Hosts

Antibiotics with antipseudomonal activity include the aminoglycosides, ticarcillin,

piperacillin, ceftazidime, cefepime, aztreonam, the carbapenems (except for ertap-
enem), ciprofloxacin and levofloxacin.5 Higher-dose therapy is suggested in cases
of suspected pseudomonal pneumonia due to intrinsic resistance in this organism.
The optimal antipseudomonal antibiotic choice is difficult because of a dearth
of experimental evidence, but prospective data has suggested that isolates may
become resistant to imipenem faster than to fluoroquinolones or cephalosporins.
Among the fluoroquinolone antibiotics, ciprofloxacin is the most potent antip-
seudomonal agent.4,5 The use of combination therapy with two classes of antibiot-
ics for Pseudomonas infection is controversial, but the use of aminoglycosides as
a single agent has been associated with a higher failure rate.5 Prospective studies
have suggested that empiric dual therapy may be associated with greater rates of
microbiologic cure and lower incidences of antimicrobial resistance, but limited
CHAPTER 7 Pulmonary

data exists to support a mortality benefit with this strategy.5 Patients with known
MDR pseudomonas colonization, or with previous exposure to antipseudomonal
antibiotics, may benefit the most from dual therapy.5
Because of enhanced risk of Pseudomonas and other resistant Gram-negative
pathogens in hospital acquired pneumonias, empiric antibiotic regimens
should take into consideration both local and institution-specific antimicrobial
susceptibility profiles, as well as the patient’s underlying immune status. Empiric
166

therapy for healthcare-associated pneumonia should include a E-lactam anti-

biotic with antipseudomonal activity, and vancomycin or linezolid for empiric
MRSA coverage if local or institutional MRSA rates are high.4 Response to
therapy should be monitored, and results of initial diagnostic testing, includ-
ing culture data and bacterial antigens, can be used to streamline the initial
antimicrobial regimen. Patients that do not improve within 48–72 hours of
initial antimicrobial therapy should be considered for additional diagnostic test-
ing including bronchoscopy with bronchoalveolar lavage, and evaluation for
non-bacterial pathogens or alternate diagnoses.4

References
1. Carratalà J, Mykietiuk A, Fernández-Sabé N, et al. Healthcare-associated pneu-
monia requiring hospital admission: epidemiology, antibiotic therapy, and clinical
outcomes. Arch Intern Med. 2007;167:1393–1399.
2. Micek ST, Kollef KE, Reichley RM, et al. Healthcare-associated pneumonia and
community-acquired pneumonia: a single-center experience. Antimicrob Agents
Chemother. 2007;51:3568–3573.
3. Shorr AF, Zilberberg MD, Micek ST, Kollef MH. Prediction of infection due to
antibiotic-resistant bacteria by select risk factors for healthcare-associated pneu-
monia. Arch Intern Med. 2008;168:2205–2210.
4. Zilberberg MD, Shorr AF, Micek ST, et al. Antimicrobial therapy escalation and
hospital mortality among patients with HCAP: a single center experience. Chest.
2008;134:963–968.
5. El Solh AA, Alhajhusain A. Update on the treatment of Pseudomonas Aeruginosa
pneumonia. J Antimicrob Chemother. 2009;64(2):229–238.
 Infections in Immunocompromised Hosts
Case
C a e 7b:
7b: A 772
72-Year-Old
2-Y
Year-O
Old W
Woman with
wit
ith
h Persi
P
Persistent
e iste
t ntt C
Cou
Cough
ugh
gh
and
an d Neutropenia
Neutropeniaa

Daniel Caplivski and Shirish Huprikar

Case Presentation
A 72-year-old woman from Russia with a history of breast cancer and non-
Hodgkin’s lymphoma was subsequently diagnosed with acute myelogenous leu-
kemia. She was treated with a chemotherapy regimen that included decitabine
and azacitidine, and several days later developed febrile neutropenia. She was
empirically treated with vancomycin and cefepime, and discharged with levo-
floxacin after resolution of fever. Three days later she was readmitted with
recurrent fever, chills, headache, and worsening cough with clear sputum.

CHAPTER 7 Pulmonary
On physical examination, her maximum temperature was 38.1º C, and she was
noted to have rigors in the emergency department. She had slightly decreased
breath sounds and a few wheezes and rales in both lung bases, but the remainder
of her physical examination was unrevealing. Her laboratory studies were sig-
nificant for leukopenia (WBC 0.7 x 10³ WBC/ μl, 16% polymorphonuclear cells,
68% lymphocytes, 8% blasts), anemia (hemoglobin 9.9 gm/dl), thrombocytopenia
(platelets 6 x 10³ WBC/μl) and elevated lactate dehydrogenase (445 U/L).

167
Initial chest radiography revealed slightly increased interstitial markings, and
a high-resolution CT scan of the lungs three days later showed patchy alveolar
consolidations with surrounding ground glass opacities (Figure 7b.1 and 7b.2).
She was empirically treated with vancomycin and cefepime, but continued to
have cough and low grade fevers. A sputum sample for respiratory viruses was
collected, and the direct fluorescence antibody for respiratory syncytial virus
was positive (Figure 7b.3). Her fever and cough abated with supportive care,

Figure 7b.1 Chest radiograph, posterior-anterior view with mildly increased interstitial
markings.
Infections in Immunocompromised Hosts
CHAPTER 7 Pulmonary

Figure 7b.2 High resolution CT scan of the lungs, axial view showing patchy alveolar
consolidations with surrounding ground glass opacities.
168

Figure 7b.3 Direct fluorescence antibody test showing green fluorescence where RSV
antigens are present.

and she was discharged with oral levofloxacin as a prophylactic agent until her
neutropenia resolved.
Case 7b Discussion: Respiratory Syncytial Virus
Clinical Presentation and Diagnosis
Respiratory syncytial virus (RSV) is a common cause of serious illness in chil-
dren and immunocompromised adults, particularly among hematopoietic
stem cell transplant (HSCT) and lung transplant recipients. The virus is readily
transmitted by contact with infected respiratory secretions, and can cause dis-

Infections in Immunocompromised Hosts

ease of the upper and lower respiratory tract. Higher rates of RSV are seen
during winter months in temperate climates, and the virus is responsible for
hundreds of thousands of hospitalizations of children and adults each year. By
the first year of life, most children have been exposed to RSV; however, immu-
nity is not protective because of seasonal antigenic variation.1
Disease in both children and adults may begin as upper airway disease
and progress to lower airway disease, including bronchiolitis and pneumo-
nia. Initially, patients may present with nasal congestion, cough, and fever, but
then progress to dyspnea, tachypnea, and respiratory failure. Physical examina-
tion may be notable for wheezing and crackles when bronchiolitis and pneu-
monia are present. Among HSCT recipients, 40%–50 % of those presenting
with upper respiratory tract disease will progress to lower respiratory tract
disease, and the mortality of HSCT recipients with lower tract RSV disease

CHAPTER 7 Pulmonary
approaches 80%.1,2 Since RSV is the most common respiratory virus to cause
infection in this population, efforts at early diagnosis, treatment, and preven-
tion are crucial.
Radiographic findings can range from diffuse ground-glass opacities to focal
alveolar airspace consolidations. Children and adults with RSV disease may also
present with hyperinflation of the lungs as a result of air trapping.1 Confirmation
of RSV pneumonia can be achieved with viral culture, PCR, or direct fluores-
cence antibody testing on samples from bronchial washings, sputum, or nasal

169
washings. Rapid antigen tests are also available, with sensitivity ranging from
50%–90% and specificity ranging from 73%–100%.1
Management
No definitive guidelines have been published regarding the optimal manage-
ment of RSV in the adult immunocompromised population, and large controlled
trials are lacking. Aerosolized ribavirin has been used to treat HSCT recipients
with both upper airway and lower airway RSV disease.3 A major limitation of
this strategy is that ribavirin is teratogenic and, therefore, potentially a risk to
healthcare workers caring for patients treated with ribavirin.3,4 In a multicenter
study in which fourteen patients with upper respiratory tract infection with RSV
were randomized to receive either aerosolized ribavirin or supportive care,
no significant difference in progression to lower respiratory tract disease was
observed. Although a trend toward lower levels of viral load in nasal washings
was observed, the difference was not statistically significant.4
Palivizumab is an RSV-specific monoclonal antibody that has been shown
in murine models to significantly reduce the RSV viral load.2 In humans, it has
been studied mainly in children with RSV infection; however, small trials in
adults have also been conducted.2 In a retrospective analysis of 40 allogeneic
stem cell transplant recipients with symptomatic RSV infection, 19 received
palivizumab, while a control group was treated mainly with supportive care
and, in some cases, intravenous ribavirin. In comparing the groups, no significant
differences were seen in progression to lower respiratory tract disease or in
overall survival.2
 RSV is readily transmitted by contact with infectious secretions that contam-
Infections in Immunocompromised Hosts

inate surfaces, and self-inoculation via mucous membranes. Patients with RSV
disease should therefore be placed on contact isolation during their hospital-
ization; transmission via airborne particles appears to play a less important role
and respiratory isolation is not necessary.1 The use of prophylactic palivizumab
in high-risk infants or adult HSCT recipients remains controversial because of
limited supportive data and high cost.

References
1. Breese Hall, C. Respiratory syncytial virus. In Mandell GL, Bennett JE, Dolin R.
eds Principles and Practice of Infectious Diseases, 7th ed. Philadelphia: Elsevier
Churchill Livingston; 2009:2207–2221.
2. de Fontbrune FS, Robin M, Porcher R, et al. Palivizumab treatment of respiratory
CHAPTER 7 Pulmonary

syncytial virus infection after allogeneic hematopoietic stem cell transplantation.

Clin Infect Dis. 2007;45(8):1019–1024.
3. Boeckh M, Englund J, Li Y, Miller C, Cross A, Fernandez H, Kuypers J, Kim H,
Gnann J, Whitley R; NIAID Collaborative Antiviral Study Group. Randomized
controlled multicenter trial of aerosolized ribavirin for respiratory syncytial virus
upper respiratory tract infection in hematopoietic cell transplant recipients. Clin
Infect Dis. 2007;44(2):245–249.
4. Whimbey E, Champlin RE, Englund JA, et al. Combination therapy with aero-
solized ribavirin and intravenous immunoglobulin for respiratory syncytial virus
170

disease in adult bone marrow transplant recipients. Bone Marrow Transplant.

1995;16(3):393–399.

Case
C a e 77c:
c: A 556
56-Year-Old
6-Y
Year-O
Old W
Woman wit
with
ithh Pul
P
Pulmonary
ulmon
nary
Nodules
Nodu
No dules

Daniel Caplivski, Mary Beth Beasley, and Shirish Huprikar

Case Presentation
A 56-year-old woman with a history of asthma and refractory non-Hodgkin’s
lymphoma underwent allogeneic bone marrow transplantation from her HLA-
identical sister. Her course was complicated by pulmonary embolism and sev-
eral episodes of graft versus host disease of the skin, treated with increased
immunosuppression. One year after her transplant she had engrafted and was
in remission. Her medications included mycophenolate mofetil, prednisone,
albuterol, dalteparin, valacyclovir, trimethoprim-sulfamethoxazole, and flu-
conazole. She presented with dyspnea, chest tightness and wheezing, and was
admitted with a presumed asthma exacerbation. She also noted fever, cough,
and pleuritic chest pain.
On physical examination she was in no acute distress, but she was febrile
(38.1ºC), hypoxic (oxygen saturation 92% on ambient air), and her pulmo-
nary examination was notable for wheezing. Her initial laboratory values were
significant for leukocytosis (15.7 WBC x 10³ WBC per μl, 74% neutrophils)
and mildly elevated lactate dehydrogenase (267 U/L). A CT scan of the lungs
identified a new cluster of nodules and associated bronchiectasis in the right

Infections in Immunocompromised Hosts

lower lobe (Figure 7c.1) and the patient underwent flexible bronchoscopy and
video-assisted thoracoscopy with lung biopsy.
Histopathologic examination of the lung tissue revealed thin, septated
hyphae with acute-angle branching (Figures 7c.2, 7c.3, and 7c.4). While the
fungal cultures of the lung biopsy were sterile, the cultures from the bron-
chial washings grew Aspergillus fumigatus (Figures 7c.5 and 7c.6). The patient

CHAPTER 7 Pulmonary
171
Figure 7c.1 CT scan of the lungs, axial view showing a cluster of nodules and associ-
ated bronchiectasis in the right lower lobe.

Figure 7c.2 Lung biopsy, hematoxylin and eosin stain showing angioinvasive fungal
hyphae with septations and and acute-angle branching.
Infections in Immunocompromised Hosts
CHAPTER 7 Pulmonary

Figure 7c.3 Lung biopsy, hematoxylin and eosin stain at higher magnification showing
thin septated hyphae with acute-angle branching.
172

Figure 7c.4 Lung biopsy, Gomori methenamine silver stain showing angioinvasive fungal
hyphae with thin septated hyphae with acute-angle branching.

was initially treated with intravenous liposomal amphotericin, and eventually

discharged with oral voriconazole.
Case 7c Discussion: Aspergillus fumigatus
Clinical Presentation and Diagnosis
Aspergillus species are a group of ubiquitous hyaline molds which produce a
wide range of clinical disease. Allergic bronchopulmonary aspergillosis (ABPA)
is most commonly seen in chronic asthmatics who develop a hypersensitiv-
ity reaction to Aspergillus resulting in increased symptoms, peripheral blood
eosinophilia, and pulmonary infiltrates. Pathologically, ABPA is characterized by
 Infections in Immunocompromised Hosts
CHAPTER 7 Pulmonary
Figure 7c.5 Culture of bronchial washing with mycelial colony Aspergillus fumigatus.

173

Figure 7c.6 Culture of bronchial washing, lactophenol blue stain showing microscopic
appearance of Aspergillus fumigatus with conidiophore (fruiting head) and columnar
conidia.

mucoid impaction of the bronchi with “allergic mucin” containing eosinophils

and fungal hyphae; the bronchi and surrounding lung may show bronchiectasis,
asthma-like changes, or eosinophilic pneumonia. In some cases, histologic find-
ings of bronchocentric granulomatosis may be seen. Aspergilloma results from
Aspergillus colonizing a preexisting cavity in the lung. The cavity may be second-
ary to a variety of causes, including prior tuberculosis or other granulomatous
infection, bronchiectasis, or resolved abscess. These are generally benign forms
of aspergillosis in comparison to the consequences of invasive aspergillosis in
immunocompromised hosts.
 Invasive pulmonary aspergillosis is one of the major life-threatening com-
Infections in Immunocompromised Hosts

plications in immunocompromised patients, such as hematopoietic or solid

organ transplant recipients, and neutropenic patients following cancer
chemotherapy.1,2 The spores of the organism are inhaled routinely from the
environment, and thus the initial site of invasive disease is typically the lungs or
sinuses. In immunocompromised hosts, the organism can then disseminate via
the bloodstream to multiple sites including the central nervous system, where
the mortality of invasive disease is greatest.1 The degree and duration of neutro-
penia directly correlates with the risk of invasive disease over time. Increased
immunosuppression to treat graft versus host disease is also a major risk factor.
Mortality from invasive disease remains high, even with early recognition and
early therapy, and favorable outcomes in patients with hematopoietic stem cell
transplants range from only 20%–40%.1,3
Patients with invasive pulmonary aspergillosis may present with undiffer-
CHAPTER 7 Pulmonary

entiated fever, but cough, dyspnea, and pleuritic chest pain may also be part
of the presenting syndrome. Radiographic findings on CT scans of the lungs
vary from diffuse pulmonary infiltrates and ground-glass opacities to cavitary
nodules with surrounding areas of infarction. The presence of a halo sign (a
pulmonary nodule with surrounding ground-glass attenuation) or air-crescent
sign (crescent-shaped or circumferential area of radiolucency within a cavity or
parenchymal consolidation) suggests the angioinvasive nature of this mold in
immunocompromised hosts.1
174

Diagnosis of pulmonary invasive pulmonary aspergillosis remains a clinical

challenge because of several factors. Although sputum or bronchoalveolar
lavage cultures may be successful in isolating the organism, they lack sensitiv-
ity and a false positive result may represent airway colonization. Radiographic
studies may be helpful but lack of specificity does not allow for differentiation
from other invasive mold infections (agents of mucormycosis) or from non-
infectious causes of nodules such as malignancy. Lung biopsy (via transbron-
chial approach, or via video-assisted thoracoscopy) remains the gold standard
for a definitive diagnosis of proven invasive aspergillosis; however, the risks
of these invasive procedures in the setting of profound thrombocytopenia
(often the case in hematopoietic stem cell transplant recipients) often limit
their feasibility.1
The morphologic appearance of the hyphae in histologic specimens may
help distinguish Aspergillus from other invasive molds such as the agents of
mucormycosis. The hyphae of Aspergillus are typically thinner, with septations
and acute angle branching, while those of the agents of mucormycosis are
broad, ribbon-like, lacking septations, and branching at right angles. Areas of
invasive aspergillosis are characterized by hemorrhage, infarction, and necro-
sis, given the predilection for the organisms to invade blood vessels. Calcium
oxalate crystals may be seen in association with the organisms, especially with
Apergillus niger. Invasive aspergillosis and mucormycosis are both character-
ized by hemorrhage, infarction, and necrosis. The organism may be visible
on hematoxylin and eosin staining, but Gomori methenamine silver (GMS)
and periodic acid-Schiff (PAS) stains serve to highlight the presence of hyphae
within the tissues.1
 While the organism can be recovered on standard media from tissue biop-

Infections in Immunocompromised Hosts

sies, blood cultures are rarely positive even in cases of disseminated disease.
Aspergillus fumigatus is the species most frequently isolated in patients with
invasive pulmonary aspergillosis, but other species such as A. flavus, A. niger, and
A. terreus are also detected. On standard culture media the organism grows
within 48–72 hours and produces pigmented, feathery colonies. Microscopic
examination of hyphae stained with lactophenol blue reveal the typical spo-
rulating head with small round conidia. The genus derives its name from its
similarity to the hollow tube used in Catholic mass to spread holy water, the
aspergillum. Antimicrobial susceptibility testing of Aspergillus species is now
available, though clinical correlation is still lacking. Certain species such as A. ter-
reus are usually resistant to amphotericin B, and resistance testing is advisable.1
The role of non-culture-based assays such as galactomannan detection has
emerged in the diagnosis of invasive aspergillosis. Galactomannan is a poly-

CHAPTER 7 Pulmonary
saccharide cell wall component of Aspergillus that is released as the organism
multiplies. The use of enzyme immunoassay for the detection of galactomannan
may allow for early detection of invasive aspergillosis with sensitivities ranging
from 57%–87.5% in hematopoietic stem cell transplant recipients have been
reported. The specificity of the assay has been reported to be 92%–100% in this
group, but several conditions may yield false positive results, including treatment
with antibiotics such as piperacillin-tazobactam or amoxicillin clavulanate.4,5 The
clinical utility of the assay in non-neutropenic recipients is still being defined.

175
Management
The management of invasive aspergillosis has evolved with the adoption of either
preemptive or prophylactic strategies. Some centers treat patients with prophy-
lactic mold-active oral triazoles until neutropenia has resolved. Other centers
have adopted serial pulmonary CT scanning and galactomannan assays to try
to identify invasive aspergillosis at early stages. Clinical trials to establish the
optimal strategy are ongoing; however, adverse medication effects, medication
interactions, and possible increases in the rate of invasive zygomycete infections
are among the concerns that accompany long-term prophylactic strategies.1,2
Once the diagnosis of invasive aspergillosis has been established, several
antifungal agents are available for treatment. Voriconazole was compared to
amphotericin B deoxycholate in a direct comparison trial, and was shown to
have a superior efficacy and toxicity profile.1,6 Intravenous voriconazole includes
a cyclodextrin vehicle that accumulates in patients with renal failure, and use
of intravenous formulations in this setting should be used with caution. Lipid
formulations of amphotericin B have fewer adverse effects than conventional
amphotericin B, and allow for the infusion of higher doses. There are no studies
directly comparing voriconazole with lipid formulations of amphotericin B, and
many clinicians continue to favor the latter as initial therapy for invasive asper-
gillosis. Posaconazole is a triazole that is only available in oral formulations, and
studies demonstrating efficacy are mostly limited to salvage treatment of inva-
sive aspergillosis. Attention should also be given to the interactions between
triazoles and other medications metabolized by the p450 system, particularly
sirolimus and calcineurin inhibitors, such as tacrolimus or cyclosporine.
 Echinocandins have in vitro and in vivo activity against most species of
Infections in Immunocompromised Hosts

Aspergillus, and efficacy has been demonstrated for salvage therapy of invasive
aspergillosis. Combination antifungal therapy has been used in some cases of
refractory disease. In a retrospective analysis of patients who had progressive
aspergillosis after treatment with liposomal amphotericin B, those who received
voriconazole and caspofugin had improved outcomes when compared to those
who received voriconazole alone.3 This study, however, included comparison
of groups of patients who were treated for different time periods. Randomized,
controlled trials are ongoing to better define the role of combination therapy
as initial treatment of invasive aspergillosis.

References
1. Walsh TJ, Anaissie EJ, Denning DW, et al.; Infectious Diseases Society of America.
CHAPTER 7 Pulmonary

Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases

Society of America. Clin Infect Dis. 2008 Feb 1;46(3):327–360.
2. Pappas PG, Alexander BD, Andes DR, et al. Invasive fungal infections among organ
transplant recipients: results of the Transplant-Associated Infection Surveillance
Network (TRANSNET). Clin Infect Dis. 2010;50(8):1101–1011.
3. Marr KA, Boeckh M, Carter RA, Kim HW, Corey L. Combination antifungal ther-
apy for invasive aspergillosis. Clin Infect Dis. 2004;39(6):797–802.
4. Marr KA, Balajee SA, McLaughlin L, Tabouret M, Bentsen C, Walsh TJ. Detection of
176

galactomannan antigenemia by enzyme immunoassay for the diagnosis of invasive

aspergillosis: variables that affect performance. J Infect Dis. 2004;190(3):641–649.
5. Viscoli C, Machetti M, Cappellano P, et al. False-positive galactomannan platelia
Aspergillus test results for patients receiving piperacillin-tazobactam. Clin Infect
Dis. 2004;38(6):913–916.
6. Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus Amphotericin
B for primary therapy of invasive aspergillosis. N Engl J Med. 2002; 347:408.

Case
C a e 77d:
d: A 447
d: 47-Year-Old
7-Y
Year-OOld W
Woman ffrom Thailand
Thaila
Th iland
nd wit
with
ith
ith
Wors
Wo rsening Dyspne
Worsening neaa
Dyspnea

Jennifer Jao
Case Presentation
A 47-year-old woman from Thailand, with a history 14 years prior to admis-
sion of orthotopic liver transplant for autoimmune hepatitis, presented with
fevers, abdominal pain, diarrhea, and dry cough for 5 days. She had recently
been admitted with jaundice, increasing liver transaminases, hyperbilirubinemia
(14 mg/dl), and her liver biopsy showed chronic evolving graft rejection. She
was born in Thailand but had lived in the United States for 20 years, and denied
any recent travel, illicit drug use, animal contact, or contact with patients with
tuberculosis. Her tuberculin skin test was negative less than one year ago.
On physical examination she was afebrile, with scleral icterus but in no acute
distress. Laboratory values were significant for neutropenia (2.1 x 10³ WBC/μl)
and elevated total bilirubin (16 mg/dl). Initially, her pulmonary examination

Infections in Immunocompromised Hosts

and chest radiography were both unremarkable; however, over the next
several days, her fevers progressed and she developed increasing cough and
dyspnea. By hospital day 5, she was hypoxic with 85% oxygen saturation on
ambient air, and increasingly tachypneic. Repeat chest radiography showed
diffuse bilateral infiltrates (Figure 7d.1) and chest CT showed diffuse bilateral
ground-glass opacities with honeycombing (Figure 7d.2). Direct fluorescent
antibody (DFA) testing on a sputum sample was positive for Pneumocystis
jirovecii. (Figure 7d.3).

CHAPTER 7 Pulmonary
177

Figure 7d.1 Chest radiography, posterior-anterior view showing diffuse bilateral

infiltrates.

Figure 7d.2 Chest CT, axial view showing diffuse bilateral ground-glass opacities with
honeycombing.
Infections in Immunocompromised Hosts
CHAPTER 7 Pulmonary

Figure 7d.3 Sputum sample positive with direct fluorescent antibody testing for
Pneumocystitis jirovecii.

Case 7d Discussion: Pneumocystis jiroveci

Pneumocystis jirovecii, formerly called Pneumocystis carinii, is an agent of pneu-
monia that is the most frequent opportunistic infection in patients with AIDS.
178

In other immunocompromised patient populations, it has been less well-

described, particularly in the post-transplant population. There are several dif-
ferences in the epidemiology, clinical presentation, diagnostic methods, and
mortality between HIV-positive and HIV-negative patients.
The number of patients with Pneumocystis pneumonia (PCP) in non-HIV-
infected patients has steadily risen in the last decade. The majority of these infec-
tions have occurred in patients with hematologic malignancies or solid organ
(such as kidney and liver) transplant recipients. In addition, 90% of these patients
were reported to have been receiving steroids prior to the diagnosis of PCP.2–4
In AIDS patients, PCP has classically presented as a subacute illness over several
weeks in a patient with a CD4 count < 200 cells/mm³ with fever, dry cough, and
dyspnea. Some patients, in fact, may be treated in an ambulatory setting.
In contrast, non-HIV-infected patients with PCP present more acutely over
several days, with a more severe illness. Median CD4 counts in these patients
vary greatly in the literature. In addition, the burden of organism is much greater
in HIV-infected patients compared to non-HIV-infected patients, making diag-
nosis by GMS, Gram-Weigert, and DFA staining much more sensitive in the
former, particularly on bronchoalveolar lavage (BAL) specimens. Our patient
represents a rare case in which PCP was diagnosed on a single sputum sample
via DFA. Other methods of diagnosis include polymerase chain reaction (PCR)
of sputum or BAL specimens, though its positive predictive value (PPV) is much
lower in non-HIV-infected patients compared to HIV-infected patients.5
Antimicrobial treatment for PCP, however, remains the same in both immu-
nocompromised populations. Table 7d.1 lists first-line and alternative therapy
 Infections in Immunocompromised Hosts
Table 7d.1 Management of Pneumocystis Pneumonia
Not Acutely Ill (Ambulatory setting)
FIRST LINE
TMP/SMX 1 DS tablet every 8 hours x 21 days
Dapsone + TMP 100 mg orally every 24 hours + 5 mg/kg every 8
hours every 8 hours x 21 days
SECOND LINE
Clindamycin + Primaquine 300-450 mg orally every 6 hours + 15 mg base
every 24 hours x 21 days
Atovaquone 1500 mg orally every 24 hours x 21 days
Acutely Ill
FIRST LINE
TMP/SMX 15 mg/kg/day IV divided every 6-8 hours x 21 days

CHAPTER 7 Pulmonary
SECOND LINE
Clindamycin + Primaquine 600 mg IV every 8 hours + 30 mg base orally every
24 hours x 21 days
Pentamidine 4 mg/kg/day IV x 21 days

based on the clinical severity of disease. A clear benefit of steroids for the

179
treatment of PCP in AIDS patients who are hypoxic has been shown in the lit-
erature. The standard dose of prednisone is 40 mg twice daily over 5 days, then
tapered over the ensuing 16 days of the illness. The benefit in non-HIV-infected
patients has been less apparent. Few studies have been able to demonstrate a
clear benefit to giving steroids in this population, with two major studies show-
ing conflicting data.6,7
Despite similar treatment regimens for PCP in both HIV-positive and HIV-
negative patients, reported mortality rates between the two groups have dif-
fered widely, with the latter showing reports double that of the former. In
addition, complication rates, including rates of respiratory failure and those
requiring intensive care, have been higher in HIV-negative immunocompro-
mised patients.1–3

References
1. Sepkowitz, KA Pneumocystis carinii pneumonia in patients without AIDS. Clin
Infect Dis. 1993;17(Suppl 2):416–422
2. Yale SH, Limper AH. Pneumocystis carinii pneumonia in patients without acquired
immunodeficiency syndrome: associated illnesses and prior corticosteroid ther-
apy. Mayo Clin Proc. 1996;71:5–13.
3. Roblot F, Godet C, Le Moal G, et al. Analysis of underlying diseases and prognosis
factors associated with Pneumocystis carinii pneumonia in immunocompromised
HIV-negative patients. Eur J Clin Microbiol Infect Dis. 2002;21:523–531.
 4. Weig M, Klinker H, Bögner BH, Meier A, Gross U. Usefulness of PCR for diagno-
Infections in Immunocompromised Hosts

sis of Pneumocystis carinii pneumonia in different patient groups. J Clin Microbiol.

1997;35(6):1445–1449.
5. Delclaux C, Zahar J-R, Amraoui G, et al. Corticosteroids as adjunctive ther-
apy for severe Pneumocystis carinii pneumonia in non-human immunodefi-
ciency virus-infected patients: retrospective study of 31 patients. Clin Infect Dis.
1999;29:670–672.
6. Pareja JG, Garland R, Koziel H. Use of adjunctive corticosteroids in severe adult
non-HIV Pneumocystis carinii pneumonia. Chest. 1998;113:1215–1224.
7. Mansharamani NG, Garland R, Delaney D, Koziel H. Management and out-
come patterns for adult Pneumocystis carinii pneumonia, 1985 to 1995: com-
parison of HIV-associated cases to other immunocompromised states. Chest.
2000;118(3):704–711
CHAPTER 7 Pulmonary

Case
C a e 77e:
e SSevere P
e: Pneumonia
neu
umonia
i from
from a Gra
G
Gram-Positive
ram-Po
Positi
itive
i
Bacillus
Baci
Ba cill
llus

Meenakshi Mehrotra Rana and Mary Beth Beasley

Case Presentation
A 79-year-old man with a past medical history of myasthenia gravis presented
180

with shortness of breath and cough for 3 weeks. He had been diagnosed with
myasthenia gravis four months prior to presentation, and had been treated
with prednisone and azathioprine. He was originally from Cuba, but had not
traveled for several years, and he denied any fevers, chills, night sweats, or sick
contacts. An admission chest radiograph at an outside institution revealed a left
lower lobe infiltrate, and he was treated with broad-spectrum intravenous anti-
biotics for pneumonia. Because of progressive respiratory failure, he required
intubation and mechanical ventilation. He was transferred to our institution for
plasmapheresis for myasthenia gravis flare, and an infectious disease consulta-
tion was requested.
On physical examination, his temperature was 37.4°C with heart rate of 86
beats/minute and blood pressure of 121/65 mm/Hg. He was intubated, and
had decreased breath sounds at the left base. Laboratory examination was sig-
nificant for leukocytosis (13.4 x103 cells/μl, 94% neutrophils) and thrombocy-
topenia (80 x103 platelets/μl). Chest CT revealed multiple nodular infiltrates
(Figure 7e.1), a large left pleural effusion, and multiple air fluid collections con-
sistent with left lower lobe empyema and abscess.
Thoracotomy, pleural decortication, and wedge resection were performed,
and the patient was found to have multiple abscesses, along with areas of
necrosis and infarction in the lung parenchyma. Microscopic evaluation of the
lung parenchyma revealed empyema, acute pneumonia, and multiples abscesses
with filamentous bacillary forms visible on Gomori methenamine silver stained
tissue (Figure 7e.2). No organisms were visualized on Gram stain or acid-fast
staining of the tissue, but cultures eventually grew Gram-positive bacilli that
were initially misidentified as Coryneform bacillus. After further evaluation in
 Infections in Immunocompromised Hosts
CHAPTER 7 Pulmonary
Figure 7e.1 Chest CT, axial view showing discrete left lower lobe nodular infiltrates.

181

Figure 7e.2 Lung biopsy, Gomori methenamine silver stain showing abscesses with
filamentous bacillary forms.

the microbiology laboratory, cultures were correctly identified as Nocardia

asteroides (Figures 7e.3 and 7e.4), and the patient was treated with intrave-
nous trimethoprim-sulfamethoxazole. The patient required tracheostomy for
prolonged respiratory failure, but was eventually transferred to a rehabilitation
facility after a 4-month hospitalization.
Case 7e Discussion: Nocardia asteroides
Clinical Manifestations: Pulmonary Disease
Nocardia species are found in the environment in soil, organic matter, and
water. They can cause both superficial and disseminated disease with resultant
Infections in Immunocompromised Hosts
CHAPTER 7 Pulmonary

Figure 7e.3 Lung biopsy culture, Gram stain showing Gram-positive, beaded, branching
bacilli later identified as Nocardia asteroids.
182

Figure 7e.4 Lung biopsy culture, Modified acid fast stain positive showing shorter bacil-
lary forms of Nocardia asteroides.

cutaneous, pulmonary, and central nervous system manifestations (see case 3c

for discussion regarding classification, epidemiology, and management of CNS
infections). Pulmonary disease is the most common manifestation (40% of
patients with nocardiosis), and generally occurs in immunocompromised indi-
viduals.1 Inhalation of dust particles is the most common route of acquisition,
and men are three times as likely to be affected as women.2 Almost 90% of pul-
monary nocardiosis is caused by members of the Nocardia asteroides complex.1
 Pulmonary nocardiosis can be an acute, subacute, or chronic infection, with

Infections in Immunocompromised Hosts

both remissions and exacerbations. Patients at risk include those with chronic
lung disease, such as COPD, and immunocompromised individuals—secondary
to HIV, transplant, or prolonged treatment with immunosuppressive medica-
tions for autoimmune disorders.3 Patients often present with a variety of symp-
toms and one observational study of 31 patients with pulmonary nocardiosis
found that the most common clinical presentations were cough (77%), fever
(71%), sputum production (65%), dyspnea (65%), chest pain (39%), and constitu-
tional symptoms (42%).4 Radiographic findings are also diverse and may include
focal infiltrates, irregular densities, subpleural plaques, scattered nodules or
masses which may or may not cavitate, single or multiple abscesses, and inter-
stitial reticulonodular infiltrates.2 Acute infections may progress to empyema in
up to one-third of cases.5 Because of the nonspecific radiographic findings, the
initial differential diagnosis may include bacterial pneumonia, tuberculosis, fun-

CHAPTER 7 Pulmonary
gal infections such as aspergillosis, and malignancy.3 Rhodococcus equi infections
can present a particular challenge because of the microbiologic similarities to
Nocardia species (see below).
Laboratory Diagnosis
Bronchoalveolar lavage fluid, sputum samples, abscesses, wound cultures, tis-
sue biopsy, and cerebrospinal fluid are the most common specimens sent to the
laboratory for diagnosis. The microbiology laboratory should be alerted when

183
nocardiosis is suspected because routine laboratory and culture methods may fail
to isolate the organism from normal commensal flora, and because Nocardia is
a slow-growing organism.3 While Nocardia will grow on standard blood culture
media, initial growth can take 48–72 hours or longer; therefore, the laboratory
should be asked to incubate cultures for at least three weeks. Nocardia species
are catalase positive, and grow in the presence of lysozyme in a nutrient broth
over a wide temperature range. Yield is increased by use of certain media, includ-
ing Thayer-Martin agar with selective antibiotics in order to prevent the growth
of more rapidly growing commensal flora that may obscure the diagnosis. The
organism may also be isolated on Lowenstein-Jensen media (used for isolation
of mycobacteria), Sabouraud’s dextrose media (used for isolation of fungi), or
buffered charcoal-yeast extract agar (used for growth of Legionella species).2
Typical colonies can be seen after 3–5 days and have a dry, chalky appear-
ance, often produce aerial hyphae, and can have a “cotton candy” like appear-
ance and an earthy odor. Direct smears show Gram-positive, beaded, branching
filaments. The filaments may fragment to form rods or coccoid forms, giving the
mistaken appearance typical of other bacterial forms, as in the case above. Other
organisms with a similar appearance include Actinomyces species, Rhodococcus
equi, and rapid-growing mycobacteria. When Nocardia is suspected on Gram
stain, a modified Kinyoun technique using a weak acid (1% sulfuric acid) for
decolorization can be done, as isolates are usually partially acid-fast.2
Biochemical methods are used for species identification, and involve the use
of different metabolic reagents. The diagnosis of Nocardia asteroides, for exam-
ple, is based on the hydrolysis of casein, tyrosine, xanthine, and hypoxanthine.1
Newer molecular techniques such as PCR, restriction enzyme analysis, and 16S
 rRNA gene sequencing are useful for species confirmation, but are generally
Infections in Immunocompromised Hosts

only performed in referral laboratories.6

Management and Prognosis
Sulfonamides remain the drug of choice for pulmonary nocardiosis; however,
because of increasing antimicrobial resistance, susceptibility testing should be
performed. The Clinical and Laboratory Standard Institute (CLSI) has approved
a standard susceptibility testing and interpretation method for Nocardia spe-
cies.6 Besides sulfonamides other antimicrobial classes with varying efficacy
include carbapenems, fluorquinolones, macrolides, oxazolidinones and amin-
oglycosides, and a combination of agents may be indicated in severe cases.
Mortality from pulmonary nocardiosis in some series has been reported as
varying from 14%–40%; however, mortality with disseminated or CNS disease
can approach 100%.4 Duration of therapy should be prolonged, given the high
rate of relapses: most experts recommend 6–12 months of therapy for immu-
CHAPTER 7 Pulmonary

nocompetent patients, and one year for immunosuppressed patients. Given

the high mortality rate and microbiologic challenges, clinical suspicion and early
diagnosis are important factors in the management of pulmonary nocardiosis.

References
1. Sorrell, TC, Mitchell DH, Iredell, JR, Chen, SC. Nocardia species. In Mandell GL,
184

Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett’s Principles and Practice
of Infectious Diseases. 7th ed. Philadelphia, PA: Churchill, Livingston, Elsevier;
2009:3199–3207.
2. Lerner P. Nocardiosis. Clin Infect Dis. 2006;22(6):891–903
3. Martinez R, Reyes S, Menedez R. Pulmonary nocardiosis: risk factors, clinical fea-
tures, diagnosis and prognosis.” Curr Opin Pulm Med. 2008;14:219–227.
4. Martinez TR, Menendez VR, Reyes CS, et al. Pulmonary nocardiosis: risk factors
and outcomes. Respirology. 2007;12:394–400
5. Brown-Elliott BA, Brown JM, Conville PS, Wallace RJ Jr. Clinical and laboratory
features of the Nocardia spp. based on current molecular taxonomy. Clin Microbiol
Rev. 2006;19(2):259–282
6. Saubolle MA, Sussland D. Nocardiosis: Review of clinical and laboratory experi-
ence.” J Clin Microbiol. 2003;41(10): 4497–4501

Case
C a e 77f:
f: Fever,
f: F C
Cough,
ouggh,
h, aand
nd
d SShortness
Sh
hortness
t off B
o Breath
rea
eath
th in
i an
Immunocompromised
Immu
Im munocompromi mise
sed HoHost
H st

Luciano Kapelusznik
Case Presentation
A 52-year-old male with history of kidney transplantation secondary to
hypertensive nephropathy presented to the emergency room complaining
of fever, cough, blood-tinged sputum, and shortness of breath for one week.
His cadaveric kidney transplant was three years prior to presentation, and his
immunosuppressive medications included tacrolimus and mycophenolic acid.

Infections in Immunocompromised Hosts

Antimicrobial prophylaxis with trimethoprim/sulfamethoxazole and valganci-
clovir had been discontinued a year prior, as recommended by his treating
physician. On review of symptoms he admitted to an unintentional 15-pound
weight loss over the prior month, as well as nausea and diarrhea for the preced-
ing 3 days. He denied any other constitutional symptoms, and his last tuberculin
skin test was negative prior to transplant. He was working as a school facilities
inspector, and denied any recent travel history or sick contacts.
On physical examination he looked acutely ill, in moderate respiratory distress,
and was febrile to 38.3°C, tachycardic (HR 124 beats/minute), tachypneic (RR 30
breaths/minute), and hypoxic (oxygen saturation 85% on ambient air). He had dry
mucous membranes and deep bronchial breath sounds on the lower half of his
right chest without dullness to percussion or egophony. Except for a well-healed
scar on his abdomen, the rest of the physical examination was unremarkable.

CHAPTER 7 Pulmonary
His WBC was 22 x 103/μl with 99% neutrophils, creatinine 3.3mg/dl, sodium
132 mEq/L, alanine aminotransferase 136 UI/mL, aspartate aminotransferase
135 UI/mL, total bilirubin 4 mg/dl, and direct bilirubin 3.5mg/dL. Chest radiogra-
phy revealed a dense consolidation of almost the entirety of the right lung and
a much smaller part of the left upper lobe (Figure 7f.1), and chest CT confirmed
severe bilateral pneumonia (Figure 7f.2).
He was intubated on admission and underwent bronchoscopy with bron-
choalveolar lavage (BAL). A urinary Legionella antigen test sent on admission

185
came back positive on hospital day 2 (Figure 7f.3), and direct fluorescence anti-
body (DFA) for Legionella of the BAL sample revealed apple green fluorescence
around the alveolar cells (Figure 7f.4) confirming the diagnosis of Legionnaire’s

Figure 7f.1 Chest radiography, anterior-posterior view showing a dense consolidation

of almost the entirety of the right lung and a much smaller part of the left upper lobe.
Infections in Immunocompromised Hosts
CHAPTER 7 Pulmonary

Figure 7f.2 Chest CT, axial view with severe bilateral pneumonia.
186

Figure 7f.3 Positive rapid urine Legionella antigen test.

 Infections in Immunocompromised Hosts
CHAPTER 7 Pulmonary
Figure 7f.4 Positive direct fluorescence antibody (DFA) stain for Legionella on bron-
choalveolar lavage sample.

disease. He was treated for 14 days with levofloxacin 500mg daily, became
afebrile after 5 days, and was extubated after 10 days. He required intense

187
rehabilitation and was discharged from the hospital one month after admission.
Further questioning did not reveal any obvious exposures to possible contami-
nated water sources.
Case 7f Discussion: Legionella pneumophila
Microbiology and Epidemiology
Legionella was first identified in 1976 as the organism that caused an out-
break of pneumonia among attendants of the American Legion convention in
Philadelphia. It comprises a family of ubiquitous intracellular Gram-negative coc-
cobacilli that inhabit natural aquatic environments, manmade hot water systems,
and air-conditioning/cooling towers. The survival of Legionella is aided by its
parasitism of free-living amoebae, which encyst in environmental conditions that
are not favorable for growth. The transmission of this organism is via inhalation
of contaminated aerosols, or by microaspiration of contaminated water. There
are more than 50 recognized species of Legionella, of which 20 have been recog-
nized as human pathogens. Legionella pneumophila is by far the most common of
these species to cause human disease, and serogroup 1 accounts for over 80% of
the cases of legionellosis. The most frequently isolated non-pneumophila species
include longbeachae, bozemanae, micdadei, dumoffii, and feelii.1
Legionnaire’s disease accounts for 2% to 9% of the cases of community-
acquired pneumonia, but it has also been associated with outbreaks in hospi-
tals and long-term care facilities. Immunocompromised patients with defects in
cell-mediated immunity are particularly susceptible to Legionella infection—e.g.,
corticosteroid use, hairy cell leukemia, and organ transplantation.2,3 A retro-
spective study of 2946 solid organ transplant (SOT) patients in Spain found
 Legionnaire’s disease in 0.5%, with a prevalence of 0.8% among heart recipi-
Infections in Immunocompromised Hosts

ents, 0.5% among kidney recipients, and 0.3% among kidney recipients. Of these
patients, 21% had early onset disease (= 3 months after SOT) and 79% had late
disease (= 3 months after SOT).4
In addition, severe Legionella pneumonia has been reported in association
with the use of TNF-D antagonists such as infliximab and etanercept.4 Cigarette
smoking and chronic lung disease increase the risk of Legionella pneumonia, but
patients with AIDS are not at increased risk of Legionella infection. Nonetheless;
they tend to have more severe clinical illness when infected.2
Clinical Features and Diagnosis
Two distinct clinical syndromes characterize Legionella infection: Legionnaire’s
disease classically presents with a moderate to severe pneumonia and multisys-
temic symptoms, whereas Pontiac fever is a mild, self-limited, flu-like syndrome
without pulmonary findings. Legionnaire’s disease has an incubation time of
CHAPTER 7 Pulmonary

2 to 10 days, and symptoms range from a mild cough and low-grade fever to
stupor, respiratory failure, and multiorgan failure. Early in the illness, patients
have nonspecific symptoms including fever, malaise, myalgias, anorexia, and
headache. The temperature often exceeds 40°C, but the cough is typically only
slightly productive. Gastrointestinal symptoms are prominent, especially diar-
rhea, which occurs in 20%–40% of cases.1 Chest pain, occasionally pleuritic, can
be prominent and when coupled with hemoptysis may mistakenly suggest other
188

clinical entities such as pulmonary embolism. In a case series of 14 SOT patients

with Legionnaire’s disease,4 the most common symptoms were chills (64%),
fever (50%) and cough (50%).
Laboratory findings are nonspecific. Leukocytosis is often present, and in
severe cases it may be accompanied by thrombocytopenia. Hyponatremia
and hypophosphatemia occur more frequently in Legionnaire’s diseases than
in other pneumonias. A mild to moderate elevation of liver enzymes is also
commonly observed, and patients may develop acute kidney injury.1 The radio-
graphic findings of Legionella pneumonia can vary, and include unilateral or
bilateral dense, patchy, or nodular pulmonary infiltrates that can progress to
cavitation. Cavitary lung disease is relatively common in immunocompromised
patients, particularly solid organ recipients, and pleural effusions are present in
one-third of the patients.5
The gold standard for diagnosis of Legionnaire’s disease is culture from a
sputum or BAL specimen. This method has the advantage of being able to
identify all Legionella species, and is 100% specific. The main disadvantages are
that Legionella is difficult to culture, the method is time consuming, requiring up
to 7 days to identify most colonies, and in many cases, patients have a nonpro-
ductive cough. In addition, Legionella requires buffered charcoal yeast extract
agar supplemented with D-ketoglutarate medium for growth (BYCE), with a
reported sensitivity ranging from 10%-80%.5
Measurement of acute and convalescent antibodies by IFA or ELISA to
detect a fourfold rise in Legionella IgG titers is useful as an epidemiologic
tool, but does not provide clinically applicable information for diagnosis of
the acutely ill patient. One of the most useful methods is the detection of
Legionella pneumophila Type 1 urinary antigen by EIA, which has a reported

Infections in Immunocompromised Hosts

sensitivity of 60%–100% and a specificity of >99% . Several studies have shown
that the sensitivity of the test is highest among patients with severe disease, and
a rapid immunochromatographic test has a similar sensitivity and specificity.
Antigenuria can be detected as early as one day after the onset of symptoms,
and persists for weeks. The major disadvantage of the test is the inability to
detect the other serogroups or species that comprise up to 20% of the cases
of legionellosis.5
Direct fluorescent antibody (DFA) assay can be performed with polyclonal
or monoclonal antibodies against Legionella pneumophila. The sensitivity of
the test has been reported to be between 25%–85% with a specificity of 95%.
Advantages of this test are that it is rapid and that it can detect species or
serogroups other than L. pneumophila serogroup 1. The main disadvantage is
that cross-reactivity with non-legionella bacteria, and background fluorescence,

CHAPTER 7 Pulmonary
can decrease its performance. PCR is another diagnostic modality that has
been applied to sputum, blood, and urine samples. Diagnostic PCR assays have
principally targeted specific regions within 16S rRNA genes, the 23S-5S spacer
region, 5S rDNA, or the macrophage inhibitor potentiator (mip) gene. In sam-
ples from the lower respiratory tract, PCR has shown a sensitivity equivalent to
culture: however, false positive results have been reported.5
Treatment

189
Mortality without treatment ranges from 16% to 30%, and with treatment it has
been reduced to 5%–10% in patients with community-acquired disease. In one
study of SOT patients, the mortality was found to be 14%, though large-scale
studies of this population are lacking.4 Fluoroquinolones, macrolides, rifampin,
and tetracyclines are active against Legionella. Because Legionella is an intra-
cellular organism, high intracellular levels of antibiotics favor bacterial killing.
In immunocompetent patients, four small observational studies showed faster
resolution of fever and shorter hospital stay with fluoroquinolones than with
macrolides, but no difference in mortality rates. Newer macrolides, such as
azithromycin 500 qd, and “respiratory” fluoroquinolones such as levofloxacin
500 qd, moxifloxacin 400 qd and gatifloxacin 400 qd, are currently recom-
mended as the treatment of choice because of their potency and high intra-
cellular concentration in the lungs. A 10-day to 14-day duration of antibiotics
is usually sufficient in immunocompetent patients, but up to 21 days may be
needed for immunocompromised patients with severe disease. In transplant
recipients, fluoroquinolones are advantageous since some macrolides may
inhibit the metabolism of immunosuppressant agents such as tacrolimus and
cyclosporine.3

References
1. Stout JE, Yu VL. Legionellosis. N Engl J Med. 1997 Sep 4;337(10):682–687
2. Schlossberg D, Bonoan J. Legionella and immunosuppression. Semin Respir Infect.
1998;13(2):128–131.
 3. Chow JW, Yu VL. Legionella: a major opportunistic pathogen in transplant recipi-
Infections in Immunocompromised Hosts

ents. Semin Respir Infect. 1998;13(2):132–139

4. Gudiol C, Garcia-Vidal C, Fernández-Sabé N, Verdaguer R, Lladó L, Roca J, Gil-
Vernet S, Carratalà J. Clinical features and outcomes of Legionnaires’ disease in
solid organ transplant recipients. Transpl Infect Dis. 2009;11(1):78–82.
5. Edelstein PH. Clinical features of Legionnaires’ disease: a selected review. In:
Cianciotto NP, Kwaik Y, Edelstein PS, et al., eds. Legionella: state of the art 30 years
after its recognition. Washington DC: American Society for Microbiology; 2006:3–7.
CHAPTER 7 Pulmonary
190
 Chapter 8

Cardiac Infections

Case
C a e 8a:
8a: A 336
36-Year-Old
6-Y
Year-O
Old Man
M wit
with
ith
hHHomonymous
om
monymo
mous
Hemi
He mianopsia
Hemianopsia

Meenakshi Mehrotra Rana

Case Presentation
A 36-year-old man with a past medical history significant for non-insulin-depen-

191
dent diabetes mellitus presented with abdominal pain, nausea, vomiting, and
a low grade fever to 100.7º Fahrenheit. CT scan of the abdomen during that
admission was significant for splenic infarctions, as well a wedge-shaped renal
infarct (Figures 8a.1 and 8a.2). A transesophageal echocardiogram was done to
evaluate for a source of possible emboli, but no evidence of a vegetation was
seen. One set of blood cultures was done and were negative. An evaluation for
possible causes of hypercoagulability was pursued, and he was discharged on
warfarin while results were pending.
One month later, he presented again to the emergency room with headache
and visual complaints. He complained specifically of difficulty seeing out of the
left eye and tunneled vision, and again reported some low grade fever and
chills over the past month. He worked for the department of transportation
and denied any recent sick contacts, pets, recent travel, dental extractions, or
intravenous drug use.
On physical examination in the emergency room, his vital signs were 38.6º
Farenheit and he was tachycardic to 119 beats per minute, with a blood pres-
sure of 145/69. He had anisocoria (right pupil 4mm, left pupil 3mm)and left
homonymous hemianopsia; visual acuity was 20/50 bilaterally. His extraocular
movements were intact, and facial movements were symmetric. His reflexes
were 2+ throughout, though slightly brisker on the right side than on the left.
He had a soft diastolic murmur on cardiac exam, but the remainder of his physi-
cal examination was unremarkable.
Laboratory examination was significant for leukocytosis (13.6 x 10 WBC/
μl, 81% neutrophils), elevated erythrocyte sedimentation rate (105 mm/hour),
CRP (55, nl range 0–8), and therapeutic INR (2.7). A non-contrast head CT scan
Cardiac Infections
CHAPTER 8

Figure 8a.1 CT scan of the abdomen, axial view with splenic infarctions.
192

Figure 8a.2 CT scan of the abdomen, axial view with multiple wedge-shaped renal
infarcts.

and MRI showed multiple hemorrhagic infarcts, including 3.8 cm hemorrhage

within the right posterior parietal lobe and 6 mm hemorrhage in the right tem-
poral lobe, and 1.9 cm hemorrhage in the left occipital lobe (Figures 8a.3 and
8a.4). He was admitted to the neurology service for management of intracranial
hemorrhage.
A repeat transesophageal echocardiogram showed a small mobile mass on
the noncoronary cusp of the aortic valve and abscess on the anterior leaf-
let of the mitral valve, with mild to moderate aortic regurgitation, mild mitral
regurgitation and mildly decreased left ventricular systolic function of 40%
 Cardiac Infections
193CHAPTER 8
Figure 8a.3 MRI brain, axial view showing 3.8 cm hemorrhagic infarct within the right
posterior parietal lobe.

Figure 8a.4 MRI brain, axial view showing 1.9 cm hemorrhagic infarct in the left
occipital lobe.
 (Figure 8a.5). Blood cultures were drawn and grew Streptococcus constellatus
Cardiac Infections

from four different sets; penicillin MIC was 0.06 (Figure 8a.6). He was started
on ceftriaxone 2 grams IV daily for 4 weeks, and his visual deficit improved to a
minor left inferior quadrantanopsia.
He was discharged and readmitted after 4 weeks of intravenous antibiotics
for valve replacement and repair. In the operating room, he had vegetations on
the noncoronary and right coronary cusps of the aortic valve, and the aortic
CHAPTER 8

valve was excised. An abscess cavity was also seen on the ventricular surface
194

Figure 8a.5 Transesophageal echocardiogram showed a small mobile mass on the

non-coronary cusp of aortic valve and abscess on anterior leaflet of mitral valve with
mild to moderate aortic regurgitation, mild mitral regurgitation and mildly decreased left
ventricular systolic function of 40%.

Figure 8a.6 Blood cultures with Gram-positive cocci in chains, later identified as
Streptococcus constellatus.
of the mitral valve which was debrided and the mitral valve was repaired. The

Cardiac Infections
aortic valve was replaced with a St. Jude’s mechanical valve. Gram-stain of the
mitral valve abscess showed few Gram-positive cocci in pairs, but final cul-
tures were negative. The microscopic examination of the excised valves was
consistent with healing vegetations of infectious endocarditis. The patient had
no further complications, and was discharged to complete 4 more weeks of
intravenous ceftriaxone.

CHAPTER 8
Case 8a Discussion: Streptococcus constellatus Endocarditis
Diagnosis
The diagnosis of infective endocarditis (IE) can be straightforward in many
patients with classical clinical manifestations; in other cases, such as the patient
described above, it may initially be more challenging. The Duke criteria,
described by Durack and colleagues in 1994, are most commonly used by most
clinicians in the diagnosis of IE. Diagnosis is based on the presence of either
major or minor clinical criteria. Major criteria include echocardiographic data
or positive blood cultures with typical microorganisms, including Staphylococcus
aureus, viridians streptococci, Streptococcus bovis, HACEK group, or communi-
ty-acquired enterococci. Minor criteria include fever, immunologic phenomena,
vascular phenomena, a positive blood culture with an organism not meeting
one of the major criteria, or predisposing condition. Criteria for diagnosis of
clinically definite IE include 2 major criteria, 1 major criterion and 3 minor cri-

195
teria, or 5 minor criteria (see Table 8a.1). Several studies of the Duke criteria
have consistently shown high sensitivity and specificity in diagnosis of IE.1
Both microbiological and echocardiographic data are central to the diagnosis
of IE, as described by the Duke criteria above. At least three sets of blood
cultures should be taken in the first 24 hours. If the patient has received any
antibiotics in the preceding two weeks, more specimens may be necessary.
Since the bacteremia is usually continuous and low grade, the first two blood
cultures reveal the etiologic agent more than 90% of the time.2
Echocardiography should also be performed in patients with suspected
endocarditis. Evidence of an oscillating mass or vegetation, an annular abscess,
prosthetic valve partial dehiscence, or new valvular regurgitation, meet major
echocardiographic criteria for IE. Whether transthoracic echocardiography
(TTE) or transesophageal echocardiography (TEE) is performed first may
depend on the clinical scenario. TTE is often not a sensitive as TEE for the
detection of vegetations on posterior valves (aortic and mitral) and therefore a
negative test does not exclude left-sided IE. In addition, it may be less adequate
in cases of obesity, COPD, or chest wall deformities. It does, however, have
a high sensitivity for detecting right-sided endocarditis, since the pulmonic and
tricuspid valves are more anterior structures.1
Transesophageal echocardiography is more sensitive than TTE in the detec-
tion of vegetations, especially in prosthetic valves. Studies have reported sen-
sitivities of 48%–100% for TEE as compared with 18%–63% in TTE; however, a
negative result on TEE also does not exclude endocarditis. There may be false
negatives in the case of small vegetations, and vegetations that may have already
Cardiac Infections

Table 8a.1 (taken from Baddour et al, Circulation 2005)

Major criteria
Blood culture positive for IE
Typical microorganisms consistent with IE from separate blood cultures: Viridians
streptococci, Streptococcus bovis, HACEK group, Staphylococcus aureus; or
community-acquired enterococci in the absence of a primary focus; or
Microorganisms consistent with IE from persistently positive blood cultures
CHAPTER 8

defined as follows: At least 2 positive cultures of blood samples drawn >12 h

apart; or all of 3 or a majority of t4 separate cultures of blood (with first and last
sample drawn at least 1 h apart)
Single positive blood culture for Coxiella burnetii or anti-phase 1 IgG antibody
titer >1:800
Evidence of endocardial involvement
Echocardiogram positive for IE (TEE recommended for patients with prosthetic
valves, rated at least “possible IE” by clinical criteria, or complicated IE
[paravalvular abscess]; TTE as first test in other patients) defined as follows:
Oscillating intracardiac mass on valve or supporting structures, in the path
of regurgitant jets, or on implanted material in the absence of an alternative
anatomic explanation; or abscess; or new partial dehiscence of prosthetic valve;
new valvular regurgitation (worsening or changing or preexisting murmur not
sufficient)
Minor criteria
Predisposition, predisposing heart condition, or IDU
196

Fever, temperature >38°C

Vascular phenomena, major arterial emboli, septic pulmonary infarcts, mycotic
aneurysm, intracranial hemorrhage, conjuctival hemorrhages, and Janeway’s lesions
Immunologic phenomena: glomerulonephritis, Osler’s nodes, Roth’s spots, and
rheumatoid factor
Microbiological evidence: positive blood culture but does not meet a major criterion
as noted above* or serological evidence of active infection with organism consistent
with IE
Echocardiographic minor criteria eliminated
Modifications shown in boldface.
* Excludes single positive for coagulase-negative staphylococci and organisms that do not cause
endocarditis.
Reprinted with permission from The University of Chicago Press. Li JS, Sexton DJ, Mick N, et al.
Proposed Modifications to the Duke Criteria for the Diagnosis of Infective Endocarditis. Clinical
Infectious Diseases 2000;30:633–638. © 2000 by the Infectious Diseases Society of America. All
rights reserved.

embolized. In cases of high clinical suspicion such as the patient described

above, TEE should be repeated in 7–10 days. In such cases, an increase in the
vegetation size or presence of abscess cavity may become visible.1
Management
The microorganisms that are most commonly responsible for IE include
those of the Streptococcus and Staphylococcus genera. While Staphylococcus
aureus has developed increasing importance in recent years, the most com-
mon cause of endocarditis has traditionally been members of the Streptococcus
genus. Specifically, the viridians group streptococci cause the most cases of IE,

Cardiac Infections
accounting for 30%–40% of all infective endocarditis. Usually the presentation is
subacute, and may present with nonspecific symptoms as described in the case
above; 20% of cases come to attention because of embolic phenomena.2
Viridans group streptococci are facultatively anaerobic, Gram-positive
cocci that do not produce catalase or coagulase. They are usually alpha-
hemolytic, but can rarely be beta-hemolytic. The term viridans comes from

CHAPTER 8
the greenish discoloration on blood agar caused by partial destruction of
erythrocytes. They are associated with the GI tract, most commonly as a
part of normal human oral commensal flora. The viridians group streptococci
have undergone multiple changes in taxonomy and naming, but the most
clinically significant species can be assigned to one of the following groups:
the anginosus group, the mitis group, the mutans group, the salivarius group,
and the sanguinis group. Members of the anginosus group, also known as the
Streptococcus milleri group, include Streptococcus intermedius, constellatus and
anginosus. The Streptococcus anginosus group is known for causing abscesses
and hematogenously disseminated infections. The nutritionally variant strep-
tococci, specifically Gemella, are also known for causing endocarditis, as is the
Group D, nonenteroccocal Streptococcus associated with colon malignancy,
Streptococcus bovis.2
Antibiotic therapy for infective endocarditis caused by the viridans group
streptococci is guided by the penicillin minimal inhibitory concentration (MIC).

197
For highly penicillin-susceptible strains (PCN MIC < 0.12 μg/ml), there are
four possible options. These include intravenous penicillin or ceftriaxone for
4 weeks, penicillin or ceftriaxone plus gentamicin for 2 weeks, or vancomycin.
Previous studies have shown that the synergistic addition of gentamicin allows
for shortening the duration of therapy with equivalent cure rates; however,
patients require careful monitoring for potential ototoxicity or nephrotoxic-
ity. For strains relatively resistant to penicillin with an MIC of 0.12 to 0.5 μg/
ml, treatment options include intravenous penicillin or ceftriaxone for 4 weeks
with single daily-dose gentamicin for 2 weeks, or vancomycin. For resistant
viridians streptococci, treatment requires 4–6 weeks of intravenous penicillin
and gentamicin or vancomycin.1
Complications
Surgical intervention in patients with infective endocarditis is indicated in cer-
tain clinical scenarios. Patients with infective endocarditis and congestive heart
failure have a higher mortality when treated with medical therapy alone, and
should undergo valve replacement or repair. In addition, other indications for
surgical management include fungal endocarditis, persistent infection or bac-
teremia, evidence of one or more embolic events during the first 2 weeks of
therapy, vegetations larger than 10 mm on the anterior mitral valve leaflet,
echocardiographic evidence of valve dehiscence, perforation, rupture or fistula,
or a large perivalvular abscess’ 3,4
In this case, the patient had evidence of both perivalvular abscess and mul-
tiple embolic events, which were an indication for surgical valve replacement.
 Perivalvular abscess may be difficult to diagnose even by TEE. This complication
Cardiac Infections

occurs more in aortic IE, and can often result in AV heart block—a finding with
a high positive predictive value for abscess formation. Acute surgery is benefi-
cial in these patients to prevent further deterioration of cardiac function.4
Embolic events occur in 10%–50% of cases and often involve the lungs, coro-
nary arteries, spleen, bowel, and extremities. Up to 50%–65% of embolic events
involve the central nervous system and include stroke or mycotic aneurysm.
CHAPTER 8

Prediction of embolic events can be difficult; in some studies, size of vegetation

appears to correlate with risk of embolization, but other studies have shown
this not to be the case. Mitral valve vegetations do appear to carry a greater risk
of embolization than aortic valve vegetations, and an increase in vegetation size
over 4–8 weeks also appears to carry a greater risk of embolization.4 The timing
of surgical intervention in these patients is often complicated by the concern for
conversion of an ischemic stroke to hemorrhagic stroke, secondary to cardio-
pulmonary bypass during surgery and postoperative anticoagulation. Therefore,
surgery is often delayed at least 10–14 days in such patients. Decisions in each
case need to be individualized, and should be made in conjunction with cardio-
thoracic surgeons, neurologists, and infectious disease specialists.
Prophylaxis
Guidelines for the prevention of infective endocarditis were recently updated
in 2007. Previous guidelines stratified risk for infective endocarditis based on
198

high, moderate, or low risk cardiac conditions and also provided a list of dental,
GI, GU, and respiratory procedures for which prophylaxis was and was not
indicated; however, more recently the guidelines have been revised to reflect
more evidence-based literature. The revisions were made based on the premise
that endocarditis is likely to result more from bacteremia associated with daily
activities, rather than bacteremia associated with dental care or GI/GU proce-
dures, and that antibiotic prophylaxis may only prevent a very small number of
cases of IE after such procedures. In addition, the newer guidelines emphasize
that routine dental care was more important in preventing IE, rather than anti-
biotic prophylaxis, and that the risk of antimicrobial therapy may exceed any
possible benefit, if any existed.5
The current guidelines suggest that endocarditis prophylaxis only be recom-
mended in patients with certain cardiac conditions in which the highest risk
of adverse outcomes from IE exists. These include patients with a prosthetic
cardiac valve, or where prosthetic material was used for a cardiac valve repair,
those with a history of IE or congenital heart disease, and cardiac transplant
patients who develop cardiac valvuloplasty.5 As no randomized controlled trial
or convincing data exists demonstrating that antibiotic prophylaxis prevents IE
associated with bacteremia after an invasive procedure, these guidelines were
revised to recommend prophylaxis only in those patients in whom the develop-
ment of IE would be more likely to lead to an adverse outcome, and not neces-
sarily based on an increased lifetime risk of acquiring IE.
Antibiotics for prophylaxis should be administered as a single dose prior to
the procedure; administration of the dose after the procedure should only be
indicated in patients who did not receive their dose prior to the procedure.
As bacteremia may result from minor manipulations or dental work, dental

Cardiac Infections
prophylaxis is recommended in the groups listed above when undergoing any
dental procedure involving manipulation of the gingival or periapical region of
the teeth, or perforation of the oral mucosa. Amoxicillin is the drug of choice
given that it is well absorbed in the GI tract and achieves high serum concentra-
tions. Other alternatives in penicillin-allergic patients include first-generation
cephalosporins, clindamycin, or macrolide antibiotics.5 These antibiotics are

CHAPTER 8
chosen for their low cost, wide availability, and activity against viridians group
streptococci; however, the effect of the development of recent resistant strains
of viridians group streptococci is unknown and should not impact the drug cho-
sen for prophylaxis.
Lastly, antibiotic prophylaxis is deemed reasonable by the revised guidelines
in patients undergoing respiratory invasive procedures in which incision or
biopsy of the respiratory mucosa is performed; i.e., bronchoscopy with biopsy.
The administration of antibiotics to prevent IE in patients undergoing GI or
GU procedures is no longer recommended. In patients undergoing a surgical
procedure involving infected skin, soft tissue, or musculoskeletal tissue, the
guidelines recommend antibiotics with activity against Staphylococcus aureus
and B-hemolytic Streptococcus. For further circumstances and exceptions,
please see the guidelines for prophylaxis of infective endocarditis referenced
below.5

199
References
1. Baddour et al. Infective endocarditis: diagnosis, antimicrobial therapy, and man-
agement of complications: a statement for healthcare professionals from the
Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on
Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology,
Stroke, and Cardiovascular Surgery and Anesthesia. American Heart Association:
Endorsed by the Infectious Diseases Society of America. Circulation. 2005; 111:
e393–e434
2. Fowler VG, Scheld WM, Bayer, AS. Endocarditis and Intravascular Infections. In
Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett’s Principles
and Practice of Infectious Diseases. 7th ed. Philadelphia, PA: Churchill, Livingston,
Elsevier; 2009:1067–1112.
3. Olaison L, Pettersson G. Current best practices and guidelines: indications
for surgical intervention in infective endocarditis.” Infect Dis Clin North Am.
2002;16:453–475
4. Sexton D, Spelman D. Current best practices and guidelines: assessment and
management of complications in infective endocarditis. Infect Dis Clin North Am.
2002;16:507–521
5. Wilson et al. Prevention of Infective Endocarditis. Guidelines from the American
Heart Association; A Guideline from the American Heart Association Rheumatic
Fever, Endocarditis and Kawasaki Disease Committee, Council on Cardiovascular
Disease in the Young and the Council on Clinical Cardiology, Council on
Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes
Research Interdisciplinary Working group. Endorsed by the Infectious Diseases
Society of America. Circulation. 2007;116:1736–1754.
Cardiac Infections

Case
C a e 88b:
b: SSh
Shortness
hortness
t o
off B
Breath
reath
th aand
nd
dWWeight
eiight
ht Lo
Loss
in a Patient
P with
h Hypertrophic
Hyperttrophic Obs
Hy bstructitive
Obstructiveve
Cardiomyopathy
Ca hy

Luciano Kapelusznik and Jeffrey Gumprecht

CHAPTER 8

Case Presentation
A 34-year-old man was admitted with 3 days of worsening shortness of breath,
four-pillow orthopnea, and left-sided chest pain. Three months prior to admis-
sion, he was evaluated for a longstanding history of dyspnea on exertion and
palpitations. At the time, an echocardiogram revealed an asymmetrically thick-
ened septum, along with borderline left-ventricular outflow obstruction and
mild mitral regurgitation with systolic anterior motion. He was diagnosed with
hypertrophic obstructive cardiomyopathy and was treated with a beta-blocker.
Over the next 3 months his symptoms gradually worsened, and he unintention-
ally lost 40 pounds, but denied fevers, chills or night sweats. During the days
prior to admission, his symptoms acutely exacerbated and he was admitted
electively for a cardiac catheterization and alcohol ablation of the interven-
tricular septum.
Before the procedure was performed, a repeat echocardiogram revealed
200

a new vegetation on the anterior leaflet of the mitral valve, along with new
severe mitral regurgitation. On admission he was afebrile, and his physical
examination was notable for bibasilar crackles, a loud 4/6 systolic murmur, and
a laterally displaced apex, but no jugular venous distention or peripheral edema.
His oropharyngeal exam was unremarkable and his dentition did not appear to
hold gross pathology. Laboratory analyses revealed leukocytosis (15.6 x 103
WBC/ul, 80% neutrophils), anemia (hemoglobin 11.4 g/dl), and mildly elevated
liver enzymes (ALT 143 IU/L, AST 96 IU/L). Blood cultures drawn on admission
grew Cardiobacterium hominis after fifty-four hours of incubation (Figure 8b.1).
He later revealed that he had undergone dental extraction 4 months prior to
admission. The patient underwent mitral valve replacement and septal myo-
mectomy. Gram stain of the mitral valve showed gram-negative bacilli but the
valve culture was sterile, and he was discharged home to complete 6 weeks of
intravenous ceftriaxone.
Case 8b Discussion: Cardiobacterium hominis Endocarditis
Clinical Features and Diagnosis
Cardiobacterium hominis is Gram-negative bacillus that often appears as pairs,
short chains, teardrops, rosettes or clusters.1 Although it is part of the nor-
mal oropharyngeal flora, it can cause endocarditis in patients with (76%) or
without (24%) predisposing heart conditions.2 It is often classified as part of
the HACEK group of oropharyngeal bacteria, together with Haemophilus spe-
cies (Haemophilus parainfluenzae, Haemophilus aphrophilus, and Haemophilus
paraphrophilus), Aggregatibacter actinomycetemcomitans (formerly known as
Actinobacillus), Eikenella corrodens, and Kingella species (Kingella kingae and
 Cardiac Infections
CHAPTER 8
Figure 8b.1 Gram stain showing Cardiobacterium hominis.

Kingella denitrificans). These organisms grow slowly in standard blood culture

media, and they account for part of the cases of culture-negative endocarditis.

201
Culture-negative endocarditis is a broad term that groups together organ-
isms such as HACEK, but also includes Coxiella burnetti, Bartonella spp. and
several other fastidious organisms. Nonetheless, the most common cause of
culture-negative endocarditis is, undoubtedly, partially treated staphylococcal
or streptococcal infections3 (Table 8b.1). The yield of growth of HACEK organ-
isms can be increased by holding blood cultures for a prolonged period of time,
t 2 weeks being typically recommended, and their growth is enhanced by the
presence of increased carbon dioxide tension.4 Nonetheless, in a study pub-
lished in the late 1990s, the mean time to growth was found to be 3.3 days, with
most organisms growing by day 10.5 Most modern laboratories have greatly
improved their culture techniques, but unfortunately, there is no new published
data looking at the growth yield since then. More recently, some laboratories
have successfully reported the use of PCR and gene sequence analysis of the
16S rRNA of the organisms as a means to identify HACEK organisms in both
blood and valve tissue.6–8
The prevalence of HACEK endocarditis remains low across different com-
munities. In a study from Olmstead County, Minnesota the HACEK group
accounted for 3% of the cases of community-acquired native valve endocardi-
tis and 6% of the referral population.9 A more recent study from Argentina10
showed a prevalence of 6%. Factors such as the number of intravenous drug
users and circulating local flora including the prevalence of community-
acquired methicillin resistant Staphylococcus aureus, might affect the prevalence
of HACEK infections.
The largest published case series of HACEK endocarditis showed that of
45 confirmed cases, 19 (42%) grew Haemophilus spp.; 9 (20%) Actinobacillus
Cardiac Infections

Table 8b.1 Bacteria Associated with CNE

Bacteria Number of published cases
Staphylococcus spp Principle cause
Streptococcus spp 2nd most common
Enterococcus spp 3rd most common
Pseudomonas aeruginosa Frequent in IV drug abusers
CHAPTER 8

Coxiella burnetii 485

Bartonella spp 252
Corynebacterium spp 201
Brucella spp 155
Abiotrophia spp 120
Neisseria spp 119
Actinobacillus actinomycetemcomitans* 103
Haemophilus aphrophilus* 80
Cardiobacterium hominis* 80
Listeria monocytogenes 73
Haemophilus parainfluenzae 72
Erysipelothrix spp 65
Gemella spp 44
Pasteurella spp 33
202

Kinglella kingae* 33
Eikenella corrodens* 25
Mycobacterium spp 23
Capnocytophaga spp 23
Campylobacter spp 20
Yersinia spp 15
Mycoplasma spp 13
Granulicatella spp 13
Legionella spp 9
Tropheryma whipplei 9
* Organisms belonging to the HACEK group.
CNE—culture-negative endocarditis; IE—infective endocarditis; IV—intravenous.
With kind permission from Springer Science+Business Media: Madico GE, Rice PA. 16S-Ribosomal
DNA to Diagnose Culture-Negative Endocarditis. Curr Infect Dis Rep. 2008;10(4):280–286. Table 1.

actinomycetemcomitans; 12 (27%) Cardiobacterium hominis; 2 (4%), Eikenella cor-

rodens; and 3 (7%) Kingella kingae. Almost all of these patients had fever as
a presenting symptom (98%), followed by a new or changing murmur (78%),
microemboli (67%), splenomegaly (51%), and macroemboli (7%). Of this group,
39 (87%) had prior structural heart disease or a prosthetic valve, 9 (20%) had
poor dentition, and 17 (38%) had undergone prior dental work. Twenty patients
(45%) had aortic valve involvement and 20 (45%) had mitral valve involvement.
Both valves were involved in only 2 cases (4%). Overall, 2 patients died (2%),

Cardiac Infections
with 18 (40%) requiring surgery.5
Treatment
Previously, the HACEK group was uniformly susceptible to ampicillin; how-
ever, E-lactamase producing strains of HACEK are appearing with increased
frequency. Acknowledging that there is limited published data supporting a

CHAPTER 8
specific treatment or duration, the American Heart Association released a
set of guidelines, which has been endorsed by the Infectious Disease Society
of America, recommending ceftriaxone or ampicillin-sulbactam as first-line
therapy.11 The HACEK group is susceptible in vitro to fluoroquinolones, but
there are only a few case reports of the use of this class of antibiotics for
endocarditis treatment; therefore, fluoroquinolones are only recommended
for patients who cannot tolerate E-lactams.

References
1. Slotnick IJ, Dougherty M. Further characterization of an unclassified group of bacte-
ria causing endocarditis in man: Cardiobacterium hominis gen. et sp. n. Antonie Van
Leeuwenhoek. 1964;30:261–272.
2. Walkty A. Cardiobacterium hominis endocarditis: A case report and review of
the literature. Can J Infect Dis Med Microbiol. 2005;16(5):293–297.

203
3. Madico GE, Rice PA. 16s-ribosomal dna to diagnose culture-negative endocardi-
tis. Curr Infect Dis Rep. 2008;10(4):280–286.
4. Wormser GP, Bottone EJ. Cardiobacterium hominis: review of microbiologic
and clinical features. Rev Infect Dis. 1983 Jul-Aug;5(4):680–691.
5. Das M, Badley AD, Cockerill FR, Steckelberg JM, Wilson WR. Infective endo-
carditis caused by HACEK microorganisms. Annu Rev Med. 1997;48:25–33.
6. Westling K, Vondracek M. Actinobacillus (Aggregatibacter) actinomycetem-
comitans (HACEK) identified by PCR/16S rRNA sequence analysis from the
heart valve in a patient with blood culture negative endocarditis. Scand J Infect
Dis. 2008;40(11–12):981–983.
7. Das I, DeGiovanni JV, Gray J. Endocarditis caused by Haemophilus parainfluenzae
identified by 16S ribosomal RNA sequencing. J Clin Pathol. 1997;50(1):72–74.
8. Gatselis N, Malli E, Papadamou G, Petinaki E, Dalekos GN. Direct detection of
Cardiobacterium hominis in serum from a patient with infective endocarditis by
broad-range bacterial PCR. J Clin Microbiol. 2006;44(2):669–672.
9. Steckelberg JM, Melton LJ 3rd, Ilstrup DM, Rouse MS, Wilson WR. Influence
of referral bias on the apparent clinical spectrum of infective endocarditis. Am J
Med. 1990;88(6):582–588.
10. Ferreiros E, Nacinovich F, Casabé JH, et al.; EIRA-2 Investigators. Epidemiologic,
clinical, and microbiologic profile of infective endocarditis in Argentina: a national
survey. The Endocarditis Infecciosa en la República Argentina-2 (EIRA-2) Study.
Am Heart J. 2006;151(2):545–552.
11. Baddour LM, Wilson WR, Bayer AS, et al; Committee on Rheumatic Fever,
Endocarditis, and Kawasaki Disease; Council on Cardiovascular Disease in the
Young; Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery
and Anesthesia; American Heart Association; Infectious Diseases Society of
America. Circulation. 2005;111(23):e394-e434.
Cardiac Infections

Case
C a e 88c:
c: A 224
24-Year-Old
4-Y
Year-OOld M
Man ffrom Botswana
Bottswana
ts awwith
ith
ith
P
Pl euri
eur tic Chest Pa
Pleuritic ain
Pain

Florence Nana and W. Michael Scheld

Case Presentation
CHAPTER 8

A 24-year-old African student presented to a local emergency department with

a one week history of lower back pain, fever, chills, shortness of breath, and
pleuritic chest pain. The patient had recently immigrated to the United States
from Botswana ,one month prior to presentation. He had been treated for
malaria approximately 10 years ago, but otherwise had no significant medical
history. His review of systems was also notable for decreased appetite and a
mild nonproductive cough. On physical examination, he was a thin male in no
acute distress, whose blood pressure was 94/57 and whose oxygen saturation
was 97% on ambient air. His physical exam was otherwise unremarkable, but a
chest radiograph revealed an enlarged cardiac silhouette (Figure 8c.1).
Echocardiography revealed a large pericardial effusion with early cardiac
tamponade, and a pericardiocentesis was performed. Pericardial fluid analysis
revealed protein 5.6, glucose 44, LDH 423, WBC 4144 (62% lymphocytes, 32%
polymorphonuclear cells), and the direct smear of the pericardial fluid was
204

negative for acid-fast bacilli. The patient felt better after the pericardiocen-
tesis, but his fevers persisted. HIV serology, malaria smears, blood cultures,

Figure 8c.1 Chest radiography anterior posterior view showing an enlarged cardiac
silhouette.
and sputum for acid-fast bacilli were all negative. Pericardial biopsy did not

Cardiac Infections
reveal granulomas; however, cultures of pericardial fluid and tissue later grew
Mycobacterium tuberculosis complex (MTB), and the patient was treated with
rifampin, isoniazid, pyrizinamide, and ethambutol.
Case 8c Discussion: Tuberculous Pericarditis
Epidemiology

CHAPTER 8
Tuberculous pericarditis is a rare manifestation of tuberculosis that can be
fatal even with proper diagnosis and treatment. The incidence of this form
of tuberculosis has declined in the United States but it is reemerging in areas
with significant populations of recent immigrants from endemic countries.1 It
remains an especially important problem in countries with high HIV preva-
lence. One study from Tanzania enrolled 28 patients with large pericardial
effusions, and of the 14 patients who were HIV positive, all had tuberculous
pericarditis.2
Pericardial infection with Mycobacterium tuberculosis may occur via extension
of infection from the lung, tracheobronchial tree, adjacent lymph nodes, spine,
and sternum, or via miliary spread. In most adults, pericardial tuberculosis rep-
resents reactivation of the disease, and the primary pulmonary focus may not
be apparent.
Clinical Manifestations and Diagnosis

205
The symptoms of tuberculous pericarditis are nonspecific, and diagnosis may
be delayed or missed because of the challenges of confirming this manifesta-
tion of TB. Patients may present with acute pleuritic chest pain, or with more
insidious symptoms suggesting heart failure, such as cough, dyspnea, and ortho-
pnea. Typical systemic symptoms of tuberculosis such as night sweats, fever,
and weight loss may also be present. Physical findings of TB pericarditis include
fever, pulsus paradoxus, pericardial rub, hepatomegaly, and internal jugular vein
distention. In areas of high endemicity, symptoms and signs of pericarditis may
be enough to prompt empiric therapy because most of the cases of exudative
pericarditis are secondary to tuberculosis.2
A positive tuberculin skin test result may increase the suspicion of TB peri-
carditis, but a negative skin test result does not exclude the diagnosis.
Nontraumatic hemopericardium is most suggestive of tuberculous or malig-
nant etiologies. In most patients with TB pericarditis, the fluid is exudative,
with a leukocyte count ranging from 700–54,000/μl. Examination of smears of
pericardial fluid has poor sensitivity, and cultures are positive in less than 50%
of cases.3
Pericardial biopsy with tissue sent for both culture and histopathological
examination is the diagnostic procedure with the highest yield (Figure 8c.2
and 8c.3). Adenosine deaminase (ADA) levels and measurement of interferon
gamma levels in pericardial fluid are adjunctive studies that can be useful. The
sensitivity of elevated IFN is 92%, that of elevated ADA is 87%, and their speci-
ficities are 100% and 89%, respectively.4
Reuter et al. suggested a classification tree for diagnosis of tuberculous
pericarditis based on pericardial fluid ADA and interferon gamma levels
Cardiac Infections
206CHAPTER 8

Figure 8c.2 and 8c.3 Oil immersion and low power view of the pericardium stained
with Fites stain showing Mycobacterium tuberculosis.

(Figures 8c.4 and 8c.5).4 PCR for mycobacterial DNA has been used for diagno-
sis of pericardial TB, but its sensitivity has been reported to be as low as 30% in
a study in an endemic area.4
Management
The treatment of most extrapulmonary manifestations of tuberculosis, such as
tuberculous pericarditis, is the same as pulmonary tuberculosis (see Chapter 6
for full discussion). If cultures are positive for Mycobacterium tuberculosis that
is susceptible to isoniazid and rifampin, 2 months of treatment with isoniazid,
rifampin, pyrazinamide, and ethambutol is followed by an additional 4 months
of isoniazid and rifampin. The addition of corticosteroids is recommended dur-
ing the first 11 weeks of treatment in order to decrease the likelihood of late
constrictive pericarditis. In one study, the addition of corticosteroids reduced
 Cardiac Infections
Pc-ADA activity
>40 U/L
No Yes

HIV serology positive

No Yes

CHAPTER 8
PB-WCC
<10 x 109 /L

No Yes

Pc L/N ratio >1

No Yes

Non-tuberculous Tuberculous
pericarditis pericarditis

Figure 8c.4 Classification tree developed for the diagnosis of pericardial TB based on
Pc-ADA, pericardial adenosine deaminase; PB-WCC, peripheral blood white cell count;
Pc L/N ratio, pericardial lymphocyte/neutrophil ratio. Reprinted with permission from
Reuter H, Burgess L, van Vuuren W, Doubell A. Diagnosing tuberculous pericarditis.
QJM. 2006; 99(12): 827–839.

207
Pc-IFN
>50 pg/mL
Yes No

PB-WCC
>10 x 109 /L

No Yes

Pc L/N ratio
>1
Yes No

Tuberculous Non-tuberculous
pericarditis pericarditis

Figure 8c.5 Classification tree based on the determination of IFN-gamma levels for the
diagnosis of pericardial TB. Pc-IFN, pericardial interferon-gamma; PB-WCC, peripheral
blood white-cell count; Pc L/N ratio, pericardial lymphocyte/neutrophil ratio. Reprinted
with permission from Reuter H, Burgess L, van Vuuren W, Doubell A. Diagnosing tuber-
culous pericarditis. QJM. 2006;99(12):827–839.
 mortality and the need for subsequent pericardiectomy.5 Pericardiectomy is
Cardiac Infections

generally reserved for patients who remain hemodynamically compromised

after 4–6 weeks of adequate therapy. 3,5

References
1. Trautner BW, Darouiche RO: Tuberculous pericarditis: optimal diagnosis and
CHAPTER 8

management. Clin Infect Dis. 2001 Oct 1;33(7):954–961.

2. Cegieslski JP, et al. Tuberculous pericarditis in Tanzanian patients with and with-
out HIV infection. Tuber Lung Dis. 1994; 75(6): 429–434.
3. Fitzgerald D, Sterling T, Haas D. Mycobacterium tuberculosis. In Mandell GL,
Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett’s Principles and Practice
of Infectious Diseases. 7th ed. Philadelphia, PA: Churchill, Livingston, Elsevier;
2009:3129–3163.
4. Reuter H, Burgess L, van Vuuren W, Doubell A. Diagnosing tuberculous peri-
carditis. QJM.2006;99(12):827–839
5. Strang JI, Nunn AJ, Johnson DA, et al: Management of tuberculous constrictive
pericarditis and tuberculous pericardial effusion in Transkei: results at 10 years
follow-up. QJM 2004; 97:525–535.

Case
C a e 88d:
d: Ski
SSkin
kin LLesion
ki esion
i n in
i aP
Patient
ati
tientt with
ith
h Recen
R
Recent
nt H
Heart
earrt
208

Transplant
Tran
Tr anssplant

Mahesh Swaminathan and Shirish Huprikar

Case Presentation
A 53-year-old man with a history of dilated cardiomyopathy (DCM) under-
went heart transplantation 2 months prior to presenting with left lower
extremity pain, swelling and erythema. Two weeks prior to admission, he
noticed pain and swelling in his left ankle, and a few days later he noticed an
area of skin ulceration that had steadily grown larger. He was treated with
cephalexin for a presumed cellulitis, and colchicine for a possible diagnosis of
gout without improvement. He had subjective fevers and a measured tem-
perature of 101.7º F one day prior to admission.
His past medical history was notable hypertension and diabetes, and his
medications included mycophenolate, tacrolimus, prednisone, trimethoprim/
sulfamethoxazole, valganciclovir, insulin, furosemide, calcium, ferrous sulfate,
and diltiazem. The patient was from a small rural village in El Salvador, but he
had lived United States for 10 years prior to admission. On physical examina-
tion, he was afebrile, and on the left ankle there was a 2cm area of swelling,
ulceration, and erythema over the left lateral malleolus (Figure 8d.1). There
were also painful nodules on the calf proximal to the skin ulcer (Figure 8d.2).
The remainder of the physical examination was unremarkable.
Laboratory analyses were notable for anemia (8.8 mg/dl) and renal insuffi-
ciency (creatinine 2.5mg/dl), but the white blood cell count, platelets, liver func-
tion panel, and serum electrolytes were within normal limits. A plain radiograph
 Cardiac Infections
CHAPTER 8
Figure 8d.1 Physical examination revealed a 2cm area of swelling, ulceration and
erythema over the left lateral malleolus.

209

Figure 8d.2 Physical examination revealed painful nodules on the calf proximal to the
skin ulcer.

of the left ankle showed no evidence of fracture, periosteal reaction, or joint

space disease. After 48 hours of treatment with vancomycin, the patient had
no obvious improvement in his symptoms. Intravenous acyclovir was initiated
for the possibility of an atypical presentation of herpes zoster in the setting of
valganciclovir prophylaxis; however, there was no improvement and biopsy was
recommended to assess for another opportunistic pathogen, such as a myco-
bacterium, fungus, Nocardia, or a parasitic infection, such as Chagas’ disease. A
biopsy of the lesions was performed, revealing the presence of the amastigotes
of Trypanosoma cruzi at the dermal–epidermal junction (Figure 8d.3).
Cardiac Infections
CHAPTER 8

Figure 8d.3 Skin biopsy, hematoxylin and eosin stain revealing the presence of the
amastigotes of Trypanosoma cruzi at the dermal-epidermal junction. Note the bar-like
kinetoplast adjacent to the protozoan nucleus.

PCR of the patient’s serum, as well as skin scrapings taken from the lesion
(performed by the Division of Parasitic Diseases branch of the Centers for
Disease Control and Prevention), confirmed the diagnosis of T. cruzi. Peripheral
210

blood smears did not show evidence of trypomastigotes, but serology for
T.cruzi was positive. Reevaluation of the explanted heart pathology did not
reveal amastigotes within the cardiac tissue. The patient was treated with ben-
znidazole, and after 60 days of therapy the skin lesion had largely resolved
(Figure 8d.4). Subsequent monthly monitoring with T. cruzi PCR testing has
been negative for further reactivation.
Case 8d Discussion: Chagas Disease
Epidemiology and Parasitology
T. cruzi, the causative pathogen of Chagas’ disease, is a protozoan flagellate
of the family Trypanosomatidae, order Kinetoplastida. The motile trypomas-
tigote form has a single flagellum originating near the kinetoplast, which is a
DNA-containing structure located in the parasite’s single, complex mitochon-
drion. The flagellum is enveloped in an undulating membrane and runs parallel
to long axis of the organism, extending beyond the body as a free, thread-
like structure. T. cruzi is a zoonosis that has been isolated in a large number
of natural reservoir hosts, including over 150 species of wild and domestic
mammals.1
T. cruzi is transmitted by the Triatoma infestans, also known as “the kissing
bug” (Figure 8d.5), which acquires the parasite when it takes a blood meal
from an infected animal. The infected insect then takes another blood meal
from an uninfected host, and during the feeding process the vector defecates
near the wound, excreting infective trypomastigotes. The infective trypomastig-
otes enter the new host’s bloodstream through the bite wound or an exposed
 Cardiac Infections
CHAPTER 8
Figure 8d.4 Physical examination after treatment with benznidazole.

211

Figure 8d.5 Example of a triatomine bug. Source: Centers for Disease Control and
Prevention.

mucosal surface, and establish acute infection (Figure 8d.6).2 While the vast
majority of cases of Chagas’ disease are transmitted in this manner, there have
been reports of acquisition via oral ingestion of infected food, blood transfu-
sion, solid organ transplantation, and congenital routes.3 Much of the blood
supply in the United States is screened for antibodies to T. cruzi, and screening
in many endemic countries is compulsory.4 Vertical transmission from infected
mother to fetus can occur as well.2
It is estimated that 8 to 9 million people are currently infected with
40,000 incident cases of vector-borne Chagas’ disease occurring every year.
 212 CHAPTER 8 Cardiac Infections

Triatomine Bug Stages Human Stages

Triatomine bug takes a blood meal
(passes metacyclic trypomastigotes in feces
1 trypomastigotes enter bite wound or 2 Metacyclic trypomastigotes
penetrate various cells at bite
mucosal membrances such as the conjuctiva) wound site. Inside cells they
transform into amastigores

Metacyclic trypomastigotes
in hindgut i
8

3 Amastigotes multiply
Trypomastigotes by binary fission in cells
Multiply in midgut can infect other cells of infected tissues
7 and transform into
intracellular amastigotes
in new infection sites.
Clinical manifestations can
Triatomine bug takes result from this infective cycle.
5 a blood meal
6 Epimastigotes (trypomastigotes ingested)
in midgut

d
Intracellular amastigotes
4 transform in to trypomastigotes,
i = Infective Stage then burst out of the cell
and enter the bloodstream
d = Diagnostic Stage

Figure 8d.6 Lifecycle of Trypanosoma cruzi. Source: Centers for Disease Control and Prevention.
http://www.dpd.cdc.gov/dpdx
Approximately 20,000 persons die every year from Chagas’ disease, and most

Cardiac Infections
of the disease burden occurs in Latin America where the insect vectors of
T. Cruzi are native.5 Chagas’ disease is primarily a public health problem among
poor persons who live in rural areas.1 Humans enter the cycle of transmission
when undeveloped land is opened for cultivation in areas where Triatoma infes-
tans is prevalent. With their habitat and those of their typical mammalian prey
violated, the vectors take up residence in the settler’s homes, which are fre-

CHAPTER 8
quently primitive and constructed from thatched roofs, mud walls, and stone,
which contain numerous niches for the insects to live and thrive. The insects
become domiciliary and begin to prey on the resident humans and livestock
in the community. Approximately 100,000 persons in the United States are
infected with T. Cruzi,6 the vast majority of whom acquired their infections in
endemic countries. Triatoma infestans is found in the United States, but docu-
mented vector-borne cases of Chagas’ disease are rare.2
Reactivation of Chagas’ disease can occur in patients who become immu-
nosuppressed for a variety of reasons including HIV and solid organ trans-
plantation. This issue is particularly germane in patients who undergo heart
transplantation for cardiomyopathy caused by chronic T. cruzi infection. While
post-transplant reactivation of T. cruzi infection occurs in approximately one-
fourth of patients who undergo heart transplantation for Chagas’ disease.7 The
associated mortality is low and can be treated with appropriate antiparasitic
therapy.8

213
Most new vector-borne infections occur in children younger than 10 years
old.1 In a study of selected patients, the case fatality rate for untreated acute
Chagas’ disease was 12%,1 but such a high rate likely reflects the fact that only
seriously ill patients come to medical attention. The case fatality rate for all new
infections is probably less than 1%.
Clinical Manifestations
Acute Chagas’ disease usually occurs during childhood in endemic areas, and
frequently goes unrecognized because of the mild and nonspecific nature of the
symptoms in most patients. Symptoms appear at least a week after infection
with the appearance of a chagoma, a characteristic area of erythema, swelling,
and induration at the site of entry accompanied by local lymph node involve-
ment. This can be followed by fever, malaise, anorexia, edema of the face and
lower extremities, generalized lymphadenopathy, and hepatosplenomegaly.
Meningoencephalitis is a rare but serious complication with a poor progno-
sis. Severe myocarditis resulting in heart failure is uncommon, but can result
in death in a small proportion of patients. In untreated patients symptoms
gradually improve over weeks to months, eventually resulting in spontaneous
resolution of symptoms. The patient subsequently enters the indeterminate or
chronic phase of Chagas’ disease, characterized by asymptomatic, sub-patent
parasitemia, and antibodies to a variety of T. cruzi antigens.1
Approximately 10% to 30% of persons with chronic T. cruzi infections will
develop symptomatic Chagas’ disease years after resolution of the acute infec-
tion, with the heart, esophagus, and colon being the organs most frequently
affected. Cardiomyopathy develops insidiously, usually affecting the right ven-
tricle first, but often causing disease in the left ventricle as well. Destruction
 of the cardiac conduction system results in arrhythmias, a frequent cause of
Cardiac Infections

death. Thromboembolism to the systemic and pulmonary vasculature is a fre-

quent complication of severe disease. Symptoms of megaesophagus are similar
to those of idiopathic achalasia, and include weight loss, cachexia, dysphagia,
odynophasia, chest pain, cough, regurgitation of undigested food, and aspira-
tion pneumonitis. Megacolon is characterized by severe, chronic constipation
and abdominal pain. Patients with advanced disease may go weeks between
CHAPTER 8

bowel movements, occasionally resulting in obstruction, perforation, volvulus,

and death. The symptoms of recrudescent T. cruzi infection, which can include
fever, myocarditis, and skin lesions (often containing a large number of para-
sites), can be more severe than those of acute infection in immunocompetent
hosts.1
Diagnosis
In acute infection, the level of parasitemia is high, allowing the diagnosis of
T. Cruzi infection via detection of motile trypomastigotes in a peripheral blood
smear or buffy coat. The level of parasitemia will decrease after 90 days, regard-
less of treatment, making this method of detection unlikely to prove useful in
patients with chronic disease. Amastigotes can be found in cutaneous lesions
as well, particularly in immunocompromised patients with reactivated disease.
Confirmation of chronic Chagas’ disease is based on serological methods.6 PCR
techniques are very sensitive in acute disease, although their performance in
214

chronic disease is variable. PCR is becoming an important tool in monitoring

patients with Chagas’ associated cardiomyopathy who have undergone cardiac
transplantation; it frequently detects parasitic reactivation more reliably than
traditional microscopic techniques.9
Treatment
There are currently two drugs used in the treatment of Chagas’ disease:
nifurtimox and benznidazole. Nifurtimox has been shown to be effective in
reducing the duration of illness and mortality associated with acute and con-
genital infection with T. cruzi; however, it is associated with a variety of side
effects and has a parasitologic cure rate of 70%. The duration of treatment is
usually 90 days with nifurtimox, but 60 days with benznidazole. Both agents
have a similar efficacy, but benznidazole has fewer medication interactions, a
more favorable side-effect profile, and shorter duration of treatment, so it has
emerged as the drug of choice.6 Treatment should be offered to all infants with
congenital T. cruzi infection, persons with acute or recrudescent disease, and
chronically infected children 18 years of age or younger.6
Antiparasitic treatment of adults with indeterminate or chronic Chagas’
disease is controversial and still being evaluated,1 though some experts rec-
ommend treatment in the absence of advanced Chagas’ disease-associated car-
diomyopathy.6 Treatment is mainly supportive for patients with gastrointestinal
or cardiac manifestations of chronic Chagas’ disease. As noted above, cardiac
transplantation is a viable option for patients with severe cardiomyopathy. In
one study performed in Brazil, patients who underwent cardiac transplantation
because of Chagas’ disease associated cardiomyopathy had a better 12 year sur-
vival when compared to patients with ischemic or idiopathic cardiomyopathy.8
References

Cardiac Infections
1. Kirchhoff LV. Trypanosoma species (American trypanosomiasis, Chagas’ disease):
biology of trypanosomes. In: Mandell GL, Bennett JE, Dolin R eds. Mandell, Douglas,
and Bennett’s Principles and Practice of Infectious Diseases. 7th ed. Philadelphia, PA:
Churchill, Livingston, Elsevier; 2009:3481–3488.
2. Centers for Disease Control and Prevention: http://www.cdc.gov/Chagas

CHAPTER 8
3. Roque AL; Xavier SC; da Rocha MG; et al. Trypanosoma cruzi Transmission
Cycle Among Wild and Domestic Mammals in Three Areas of Orally Transmitted
Chagas’ Disease Outbreaks. American Journal of Tropical Medicine and Hygiene;
2008, 79(5): 742–749.
4. Bern C, Montgomery SP, Katz L, et al. Chagas’ disease and the US blood supply.
Current Opinion in Infectious Diseases; 2008, 21:476–482.
5. Pan American Health Organization. Epidemiological profiles of neglected diseases
and other infections related to poverty in Latin America and the Caribbean. Pan
American Health Organization; 2009. Available at: http://new.paho.org/hq/index.
php?option=com_content&task=view&id=1247&Itemid=259&lang=en
6. Bern C, Montgomery SP, Herwaldt BL, et al. Evaluation and treatment of Chagas’
disease in the United States: a systematic review. JAMA. 2007;298(18):2171–2181.
7. Dummer JT, Singh N. Infections in solid organ transplant recipients. In: Mandell
GL, Bennett JE, Dolin R eds. Mandell, Douglas, and Bennett’s Principles and Practice
of Infectious Diseases. 7th ed. Philadelphia, PA: Churchill, Livingston, Elsevier;
2009:3839–3850.

215
8. Bocchi EA, Fiorelli A. The paradox of survival results after heart transplanta-
tion for cardiomyopathy caused by Trypanosoma cruzi. First Guidelines Group
for Heart Transplantation of the Brazilian Society of Cardiology. Ann Thorac Surg.
2001;71:1833–1838.
9. Diez L, Favaloro L, Bertolotti et al. Usefulness of PCR strategies for early diagno-
sis of Chagas’ disease reactivation and treatment follow-up in heart transplanta-
tion. Am J Transplant. 2007;7:1633–1640.
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 Chapter 9

Gastrointestinal Infections

Ca e 9a:
Case 9a: Dif
D
Diffuse
ifffuse Colitis
if Coli
lit
itis and
iti and
d Pseudomembranes
Pse
P udome
d embbran
anes

David P. Calfee
Case Presentation
A 73-year-old man with multiple medical problems, including diabetes mellitus,
COPD, and congestive heart failure, was admitted to the hospital from a long-
term care facility with an ankle fracture that resulted from a fall. He underwent

217
open reduction and internal fixation of his ankle fracture, and received cefazolin
for perioperative prophylaxis.
On his fourth hospital day, the patient’s roommate was diagnosed with
C. difficile during work-up of diarrhea that began 3 days earlier. Two days later,
the patient developed fever, abdominal pain, and altered mental status. The
following day, he was found to be hypotensive with persistent abdominal pain
and fever. He received fluid resuscitation and was treated empirically with met-
ronidazole. The hypotension resolved, but diarrhea and abdominal pain per-
sisted. A CT scan demonstrated diffuse colitis, and endoscopy revealed colonic
pseudomembranes (Figures 9a.1 and 9a.2).
Over the following days, the patient had progressive leukocytosis, reaching
a maximum of 45,000 WBC per mm3. On the eleventh hospital day, the patient
developed recurrent hypotension, and orally administered vancomycin was
added to his treatment regimen. The following day, vasopressors were initiated
for refractory hypotension, and a surgery consult was obtained (Figures 9a.3
and 9a.4). Later that day, the patient was taken to the OR for partial colectomy.
In the recovery room, the patient remained critically ill with lactic acidosis,
elevated liver enzymes, and hypotension. His course was further complicated
by ARDS and multiorgan failure. The patient died on hospital day 13.
Case 9a Discussion: Clostridium difficile Colitis
Epidemiology and Clinical Presentation
The clinical manifestations associated with CDI range from a mild diarrheal
illness to more significant diarrhea with abdominal pain and systemic symp-
toms, life-threatening pseudomembranous colitis, toxic megacolon, bowel
Gastrointestinal Infections
CHAPTER 9

Figure 9a.1 CT scan abdomen, axial view showing diffuse bowel wall thickening
consistent with colitis.
218

Figure 9a.2 Colonoscopy showing diffuse pseudomembranes.

 Gastrointestinal Infections
CHAPTER 9
Figure 9a.3 Resected large intestine with diffuse pseudomembranes and bowel wall
edema.

219

Figure 9a.4 Pathologic section of colon with pseudomembrane, hematoxylin and eosin
stain, showing extensive neutrophilic infiltrate.

perforation, and death. In addition to these adverse clinical outcomes, patients

with CDI also frequently experience prolonged hospitalization and increased
healthcare costs.1,2
During the past decade, there has been an increase in the reported incidence
of CDI in the United States, Canada, and Europe. During the same time period,
increases in the frequency of disease recurrence and severe disease have also
been reported. These changes in the epidemiology of CDI are temporally
associated with the emergence of a previously uncommon strain of C. difficile,
known as the BI or NAP1 strain.3,4
 Although acquisition of C. difficile can occur in the community, healthcare
Gastrointestinal Infections

settings are associated with the greatest risk of acquisition of, and infection
with, C. difficile. C. difficile frequently contaminates the skin of persons with CDI,
as well as surfaces (e.g., bed rails, bedside tables, toilets, sinks) and equipment
(e.g., IV poles, blood pressure cuffs) in hospital rooms. Healthcare workers may
also play a substantial role in C. difficile transmission. Studies have shown that
C. difficile frequently contaminates the hands or gloves of healthcare workers
after providing care to patients with CDI.5
A number of host-associated and healthcare-associated factors contribute
to the establishment of colonization, and subsequent progression to symptom-
CHAPTER 9

atic disease, following exposure to C. difficile. The major risk factor for CDI is
receipt of antimicrobial therapy. Although clindamycin, penicillins, and cepha-
losporins have historically been most commonly associated with CDI, other
classes of antimicrobial agents, including the fluoroquinolones, have been well
established as risk factors for CDI. Gastric acid suppressants, such as proton
pump inhibitors, have also been associated with CDI in some studies.3
A number of host-level factors have also been associated with CDI. These
include the presence of certain medical conditions (e.g., chronic renal failure,
malignancy, inflammatory bowel disease), malnutrition, severity of illness, and
older age.
The humoral immune system also appears to play a role in CDI. Development
of serum IgG antibodies against toxin A appears to be associated with a reduced
220

risk of progression to symptomatic disease following colonization, and of recur-

rence of disease following an initial episode of CDI.3,2
Diagnosis
There are several diagnostic tests that can be useful in confirming a diagnosis
of CDI. The most widely used diagnostic test is an enzyme immunoassay
(EIA) for C. difficile toxin. These assays are somewhat less sensitive than cell-
culture-based cytotoxicity assays and stool cultures for toxigenic C. difficile,
but these more sensitive tests do not provide results as rapidly as EIA-based
testing, and require laboratory resources and expertise that are not avail-
able in all healthcare facilities. The EIA for glutamate dehydrogenase (GDH)
antigen is more sensitive than the EIA for toxins A and B, and has a rapid turn-
around time. However, it is relatively nonspecific, and positive tests must be
confirmed with a more specific test. Recently, PCR-based testing has become
commercially available for use in the diagnosis of CDI. The sensitivity of PCR-
based testing has been shown to exceed that of the EIA tests that detect
C. difficile toxins.2
Treatment
If possible, the antimicrobial therapy associated with the development of CDI
should be discontinued. In some instances, this may be the only intervention
necessary. However, many patients will require specific treatment of CDI.
Orally administered vancomycin remains the only FDA-approved drug for the
treatment of CDI. Metronidazole, however, has been the agent most commonly
recommended for treatment of mild to moderate disease, due to its lower
cost and concerns regarding the potential for selection of vancomycin-resistant

Gastrointestinal Infections
organisms, such as Enterococcus, with use of vancomycin. Metronidazole also
has the advantage of allowing intravenous administration in patients with ileus,
or who are otherwise unable to take oral medications. Vancomycin is recom-
mended, however, for patients with severe CDI.1
Several alternative antimicrobial agents, including nitazoxanide, ramoplanin,
and rifamycins, have been studied for use in the management of CDI. Although
some of these agents may offer benefit to some persons with CDI, none appear
to provide major advantages over currently available agents, and none have
received FDA approval for treatment of CDI. In addition, several non-antimi-

CHAPTER 9
crobial agents, including toxin-binding agents (e.g., cholestyramine, tolevamer),
probiotics (e.g., Saccharomyces boulardii), and anti toxin A monoclonal antibod-
ies have been evaluated or are being evaluated for use in combination with
standard therapy for CDI.1
Approximately 20% of patients with CDI will experience at least one recur-
rence of the disease. First recurrences can typically be treated using the same
approach used for treatment of the primary episode. For patients with multiple
recurrences of CDI, or CDI that is not responsive to standard treatments, addi-
tional interventions may include higher doses of orally administered vancomy-
cin (250–500 mg every 6 hours), intracolonic administration of vancomycin,
intravenous immune globulin, and administration of donor stool. The use of
tapering doses of vancomycin has been suggested for treatment of patients with

221
multiple recurrences of CDI.1
Finally, some patients with fulminant CDI may benefit from surgical interven-
tion. Factors that have been associated with benefit from colectomy include
older age, non-immunocompromised status, WBC count >20,000 cells per
mm3, and serum lactate between 2.2 and 4.9 mmol/L.1 Others have found that a
requirement for vasopressors and the presence of mental status changes prior
to surgery are associated with mortality following colectomy. This suggests
that once multisystem organ failure has developed, the opportunity for benefit
from surgical intervention may have been lost. Thus, early surgical consultation
should be considered in patients with severe CDI.1
Prevention
Preventive measures attempt to modify factors associated with either exposure
to C. difficile or the development of symptomatic disease following exposure.
Although antibiotic exposure cannot be completely avoided in many patients,
judicious use of antimicrobial agents (e.g., appropriate spectrum and duration
of treatment) may minimize the risk introduced during necessary courses of
therapy. The necessity of other agents that may be associated with CDI, such as
proton pump inhibitors, should also be routinely evaluated.5
Healthcare-associated exposure to C. difficile is perhaps the risk factor for
which there is the greatest opportunity for intervention. Interventions that can
minimize or prevent contamination of the environment, and the hands and
clothing of healthcare workers, such as environmental disinfection, proper hand
hygiene, and use of contact precautions, are key components of a C. difficile
transmission prevention program.5
 References
Gastrointestinal Infections

1. Gerding D, Muto C, Owens R. Treatment of Clostridium difficile infection. Clin

Infect Dis. 2008;46(Suppl 1):S32–S42.
2. Bartlett J, Gerding D. Clinical recognition and diagnosis of Clostridium difficile
infection. Clin Infect Dis. 2008; 46(Suppl 1):S12–S18.
3. McDonald L, Owings M, Jernigan D. Clostridium difficile infection in patients
discharged from US short-stay hospitals, 1996–2003. Emerg Infect Dis.
2006;12(3):409–415.
4. McDonald L, Killgore G, Thompson A, et al. An epidemic, toxin gene-variant
strain of Clostridium difficile. N Engl J Med. 2005;353(23):2433–2441.
CHAPTER 9

5. Dubberke ER, Gerding DN, Classen D, et al. Strategies to prevent Clostridium

difficile infections in acute care hospitals. Infect Control Hosp Epidemiol.
2008;29(Suppl1):S81–S92.

Case
C a e 99b:
b: A
b: Abd
Abdominal
bdomiinall P
bd Pain,
ain,
i Fever,
F and
d Weight
Weight
Wei ht Loss
L in a
in
Patient
Pati
Pa Crohn’s
tieent with Crohn ’s Disease
hn’s Dissease

Marion-Anna Protano, Luciano Kapelusznik, and Daniel

Caplivski
222

Presentation and Case History

A 17-year-old man with Crohn’s disease presented with fevers, right lower
quadrant abdominal pain, and a 25-pound weight loss over several months. He
had been diagnosed with Crohn’s disease 6 weeks prior to admission, and had
been managed with oral mesalamine and prednisone (20mg daily). His recent
exacerbation of abdominal pain was also accompanied by night sweats, right
shoulder pain, constipation, and nonbloody emesis.
On physical examination, he was febrile (38.6°C) and had tenderness and
guarding of the right lower quadrant of the abdomen. Laboratory studies were
significant for leukocytosis (15 x103 WBC/μl, 90 % neutrophils) and hyperbili-
rubinemia (total bilirubin 2.3 mg/dl, direct bilirubin 0.5 mg/dl), but otherwise
normal liver enzymes (alkaline phosphatase 127 UI/L, alanine aminotransferase
38 UI/L, and aspartate aminotransferase 22 UI/L).
Computerized tomography (CT) of the abdomen showed two adjacent
low density lesions in the periphery of the right lobe of the liver, measuring
4.7 cm and 4.4 cm in greatest diameter, consistent with abscesses (Figure 9b.1).
Additionally, there were severe inflammatory changes in the right lower quad-
rant involving the cecum and terminal ileum consistent with a phlegmon or
early abscess.
Percutaneous drainage of one of the liver abscesses yielded 30 ml of bloody
purulent fluid, and drain was left in place for several days. The direct Gram stain
revealed many white blood cells, and moderate Gram-positive cocci in pairs
and long chains (Figure 9b.2), and a pure culture of Gemella morbillorum was
isolated from the liver aspirate. The patient also underwent surgical resection
of the terminal ileum, which was diffusely diseased and associated with abscess;
 Gastrointestinal Infections
CHAPTER 9
Figure 9b.1 CT abdomen, axial view showed two large liver abscesses.

223

Figure 9b.2 Liver aspirate Gram stain with many white blood cells and moderate Gram
positive cocci in pairs and long chains.

pathologic examination revealed typical findings of Crohn’s inflammation and

evidence of healed perforation. He was treated with ceftriaxone and metron-
idazole to complete 6 weeks of total antibiotic therapy, and subsequent imaging
revealed resolving hepatic abscesses.
Case 9b Discussion: Gemella morbillorum Liver Abscess
Clinical Features and Diagnosis
The liver is the most common organ for visceral abscesses, and there
are several pathophysiological mechanisms that may lead to liver abscess
 formation. Hematogenous seeding, direct extension by contiguity, local
Gastrointestinal Infections

spread via portal vein, indirect (from a biliary source), hepatic destruction,
penetrating trauma, previous surgery or interventional endoscopy, may all
lead to formation of pyogenic abscesses. Patients with Crohn’s disease tend
to have portal bacteremia and, in some cases, pylephlebitis. In some cases,
no direct cause is found, but most pyogenic liver abscesses derive from a
biliary source.1
Once infected, patients may present with constitutional symptoms such as
fatigue, fever, weight loss, or anorexia, or can develop nausea, emesis, right
upper quadrant pain, diffuse abdominal discomfort, pleuritic chest pain, jaun-
CHAPTER 9

dice, cough, or right shoulder pain. If there are multiple abscesses, shock may be
the initial presentation. Common laboratory findings include leukocytosis with
a left shift, elevated alkaline phosphatase, and slightly elevated transaminases
and bilirubin. Blood cultures are positive in 32%–60% of patients. Diagnosis is
confirmed with ultrasound or CT. When found on imagining, pyogenic liver
abscesses must be distinguished from other mass lesions such as amebic hepatic
abscess, benign and malignant tumors, cystic lesions (including echinococcal
cysts), hemangiomas, focal nodular hyperplasia, soft tissue tumors, and inflam-
matory pseudotumors.2
Pyogenic hepatic abscesses are polymicrobial in 11%–65% of cases and
monomicrobial in 21%–69% of cases, with anaerobic bacteria growing in 15% to
45% of the culture specimens.2 The majority of abscesses are caused by enteric
224

flora (particularly Gram-negative bacilli), but anaerobes should be suspected

in all polymicrobial abscesses, as they are notoriously difficult to recover in
culture. The most frequently isolated organisms are: Escherichia coli, Klebsiella,
Proteus, Enterococcus, Bacteroides and Streptococcus spp.2
Gemella morbillorum is a rare cause of liver abscess, especially in patients
with Crohn’s diseases. G. morbillorum is a nonmotile, catalase-negative, faculta-
tive anaerobic Gram-positive coccus that occurs singly, in pairs, or in chains.3
It was once considered to be a member of the viridians group of streptococci
that are normal human commensals in the lumen of the gastrointestinal tract,
but further biochemical analysis resulted in its classification under a separate
genus. Fungi are a rare cause of hepatic abscess that occurs more commonly in
immunocompromised hosts; Candida is the most frequently isolated pathogen,
followed by Aspergillus species.4
In the past, E. coli was uniformly the most commonly isolated pathogen in
liver abscesses; however, the incidence of Klebsiella pneumoniae liver abscesses
is increasing, especially in patients with diabetes and of Asian descent. In Taiwan,
and in North American cities with large Asian population, such as San Diego,
Klebsiella pneumoniae has become the most common cause of liver abscess.
These patients are found to have positive blood cultures in 95% of cases, with
a high incidence of end-organ seeding including eye, lung, pleura, meninges,
epidural space, brain, inner ear, spleen, skin, bone, and soft tissue. Metastatic
complications occur in 10% to 16% of cases, but endophthalmitis has a greater
incidence of 6% to 61%. Diabetic patients are at increased risk for embolic com-
plications with K. pneumoniae.5
 Entamoeba histolytica is a protozoan parasite that infects the colon but may

Gastrointestinal Infections
also cause hepatic, pulmonary, or brain abscess. Typically, patients with amebic
liver abscess present more acutely than those with pyogenic abscess, though
similar symptoms of right upper quadrant pain, fever, rigors, chills, and hepato-
megaly are reported. Amebiasis is transmitted by ingestion of the cysts in focally
contaminated water or food, and occurs more frequently in tropical and sub-
tropical countries, or in returned travelers from endemic regions. Trophozoites
invade the wall of the colon and reach the liver via the portal circulation. Two
percent of patients may present with concomitant diarrhea, and some patients
may report bloody diarrhea weeks prior to presentation, but the majority of

CHAPTER 9
patients do not report preceding symptoms.
In many cases, amebiasis cannot be distinguished from pyogenic liver abscess
by clinical presentation or imaging. Stool studies will detect E. histolytica in less
than 30% of cases, and while serology has a high sensitivity and specificity, it can-
not distinguish acute infection from prior exposure in patients from endemic
areas. Liver abscess aspiration is generally of low diagnostic value in cases of
presumptive amebic abscess. It is rare to find trophozoites in aspirated fluid, as
they are typically on the periphery of the abscess and not in the necrotic center.
The reddish-brown aspirate is classically described as “anchovy paste” because
of the appearance of liquefied necrotic hepatic tissue.6
Treatment

225
Systemic antibiotics are the mainstay of treatment for liver abscess, and are
targeted to the organism’s susceptibility.7 Antibiotics alone may be insuf-
ficient to manage large abscesses, due to large bacterial load, inactivation
of antibiotics, and ineffective medium for bacterial elimination within the
abscess.7 The initial antibiotic regimen may include a beta-lactam/beta-lac-
tamase inhibitor (ampicillin-sulbactam 3 g IV q6h, piperacillin/tazobactam
3.375 g IV q6h, ticarcillin-clavulanate 3.1 g IV q4h) or a third-generation
cephalosporin (ceftriaxone 1g IV q24h) plus metronidazole (500 mg IV q8h).
Alternatives for patients with beta-lactam allergies include fluoroquinolones
(ciprofloxacin 400 mg IV q12h, levofloxacin 500 mg IV q24h) plus metronida-
zole (500 mg IV q8h) or carbapenems (imipenem 500 mg IV q6h, meropenem
1g IV q8h, ertapenem 1 g IV q24h). Antibiotic choices should be informed
by culture data, but if multiple pathogens are recovered, anaerobes should
be assumed to be present. Two to three weeks of intravenous therapy is
generally followed by oral antibiotics for a total of 4–6 weeks of treatment.
For K. pneumoniae, the therapy of choice is a combination of an extended
spectrum beta-lactam and a second- or third-generation cephalosporin, with
or without an aminoglycoside.5
Most pyogenic hepatic abscesses require drainage. Percutaneous drainage is
often used as first-line treatment unless urgent surgery is indicated for perito-
nitis or sepsis, the abscess is large and multiloculated, or there is concomitant
biliary or intra-abdominal pathology.7 If multiple abscesses are present, drainage
of the largest abscess may be adequate, as the smaller ones may resolve with
antibiotics. Despite advances in treatment, mortality in pyogenic liver abscesses
is high; Lee et al.8 (2001), reported a mortality of 6%.
 Amebic abscess generally do not require drainage unless they are large and
Gastrointestinal Infections

at risk for rupture. For E. histolytica, metronidazole 500–750 mg thrice daily

orally for 7–10 days is the treatment of choice; alternatives are tinidazole or
chloroquine. After the course of metronidazole, patients are treated with an
oral luminal amebicide: iodoquinol 650 mg thrice daily for 20 days, paromomy-
cin 25 to 35 mg/kg daily in three divided doses for 7–10 days.6

References
1. Margalit M, Elinav H, Ilan Y, Shalit M. Liver abscesses in inflammatory bowel dis-
CHAPTER 9

ease: report of two cases and review of the literature. J Gastroenterol Hepatol.
2004;19(12):1338–1342.
2. Johannsen EC, Sifri CD, Madoff LC. Pyogenic liver abscesses. Infect Dis Clin North
Am. 2000 Sep; 14(3):547–63
3. Hsu CY, Su YC, Wang TL, Chong CF, Chen CC. Gemella morbillorum liver
abscess. Scand J Infect Dis. 2007; 39 (6–7):637–638.
4. Lipsett PA, Huang CJ, Lillemoe KD, Cameron JL, Pitt HA. Fungal hepatic abscesses:
characterization and management. J Gastrointest Surg. 1997;1(1):78.
5. Lederman ER, Crum NF. Pyogenic liver abscess with a focus on Klebsiella pneu-
moniae as a primary pathogen: an emerging disease with unique clinical character-
istics. Am J of Gastroenterol. 2005;100(2):322–331.
6. Pritt BS, Clark CG. Amebiasis. Mayo Clin Proc. 2008;83(10):1154–1159.
226

7. Chung YF, Tan YM, Lui HF, Tay KH, Lo RH, Kurup A, Tan BH. Management
of pyogenic liver abscess – percutaneous or open drainage? Singapore Med J.
2007;48(12):1158–1165.
8. Lee, KT, Wong SR, Sheen PC. Pyogenic liver abscess: an audit of 10 years’ expe-
rience and analysis of risk factors. Dig Surg. 2001;18(6):459–465.

Ca e 99c:
Case c: Fevers
F and
d Ch
C
Chil
Chills
hil
illls af
after
ft T
fter Trave
Travel
el tto
o IInd
India
ndi
dia

Jennifer Jao
Case Presentation
A 24-year-old software programmer from India presented with fevers and chills
6 days after returning from a 3-month trip to India. His symptoms began during
his flight back to the United States, and were accompanied by sweats, fatigue,
arthralgias, headache, and neck pain. He denied cough, abdominal pain, diarrhea,
or urinary symptoms. While in India, he did not take malaria prophylaxis or apply
insect repellants, and he reported having consumed tap water while there.
On physical examination, he was febrile (39.2º Celsius) and had mild diffuse
abdominal pain on deep palpation, but the remainder of his physical examination
was unremarkable. His laboratory studies were notable for mildly elevated liver
enzymes (ALT 140 IU/L, ALT 160, IU/L, total bilirubin 2.3 mg/dl, lactate dehy-
drogenase 720 U/L), but normal white blood cell count (8.1 x10³ cells/μl) and
platelets (446 x10³ cells/μl). Peripheral blood smear for parasites was negative
and cerebrospinal fluid analysis was normal (glucose 66 mg/dl, protein 45 mg/
dl, 1 white blood cell/μl). The patient was treated with intravenous ceftriaxone,

Gastrointestinal Infections
and three sets of initial blood cultures grew ampicillin-susceptible Salmonella
typhi within 24 hours (Figures 9c.1 and 9c.2). The patient was switched to ampi-
cillin, continued to improve over the course of several days, and was discharged
home on oral amoxicillin.

227 CHAPTER 9
Figure 9c.1 Gram stain from blood cultures with Gram-negative bacilli.

Figure 9c.2 MacConkey media with colonies of a non-lactose fermenting organism

later identified as Salmonella typhi.
 Case 9c Discussion: Typhoid Fever
Gastrointestinal Infections

Salmonella enterica serotype Typhi causes the systemic illness known as typhoid
fever, which is endemic in Central and South America, Africa, the Middle
East, and Asia.1 Infection is transmitted from person to person via fecal–oral
spread, in contaminated food or water. The incubation period between inges-
tion and clinical illness ranges from 3 to 60 days and depends on the inoculum
of ingested bacteria. Patients typically present with vague symptoms of fever,
headache, flu-like symptoms, nausea, abdominal discomfort, and anorexia.
Bacteremia is marked by fever and malaise, and in some cases a relative bra-
dycardia (pulse–temperature dissociation) may be present. Other electrocar-
CHAPTER 9

diogram findings that may be observed (particularly in children) include heart

block or Wenkebach phenomenon. Rose spots, blanching erythematous macu-
lopapular lesions about 0.5 cm in diameter, may be seen in up to 30% of cases,
but may not be visible in darker-skinned patients.2
Complications can occur in 10%–15% of patients and include gastrointesti-
nal perforation or hemorrhage, hepatitis, subclinical cholecystitis, heart block,
myocarditis, encephalopathy, meningitis, delirium, pneumonia, anemia, dissemi-
nated intravascular coagulation, and rarely, shock.3 Gastrointestinal perforation
results from rapid enlargement of lymphoid tissue in the terminal ileum, as the
bacteria replicates intracellularly within tissue macrophages. Mother-to-child
transmission is rare but has been reported. Relapse is an important complica-
228

tion, which occurs in 5%–10% of patients and is usually defined as recurrence of

fever, with or without bacteremia, 2–3 weeks after resolution of the symptoms.
Relapses are generally not as severe as the original attack, and blood culture
isolates generally exhibit the same antimicrobial susceptibility pattern as the
isolate cultured during the initial episode. A small percentage of patients even-
tually go on to become chronic carriers, excreting the bacteria in stool for up
to one year.2,4
The gold standard of diagnosis of typhoid fever is a positive blood culture;
however, this requires a large volume of blood to be cultured initially (15 ml) in
order to increase the sensitivity to 60%–80%. Culture of bone marrow is more
sensitive (80%–95% sensitivity) but much less feasible in many resource-limited
settings. On blood agar, the organism typically produces nonhemolytic, smooth
white colonies, and on MacConkey agar, they produce lactose nonferment-
ing smooth colonies with a gunmetal-grey appearance. Stool specimens may
be cultured for S. typhi in acutely ill patients, but are positive in only 30% of
patients; nonetheless, they are useful in evaluating possible typhoid carriers.1,2
Other non-culture methods of diagnosis include the Felix-Widal test, and
newer rapid serological tests such as the Typhidot. The Felix-Widal test mea-
sures agglutinating antibody levels against salmonella type O and H antigens.
The test has moderate sensitivity and specificity, and can have a false nega-
tive rate of up to 30%. In addition, in areas of low endemicity, levels of these
antibodies may be high without active disease. The dot enzyme immunoassay
(Typhidot) was developed in Malaysia for the detection of IgM and IgG antibod-
ies against a specific S. typhi antigen. It takes three hours to perform and has a
95% sensitivity rate, as well as high negative and positive predictive values.2,4
 Uncomplicated typhoid fever may be managed with oral antibiotics, but

Gastrointestinal Infections
resistance to antimicrobials has been an emerging problem. The introduction of
chloramphenicol after WWII transformed the disease into a treatable infection
that no longer claimed the lives of millions worldwide. Later antibiotics such
as ampicillin and trimethoprim/sulfamethoxazole were also found to be effec-
tive, but in the last decade, emerging multidrug resistance to these antibiotics
has occurred.1,5 Fluoroquinolones were subsequently accepted to be an opti-
mal treatment for typhoid strains resistant to beta lactam antibiotics, but many
parts of Asia now report increasing nalidixic acid-resistant strains. Resistance to
nalidixic acid predicts clinical relapse in patients treated with ciprofloxacin even

CHAPTER 9
when their isolates appear to be susceptible to ciprofloxacin in vitro.6 Third-
generation cephalosporins and macrolides have been found to be efficacious in
treating typhoid fever.5 Randomized trials have compared macrolides to fluo-
roquinolones, as well as macrolides to ceftriaxone, with comparable rates of
cure and relapse.6
Prevention of typhoid fever for travelers to endemic areas includes both vac-
cination and proper sanitation. Drinking water should be boiled or bottled, and
food should be thoroughly cooked before ingestion. Early vaccines, including
the killed whole-cell vaccine, had a propensity to cause local swelling and sys-
temic side effects in up to 50% of recipients and are now rarely used. The Ty21a
live oral attenuated bacterial vaccine is available in capsule or liquid form, and
has been shown to provide individual and herd immunity. It is well tolerated and

229
approved for use in adults and children over 5 years of age, and the duration of
protection is estimated to be 3–5 years. The parenteral typhoid Vi-based vac-
cine is most used in travelers to endemic areas, as it harbors relatively few side
effects and may be administered in adults and younger children over 2 years of
age. A single intramuscular dose confers immunity for 2–3 years.2,4

References
1. John A. Crump and Eric D. Mintz. Emerging infections: global trends in typhoid
and paratyphoid fever. Clin Infect Dis. 2010;50(2):241–246.
2. Parry CM, Hien TT, Dougan G, White NJ, Farrar JJ. Typhoid fever. (Review).
N Engl J Med. 2002;347(22):1770–1782.
3. Huang DB, DuPont HL. Problem pathogens: extra-intestinal complications
of Salmonella enterica serotype Typhi infection. (Review). Lancet Infect Dis.
2005;5(6):341–348.
4. WHO. 2003 report: Background document: The diagnosis, treatment and preven-
tion of typhoid fever. Accessed 2008 from http://www.who.int/vaccine_research/
diseases/diarrhoeal/en/index7.html www.who.int/vaccines-documents/
5. Robert W. Frenck, Jr., Isabelle Nakhla, Yehia Sultan, et al. Azithromycin versus
ceftriaxone for the treatment of uncomplicated typhoid fever in children. Clin
Infect Dis. 2000;31(5):1134–1138.
6. Girgis NI, Butler T, Frenck RW, et al. Azithromycin versus ciprofloxacin for
treatment of uncomplicated typhoid fever in a randomized trial in Egypt that
included patients with multidrug resistance. Antimicrob Agents Chemother.
1999;43(6):1441–1444.
Gastrointestinal Infections

Case
C a e 99d:
d: E
d: Enlarging
nlar
l ging
i LLiver
iv C
iver Cyst
Cysts
ts in
i a Woman
Wo ffrom
fr om
Uzbe
Uz bekistan
Uzbekistan

Daniel Seth Fierer and Daniel Caplivski

Case Presentation
A 58-year-old woman from rural Uzbekistan was diagnosed with hydatid cysts
while in her home country. While there, she had also been given a trial of
albendazole, but discontinued the medication due to severe nausea, swelling,
CHAPTER 9

and pruritus. She had undergone one previous liver resection in her home
country, and subsequently had an injection/resection procedure in New York.
Several years later, she again presented with increasing right upper quadrant
abdominal pain. She was also having fevers (38.5 Celsius) and had lost approxi-
mately 10 pounds over the preceding 3 months due to early satiety. Computed
tomography scanning revealed a large multiloculated cyst that was 11.5cm by
7.4 cm in size (Figure 9d.1).
Echinococcus granulosus IgG antibodies were positive and the patient was
noted to have a slight eosinophilia (9%). The swelling she had previously expe-
rienced when taking albendazole was thought most likely to be secondary to
exposure to parasite antigens, due to leakage of the cyst contents. She was
230

treated again with albendazole and praziquantel, and underwent the PAIR pro-
cedure (percutaneous aspiration, installation, and re-aspiration). This proce-
dure allowed for the aspiration of cyst contents, installation of hypertonic saline
(to kill the remaining parasites in case they are spilled), and re-aspiration of the
main cyst. The contents of the cyst revealed hooklets of the larval form of the
parasite, Echinococcus granulosus (Figure 9d.2). The patient’s course was compli-
cated by albendazole-induced alopecia and mild hepatitis, but these side effects
reversed upon discontinuation of the medication.

Figure 9d.1 CT abdomen, axial view showing a large multiloculated hepatic cyst,
11.5cm by 7.4 cm.
 Gastrointestinal Infections
CHAPTER 9
Figure 9d.2 Microscopic examination of cyst contents, showing protoscolex with rings
of hooklets.

Case 9d Discussion: Hydatid Cysts from Echinococcus granulosus

Clinical Presentation and Diagnosis
Hydatid cysts are caused by the zoonotic cestode, Echinococcus granulo-

231
sus. Humans become intermediate hosts in this tapeworm’s natural lifecycle
between dogs and sheep when they inadvertently consume the eggs of the par-
asite excreted in dog feces (Figure 9d.3). The dissemination of the larval form
of the organism most commonly causes large fluid-filled cysts in the liver, but
these can be found in any organ, including the lungs and the brain.1,2 The disease
is most common in rural societies in Africa, the Middle East, South America,
and Southern Europe, in which humans are in close contact with sheep and
infected dogs. Another species of Echinococcus (E. multilocularis) is associated
with alveolar cyst disease, and is found in more temperate regions of Europe
and North America.2
The clinical presentation of hydatid cyst disease is often related to the space-
occupying nature of the large (10–20 cm) larval cysts. Patients with pulmonary
cysts may present with vomica, a salty tasting fluid that is the sign of a rup-
tured cyst. Cyst rupture may also lead to severe allergic responses, as parasitic
antigens are released into bronchial or abdominal spaces. Cyst rupture is par-
ticularly problematic as daughter cysts are formed by the individual parasites
within each cyst. Superinfection of cysts by bacteria can lead to the formation
of pyogenic abscesses.2 Diagnosis is often established based on the radiologic
appearance (ultrasonography, computed tomography, and magnetic resonance
imaging) and confirmed with serologic assays. Serum enzyme-linked immuno-
assay (ELISA) and Western blot have reported sensitivities of 80%–100% and
88%–96% specificity for hepatic disease, but are less sensitive for hydatid dis-
ease involving other sites.3 Examination of aspirated fluid or resected cysts may
reveal the presence of “hydatid sand”—microscopic protoscolices, which often
have visible hooklets (see Figure 9d.2).3
Gastrointestinal Infections

6
Scolex attaches 1
to intestine
4
Adult in small intestine
5
2
Protoscolex
from cyst

Ingestion of cysts
(in organs) Definitive Host 2
i 4
(dogs & other canidae)
CHAPTER 9

4
Intermediate Host of eggs Embryonated 4
(sheep, goats, swine, etc.) Ingestion
(in feces) egg in feces 4
4

d 4
3 3

i = Infective Stage
Oncosphere hatches; d = Diagnostic Stage
Hydatid cyst in liver, lungs, etc. penetrates intestinal wall

Figure 9d.3 Life cycle of Echinococcus granulosus. Source: Centers for Disease Control
and Prevention. http://www.dpd.cdc.gov/dpdx/HTML/Echinococcosis.htm
232

Management
Surgical resection of the cysts had for many years been the treatment of choice
for hydatid cyst. These resections can be complicated by spillage of the cyst
contents into the abdomen or thorax. Anaphylactoid responses to parasite
antigens and further dissemination of cysts are risks of this approach. The PAIR
procedure (percutaneous aspiration installation and re-aspiration) is designed
to remove enough of the cyst fluid so that antiparasitic agents (such as hyper-
tonic saline or 95% ethanol) may be infused to minimize the risk of dissemina-
tion the event of spillage of the cyst contents.2,3 Albendazole or mebendazole
are systemic cysticidal agents that are sometimes used in conjunction with
mechanical drainage procedures, especially in cases in which complete surgical
resection is impossible.4 Albendazole at doses of 400mg orally twice daily is
better absorbed than mebendazole, and may be given over the course of sev-
eral months for patients with inoperable hydatid cyst disease.3

References
1. Gavidia CM, Gonzalez AE, Zhang W, et al. Diagnosis of cystic echinococcosis,
central Peruvian highlands. Emerg Infect Dis. 2008;14(2):260–266.
2. Schantz PM. Progress in diagnosis, treatment and elimination of echinococcosis
and cysticercosis. Parasitol Int. 2006;55(Suppl)S7-S13.
3. King, C. Farley, J. Cestodes (tapeworms). In Mandell, Douglas, and Bennett’s
Principles and Practice of Infectious Diseases, 7th ed. 2009:3613–3615.
4. Mawhorter S, Temeck B, Chang R, Pass H, Nash T. Nonsurgical therapy for pul-
monary hydatid cyst disease. Chest. 1997 Nov 5;112(5):1432–6.
 Gastrointestinal Infections
Case
C a e 9e:
9e: A
A-65
-65
65 Y
Year-Old
ear-O
Old Hea
H
Heart
rtt Transplant
Transpl
T pla
lantt Re
Reci
Recipient
cipient
i t
with
wi th Abdominal P ain
ai
Painn an
nd Altered M
and ental
Mentalal SStatus
Sttatus

Gopi Patel, Michael Lief, and Daniel Caplivski

Case Presentation
A 65-year-old man from the Dominican Republic was admitted with a 2-day
history of fever, rigors, abdominal pain, and confusion. The patient had a his-
tory of diabetes mellitus, hypertension, and ischemic cardiomyopathy. Four

CHAPTER 9
months prior to admission, he underwent an uncomplicated orthotopic heart
transplant. He had no prior history of rejection, and he was maintained on
tacrolimus, mycophenolate mofetil, and prednisone. He worked as a building
superintendant and had not traveled back to the Dominican Republic in over
30 years.
The patient was agitated and febrile to 102.7º F with an otherwise unre-
markable physical examination. His laboratory results were significant for
hyponatremia (sodium 125 meq/l), mild renal insufficiency, (1.5 mg/dl), and
hyperglycemia (156 mg/dl). His peripheral white blood cell count was normal
(5.8 x10³/μl) without a leukocytosis or eosinophilia. Broad-spectrum antimicro-
bials were initiated for a possible systemic infection, after blood, sputum, and

233
urine cultures were collected. Initially he defervesced, but 48 hours later he had
recurrence of fevers accompanied by watery diarrhea, dyspnea, and a nonpro-
ductive cough. He became increasingly tachypneic and hypotensive, and subse-
quently required ventilator and vasopressor support. A petechial and purpuric
rash abruptly developed over the chest and abdomen (Figure 9e.1). Radiographs
of the lungs, which had been unremarkable on admission, now revealed diffuse
interstitial infiltrates and bilateral consolidations (Figures 9e.2 and 9e.3).

Figure 9e.1 Diffuse petechial and purpuric rash on chest and abdomen.
Gastrointestinal Infections
CHAPTER 9

Figure 9e.2 Chest radiograph, anterior posterior view with diffuse bilateral alveolar
infiltrates and right sided pleural effusion.
234

Figure 9e.3 CT scan chest, axial view with diffuse bilateral infiltrates and right sided
pleural effusion.

After prolonged incubation, blood and sputum cultures grew a KPC car-
bapenemase-producing Klebsiella pneumoniae. One week into his hospitaliza-
tion, the patient was not arousable off sedation, and blood cultures continued
to grow the same K. pneumoniae despite systemic polymyxin B. Non-contrast
head CT was unremarkable, and lumbar puncture revealed an elevated pro-
tein (953 mg/dl), hypoglycorrhachia (glucose <10mg/dl), and a neutrophilic
pleocytosis (650 WBC/ml, 85% polymorphonuclear cells). Cerebrospinal fluid
cultures also grew K. pneumoniae. The patient was treated with both systemic
antimicrobials, and intrathecal polymyxin B and gentamicin. A supervisor in the
microbiology laboratory noted serpentine tracks of K. pneumoniae on an agar
plate of the patient’s bronchoalveolar lavage (Figure 9e.4). She performed wet

Gastrointestinal Infections
mounts of the lavage sample, and discovered many motile Strongyloides sterc-
oralis filariform larvae (Figure 9e.5).
Despite administration of ivermectin and thiabendazole via nasogastric tube,
and daily ivermectin retention enemas, the patient demonstrated little neuro-
logic recovery. Magnetic resonance imaging revealed a discrete abscess in cau-
date nucleus, as well as diffuse enhancement of the ventricles (Figure 9e.6). Due
to the overall grave prognosis, palliation was pursued and the patient expired.

235 CHAPTER 9
Figure 9e.4 Sputum culture on MacConkey agar and chocolate agar. The colonies of
Klebsiella pneumoniae where being dragged across the plate in serpiginous tracks.

Figure 9e.5 Wet mount of sputum revealed many motile larvae of Strongyloides
stercoralis.
Gastrointestinal Infections
CHAPTER 9

Figure 9e.6 MRI brain, axial view revealed a discrete abscess in the right caudate
nucleus as well as diffuse enhancement of the ventricles.
236

Case 9e Discussion: Strongyloides stercoralis

Clinical Features and Diagnosis
Strongyloides stercoralis is prevalent in tropical and subtropical climates. Areas
of endemicity include Central and South America, Asia, Africa, the Caribbean,
the southeastern United States, and Mexico. S. stercoralis has the ability to
autoinfect a single human host and establish a latent infection that can persist
asymptomatically for years. Hyperinfection occurs when the autoinfection pro-
cess accelerates in the setting of immunosuppression, either from underlying
medical conditions or medications like corticosteroids or antithymocyte immu-
noglobulin. Strongyloides hyperinfection syndrome (SHS) has been associated
with mortality rates of as high as 87% in the immunocompromised host.
Primary strongyloidiasis begins with filariform larvae transcutaneously infect-
ing the human host. These larvae travel through the venous circulation to the
lungs, where they penetrate the alveoli. They then travel to the pharynx and
are subsequently ingested. Larvae mature into adult worms within the gastroin-
testinal tract, and eggs are deposited within the intestinal mucosa. The hatched
rhabditiform larvae are either excreted into stool or develop into filariform
larvae within the intestinal tract. Autoinfection occurs when these filariform
larvae migrate through the bowel wall, or through the perianal skin, into the
venous circulation (Figure 9e.7). A creeping purpuric rash in the perianal or
pelvic area, “larva currens,” is often suggestive of autoinfection. In the setting
of endogenous or exogenous immunosuppression, the autoinfection cycle
is accelerated. Massive larval migration through the lungs causes respiratory
symptoms that may be as mild as cough and wheezing, to as life-threatening
as acute respiratory distress syndrome and respiratory failure. Gastrointestinal
 Gastrointestinal Infections
i = Infective Stage 6 Infective fitariform larvae
penetrate the intact skin 7 The filariform larvae enter
d = Diagnostic Stage initiating the infection. the circulatory system, are
transported to the lungs, and
penetrate the alveolar
i spaces. They are carried to
the trachea and pharynx,
i swallowed, and reach the
5 The rhabditiform small intestine where they
larvae develop become adults.
into infective
filariform.
8
Developm Adult female
worm in the
intestine.
Ne

N
TIO
w

4
ge n

FEC
Rhabditiform Autoinfection:
ent
erat

Rhabditiform larvae

IN
larvae hatch from

CHAPTER 9
into

TO
embryonated eggs 10 in large intestine,
ion of

become filariform

AU
fila

larvae, penetrate
r
ifo
adults

intestinal mucosa or
rm

la r perianal skin, and

va
e follow the normal
infective cycle.
3
Eggs are produced 9
by fertilized
female worms. Eggs, deposited in intestinal mucosa,
1 d hatch, and migrate to lumen.
Rhabditiform larvae
in the intestine are
excreted in stool.

2 Development
into free-living
adult worms.

Figure 9e.7 Lifecycle of Strongyloides stercoralis. Source: Centers for Disease Control

237
and Prevention http://www.dpd.cdc.gov/dpdx.

symptoms range from diarrhea and abdominal pain to paralytic ileus and intesti-
nal obstruction. The high volume parasitic migration can also lead to the devel-
opment of diffuse larva currens. Biopsy of these lesions can reveal migrating
larvae. Bacteremias with enteric flora are often suggestive of SHS in the appro-
priate host. SHS should always be considered in the differential when treating
patients with Gram-negative meningitis. Visualization of larvae on biopsy or
on ova, and parasite examination of stool or sputum, is diagnostic. Tracking of
bacterial colonies on solid culture media is also suggestive.
In solid organ transplantation, most reported cases of SHS are the result
of reactivation of latent infection in the setting of intensified immunosuppres-
sion.1 Most reports describe patients presenting within the first 3 months after
transplantation. In retrospect, many case patients had evidence of occult infec-
tion prior to transplantation, including unexplained intermittent eosinophilia,
chronic gastrointestinal symptoms, or a history of another intestinal parasitic
infection.2 Primary Strongyloides infection in areas of endemicity and donor-
derived primary infection are rare, but have been described.3
Often the diagnosis of SHS in the solid organ transplant recipient is seren-
dipitous, as in the described case. The critical nature of Gram-negative bac-
teremia, respiratory failure, or altered mental status can delay the diagnosis.
Hallmarks of parasitic infections like diarrhea or eosinophilia are usually absent
in the setting of SHS. A thorough history, including a detailed travel history and
review of any augmentation or changes in immunosuppressive medications, can
be helpful.
 Management
Gastrointestinal Infections

The ideal treatment of SHS is not well established. Single dose ivermectin is
the treatment of choice in immunocompetent patients with intestinal strongy-
loidiasis. Treatment duration for SHS using thiabendazole monotherapy ranges
from 5 to 14 days. More aggressive regimens for SHS employ thiabendazole
or albendazole and ivermectin for variable durations. Many patients require
multiple courses of therapy because of persistent parasitosis. It has been sug-
gested that survivors of SHS should be treated monthly for at least 6 months.
Reactivation can occur in transplant recipients even after initial treatment.
These patients may benefit from indefinite therapy, but studies to support this
CHAPTER 9

practice are lacking.

A challenge in the treatment of SHS is that patients often suffer from para-
lytic ileus or intestinal obstruction, preventing both administration and absorp-
tion of oral agents. No accepted parenteral therapy exists, but employment of
alternative treatment modalities such as subcutaneous and rectal formulations
of ivermectin have been described.4,5
Pretransplant Evaluation
This case highlights the importance of developing strategies to prevent
Strongyloides infections in transplant recipients. Donors and recipients who
have resided in endemic areas should be screened for latent strongyloidiasis
prior to transplantation. Those with a history of other helminthic infections,
238

unexplained eosinophilia, or unexplained gastrointestinal complaints should

also be screened. Serology may be less sensitive in relatively immunocom-
promised patients, and diagnostic yield may be greater with concomitant
examination of stool for ova and parasites. Transplant candidates with evi-
dence of Strongyloides infection should be treated with either thiabendazole
25 mg/kg twice daily for three days, or ivermectin 200 mcg/kg once daily for
two days with documented negative stool ova and parasite exams prior to
transplantation. At the time of transplantation, with the initiation of high-dose
immunosuppression, treatment should be reinitiated. Family members and
pets should also be screened and treated as potential sources of reinfection
post-transplant.
Pretransplant screening of the deceased donor prior to organ procurement
is not practical. Targeted serologic screening for Strongyloides in donors from
endemic areas may provide useful information for the physicians caring for the
recipients of organs from an untreated cadaveric donor with latent Strongyloides.
Although formal studies are lacking, preemptive treatment in these recipients
may prevent disease.

References
1. Roxby AC, Gottlieb GS, Limaye AP. Immunocompromised hosts: Strongyloidiasis
in transplant patients. Clin Infect Dis 2009;49:1411–1423.
2. Schaeffer MW, Buell JF, Gupta M, Conway GD, Akhter SA, Wagoner LE.
Strongyloides hyperinfection syndrome after heart transplantation: case report
and review of the literature. J Heart Lung Transplant. 2004;23:905–911.
3. Patel G, Arvelakis A, Sauter BV, Gondolesi GE, Caplivski D, Huprikar S.

Gastrointestinal Infections
Strongyloides hyperinfection syndrome after intestinal transplantation. Transpl
Infect Dis. 2008;10: 137–141.
4. Tarr PE, Miele PS, Peregoy KS, Smith MA, Neva FA, Lucey DR. Case Report:
Rectal administration of ivermectin to a patient with Strongyloides hyperinfection
syndrome. Am J Trop Med Hyg. 2003;68:453–455.
5. Marty FM, Lowry CM, Rodriguez M, et al. Treatment of human disseminated
Strongyloidiasis with a Parenteral veterinary formulation of ivermectin. Clin Infect
Dis. 2005;41:5–8.

CHAPTER 9
Case
C a e 9f:
9f: A LLi
Liver
iver Trans
Transplant
T nsplant
l t Recipient
Reciipient
i t wi
with
th Fever
F aand
nd
d
Abdo
Ab dominal Pain
Abdominal

Meenakshi Mehrotra Rana, and Shirish Huprikar

Case Presentation
A 41-year-old man with hepatitis C cirrhosis and hepatocellular carcinoma who
underwent liver transplantation 6 months earlier, presented to the emergency
room with abdominal pain, nausea, and vomiting for 2 weeks. In addition to his
abdominal pain, he had multiple episodes of loose watery stools for several
days, and on the day of presentation he had chills and fever at home to 101º

239
Fahrenheit. Two months prior to presentation, his immunosuppression had
been increased because he had developed acute elevation of liver enzymes, and
liver biopsy showed moderate acute cellular rejection.
His past medical history also included diabetes and hypertension. His immu-
nosuppressive medications included cyclosporine 150 mg twice daily, pred-
nisone 5 mg daily, and mycophenolate mofetil 1000 mg twice daily (recently
increased from 500 mg twice daily). Prophylactic valganciclovir 900 mg daily
and trimethoprim-sulfamethoxazole had been discontinued per protocol 3
months prior to presentation, after having completed a 3-month course post-
transplant. Of note, he was CMVseronegative at the time of transplant, and had
received the liver from a CMV seropositive donor. He lived with his wife and
young daughter, and denied any pets or recent travel.
On physical examination, he was febrile to 38.5º Celsius and had a blood
pressure of 134/74 mm/Hg with heart rate of 72 beats per minute. He appeared
uncomfortable and was vomiting. His physical examination was also significant
for bilateral crackles at the lung bases, and diffuse abdominal tenderness to
palpation. Laboratory examination was notable for leukopenia (3.9 x10³WBC/
μl, 82% neutrophils), thrombocytopenia (60 x10³platelets/μl), elevated BUN
(31), creatinine (1.4 from a baseline of 1.1), and liver enzymes (ALT 267 U/L,
AST 78 U/L). The liver enzymes had improved from 2 months prior when, in
the setting of acute rejection, they were 350 U/L and 320 U/L respectively; the
total bilirubin was 1.8 with a direct bilirubin of 1.4.
A chest radiograph revealed bilateral interstitial infiltrates (Figure 9f.1) and
subsequent chest CT showed diffuse ground-glass opacities and nodular lung
infiltrates with small bilateral pleural effusions (Figure 9f.2). Over the next several
Gastrointestinal Infections
CHAPTER 9

Figure 9f.1 Chest radiograph, posterior anterior view showing bilateral interstitial
infiltrates.
240

Figure 9f.2 CT chest, axial view with diffuse ground glass opacities and nodular lung
infiltrates with small bilateral pleural effusions.

days, he developed worsening shortness of breath, progressive hypoxia and con-

fusion, and was intubated and transferred to the medical intensive care unit.
The admission cytomegalovirus (CMV) PCR was >100,000 copies/ml, and
the patient was treated initially with intravenous ganciclovir and subsequently
with foscarnet, for the possibility of ganciclovir-resistant CMV. Flexible sigmoi-
doscopy revealed scattered sigmoid ulcers, and typical CMV inclusions were
found on colonic biopsy and confirmed with immunohistochemical staining
(Figures 9f.3 and 9f.4). Transbronchial biopsy did not confirm CMV pneumonitis,
 Gastrointestinal Infections
CHAPTER 9
Figure 9f.3 Colon biopsy, hematoxylin and eosin stain showing characteristic viral
inclusions of cytomegalovirus. Image courtesy of Alexandros D. Polydorides.

241

Figure 9f.4 Colon biopsy, immunohistochemical stain specific for Cytomegalovirus

antigen. Image courtesy of Alexandros D. Polydorides.

but other infections were excluded, and this was thought to be the most likely
cause of the pulmonary findings. Over the course of his hospitalization he
received broad-spectrum antimicrobials in addition to foscarnet, ganciclovir
(after ganciclovir resistance was excluded), and cytomegalovirus intravenous
immune globulin (Cytogam). His CMV PCR was undetectable 4 weeks after
admission, but his course was complicated by prolonged respiratory and renal
 failure. After a 2-month hospitalization, he developed nosocomial sepsis with
Gastrointestinal Infections

multidrug resistant Acinetobacter baumannii, and died despite full ventilatory

and pressor support.
Case 9f Discussion: Cytomegalovirus Colitis
CMV is a herpesvirus that infects the majority of adults by the third decade of
life, and is a major cause of morbidity and mortality in solid organ transplant
patients. As with all herpesviruses, CMV establishes latency in different cell
types and can reactivate to cause secondary infection in the setting of immuno-
suppression in solid organ transplant recipients.
CHAPTER 9

In the absence of a preventive strategy, 30%–75% of transplant recipients

will develop CMV disease.1 As in the case described above, CMV donor posi-
tive/recipient negative (D+R-) patients are at the highest risk for CMV disease
because of the lack of previous CMV-specific immunity. These patients have a
44%–65% risk of developing CMV disease without the use of antiviral prophy-
laxis, and a 12%–30% risk with antiviral prophylaxis.2 CMV seropositive recipi-
ents are also at risk for reactivation, but the risk is lower than for D+R- patients.
Although D+R- status remains the most important risk factor, other risk factors
play a role as well. These include the use of highly immunosuppressive medi-
cations post-transplant, including antithymocyte globulin, muromonab-CD3
(OKT3), and increased doses of mycophenolate mofetil or corticosteroids after
an episode of graft rejection. Other risk factors include coinfection with other
242

viruses including HHV-6 or HHV-7, or allograft rejection itself.

The terminology surrounding CMV infection can be confusing. The term
CMV infection refers to the presence of CMV virus as detected by PCR or
antigen testing in body fluid or tissue specimen, but may be asymptomatic. The
term CMV disease refers to CMV infection with signs and symptoms such as
fever, malaise, and bone marrow suppression (leukopenia and thrombocytope-
nia). Tissue-invasive CMV disease refers to any organ system affected by CMV,
and is usually based on a biopsy for diagnosis.1
In solid organ transplant patients, CMV infection can manifest with both direct
and indirect effects. Direct effects of CMV in various organ systems include gas-
trointestinal disease such as colitis, as in the case above, hepatitis, pneumonitis,
CNS disease, or retinitis. In addition to direct effects, CMV may have a number
of indirect effects. These include an increased risk of acute or chronic allograft
rejection, with manifestations such as accelerated coronary atherosclerosis in
heart transplant recipients, and bronchiolitis obliterans in lung transplant recipi-
ents. In addition, CMV infection has been associated with the development of
other opportunistic infections, including viral infections, EBV-associated post-
transplant lymphoproliferative disease (PTLD), and fungal infections. Through
both direct and indirect effects, CMV disease has been independently associ-
ated with an increased risk of mortality in solid organ transplant recipients, and
therefore prevention plays a vital role in this population.
Prevention
There are two approaches recommended for the prevention of CMV disease:
a preemptive strategy, or universal prophylaxis. With a preemptive strategy,
patients are followed closely after transplant for CMV, with polymerase chain
reaction (PCR) assays, or markers such as pp65 antigenemia testing. If the assay

Gastrointestinal Infections
becomes positive, antiviral therapy is initiated immediately. With a prophylaxis
approach, antiviral prophylaxis is administered immediately after transplant for
a period of 3–6 months, depending on the type of transplant and transplant
center protocols.3
Both approaches have been used successfully and are effective at prevent-
ing CMV disease. Several meta-analyses have compared the preemptive and
prophylaxis approaches, and have shown both strategies to be effective. In
the meta-analysis published by Kalil et al, the authors compared 17 random-
ized controlled trials looking at CMV prevention using either prophylaxis or a

CHAPTER 9
preemptive strategy.4 In this meta-analysis, both approaches showed significant
reduction in CMV disease and allograft rejection; however, in patients who
received anti-lymphocyte antibody and were D+R-, only prophylaxis showed a
reduction in CMV disease. In addition, only the prophylactic approach showed
a significant decrease in bacterial and fungal infections, and death.
The preemptive approach has several advantages, despite these shortcom-
ings. This approach minimizes the cost and toxicities associated with the pro-
phylactic antiviral drugs. In addition, it may allow for the development of an
early CMV-specific immune response, reducing the risk of late-onset CMV
disease, which remains a significant problem after prophylaxis is discontinued.
Lastly, the use of the preemptive approach may lower the risk of the develop-
ment of CMV resistance to ganciclovir—a phenomenon that has been shown

243
to be associated with prolonged use of antiviral therapy.
The American Society of Transplantation guidelines recommend antiviral
prophylaxis in high-risk solid organ transplant recipients. In D+R- patients who
receive kidney, liver, pancreas, or heart transplants, ganciclovir or valganciclovir
is recommended for 3–6 months. In R+ or R- patients who receive a lung or
heart–lung transplant, and in patients who receive anti-lymphocyte antibody or
OKT3, prophylaxis is recommended. In R+ patients who receive a kidney, liver,
pancreas, or heart transplant, either prophylaxis or the preemptive monitoring
strategy is recommended (please see Table 9f.1).5 A preventive strategy should
be resumed in the setting of acute rejection, particularly in patients treated with
corticosteroids or anti-lymphocyte therapies.
Several agents are used for the prevention of CMV, and include either gan-
ciclovir or valganciclovir. Ganciclovir, the first antiviral approved for CMV, is
available in both intravenous (IV) formulations and oral formulations, but the
oral formulation has limited bioavailability. Valganciclovir, a valyl ester prodrug,
enhances absorption and results in systemic drug levels comparable to IV gan-
ciclovir. The role of valganciclovir in prophylaxis was evaluated in a randomized
clinical trial in which 364 D+R- SOT recipients received either 900 mg of valgan-
ciclovir once daily, or 1000 mg of ganciclovir three times daily.6 At 12 months,
the proportion of patients receiving valganciclovir who developed CMV was
similar to those who received oral ganciclovir (17.2% and 18.4%); however,
in a subset analysis performed on the 177 liver transplant recipients who par-
ticipated in this trial, the incidence of CMV disease, including tissue-invasive
disease, was higher in the valganciclovir group as opposed to the ganciclovir
group (19% vs. 12%). For this reason, valganciclovir never gained FDA approval
Gastrointestinal Infections

Table 9f.1 Guidelines for Prevention of CMV in SOT Recipients

Organ/group Recommendation/Options (see text for dose, evidence
rating and special pediatric issues)
Kidney, liver, Prophylaxis: Valganciclovir, oral ganciclovir, or intravenous
pancreas, heart ganciclovir (or valacyclovir in kidney) for 3 to 6 months. Some
centers add CMV immune globulin for heart transplant.
D+/R– Preemptive therapy an option (see Figure 1). Many authorities
prefer to use prophylaxis and reserve preemptive therapy for
lower-risk populations (see text).
Kidney, liver, Valganciclovir, oral ganciclovir, intravenous ganciclovir or
CHAPTER 9

pancreas, heart valacyclovir (kidney) for 3 months. Some centers add CMV
immune globulin for heart transplant OR
R+ Pre-emptive therapy an option (See Figure 1).
Lung, heart-lung For D+/R– patients valganciclovir or intravenous ganciclovir
for 6 months. Some centres with prolong prophylaxis beyond
6 months.
D+/R–, R+ For R+ patients, valganciclovir, oral ganciclovir or intravenous
ganciclovir for 3–6 months.
Some centres will add CMV immune globulin especially for
D+/R–.
The above guidelines do not represent an exclusive course of action. Several factors may influence
the precise nature and duration of prophylaxis or preemptive therapy.
Reprinted with permission from Humar A , Snydman D. Cytomegalovirus in Solid Organ Transplant
Recipients. American Journal of Transplantation. 2009;9(Suppl 4):S78–S86.
244

for prophylaxis against CMV disease in liver transplant patients. Despite these
findings, valganciclovir is routinely used in the prevention of CMV disease in
liver transplant patients.
Late-onset CMV disease presents a challenge almost exclusively in patients
who receive prophylaxis, and typically occurs within the first year. It is associ-
ated with D+R- status and higher mortality after transplantation. Newer strate-
gies are needed to monitor these patients once prophylaxis is discontinued.
These may include monitoring with CMV PCR, using immunological markers
such as conversion of CMV serostatus, or the development of CMV-specific
CD4+ or CD8+ cells, or extending the duration of prophylaxis. Currently, the
IMPACT (the Improved Protection Against Cytomegalovirus in Transplant)
study is an ongoing randomized, multicenter, placebo-controlled trial designed
to look at whether extending prophylaxis in high-risk renal transplant recipients
is effective in preventing late-onset CMV disease. Preliminary data at one year
shows that in D+R- renal transplant recipients who received 200 days of pro-
phylaxis, there were decreased rates of CMV disease, including tissue-invasive
disease, as compared to patients who received 100 days of prophylaxis (16.1%
vs. 36.8%).7
Treatment
For treatment of CMV disease, IV ganciclovir is recommended, and oral ganci-
clovir should not be used because of its poor bioavailability. Oral valganciclovir
has also been shown to be effective in the treatment of CMV disease. In 321
solid organ transplant recipients with CMV disease, who were randomized to

Gastrointestinal Infections
receive either valganciclovir or IV ganciclovir for treatment for 21 days followed
by 4 weeks of step-down therapy, the proportion of patients with viral eradi-
cation at 21 days and then 49 days was comparable.8 Therefore, for selected
patients, valganciclovir can be used for the treatment of disease.
Duration of therapy has not been studied in a clinical trial, but induction
treatment is generally continued until CMV DNA is no longer detectable in
the serum by PCR, and signs of clinical disease have resolved. The need for
maintenance or secondary prophylaxis or post-treatment surveillance remains
unsettled.

CHAPTER 9
Ganciclovir-resistant CMV is an emerging clinical problem in solid organ
transplant recipients. It should be suspected in patients who do not initially
respond to ganciclovir. The mechanism of resistance is related to mutations in
either the UL97 or UL54 genes of CMV. CMV D+R- recipients, recipients of
pancreas or lung transplants, and those who receive ganciclovir for prolonged
periods of immunosuppression are at high risk.9 Intravenous foscarnet should
be considered for these patients or in patients with confirmed ganciclovir-
resistant CMV. Because of its nephrotoxicity, foscarnet use requires careful
monitoring of renal function and electrolytes.

References

245
1. Legendre C, and Pascual, M. Improving outcomes from solid-organ transplant
recipients at risk from cytomegalovirus infection: late-onset disease and indirect
consequences. Clin Infect Dis. 2008;46:732–740.
2. Razonable, RR. Cytomegalovirus infection after liver transplantation: Current
concepts and challenges. World J Gastroenterol. 2008;14(31):4849–4860
3. Huprikar, S. Update in infectious diseases in liver transplant recipients. Clin Liver
Dis. 2007;11(2):337–354.
4. Kalil AC, Levitsky J, Lyden E, Stoner J, Freifeld AG. Meta-analysis: the efficacy of
strategies to prevent organ disease by cytomegalovirus in solid organ transplant
recipients. Ann Intern Med. 2005;143:870–880.
5. Humar A, Snydman D. Cytomegalovirus in solid organ transplant recipients.
Am J Transplant. 2009;9(Suppl 4):S78–S86.
6. Paya C, Humar A, Dominguez E, et al. Efficacy and safety of valganciclovir vs. oral
ganciclovir for prevention of cytomegalovirus disease in solid organ transplant
recipients. Am J Transplant. 2004;4:611–620.
7. Humar A, Lebranchu Y, Vincenti F, et al. The IMPACT study: valganciclovir pro-
phylaxis until 200 days post-transplant in high risk kidney recipients substantially
reduces the incidence of CMV disease. Abstract 201, Presented at American
Society of Transplantation, 2009.
8. Asberg A, Humar A, Rollag H, et al. Oral valganciclovir is noninferior to intra-
venous ganciclovir for the treatment of cytomegalovirus disease in solid organ
transplant recipients. Am J Transant. 2007;7:2106–2113.
9. Torres-Madriz G, Boucher HW. Perspectives in the treatment and prophylaxis
of cytomegalovirus disease in solid-organ transplant recipients. Clin Infect Dis.
2008;47:702–711.
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 Chapter 10

Urinary Tract Infections

Case
C a e 10a:
10a:
0a MMethicillin-Susceptible
eth
thi
hicil
illi
illin-
lin-SSuscepti
tibl
ble S
bl Staphylococccus
tap
aph
hylloccocccuss
aure
au reus
u (MSSA) Pye
aureus yelo
loneph
p ritis
Pyelonephritis

Florence Nana and W. Michael Scheld

Case Presentation
A 58-year-old male with history of hypertension and dyslipidemia presented

247
with a 9-day history of lower back pain leading to decreased mobility in his left
leg. He was evaluated at a local emergency department, and a CT scan of the
spine at the time was negative for any lesions. He was discharged home with
a prescription of cyclobenzaprine, but returned with severe lower back pain
with numbness and weakness in the left lower extremity. On admission to our
institution, he also reported fever and night sweats, but denied any other symp-
toms. He denied any history of substance abuse or recent travel.
Physical examination on admission was significant for fever and decreased
left lower extremity muscle strength to 2/5. His laboratory examinations were
notable for leukocytosis (32.7x103 WBC/μl) and mild renal insufficiency (BUN
33 mg/dl, creatinine 1.5 mg/dl). Urinalysis showed 1–5RBC, 10–20WBC, many
bacteria, and urine culture grew > 100,000 CFU/ml of methicillin susceptible
Staphylococcus aureus (MSSA); blood cultures were sterile (Figure 10a.1).
CT of the abdomen revealed pyelonephritis of the left kidney, and MRI of
the spine revealed discitis /osteomyelitis at L2-L3 with a small epidural abscess.
Epidural aspirate also grew MSSA. A transthoracic echocardiogram did not
reveal any evidence of endocarditis and the patient made a full recovery follow-
ing 6 weeks of intravenous nafcillin.
Case 10a Discussion: Staphylococcus aureus Pyelonephritis
Urinary tract infections (UTI) are among the most common complications
associated with the use of indwelling urinary catheters (IDUC). Staphylococcus
aureus ascending UTI is uncommon; bacteriuria in this case may be secondary
to bacteremia. The association of S. aureus bacteriuria (SABU) with S. aureus
bacteremia (SAB) has been well described in the literature.1,2,3
Urinary Tract Infections
CHAPTER 10

Figure 10a.1 Axial (A) and sagittal (B) non-contrast abdominal CT demonstrates peri-
nephric fat stranding (arrows) along with increased size of the right kidney, consistent
with right sided pyelonephritis (representative image courtesy of Joshua Dowell).

S. aureus is recognized to cause UTI or colonization in patients with IDUC,

recent instrumentation, surgery, or urinary tract obstruction. Several studies
have shown that the presence of S. aureus in the urine is not just an inciden-
tal colonization, especially in patients without IDUC.1,4,5 Staphylococcus aureus
248

bacteriuria is associated with a high risk of future invasive infection, and can be
an early surrogate of Staphylococcus aureus bacteremia.4,5 Staphylococcus aureus
bacteriuria in a recent study appears not to be, as previously reported,6 associ-
ated with more SAB fatality.5
Current risk factors associated with concomitant SABU-SAB include: the
presence of an underlying urinary tract abnormality, urinary tract surgery, or
instrumentation. Choi et al.5 found vertebral osteomyelitis to be a frequent
focus of infection associated with concurrent SABU-SAB. Community-onset
MSSA SAB vs nosocomial cases appear to be more associated with concurrent
SABU-SAB.5
Because of the severity of complications that may be related to staphylo-
coccal bacteremia, SABU should not be considered as a simple colonization.
Investigation for possible occult deep foci of staphylococcal infection should
be performed with blood cultures, imaging studies, and transthoracic and/or
transesophageal echocardiography.

References
1. Lee BK, Crossley K, Gerding DN. The association between Staphylococcus aureus
bacteremia and bacteriuria. Am J Med. 1978;65:303–306.
2. Sheth S, Dinubile NJ.. Clinical significance of Staphylococcus aureus bacteriuria
without concurrent bacteremia. Clin Infect Dis. 1997;24:1268–1269.
3. Pulcini C, Matta M, Mondain, et al. Concomitant Staphylococcus aureus
bacteriuria is associated with complicated S.aureus bacteremia. J Infect. 2009;59:
240–246.
4. Muder R, Brennen C, Rihs JD, et al. Isolation of staphylococcus aureus from the
urinary tract. Clin Infect Dis. 2006;42:46–50.
5. Choi SH, Lee SO, Choi JP, Lim SK. The clinical significance of concurrent

Urinary Tract Infections

Staphylococcus aureus bacteriuria in patients with S. aureus bacteremia. J Infect.
2009;59:37–41.
6. Huggan PJ, Murdoch DR, Gallagher K, Chambers ST. Concomitant Staphylococcus
aureus bacteriuria is associated with poor clinical outcome in adults with S.aureus
bacteremia. J Hosp Infect. 2008; 69, 345–349.

Case
C a e 10b:
10b
0b: A 19
19-Year-Old
-Year-
Y -Ol Old
d St
Stem C
Cell
ell
ll TTransplant
ranspla
lant
nt

CHAPTER 10
Reci
Re cip
pient with Hem
Recipient emaaturria
Hematuria

Daniel Caplivski and Shirish Huprikar

Case Presentation
A 19-year-old man from China with severe transfusion-dependent aplastic
anemia underwent cord transplantation from an incompletely matched donor.
His conditioning regimen included antithymocyte globulin, cyclophosphamide,
and total body irradiation. On day 47 after transplant, his bone marrow had
engrafted, but he presented to the transplant clinic with dysuria and hematuria
for 2 weeks. He reported passing blood and clots in the urine, but he had
no fevers, chills, or back pain. His immunosuppressive medications included
cyclosporine and mycophenolate mofetil.

249
On admission, he was afebrile and with no flank pain or suprapubic tender-
ness. His laboratory values were significant for anemia (hemoglobin 8.4 g/dl) and
thrombocytopenia (platelets 124,000 cells per microliter) but normal leukocyte
count (WBC 5800 cells per microliter) and creatinine (0.7 mg/dl). Abdominal
ultrasound did not show any hydronephrosis or renal calculi, but the bladder
wall had a lobular contour, and scattered internal echogenic material was seen
within the lumen (Figure 10b.1). Urine cultures were negative, but urine cytology
revealed atypical urothelial cells with ground-glass intranuclear inclusion bod-
ies (Figure 10b.2). Urine and blood PCR testing for BK virus were positive, and
serum CMV PCR was negative. Cyclosporine was discontinued and intravenous
fluids were administered, and the hematuria eventually resolved within 2 days.

Figure 10b.1 Abdominal ultrasound showing a lobular contour to the bladder wall and
scattered intraluminal echogenic material.
Urinary Tract Infections
CHAPTER 10

Figure 10b.2 Urine cytology revealed atypical urothelial cells (“decoy cells”) with
ground-glass intranuclear inclusion bodies.

Case 10b Discussion: BK Virus Hemorrhagic Cystitis

Clinical Presentation and Diagnosis
BK virus is a member of the polyoma genus of viruses that also includes JC virus,
the etiologic agent of progressive multifocal leukoencephalopathy. The poly-
oma virus genus derives its name from their ability to cause multiple tumors
250

in mice. The individual viruses were named for the initials of the patients from
whom they were first isolated. These viruses are extremely common among
healthy adults, but can cause profound invasive reactivation disease in immu-
nosuppressed patients. In kidney transplant recipients, BK virus causes a post-
transplant nephropathy or ureteral stenosis that may lead to graft loss. In stem
cell transplant (SCT) recipients, hemorrhagic cystitis is the major manifestation
of BK virus disease.
Hemorrhagic cystitis is a clinical syndrome characterized by hematuria,
caused by hemorrhagic inflammation of the bladder mucosa. Symptoms may
include dysuria, urgency, frequency, and suprapubic pain. Complications include
urinary tract obstruction and renal failure when clots are present. Hemorrhagic
cystitis may be caused by multiple etiologies, including chemotherapy (e.g.
cyclophosphamide) and bladder irradiation early after SCT, but once engraft-
ment occurs, viral infections such adenovirus and BK virus are more common
etiologies.1
The diagnosis of BK nephropathy or hemorrhagic cystitis is usually supported
in kidney transplant or SCT recipients with PCR testing of urine or blood. BK
viruria is found in up to 20% of asymptomatic individuals, but viremia is uncom-
mon outside of the setting of immunosuppression. Detection of BK virus DNA
in the blood is more useful in evaluating patients for BK nephropathy than for
those with hemorrhagic cystitis, in whom blood PCR testing is rarely positive.2
Renal biopsy or urine cytology are also used to establish the diagnosis of BK
nephropathy or hemorrhagic cystitis. Renal biopsy may reveal tubular epithe-
lium cells with large intranuclear inclusions. Decoy cells are atypical-appearing
urothelial cells, with a large basophilic intranuclear inclusion indicative of viral
infection, but are not specific to BK virus, as JC and adenovirus infections can

Urinary Tract Infections

produce similar findings.2,3
Management
The principle intervention required for BK virus nephropathy or ureteral steno-
sis is reduction in the degree of immunosuppression. Symptomatic management
of hemorrhagic cystitis with bladder irrigation, forced hydration, analgesia, and
blood transfusions, is generally adequate. Anecdotal reports of success with
the use of cidofovir and quinolone antibiotics are problematic because of the

CHAPTER 10
lack of control groups, and the fact that these patients also were treated with
reduced immunosuppression.3

References
1. Leung AY, Yuen KY, Kwong YL. Polyoma BK virus and haemorrhagic cystitis in
haematopoietic stem cell transplantation: a changing paradigm. Bone Marrow
Transplant. 2005;36(11):929–937.
2. Hirsch HH, Steiger J. Polyomavirus BK. Lancet Infect Dis. 2003;3(10):611–623.
3. Leung AY , Mak R, Lie AK, Yuen KY, Cheng VC, Liang R, Kwong YL.
Clinicopathological features and risk factors of clinically overt haemorrhagic cys-
titis complicating bone marrow transplantation. Bone Marrow Transplant. 2002
Mar;29(6):509–513.

251
Ca e 10c:
Case 10c: M
Multidrug-Resistant
ullt
ltid
ltiid -Re
idrug-Resiistant
t tO Organisms
rganiisms

Gopi Patel
Case Presentation
A 56-year-old man with hepatitis C cirrhosis underwent orthotopic liver trans-
plantation for decompensated liver failure. Prior to transplant, he required
hemodialysis for worsening renal failure from hepatorenal syndrome, as well as
ureteral stent placement for obstructive nephrolithiasis of his right kidney. His
immunosuppressant medications included prednisone, tacrolimus, and myco-
phenolate mofetil.
Ten days after liver transplantation, he was no longer requiring hemodialy-
sis but he developed fevers (39ºC), chills, and lethargy. On physical examina-
tion, he was slow to answer questions and had a flat affect. He denied any
urinary complaints; however, he was having palpitations and was found to be in
rapid atrial fibrillation. His laboratory results were significant for leukocytosis
(12 x 10³ WBC per μl) and renal insufficiency that was slowly improving (BUN
61 mg/dl, creatinine 3.1 mg/dl). His urinalysis revealed numerous white blood
cells, and both blood and urine cultures were positive for Gram-negative bacilli
(Figure 10c.1). This organism was confirmed to be a KPC-producing Klebsiella
pneumoniae resistant to all antibiotics except tigecycline (Figure 10c.2). The
patient was treated with tigecycline, but the bacteremia persisted until the ure-
teral stent was removed and the patient underwent ureteroscopy, laser litho-
tripsy, and stent exchange.
Urinary Tract Infections
CHAPTER 10

Figure 10c.1 Blood culture Gram stain showing Gram-negative bacilli. The area of
clearing around several of the organisms is caused by the polysaccharide capsule.
252

Figure 10c.2 E-test showing ertapenem-resistant Klebsiella pneumoniae.

Case 10c Discussion: KPC-producing Klebsiella pneumoniae

Epidemiology and Microbiology
Carbapenem resistance among Enterobacteriaceae was first recognized in the
early 1990s. Isolation of these bacteria remained sporadic for the better part
of that decade. In recent years, however, healthcare-associated infections with
carbapenem-resistant Gram-negative bacilli, specifically Klebsiella pneumoniae,
are being reported at an alarming rate.1 In 2007, the United States’ Centers for

Urinary Tract Infections

Disease Control and Prevention noted that 8% of all K. pneumoniae responsible
for healthcare-associated infections were carbapenem-resistant, compared
with less than 1% in 2000. Thirty-three states have reported clinical isolation of
carbapenem-resistant Enterobacteriaceae with a concentration of cases in the
northeast United States.2
Carbapenem resistance in Enterobacteriaceae results from one or a
combination of the following mechanisms: hyperproduction of AmpC
E-lactamases, loss of outer membrane porins, drug efflux, or carbapenemase

CHAPTER 10
production. In the United States, Greece, and Israel, carbapenem-resistance in
Enterobacteriaceae is attributed primarily to plasmid-mediated expression of a
Class A serine carbapenemase—Klebsiella pneumoniae carbapenemase (KPC).
These enzymes are capable of efficiently hydrolyzing carbapenems, as well as
other E-lactam antibiotics like penicillins, cephalosporins, and the monobactam
aztreonam, rendering these entire classes of agents inactive. KPC production
has been identified in many Enterobacteriaceae, and in both Acinetobacter and
Pseudomonas species. K. pneumoniae remains the most common species found
to harbor these enzymes. Nine KPC subtypes (KPC-2 through KPC-10) have
been reported, with the majority of analyzed isolates expressing either KPC-2
or KPC-3.
Microbiologic identification of these organisms is difficult, and may lead
to delays in therapeutic management and implementation of appropri-

253
ate infection control measures. KPC-mediated carbapenem resistance can
go completely unrecognized in laboratories that rely solely on automated
identification and susceptibility testing. Recommendations have been made
to perform additional testing (e.g., the Modified Hodge Test or PCR) on
isolates demonstrating discordant carbapenem susceptibilities, or elevated
MICs to any one of the carbapenems. Ertapenem has been identified as the
most sensitive agent to detect Enterobacteriaceae-producing KPCs (KPC-E)
in vitro.3
Early observational reports aiming to identify risk factors for the acquisition
of KPC-E, specifically carbapenem-resistant K. pneumoniae, suggest that patients
at risk are critically ill and have exposures to multiple antibiotic classes. In most
of these studies, clinical isolation of carbapenem-resistant Enterobacteriaceae
was associated with in-hospital mortality. A single center study from New York
City demonstrated that 48% of patients with invasive carbapenem-resistant K.
pneumoniae infections did not survive their index hospitalization. In this study,
infection was independently associated with recent transplantation, length
of stay, and exposure to cephalosporins and carbapenems.4 Clinical isola-
tion of KPC-E has also been described throughout Europe, South America,
the Caribbean, and Asia. Most reported cases are sporadic and have rarely
been associated with exposure to healthcare systems in areas of endemicity the
United States, Israel, and Greece.
Management
There is a paucity of agents available to treat KPC-E infections. There is in
vitro evidence suggesting that some KPC-E are susceptible to aminoglycosides,
 polymyxins, and the glycylcycline tigecycline. No universal agent to treat these
Urinary Tract Infections

bacteria has been identified.

Polymyxins, both polymyxin B and E (colistin), fell out of favor with the
advent of more specific and tolerable antibiotics. The clinical reintroduction
of these antimicrobials initially came with the emergence of carbapenem-
resistance in P. aeruginosa and A. baumannii. By analogy, clinicians have
extended their use to the treatment of KPC-E. Increasing isolation of KPC-E
from sites where polymyxins do not reliably penetrate (e.g., lung and cerebro-
spinal fluid) has become a concern in the treatment of the critically ill patients.
CHAPTER 10

Chemical ventriculitis can be a side effect of intrathecal polymyxin therapy,

and bronchospasm has been associated with aerosolized drug. Systemic poly-
myxins are also associated with renal insufficiency and a myriad of neurologic
sequelae. Most adverse events have been reversed with the discontinuation
of the drug.5
Tigecycline, a glycylcycline, is licensed for use in the treatment of skin and
soft tissue infections, community-acquired pneumonia, as well as complicated
intra-abdominal infections. Tigecycline has demonstrated in vitro activity
against many highly drug-resistant bacteria including carbapenem-susceptible
ESBL-producing Escherichia coli and K. pneumoniae. The pharmacodynamics of
glycylcylines indicate that they may not achieve appropriate concentrations in
the bloodstream or genitourinary system, however, further clinical studies are
indicated.6
254

There are a number of case reports and case series recounting the success-
ful treatment of KPC-E with both polymyxins and tigecycline. Many accounts
involve employment of an adjunctive therapeutic procedure (e.g., catheter
removal, peritoneal lavage, or decortication of an empyema), in addition to
systemic antimicrobials. One study suggested that in patients with invasive
carbapenem-resistant K. pneumoniae, use of an adjunctive procedure to remove
a focus of infection was independently associated with survival.4 Anecdotal
successes aside, the true clinical efficacy of these salvage antibiotics remains
unclear.
The increasing prevalence of KPC-E is not only a diagnostic and therapeu-
tic challenge, but also presents a significant threat to patient safety. Evolving
epidemiology, an awareness of limitations in the clinical microbiology labo-
ratory, and an appreciation of risks for the development of drug resistance
should prime practitioners to suspect possible infection with these highly
resistant bacteria in appropriate populations. In regard to management, cli-
nicians are to be encouraged to remove possible foci of infection, and to
be familiar with susceptibility patterns within their own institutions. Due to
the limited antimicrobial options available to treat infections with KPC-E,
an increased emphasis should be placed on early and accurate laboratory
detection of these carbapenemases, and early implementation of appropri-
ate infection control measures to decrease potential healthcare-associated
transmission.
References

Urinary Tract Infections

1. Schwaber MJ, Carmeli Y. Carbapenem-resistant Enterobacteriaceae a potential
threat. JAMA. 2008; 300:2911–2913.
2. Hidron AI, Edwards JR, Patel J, et al. NHSN annual update: antimicrobial-resistant
pathogens associated with healthcare-associated infections: annual summary of
data reported to the National Healthcare Safety Network at the Centers for
Disease Control and Prevention, 2006–2007. Infect Control Hosp Epidemiol.
2008;29:996–1011.
3. Anderson KF, Lonsway DR, Rasheed JK, et al. Evaluation of methods to identify

CHAPTER 10
the Klebsiella pneumoniae carbapenemase in Enterobacteriaceae. J Clin Microbiol.
2007;45:2723–2725.
4. Patel G, Huprikar S, Factor SH, Jenkins SG, Calfee DP. Outcomes of carbapen-
em-resistant Klebsiella pneumoniae infection and the impact of antimicrobial and
adjunctive therapies. Infect Control Hosp Epidemiol. 2008;29:1099–1106.
5. Falagas ME, Kasiakou SK. Colistin: the revival of polymyxins for the manage-
ment of multidrug-resistant gram-negative bacterial infections. Clin Infect Dis.
2005;40:1333–1341.
6. Anthony KB, Fishman NO, Linkin DR, et al. Clinical and microbiological outcomes
of serious infections with multidrug-resistant gram-negative organisms treated
with tigecycline. Clin Infect Dis. 2008;46:567–570.

255
Ca e 10d:
Case 10d
0d: A
An
n 884
84-Year-Old
4-Y
Year
ar-Old
Old M
Man iin SSeptic
ept
pti
tic SSho
Shock
hock
k

Meenakshi Mehrotra Rana

Case Presentation
An 84-year old man with a past medical history significant for atrial fibrillation,
congestive heart failure, hypertension, BPH, and spinal stenosis presented to
the emergency department with fevers, chills, shortness of breath, and increas-
ing confusion. His medications at home included atenolol, digoxin, furosemide,
coumadin, prednisone, and terazosin.
On physical examination, he was febrile (38.7°C) and tachycardic (190 bpm);
after receiving diltiazem for atrial fibrillation with rapid ventricular rate, he
became hypotensive (70s systolic) and tachypneic (32 bpm) and was admitted
to the medical intensive care unit for management of sepsis.
His laboratory examinations were notable for leukocytosis (28x103 WBC/
μl and acute renal failure (3.9mg/dl). His initial urinalysis showed numerous
white blood cells and 4+ bacteria. He was treated with empiric cefepime for
management of septic shock. CT of the abdomen revealed an enlarged pros-
tate gland with a 7.6 x 6.4 cm abscess with bubbles of air (Figure 10d.1). Blood
cultures grew Escherichia coli, and urine culture grew Group B Streptococcus and
Escherichia coli (Figure 10d.2). The antibiotic was changed to ampicillin-sulbac-
tam for coverage of a likely mixed infection including anaerobic organisms.
The patient underwent transurethral unroofing of the prostatic abscess;
using transrectal ultrasound, a pus collection was identified and drained.
Urinary Tract Infections
CHAPTER 10

Figure 10d.1 CT abdomen, axial view showing an enlarged prostate gland with a 7.6 x
6.4 cm bilobed shaped complex fluid density structure with bubbles of air.
256

Figure 10d.2 Blood culture Gram stain with Gram-negative bacilli later identified as
Escherichia coli.

Several days later, the patient underwent definitive transurethral resection

of the prostate. He defervesced and his elevated white blood cell count and
renal failure resolved. He completed an extended course of oral antibiotics for
chronic prostatitis.
Case 10d Discussion: Prostatic Abscess
Prostatitis accounts for an estimated two million visits to the primary care phy-
sician or urologist yearly. About 8% of visits to urologists and 1% of visits to
the primary care doctor are coded with the diagnosis of prostatitis. The term

Urinary Tract Infections

prostatitis is used to refer to various complaints relating to the lower urogeni-
tal tract and perineum. According to NIH consensus classification guidelines,
prostatitis may be classified into four major groups—acute bacterial prostatitis,
chronic bacterial prostatitis, chronic prostatitis/chronic pelvic pain syndrome,
and asymptomatic inflammatory prostatitis. Prostatic abscess, as described in
the patient above, is a rare complication of acute or chronic prostatitis.1
Patients with acute bacterial prostatitis often present with symptoms of
urinary tract infections, dysuria, or urinary frequency. In addition, they may

CHAPTER 10
experience obstruction caused by prostatic edema, and associated systemic
symptoms including fever, chills, lower abdominal discomfort, and myalgias. On
physical examination, rectal examination reveals a tender prostate on palpation.
On laboratory examination, there is pyuria and bacteriuria on urinalysis. Urine
culture is frequently positive, and Gram-negative organisms predominate with
Escherichia coli being the most frequently isolated organism. Treatment involves
urinary catheter drainage along with 4 weeks of antimicrobial therapy.2,3
Unlike acute bacterial prostatitis, chronic prostatitis accounts for the majority
of patients presenting with prostatic symptoms, and remains a challenging group
to both diagnose and treat. These patients often have recurrent symptomatic
infections, despite being asymptomatic in between infections. Traditionally, the
gold standard for diagnosis of bacterial prostatitis is the “four-glass test,” and
was first described by Meares and Stamey in 1968. This involves obtaining seg-

257
mented urine cultures of the lower urinary tract to localize infection to the
prostate gland (Table 1, from Mandell). Bacterial prostatitis is confirmed by
the presence of leukocytes in the expressed prostatic secretions, and bacterial
counts in the voided bladder 3 (VB3) sample that greatly exceed the bacterial
counts in the voided bladder 1 or 2 sample (VB1 or VB2). Despite being the
gold standard, the “four-glass test” is often not carried out in clinical practice
because it is considered time-consuming and expensive; therefore, a simpler
screen, the pre- and post-massage test (PPMT), has been described. This test
involves microbiological evaluation of the urine prior to and after massage of
the prostate gland, and was found to have a sensitivity and specificity of 91%.2
In chronic prostatitis, a positive bacterial culture is only obtained in about 5%
of patients. This group is categorized by the NIH as chronic bacterial prostatitis,
and diagnosis is characterized by bacterial persistence despite being treated
with multiple antimicrobial courses. Microorganisms frequently isolated include
Gram-negative rods of the enterobacteriaceae or pseudomonas family; Gram-
positive organisms can be seen in a few cases (most commonly Enterococcus). In
patients in whom an organism is isolated, antibiotic treatment is recommended
for 4–6 weeks. Because penetration into the prostatic secretions is poor, given
the barrier between prostatic stroma and the microcirculation, and because
of the acidic pH of the prostate, low dose oral antibiotics are recommended
for an extended duration. This is done in order to achieve maximal penetra-
tion and prevent long-term consequences of untreated prostatitis, including
abscesses. Recommended antibiotics include sulfonamides, macrolide, or fluo-
roquinolones, which have been shown to achieve higher therapeutic levels in
 prostatic secretions as well as to penetrate bacterial “biofilms” that often form
Urinary Tract Infections

in prostatic ducts and can lead to microabscesses.

Prostatic abscess is a rare entity that is described as a complication of acute
or bacterial prostatitis, and may occur in patients not treated or treated inad-
equately for prostatitis. Patients at risk include those immunocompromised
from HIV/AIDS or diabetes, and patients with bladder outlet obstruction or
recent urethral manipulation. In the pre-antibiotic era, prostatic abscesses were
commonly found in young men in association with gonococcal urethritis. More
recently, the pathologic mechanism is thought to be related to either urinary
CHAPTER 10

reflux or hematogenous dissemination from a primary focus. In the first, micro-

organisms isolated include those from the Enterobacteriaceae family; in the sec-
ond, Staphylococcus aureus is the most common organism isolated.4–6
The signs and symptoms of prostatic abscess are not specific, but are com-
parable to those of acute prostatitis. On rectal examination, a large boggy pros-
tate is usually felt and, rarely, fluctuance may be detected as well. Delay in
treatment can cause bladder or urethra fistulization, or rectal or anal fistulas
depending on the location; alternatively rupture of the abscess into the ischi-
orectal fossa or into the perivesical space is associated with high morbidity and
mortality.
More recent imaging modalities such as transrectal ultrasound, CT, and MRI
have increased diagnostic reliability preoperatively, and have also influenced
therapeutic options. Unroofing of the abscess via transurethral drainage or
258

transurethral radical prostectomy are surgical options for treating the infection,
as well as related hypertrophy. Transperineal needle aspiration has also been
described as an alternative form of drainage. Transrectal ultrasound guidance
may aid in aspiration of the abscess, and can also be used to aid in transperineal
drainage.7
Patients with chronic prostatitis/chronic pelvic pain syndrome, in which no
microorganism is isolated, represent greater than 90% of patients evaluated for
prostatitis, and remain the most difficult group to treat. These patients have
vague pelvic and perineal symptoms, mainly consisting of urological pain, but
also urinary symptoms or sexual dysfunction. The hallmark characteristic of
patients in this category is the lack of microbiological evidence revealing bacte-
rial infection of the prostate. Two subtypes are described—inflammatory and
noninflammatory. In the inflammatory subtype, formerly termed nonbacterial
prostatitis, leukocytes may be detected in the urine, prostatic secretions, or
semen. In the noninflammatory subtype, formerly known as prostatodynia,
no inflammatory evidence or leukocytes are seen. Current therapy includes
anti-inflammatory therapy and pain management. A trial of initial antimicro-
bial therapy may be useful in patients with inflammation; however, in patients
with prolonged symptoms without inflammation, several studies, including two
randomized trials, have shown that antimicrobial therapy in this group is not
effective.1 In one study of Veteran’s Affairs patients, fluoroquinolones were
shown to be inappropriately prescribed and overused in patients with chronic
pelvic pain syndrome.8
 Asymptomatic inflammatory prostatitis includes men who are asymptomatic

Urinary Tract Infections

but found to have evidence of prostate inflammation. This may be found in the
form of inflammatory infiltrates on pathology after prostate biopsy for elevated
PSA, or during removal of benign prostate tissue for treatment of obstruc-
tion. Many men may also be diagnosed by semen analysis during evaluation for
infertility, and are often treated with an empiric antimicrobial therapy.1

References

CHAPTER 10
1. Domingue GJ and Hellstrom WJ. Prostatitis. Clin Microbiol Rev. Oct
1998;2(4):604–613.
2. Ludwig M, Schroeder-Printzen I, Schiefer HG, Weidner W. Diagnosis and
therapeutic management of 18 patients with prostatic abscess. Urology.
1999;53(2):340–345.
3. Krieger JH. Prostatis, epididymitis, and orchitis. In Mandell GL, Bennett JE, Dolin
R. Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases. 7th
ed. Philadelphia: Elsevier Churchill Livingston; 2009:1521–1524.
4. Nickel JC, Nyberg LM, Hennenfent M. NIH consensus definition and classifica-
tion of prostatitis. JAMA. 1999;281(3):236–237.
5. Nickel JC. Prostatitis: myths and realities. Urology. 1998;51(3):362–366.
6. Taylor BC, Noorbaloochi S, McNaughton-Collins M, et al. Excessive antibiotic
use in men with prostatitis. Am J Med. 2008;121(5): 444–449.

259
7. Wagenlehner FME, Naber KG. Prostatitis: the role of antibiotic treatment.
World J Urol. 2003;21: 105–108.
8. Weinberger M, Cytron S, Servadio C, Block C, Rosenfeld J, Pitlik SD. Prostatic
abscess in the antibiotic era. Rev Infect Dis. 1998;10(2):239–349.
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 Chapter 11

Skin and Soft Tissue

Infections

Ca e 111a:
Case 1a A 21
1a: 21-Year-Old
-Year-
Y -OlOld
dMMan
an wi
with
ith
h Rec
R
Recurrent
current
nt A
Ab
Abscesses
bscess
sses
e

Rachel Chasan
Clinical Presentation and History
A 21-year-old man with a diagnosis of Job’s syndrome (Hyper-IgE syndrome)
was admitted to the hospital with a large right buttock abscess. The patient
had a history of recurrent skin abscesses resulting in frequent hospital admis-

261
sions, as well as an empyema in 2006 that had required surgical drainage. An
IgE level performed at an outside hospital in 2004 was markedly elevated at
68,424 (normal < 180). Cultures from prior drainage procedures were positive
for methicillin-susceptible Staphylococcus aureus (MSSA), and his most recent
admission had been 10 months prior to this presentation, at which time he had
bilateral axillary abscesses (Figure 11a.1).
He had been prescribed trimethoprim/sulfamethoxazole for chronic sup-
pression of staphylococcal skin and soft tissue infections in the past, but was
nonadherent with this treatment. According to the patient, the current buttock
abscess began approximately 3 months prior to presentation, but the patient
was living out of state at that time, and had not sought care sooner due to
insurance concerns. On physical examination, he appeared older than stated
age, with multiple healed acne scars on the face and coarse porous facial skin.
He had a broad nose and prominent forehead. He was febrile to 38.6º Celsius
but his cardiovascular and pulmonary examinations were unremarkable. The
patient had a large abscess on the right buttock, with purulent and foul-smelling
drainage.
Computed tomography of the pelvis demonstrated a large multiloculated
subcutaneous abscess in the right buttock, extending from the level of the
sacral coccyx to the right iliac wing abutting the gluteal muscles, measuring 18 x
13 x 6.5 cm (Figure 11a.2). The initial white blood cell count was 16,500/μl, with
76% neutrophils, and the patient’s other laboratory values were unremarkable.
The patient was treated with intravenous vancomycin, and on the day follow-
ing admission he was taken to the operating room for incision and drainage
Skin and Soft Tissue Infections
CHAPTER 11

Figure 11a.1 CT thorax, coronal view showing large complex axillary abscess.
262

Figure 11a.2 CT of the pelvis, axial view showing a large multiloculated subcutaneous
abscess in the right buttock, extending from the level of the sacral coccyx to the right
iliac wing abutting the gluteal muscles, measuring 18 x 13 x 6.5 cm.

of the abscess. Gram stain of the pus revealed Gram-positive cocci in clusters
engulfed by neutrophils, and culture grew methicillin-resistant Staphylococcus
aureus (Figure 11a.3).
The patient remained afebrile postoperatively and he was discharged
home to reinitiate suppressive trimethoprim-sulfamethoxazole. Following
discharge, the patient was readmitted 3 times over a 3-month period,
 Skin and Soft Tissue Infections
CHAPTER 11
Figure 11a.3 Gram stain of the pus revealed Gram-positive cocci in clusters engulfed
by neutrophils.

with a forearm cellulitis and abscess, an axillary abscess, and a right thumb
paronychia.
Case 11a Discussion: Methicillin-Resistant Staphylococcus aureus

263
Infection
Clinical Features and Diagnosis
The hyper-IgE syndrome (HIES), or Job’s syndrome, is a rare immunodeficiency
disease characterized by elevated levels of IgE, eczema, and recurrent skin and
pulmonary infections, first described1 in the 1960s. The disease was given this
name after the biblical character Job, who was covered in boils from head to
toe, and was later termed HIES, once the association with elevated IgE levels
was discovered. In addition to recurrent skin and pulmonary infections, many
patients with the disease share physical characteristics unrelated to the immune
defect, including craniofacial abnormalities, hyperextensibility of joints, retained
primary teeth, and fractures with only minimal trauma.1 The typical facial fea-
tures of Job’s syndrome patients include asymmetry, a prominent forehead, and
broad nose. A higher rate of vascular abnormalities (such as aneurysms) and
non-Hodgkin’s lymphoma has also been described in HIES.1
Recurrent skin and pulmonary infections begin in early life for patients
with hyper-IgE syndrome. Dermatologic findings include moderate to severe
eczematous rashes, as well as boils or abscesses. Staphylococcus aureus is usu-
ally responsible for the abscesses associated with this disease.1 The other major
infectious complication is pneumonia, frequently leading to the development of
pneumatoceles, which can become superinfected, requiring thoracotomy and
drainage.2 While the acute pneumonia is often caused by S. aureus, Streptococcus
pneumoniae or Haemophilus influenza,1 these pneumatoceles typically become
superinfected with Gram-negative organisms (such as Pseudomonas), molds
(including Aspergillus) and nontuberculous Mycobacteria.1
Case series have demonstrated significant fluctuation in the IgE levels of
patients with Job’s syndrome.2 Notably, the IgE level also does not appear to
 correlate with infectious or dermatologic complications of the disease. The
Skin and Soft Tissue Infections

hyper-IgE syndrome is inherited as an autosomal disorder with incomplete

penetrance, but numerous sporadic cases have been reported as well.1 The
disorder has no predilection for a specific race or gender.1
Although no unifying mechanism to explain the immunologic and nonimmu-
nologic findings of HIES is as yet understood, the immunologic defect is thought
to be due to a mutation in STAT 3.1 STAT 3 is a cytoplasmic protein involved
in signal transduction pathways for many cell types, including multiple cytokines
such as IL-6 and IL-10.1 Recent developments have demonstrated that one major
impact of STAT 3 mutation is the impaired production of Th17 cells (CD4 lym-
phocytes that produce IL-17). These cells are integral in fighting infection through
CHAPTER 11

the recruitment of neutrophils and macrophages; this defect is central to the

vulnerability of HIES patients to infections with fungi and extracellular bacteria.1
Therapy
There is no treatment for HIES itself; therefore, the management of patients
with the disease revolves around the treatment and prevention of recurrent
infections. Surgical drainage is essential to the cure of soft tissue abscesses, and
antibiotic therapy is often administered adjunctively. Because S. aureus is usually
the cause of skin and soft tissue infections in this population, antibiotics that tar-
get Staphylococcus including MRSA are appropriate empiric therapeutic choices.
Vancomycin is the standard antibiotic for skin and soft tissue infections due to
264

MRSA, but alternatives include linezolid, daptomycin, and tigecyline.3

Despite the fact that there is little data to support therapy aimed at eliminat-
ing S. aureus colonization, this approach is worthy of consideration in patients
with recurrent staphylococcal infections, such as those with Job’s syndrome.4
Preventive strategies include chlorhexidine body washes, mupirocin nasal
decolonization, and suppressive antibiotic therapy with anti-staphylococcal
agents such as trimethoprim-sulfamethoxazole.

References
1. Paulson ML, Freeman AF, Holland, SM. Hyper IgE syndrome: an update on clinical
aspects and the role of the signal transducer and activator of transcription 3. Curr
Opin Allergy Clin Immunol. 2008; 8:527–533.
2. Grimbacher, B, Holland, SM, Gallin, JI, et al. Hyper-IgE syndrome with recurrent
infections – an autosomal dominant multisystem disorder. N Engl J Med. 1999;340:
692–702.
3. Stryjewski, ME, Chambers, HF. Skin and soft-tissue infections caused by com-
munity-acquired methicillin-resistant Staphylococcus Aureus. Clin Infect Dis.
2008;46:S368–S377.
4. Gorwitz RJ, Jernigan DB, Powers JH, Jernigan JA, Participants in the Centers for
Disease Control and Prevention–Convened Experts Meeting on Management of
MRSA in the Community. Strategies for clinical management of MRSA in the com-
munity: summary of an experts’ meeting convened by the Centers for Disease
Control and Prevention. Washington, DC: Department of Health and Human
Services, Centers for Disease Control and Prevention, March 2006. Available at:
http://www.cdc.gov/ncidod/dhqp/ar_mrsa_ca_04meeting.html.
 Skin and Soft Tissue Infections
Case
C a e 11b:
11b
1b: A 60
60-Year-Old
-Year-
Y -Ol Old
dWWoman
oman with
ith
h Di
D
Diabetes
iabe
bettes
Mell
Me llit
itus and Sever
Mellitus eree Leg Pain
Severe

Mahesh Swaminathan, Marco Harmaty, and Daniel Caplivski

Case Presentation
A 60-year-old woman with diabetes mellitus, chronic obstructive pulmonary dis-
ease, and vulvar cancer presented with 5 days of severe right leg pain and swell-
ing. She had been treated for stage IV vulvar cancer with chemotherapy and local
radiation, and had been in remission for 2 years. When she initially presented,

CHAPTER 11
her pain was severe enough that it was interfering with her ability to walk.
Upon admission to the hospital, she was febrile (temperature of 38.7), tachy-
cardic (109 beats per minute), hypoxic (88% on ambient air), and hypertensive
(144/64). Her physical examination was notable for erythema and swelling of
the right lower extremity that extended from her calf to the vulva. There was
no numbness, fluctuance, or crepitus noted, but the leg was so exquisitely ten-
der that she was unable to cooperate completely with physical examination.
Her initial laboratory values revealed a leukocytosis (14,000 WBC/μl, 67% neu-
trophils, 26% bands), thrombocytosis (platelets 591,000 per μl), mild anemia
(hemoglobin of 11.3 grams/dl), and hyperglycemia (glucose 267 mg/dl). She was

265
treated initially with intravenous ampicillin/sulbactam and vancomycin. Over
the course of several hours, her pain became progressively worse, and she
required intravenous morphine in order to tolerate the computed tomography
scan of her lower extremities (Figures 11b.1 and 11b.2).
Computed tomography scanning revealed multiple rim enhancing fluid col-
lections within the right obturator internus, the adductor, gluteal, the vastus,
and the biceps femoris muscles. The collections contained fluid and air, and
the largest measured 6.5 x 10.7 cm and extended to the knee inferiorly. The
patient was emergently taken to the operating room for extensive debride-
ment of the necrotic tissues in her leg. The Gram stain of the debrided tissue
revealed Gram-positive cocci in short chains, and cultures of all the debrided
material were positive for the beta-hemolytic colonies of Streptococcus agalac-
tiae (Group B Streptococcus; Figures 11b.3 and 11b.4).
The patient would eventually require 12 separate operations for debride-
ment, skin grafts, and colostomy, because of the necrotic tissue that extended
to the perineal region. After the first debridement, she was in septic shock
and required vasopressors for several days, but she eventually recovered.
Her hospitalization lasted 3 months and she was eventually discharged to a
rehabilitation facility after several weeks of intravenous antibiotics and surgical
debridements.
Case 11b Discussion: Streptococcus agalactiae Necrotizing Fasciitis
Microbiology and Epidemiology
Group B Streptococcus (GBS) is a facultative, beta-hemolytic, Gram-positive
coccus that divides in pairs and chains and grows readily on a variety of growth
mediums. Identification of Group B streptococci may be confirmed with
Skin and Soft Tissue Infections
266 CHAPTER 11

Figure 11b.1 and 11b.2 CT lower extremities, axial view showing multiple rim-
enhancing fluid collections within fluid and air.

Figure 11b.3 Gram stain of the debrided tissue showing Gram-positive cocci in short
chains.
 Skin and Soft Tissue Infections
CHAPTER 11
Figure 11b.4 Cultures of all the debrided material showing the beta-hemolytic colonies
of Streptococcus agalactiae (Group B Streptococcus).

detection of Group B–specific cell wall antigen via latex agglutination, though
many labs now employ automated biochemical methods. Group B strepto-
cocci have the ability to adhere to numerous mucosal and endothelial surfaces,

267
including the vaginal, intestinal, and respiratory epithelium, the endothelium of
the blood–brain barrier, and placental membranes. These organisms may cross
these barriers paracellularly, and disseminate via translocation from colonized
epithelial surfaces to otherwise sterile sites. Group B streptococci possess a
polysaccharide capsule that inhibits complement fixation and phagocytosis, and
is an important virulence factor.1
Group B Streptococcus is a frequent colonizer of the rectum and female geni-
tal tract, with a colonization rate of approximately 20%. Higher colonization
rates are associated with frequent sexual intercourse or multiple sexual part-
ners, African-American race, and lower socioeconomic status. The prevalence
of oropharyngeal colonization in adults is about 5%, but approaches 20% in men
who have sex with men. The rate of colonization in older, otherwise healthy
adults is 20%.1
The incidence of invasive Group B streptococcal disease in neonates has
decreased since the institution of intrapartum prophylactic antibiotic therapy in
pregnant women found to be colonized with Group B streptococci.2,3 Among
infants younger than 6 days of age, the rate of invasive Group B streptococcus
infections decreased from 0.47 per 1000 live births in 1999–2001 to 0.34 per
1000 live births in 2003–2005. The incidence in infants aged 7–89 days and
pregnant women was unchanged at 0.34 per 1000 live births and 0.12 per 1000
live births, respectively.1
While the incidence of Group B streptococci infection in neonates has
decreased, recent studies have shown an increase in the incidence of invasive
infections in adults. From 1999 to 2005, the incidence of invasive infections with
Group B streptococci increased from 3.4 per 100,000 to 5.0 per 100,000 in
 persons between the ages of 15 and 64, and from 21.5 per 100,000 to 26.0 per
Skin and Soft Tissue Infections

100,000 in adults greater than 65 years of age; the overall incidence in adults
increased from 6.0 per 100,000 in 1999 to 7.9 per 100,000 in 2005.4
Clinical Presentation and Diagnosis
Group B streptococcal infection in neonates is a serious disease, and typi-
cally presents with bacteremia/sepsis, meningitis, or pneumonia. In neonates
younger than 7 days of age, presenting symptoms typically occur at birth or
in the first few hours of life, and include lethargy, poor feeding, abnormal
temperature, grunting respirations, pallor, and hypotension. Chest radiogra-
phy will frequently reveal pulmonary infiltrates, and analysis of CSF will show
evidence of meningitis. Maternal complications are frequently associated with
CHAPTER 11

higher rates of invasive disease in this age group. Group B streptococcal infec-
tion in infants between the ages of 7 and 89 days may present similarly to that
in younger infants, but is frequently associated with a variety of focal infections,
including osteomyelitis, septic arthritis, and cellulitis. Preterm infants are at a
much higher risk for invasive Group B streptococcal infection then those born
at term.1
Invasive infection in adults is frequently severe and associated with substan-
tial morbidity and mortality. The most frequent clinical syndromes are primary
bacteremia without an evident focus, and skin or soft tissue infections, such
as cellulitis, infected decubitus ulcer, osteomyelitis, septic arthritis, and wound
268

infection. Less common syndromes include pneumonia, urinary tract infec-

tions, meningitis, peritonitis, and endocarditis. Risk factors for invasive infection
include older age, HIV infection, the presence of malignant neoplasms, cirrho-
sis, diabetes, stroke, decubitus ulcer, and neurogenic bladder.5,6
The diagnosis of invasive Group B streptococci infection requires the isolation
of the organism from an otherwise sterile site. Group B streptococci grow
easily on most growth mediums and can be readily distinguished from other
streptococcal species via detection of Group B–specific cell wall antigen (see
above).
Management and Prevention
Group B streptococci are susceptible to penicillin, the cephalosporins, and
carbapenems. Penicillin G remains the drug of choice for the vast majority of
invasive infections in adults, though vancomycin can be used in patients with
serious allergies to penicillin. Combination therapy with ampicillin and an amin-
oglycoside is typically used in cases of neonatal bacteremia or meningitis as
initial treatment, though treatment can be completed with penicillin G once
the diagnosis of invasive infection with Group B streptococci is established and
clinical response is documented.2
As noted earlier, neonatal infection with group B streptococci can be pre-
vented with appropriate prophylaxis of pregnant women. Lower vaginal and
rectal swab screening cultures should be performed at 35 to 37 weeks of
gestation for all pregnant women, with the exception of patients with docu-
mented Group B streptococcal bacteriuria during the current pregnancy, or
with a previous infant with invasive Group B streptococcal disease.2 Indications
for antibiotic prophylaxis are presented in Figure 11b.5. When culture data
 Vaginal and rectal GBS screening cultures at 35–37 weeks’ gestation for ALL pregnant women (unless patient had GBS bacteriuria
during the current pregnancy or a previous infant with invasive GBS disease)

Intrapartum prophylasis Indicated Intrapartum prophylaxis not Indicated

• Previous infant with invasive GBS disease • Previous pregnancy with a positive GBS
screening culture (unless a culture was also
• GBS bacteriuria during current pregnancy positive during the current pregnancy)
• Positive GBS screening culture during current pregnancy • Planned cesarean delivery performed in the
(unless a planned cesarean delivery, in the absence of labor absence of labor or membrane rupture
or amniotic membrane rupture, is performed) (regardless of maternal GBS culture status)
• Unknown GBS status (culture not done, incomplete, • Negative vaginal and rectal GBS screening
or results unknown) and any of the following: culture in late gestation during the current
• Delivery at <37 weeks’ gestation* pregnancy, regardless of intrapartum risk
• Amniotic membrane rupture 18 hours factors
• Intrapartum temperature 100.4°F ( 38.0°C)†

• If onset of labor or rupture of amniotic membranes occurs at <37 weeks’ gestation and there is a significant risk for preterm
delivery (as assessed by the clinician), a suggested algorithm for GBS prophylaxis management is provided (Figure 3).
† If amnionitis is suspected, broad-spectrum antibiotic therapy that includes an agent known to be active against GBS should replace
GBS prophylaxis.

Figure 11b.5 Indications for intrapartum antibiotic prophylaxis to prevent perinatal GBS disease under a universal
prenatal screening strategy based on combined vaginal and rectal cultures collected at 35–37 weeks’ gestation from all
pregnant women. Source: Centers for Disease Control and Prevention. Schrag S, Gorwitz R, Fultz-Butts K et al. Prevention
of Perinatal Group B Streptococcal Disease: Revised Guidelines from CDC. MMWR Recomm Rep. 2002;51(RR–11):1–77.

269 CHAPTER 11 Skin and Soft Tissue Infections

 is unavailable, prophylaxis is indicated in cases of preterm labor, if amniotic
Skin and Soft Tissue Infections

membranes rupture for 18 hours or longer, and if fever is present during labor.
Prophylaxis is never indicated for planned cesarean delivery performed in the
absence of labor or membrane rupture, regardless of culture status or history
of Group B streptococcus infection.1 Penicillin G is the preferred drug for anti-
biotic prophylaxis because of its narrow spectrum and documented efficacy;
ampicillin should be avoided because of its relatively broad spectrum and sub-
sequent risk of increased antibiotic resistance.
Necrotizing fasciitis (NF) is a subcutaneous infection that can be catego-
rized between mixed infections (Type I) and single organism infections (Type
II). Type II NF is more typically associated with Group A Streptococcus, which
CHAPTER 11

produces superantigens that cause nonspecific activation of T-cells and resul-

tant recruitment of massive numbers of neutrophils. The fascial planes pro-
vide no anatomic barrier to the spread of infection, and thus NF can progress
rapidly over several hours. Clinical presentation can be difficult to distinguish
from other causes of extremity pain and swelling, such as cellulitis and deep
venous thrombosis. Severe pain, numbness, and discoloration of tissues may
be important clues, but a high index of suspicion is required given the rap-
idly progressive nature of this infection. As with necrotizing fasciitis caused by
other organisms, necrotizing fasciitis associated with Group B Streptococcus
is a medical emergency requiring immediate surgical debridement. While
appropriate antibiotic therapy is important in the management of this disease,
270

medical therapy should be considered an adjunct to, not a substitute for, early
aggressive surgical management.

References
1. Edwards MS, Baker CJ. Streptococcus agalactiae (group b streptococcus).
In: Mandell GL, Bennett JE, Dolin R eds. Mandell, Douglas, and Bennett’s Principles
and Practice of Infectious Diseases. 7th ed. Philadelphia, PA: Churchill, Livingston,
Elsevier; 2009:2655–2663.
2. Schrag S, Gorwitz R, Fultz-Butts K at al. Prevention of perinatal group B
streptococcal disease: revised guidelines from CDC. MMWR Recomm Rep.
2002;51(RR–11):1–22.
3. Schrag SJ, Zywicki S, Farley MM et al. Group B streptococcal disease in the
era of intrapartum anitbiotic prophylaxis. New England Journal of Medicine
2000;342:15–20.
4. Phares CR, Lynfield R, Farley MM et al. Epidemiology of invasive group B
streptococcal disease in the United States, 1999 – 2005. JAMA 2008;299(17):
2056–2065.
5. Jackson LA, Hilsdon R, Farley MM, et al. Risk factors for group B streptococcal
disease in adults. Ann Intern Med. 1995;123:415–420.
6. Farley MM, Harvey C, Stull T, et al. A population-based assessment of invasive
disease due to group B streptococcus in nonpregnant adults. N Engl J Med.
1993;328:1807–1811.
 Skin and Soft Tissue Infections
Case
C a e 11c:
11c:
1c PPostoperative
ostoper
t ati
at
tive Dehiscence
Deh
hi
hiscence FFollowing
olllowi
ol wing
n Gast
G
Gastric
tric
tri
Band
Ba nding Surgery
Banding

Meenakshi Mehrotra Rana, Marco Harmaty, and

Daniel Caplivski
Case Presentation
A 55-year-old woman with no significant past medical history underwent gastric
banding surgery for weight loss. Three years later, she had erosion of the lap band
into the gastric wall, and the lap band was surgically removed. Postoperatively,

CHAPTER 11
she underwent bedside debridement and over the next several months devel-
oped dehiscence of the wound, with formation of sinus tracts and abscesses with
significant drainage. One year later, she required further debridement, and infec-
tious disease consultation was prompted by the results of operative cultures.
She reported generalized malaise, fatigue, and a 10-pound weight loss over
a period of one year, but denied fevers and chills. On physical examination,
she had impending dehiscence of the wound with mild tenderness around
the surgical site (Figure 11c.1). Cultures of purulent material sent from the
operating room grew Gram-positive, beaded bacilli after 7 days of incubation
(Figure 11c.2), and blood cultures also grew the same organism (Figure 11c.3).

271
Both wound and blood cultures were later identified as the rapid-growing
mycobacterium Mycobacterium fortuitum (Figures 11c.4 to 11c.6). The patient was
treated initially with intravenous clarithromycin, imipenem, and amikacin until the

Figure 11c.1 Impending dehiscence of the midline abdominal wound.

Skin and Soft Tissue Infections
CHAPTER 11

Figure 11c.2 Wound culture Gram stain showing Gram-positive, beaded bacilli.
272

Figure 11c.3 Blood culture Gram stain showing Gram positive bacilli that were
clumping in culture.
 Skin and Soft Tissue Infections
CHAPTER 11
Figure 11c.4 Sheep’s blood agar with dry colonies of Mycobacterium fortuitum.

273

Figure 11c.5 Lowenstein-Jensen media with dry colonies of Mycobacterium fortuitum.

Skin and Soft Tissue Infections
CHAPTER 11

Figure 11c.6 Acid-fast stain showing acid-fast bacilli.

isolate was confirmed to be susceptible to amoxicillin/clavulanate and clarithrom-

cyin. She required several procedures for surgical debridement, and was treated
274

with oral antibiotics for 9 months, but eventually had satisfactory wound closure.
Case 11c Discussion: Mycobacterium fortuitum
Nontuberculous mycobacteria (NTM) are composed of mycobacteria other
than the species of Mycobacterium tuberculosis complex (M. tuberculosis,
Mycobacterium africanum, Mycobacterium bovis, and Mycobacterium leprae).
Originally known as atypical mycobacteria, they have become the focus of
more interest over the past few decades due to their role in an increasing num-
ber of infections. NTM are found in the environment in soil, water, animal, and
plant material, and will sometimes stain as Gram-positive, beaded bacilli. They
are slender, nonmotile, acid-fast bacilli, and have traditionally been classified by
the Runyon system of classification. This categorizes NTM into different groups
based on growth rate, colony morphology, and pigmentation. Rapidly grow-
ing mycobacteria (RGM) describe nontuberculous mycobacteria that produce
growth on media plates in 7 days. The nonpigmented RGM include M. for-
tuitum, M. chelonae/abscessus group, M. mucogenicum group, and M. smegmatis
group. The fifth group are pigmenting RGM that can be difficult to identify, and
include several lesser-known species. Slowly growing mycobacteria take more
than 7 days to grow, and the major species in this group include members of
the M. avium complex, M. kansaii, M. xenopi, and other lesser-known species.
M. ulcerans is also a member of this group, and is a major cause of cutaneous
infection in Africa and Asia. M. marinum and M. gordonae are pigmented and are
considered intermediately growing mycobacteria because they require 7–10
days to mature.1
Six different clinical syndromes caused by NTM have been described,
including pulmonary infection, lymphadenitis, skin and soft tissue infections,
disseminated disease, catheter-related infection, and infection of the tendon

Skin and Soft Tissue Infections

sheaths, bones, bursae and joints.1 This review will focus mostly on skin and soft
tissue infections caused by the nontuberculous mycobacteria.
Many of the NTM species have been implicated in causing cutaneous disease.
The most common species to cause skin and soft tissue infections in the United
States and Europe is M. marinum. M. marinum traditionally causes infection
known as “swimming pool” or “fish tank” granuloma. It is associated with skin
lesions that develop at the site of trauma after cleaning a fish tank or aquarium.
Lesions usually involve the extremities— the finger is the most common site—
and can spread up proximally in a sporotrichoid pattern. The lesions can be
superficial nodules or ulcers, but may progress to disseminated or deep infec-

CHAPTER 11
tions involving tendons, bones, joints, and bursae. No specific treatment guide-
lines exist for M. marinum infections, but treatment regimens usually involve
single or dual therapy with clarithromycin, rifampin, ethambutol, doxycycline,
or trimethoprim-sulfamethoxazole. Antimicrobials are continued for several
months, with at least 4 to 8 weeks after resolution of lesions.1
M. ulcerans is a slow-growing, nonpigmented, nontuberculous mycobacteria
that causes African Buruli ulcer and Bairnsdale ulcer; it is a common cause of
cutaneous disease worldwide. It is not found in the United States, but is found
in warmer climates in Australia, Africa, Mexico, and Indonesia. It enters the skin
at sites of trauma, and lesions ulcerate with extensive undermining of the ulcer.
Buruli ulcer is principally treated with surgical excision, but adjunctive antimi-

275
crobials, including rifampin, amikacin, or streptomycin, are also used.2
The rapidly growing mycobacteria, specifically M. abscessus, M. chelonae
and M. fortuitum, are among the most common NTM involved in cases of skin
and soft tissue infections in the United States. Localized infections with M.
chelonae and M. abscessus tend to cause disease in immunosuppressed hosts,
whereas M. fortuitum usually causes infection in previously healthy individuals.
In a retrospective medical review conducted at the Mayo Clinic, 63 patients
with M. chelonae, M. abscessus, or M. fortuitum skin or soft tissue infection
were compared. Patients with M. chelonae or M. abscessus were significantly
more likely to be older or taking immunosuppressive medications, as com-
pared to patients with M. fortuitum infection. More patients with M. fortuitum
infection were likely to have had prior invasive surgical procedures.3
Many case studies of healthcare-associated infection with M. chelonae, M.
abscessus, and M. fortuitum after surgical procedures have been described. These
include outbreaks associated with hemodialysis, peritoneal dialysis, central venous
catheters, acupuncture, liposuction, silicone injection, augmentation mammo-
plasty, cardiac bypass surgery, and dermatologic surgery.3 Typically, the surgical
devices or equipment used are contaminated from tap water or ice water.
While traditionally, skin and soft tissue infection with rapidly growing myco-
bacteria are hospital acquired, community-associated infections have been on
the rise. Recently, Winthrop et al. described a large outbreak of M. fortuitum
infections among clients receiving footbaths and pedicures at a nail salon in
California.4 They identified 100 customers of the nail salon who developed
furunculosis, and cultures from 34 patients were positive for rapidly growing
mycobacteria. In this outbreak, cultures from all the footbaths at the salon
 yielded M. fortuitum, and isolates from 3 of the footbaths and 14 patients were
Skin and Soft Tissue Infections

identical by pulsed-field gel electrophoresis.

Cutaneous infections secondary to rapidly growing mycobacteria were
recently described as a complication of mesotherapy, a cosmetic dermato-
logical procedure. Sixteen patients were infected after mesotherapy injections
from the same physician; M. chelonae was identified in 11 patients and M. fred-
eriksbergense was identified in 2 patients. Patients presented with painful nod-
ules that progressed to fistulizing skin lesions with purulent drainage, about 9.5
weeks after the first mesotherapy procedure. All patients underwent surgical
procedures to drain existing abscess and resect nodules; the majority received
dual or triple antibiotic therapy for a mean duration of 14 weeks.5
CHAPTER 11

Treatment can be challenging in patients with cutaneous infections second-

ary to rapidly growing mycobacterial infections, and usually involves multiple
antimicrobials in order to minimize the risk of development of resistance. No
controlled clinical trials of treatment have been conducted, and most recom-
mendations are based on case studies and clinical experience along with in
vitro susceptibility data. The majority of patients require a combination of
prolonged duration of antimicrobial therapy for several months, and surgical
excision or drainage and removal of any foreign devices that become infected,
(e.g., implants or catheters).
In susceptibility testing done by Uslan et al., of 14 isolates of M. fortuitum and
47 isolates of M. chelonae or M. abscessus, 100% of isolates of M. fortuitum were
276

susceptible to amikacin, as opposed to only 64% of M. chelonae/M. abscessus

isolates. Susceptibility testing of M. fortuitum isolates found that the majority
of isolates were also sensitive to imipenem and ciprofloxacin (70% and 86%
respectively). For the M. chelonae/M. abscessus isolates, 100% were sensitive
to clarithromycin and 80% were susceptible to tobramycin. This data therefore
supports the use of amikacin as first-line therapy for M. fortuitum infection, and
clarithromycin for M. chelonae or M. abscessus infection.3
According to most guidelines,1,6 M. fortuitum infections are usually susceptible
to amikacin, imipenem, cefoxitin, ciprofloxacin, oxazolidinones, sulfonamides,
and doxycycline. For M. chelonae infections, various combinations of amikacin,
imipenem, tobramycin, and clarithromycin are usually recommended, and for
M. abscessus infections, amikacin, cefoxitin, imipenem, and clarithromycin usu-
ally have activity. While macrolide treatment is recommended for M. chelonae
or M. abscessus infection, and sometimes is used as monotherapy in mild infec-
tions, inducible resistance has been demonstrated; therefore, monotherapy
should be undertaken with caution. Given the variability among clinical isolates,
susceptibility testing should be used to guide treatment in individual cases.

References
1. Brown-Elliott BA, Wallace RJ. Infections due to nontuberculous mycobacteria
other than Mycobacterium avium-intracellulare. In Mandell GL, Bennett JE, Dolin R
eds. Mandell, Bennett and Dolin’s Principles and Practice of Infectious Diseases. 7th
Edition. Philadelphia: Elsevier Churchill Livingston; 2009:3191–3198.
2. Bhambri, S, Bhambri, A, Del Rosso JQ. Atypical mycobacterial cutaneous infec-
tions. Dermatol Clin. 2009;27(1):63–73.
3. Uslan DZ, Kowalski TJ, Wengenack NL, Virk A, Wilson JW. Skin and soft tissue

Skin and Soft Tissue Infections

infections due to rapidly growing mycobacteria: comparison of clinical features,
treatment and susceptibility. Arch Dermatol. 2006;142:1287–1292.
4. Winthrop KL, Abrams M, Yakrus M, et al. An outbreak of mycobacterial furunculo-
sis associated with footbaths at a nail salon. N Engl J Med. 2002;346(18):1366-1371.
5. Regnier S, Cambau E, Meningaud JP, et al. Clinical management of rapidly growing
mycobacterial cutaneous infections in patients after mesotherapy. Clin Infect Dis.
2009;49:1358–1364.
6. American Thoracic Society. An official ATS/IDSA statement: diagnosis, treatment
and prevention of nontuberculous mycobacterial diseases.” Am J Respir Crit Care
Med. 2007;175:367–415.

CHAPTER 11
Case
C a e 11d:
11d
1d: A 61
61-Year-Old
-Year-
Y -Ol Old
dWWoman
oman ffrom
rom
m Mexic
M
Mexico
ico with
ith
Cuta
Cu tan
neous Ulcerss
Cutaneous

Florence Nana and W. Michael Scheld

Case Presentation
A 61-year-old female from Mexico presented with ulcerative skin lesions
that were not improving despite empiric antibiotics. She had been treated
with trimethoprim-sulfamethoxazole for presumed MRSA infection with no

277
improvement. Initially she had two or three lesions on her thighs and arms that
began as a pimple, and later ulcerated. She had been in the United States for
two months, but had previously been working for a mulch company in Mexico.
On physical examination, she had multiple 2cm ulcerated erythematous
lesions on her upper and lower extremities (Figure 11d.1). The remainder of
the physical examination was unremarkable, and laboratory values were nota-
ble for mildly elevated liver enzymes and positive hepatitis C serology. She
reported having had similar lesions in Mexico. She had seen a physician and was
told that she had a fungal infection, but she could not afford the therapy.

Figure 11d.1 Multiple 2cm ulcerated erythematous lesions on the upper and lower
extremities.
 Skin biopsy cultures results subsequently grew Sporothrix schenckii, and fur-
Skin and Soft Tissue Infections

ther evaluation revealed no evidence of disseminated disease. She was treated

with itraconazole, with instruction to monitor liver function tests weekly.
Case 11d Discussion: Sporothrix schenckii
Clinical Manifestations
Sporotrichosis is caused by the temperature-dependent dimorphic fungus,
Sporothrix schenckii, and was first described in 1898 by Benjamin Schenck when he
was a medical student at Johns Hopkins University.1 The fungus is found world-
wide in soil, plant, or plant products. Most cases are reported from the tropical
and subtropical regions of the Americas. The infection generally is introduced
CHAPTER 11

into the dermal layer of the skin through a minor penetrating injury (e.g., by a
thorn prick). An abscess and subsequent lymphangitic spread may ensue. The
fungus may also disseminate hematogenously and cause extracutaneous lesions
of the bones, joints, CNS, or eyes, in immunocompetent hosts, or multifocal
disease in immunocompromised patients. Pulmonary infection in some patients
may also be acquired via inhalation. Sporotrichosis usually affects healthy indi-
viduals engaged in outdoor activities, such as florists, rose gardeners, and horti-
culturists. Cases of animal-to-human transmission have been reported.2
Lymphocutaneus sporotrichosis is the most common form of sporotricho-
sis. A painless, papulonodular, erythematous lesion develops at the site of
the infection days to weeks after inoculation of the fungus. The lesion may
278

be smooth or verrucous, but usually ulcerates with a raised border. If there is

drainage from the lesion, it is usually not purulent, and systemic symptoms are
generally absent. Secondary lesions may develop proximally along lymphatic
channels without contiguous spread or lymph node involvement. The lesions
are usually indolent, waxing and waning over months to years if not adequately
treated. Other organisms, including Leishmania, Nocardia, and nontuberculous
Mycobacteria (particularly M. marinum) can present with “sporotrichoid” lymp-
hangitic spread. Fixed sporotrichosis with indurated hyperkaratotic plaques has
clinical overlap with other fungal infections, such as blastomycosis and paracoc-
cidioidomycosis, as well as noninfectious causes such as malignancies, psoriasis
and pyoderma gangrenosum.1
Diagnosis
Culture of aspirated material from a lesion or a tissue biopsy is the gold stan-
dard of establishing the diagnosis. The usual histopathologic picture is that of
a mixed granulomatous and pyogenic process. Sporothrix may be difficult to
detect in histopathology, but PAS and GMS stains may improve visualization of
the characteristic 1- to 3-μm × 3- to 10-μm cigar-shaped yeast forms organism.
In some cases a central rounded yeast structure with radiating eosinophilic sub-
stance in tissue (asteroid bodies) can be seen on histopathology. Blood cultures
are rarely positive except in the disseminated form of sporotrichosis seen in
immunocompromised hosts.
Treatment
For lymphocutaneous and cutaneous sporotrichosis, itraconazole 200mg daily
is continued for 2 to 4 weeks after all lesions have resolved, usually for a total
of 3 to 6 months. Alternative treatments in case of relapse include itraconazole
at a higher dose of 200mg twice daily, or terbinafine 500mg twice daily, or satu-

Skin and Soft Tissue Infections

rated solution of potassium iodide (SSKI). Potassium iodide solution therapy
begins with 5 to 10 drops taken orally three times daily. The dose is gradually
advanced to 25–40 drops three times daily for children, or 40–50 drops three
times daily for adults.
Fluconazole has only modest clinical activity, and should only be used if
other therapies are not tolerated. Newer triazole antifungals have some in
vitro activity, but little clinical data with these agents is currently available.
Heat has been used as adjunct therapy and, on occasion, has been curative.
It may be considered in pregnancy, since itraconazole and iodides are both
potentially teratogenic. Monitoring of itraconazole blood levels is usually rec-

CHAPTER 11
ommended only for systemic disease, or in HIV patients.3

References
1. Kauffman CA, Bustamante B, Chapman SW, Peter PG: Clinical practice guidelines
for the management of Sporotrichosis: 2007 update by the Infectious Diseases
Society of America. Clin Infect Dis. 2007;45:1255–1265.
2. Schubach A, Schubach TMP, Barros MBD, et al: Cat-transmitted sporotrichosis,
Rio de Janeiro, Brazil. Emerg Infect Dis. 2005;11:1952–1954.
3. Marimon R, Serena C, Gen J, et al: In vitro antifungal susceptibilities of five species
of Sporothrix. Antimicrob Agents Chemother. 2008; 52:732–734.

279
Case
C a e 111e:
1e E
1e: Enlarging
nllargiing Skin
Skin Lesi
Ski
Sk LLesions
ions iin a Kid
K
Kidney–Pancreas
idneyy–Pancr
P rea eas
Tran
Tr ansp
s lant Recip
Transplant pieient
Recipient nt

Sean Pawlowski and W. Michael Scheld

Case Presentation
A 53-year-old man with a history of a diabetes mellitus presented with a 5-month
history of painless, progressively enlarging left knee and calf skin lesions. He
had undergone a combined pancreas and kidney transplant 18 months prior to
presentation, but his post-transplant course had been complicated by several
bouts of acute rejection. The most recent episode occurred one month prior
to the onset of his skin lesions, and was managed with high-dose intravenous
corticosteroids, thymoglobulin, and intravenous immunoglobulin in addition
to his maintenance immunosuppressive regimen of mycophenolic acid 900mg
twice daily, tacrolimus 2 mg twice daily, and prednisone 50 mg daily.
His physical examination was notable for a 3x3 cm erythematous, scaly
lesion on his left knee, and a smaller hyperpigmented subcutaneous and cutane-
ous lesion on the left calf (Figure 11e.1). Neither lesion was tender to palpation.
Prior to his arrival at the infectious diseases clinic, the patient had undergone
two biopsies of his knee lesion. Pathology from the first biopsy showed a
moderately differentiated squamous cell carcinoma, but because of continued
enlargement of the lesion, a second biopsy was performed. Histopathology of
the second specimen revealed cutaneous fungal infection with pseudoepithe-
liomatous hyperplasia (Figures 11e.2), and fungal culture from the biopsy grew
Skin and Soft Tissue Infections
CHAPTER 11

Figure 11e.1 3x3 cm erythematous, scaly lesion on the left knee.

(a) (b)
280

Figure 11e.2 Knee biopsy of tissue-invasive cutaneous Alternaria sp. infection with
hyphal elements seen on both H&E (a) and GMS staining (b).

Alternaria sp. He was treated with voriconazole, his immunosuppressive regi-

men was decreased, and he eventually underwent excision of the entire lesion
with placement of an overlying skin graft.
Case 11e Discussion: Alternaria
Alternaria is a dematiaceous (melanized) mold that is one of the agents of
phaeohyphomycosis. Infections with this heterogeneous group of fungi are
increasing in frequency as more patients are treated with immunosuppressive
medications, such as those used in organ transplantation. The Alternaria genus
encompasses hundreds of species with a worldwide distribution. Alternaria spe-
cies are ubiquitous in nature, and are found in the soil, air, in plant decay, as a
plant pathogen, and as normal flora on the skin of humans and animals.
A major portion of the Alternaria literature focuses on its association with
hypersensitivity pneumonitis, bronchial asthma, and allergic sinusitis and rhi-
nitis. In the immunocompromised host, however, cutaneous, subcutaneous,
paranasal sinusitis, soft palate, disseminated disease and, very rarely, granuloma-

Skin and Soft Tissue Infections

tous pulmonary manifestations are encountered. Biopsy and culture are needed
for diagnosis in these settings. It is a frequent agent of onychomycosis (owing to
its ubiquitous presence in soil), and a cause of ocular infections after penetrat-
ing trauma or in contact lens wearers.
Clinical Manifestations
Oculomycosis
The incidence of this clinical manifestation of Alternaria infection varies across
geographic regions, but its highest incidence is in India. Those with the greatest
risk of ocular trauma due to organic matter have the highest incidence of dis-
ease.1 Case reports and series document infections from traumatic injury from

CHAPTER 11
wheat or rice stalks, and even some from cow tails. Ocular infection most often
leads to keratitis or endophthalmitis.1 Studies have shown that Alternaria can
remain dormant in the superficial layer of the cornea for long periods of time
after trauma, and progress when the temperature allows for growth. This may
account for several reports of keratitis several years after trauma.
Rhinosinusitis
Symptoms of rhinosinusitis are generally minimal and are often found upon
evaluation of unexplained fever. Seventeen case reports/series of invasive and
noninvasive sinusitis caused by Alternaria spp. have been reported since 1977,
though this likely greatly underestimates the true number of cases.1 The major-

281
ity of these cases have been reported in the United States in patients suffering
from hematologic malignancies. In the majority of the cases, the organism was
not identified to the species level.
Cutaneous and Subcutaneous Infections
Cutaneous infections are the most common manifestations of Alternaria, sig-
nificantly more frequent in occurrence than subcutaneous infections (88.4%
vs. 5.8%).1 Concomitant cutaneous and subcutaneous infections are rarely
reported. Lesions can appear as shallow-based, nonhealing ulcers that evolve
from nodules, subcutaneous noninflammatory cysts, verrucous-like lesions, or
erythematous, confluent, scaly patches. Disseminated alternariosis can present
with papulonodular lesions or cutaneous nodules.
The majority of patients manifesting this disease are immunosuppressed
(84%), with the greatest number of cases seen in the solid organ transplant
population (kidney>liver).1,2 The major risk factor in this group, as well as other
immunosuppressed individuals, is systemic steroid use, possibly due to a combi-
nation of its immunosuppressive properties and through skin breakdown.2 Along
with the risk factor of an immunosuppressed state (solid organ or bone mar-
row transplant, immunosuppressive therapy, especially steroid use, Cushing’s
disease), many infected patients are able to identify a traumatic event leading to
the infection.1 Rarely, patients develop coinfection with other fungi; there are
case reports of coinfection with Phaeosclera and Scopulariopsis.3 Infection does
occur in patients without known immunosuppression other than diabetes as a
risk factor. Recurrence of nodules/infection after appropriate treatment, and
after apparent clearing of the infection, has been described, including one case
report of a patient with multiple recurrences spanning from 1942–1996.4
 Treatment
Skin and Soft Tissue Infections

There is no standardization in the treatment of cutaneous alternariosis. In

vitro studies indicate that itraconazole, and newer triazole antifungal show
good activity. 5 Amphotericin B and ketoconazole have variable activity, while
flucytosine and fluconazole have no activity.5 In the clinical literature, the vast
majority of cases have been treated with itraconazole with overall success,
though treatment failures are also reported. More recent clinical reports
indicate that newer triazole antifungal agents are a viable option for ocular,
cutaneous, and disseminated disease. For successful cure in the immunocom-
promised patient with a large fungal load, whether cutaneous or sinonasal,
surgical debridement is often needed in combination with prolonged antifun-
CHAPTER 11

gal therapy (6–12 months).1 A concomitant dose reduction in the immunosup-

pressive regimen is suggested as well.

References
1. Pastor FJ, Guarro J. Alternaria infections: laboratory diagnosis and relevant clinical
features Clin Microbiol Infect. 2008;14(8):734–746.
2. Gilaberte M, Bartralot R, Torres JM, Reus FS, Rodríguez V, et al. Cutaneous alter-
nariosis in transplant recipients: clinicopathologic review of 9 cases. J Am Acad
Dermatol. 2005;52(4):653–659.
3. Anandan V, Nayak V, Sundaram S, Srikanth P. An association of Alternaria alter-
282

nata and Scopulariopsis brevicaulis in cutaneous phaeohyphomycosis. Indian J

Dermatol Venereol Leprol. 2008;74(3):244–247
4. Pec J, Minarikova E, Zaborska D, Adamicova K, Krkoska D, et al. Treatment of
dermal and subcutaneous pheohyphomycosis of 55 years’ duration. Int J Dermatol.
2008;47(5):526–529.
5. Cuenca-Estrella M, Gomez-Lopez A, Mellado E, Buitrago MJ, Monzon A, et al.
Head to head comparison of the activities of currently available agents against the
3378 Spanish clinical isolates of yeasts and filamentous fungi. Antimicrob Agents
Chemother. 2006;50(3):917–921

Case
C a e 111f:
1f: O
1f Orbital,
rbi
bittall, E
bi Ear
Ear,
ar, andd Ski
SSkin
kin LLesi
Lesions
ions in
i aH
Healthy
ealth
lth
thyy
Laboratory
Labo
La Research
boratory Resea arc
rchh Assistant
Assi
s stant

Joshua C. Eby and W. Michael Scheld

Presentation
A 24-year-old male presented in July with swelling and pain of his right ear and
left eye. Six days prior to admission, the patient was stung by a bee on the left
hand while vacationing in North Carolina. He subsequently developed swelling
and pain of his right ear lobe, followed the next day by swelling around his left
eye. The swelling at both sites worsened over several days, and small white
dots formed on the right ear lobe. He had trouble seeing that he attributed
to the swelling of his eyelids, which was accompanied by an opaque, yellow
discharge. He described malaise and subjective fevers, and his symptoms did
not respond to cephalexin and prednisone. He presented to the emergency
department where he was noted to have some pain with eye movement, and he

Skin and Soft Tissue Infections

was admitted with a presumed diagnosis of orbital cellulitis. The patient denied
any past medical problems, and had tested negative for HIV a few months prior
to admission. He worked as a cancer and immunology research assistant at a
hospital-affiliated research laboratory.
On physical examination, the patient was afebrile but in obvious discomfort
due to right ear and eye pain. The lobe of his right ear was coated in crusted,
purulent material, with a crop of vesicles inferior to his ear (Figure 11f.1a).
The vesicles were all at the same stage of development. His left periorbital
soft tissue was edematous and erythematous (Figure 11f.1b). A thick purulent
discharge covered his sclera and cornea. There was no scleral injection. Pupils

CHAPTER 11
were equal, round, and reactive to light when the left palpebrae were parted.
There was some pain with extraocular movement but no proptosis. Other
cranial nerve functions were intact. His left hand (the reported site of the bee
sting) had no lesions, but there were two small vesicular lesions on his chest and
one on his flank. There was erythema of the skin surrounding each vesicle, but
the remainder of his physical examination and laboratory studies was normal.
CT scan of the left orbit showed severe inflammation restricted to the presep-
tal tissues. The consulting ophthalmologist described conjunctivitis and blephari-
tis, with possible mild keratitis. Cellular culture of a swab taken from the purulent
exudate from his eye showed a cytopathic effect (Figure 11f.2). Polymerase chain
reaction for vaccinia virus was performed on the cultured material and was pos-

283
itive. When the diagnosis was suspected, the patient’s lesions had already begun
to improve and, thus, systemic therapy was not required. The patient recovered
with some madarosis but without visual sequelae.

(a) (b)

Figure 11f.1 (a) Lobe of his right ear showing crusted, purulent material with a crop
of vesicles inferior to the ear; and (b) The left periorbital soft tissue was edematous and
erythematous.
Skin and Soft Tissue Infections
CHAPTER 11

Figure 11f.2 Cellular culture of a swab taken from the purulent exudate from the eye
showed a cytopathic effect.
284

Case 11f Discussion: Vaccinia Virus Infection

Clinical Features
Live vaccinia virus, an orthopoxvirus, is the immunogenic component of the
smallpox vaccine, which is used to induce immunity to variola, the causative
agent of smallpox. Since routine civilian vaccination was stopped in 1972,
vaccination has been limited to those with a risk of exposure to orthopox-
viruses through laboratory work or first response to a bioterrorist attack.1
Intentional inoculation with vaccinia, for the purpose of vaccination, results
in an inflammatory lesion that crusts and separates within approximately
14 days.2 Live vaccinia is shed from the inoculation site for approximately
21 days. During this period, the virus may be transmitted to other suscep-
tible individuals (accidental inoculation) or to other parts of the body of the
vaccinated individual (autoinoculation). Covering the wound with a semiper-
meable dressing and adherence to hand-washing practices reduces the risk
of transmission. In the described case, accidental acquisition from a labora-
tory animal had occurred, and subsequently spread to multiple sites, likely by
autoinoculation.
Multiple complications of vaccination with vaccinia have been reported.
Progressive vaccinia, or vaccinia gangrenosum, is fatal without treatment and
occurs in infants and in immunocompromised hosts, usually with deficient
cellular immune response. This severe disease is characterized by expan-
sion of vaccinia lesions from the site of vaccination, or spread of lesions to
distant sites.3 There is a lack of inflammation, pain, or evidence of healing
after 14 days. Lesions progress and develop into deep, necrotic ulcerations.
Amputation of affected limbs is often required, and superinfection may occur.

Skin and Soft Tissue Infections

Eczema vaccinatum, a complication that occurred in 14–44 cases per million
vaccinees prior to 1968, can occur in patients with atopic dermatitis even in
the absence of active lesions or prior diagnosis of atopy. This complication
may be acquired through vaccination or contact with a recently vaccinated
individual, and manifests as either a localized or widespread, potentially fatal,
cutaneous disease.4
In contrast to progressive vaccinia and eczema vaccinatum, generalized
vaccinia occurs in immunocompetent individuals, and is a self-limited ill-
ness characterized by systemic symptoms and scattered vesicular lesions
with surrounding erythema indicative of a proper inflammatory response.

CHAPTER 11
Postvaccination encephalomyelitis carries a high rate of death (up to 30%)
and permanent neurologic sequelae (up to 20%). Myopericarditis may com-
plicate vaccination, and was reported more frequently during military and
civilian vaccination programs in 2003, instituted in response to the threat
of bioterrorism. During this period, attention was also drawn to a risk of
postvaccination cardiac ischemic events in patients with preexisting cardiac
risk factors.
As in the case above, ocular manifestations occur as a result of accidental
inoculation or autoinoculation. Blepharitis and conjunctivitis do not frequently
result in serious long-term sequelae. While long-term sequelae are more likely
to occur after keratitis (18%), the largest prospective study of vaccinia keratitis

285
found minimal residual corneal defects 5 years after infection in the 7 patients
that were available for evaluation.5
Diagnosis and Treatment
Polymerase chain reaction of infected exudate is used for definitive, molecular
diagnosis. Electron microscopy can be used to identify intracellular viral par-
ticles after growth of the virus in cell culture. The typical cytopathic effect of
vaccinia consists of rounding, granularity without vacuolation, and expanding
cytolysis with fibrinous material at the site of dead cells.
Vaccinia immune globulin (VIG) has decreased mortality from severe com-
plications, with the exception of vaccinia-induced encephalitis. VIG is con-
traindicated in cases of isolated vaccinia keratitis, because it may increase the
likelihood of corneal scarring, although the data are mixed. Cidofovir, and the
experimental antiviral, ST-246, have in vitro activity against vaccinia and have
been used in combination.6 Topical trifluorothymidine and vidarabine are active
against vaccinia in vitro, and are used to treat keratitis. Progressive vaccinia
requires combined therapy with VIG, antiviral medications, and aggressive
debridement.

References
1. Wharton M, Strikas RA, Harpaz R, et al. Recommendations for using smallpox
vaccine in a pre-event vaccination program. Supplemental recommendations of
the Advisory Committee on Immunization Practices (ACIP) and the Healthcare
Infection Control Practices Advisory Committee (HICPAC). MMWR Recomm
Rep. 2003 Apr;52(RR-7):1–16.
 2. Lane JM and Goldstein J. Adverse events occurring after smallpox vaccination.
Skin and Soft Tissue Infections

Semin Pediatr Infect Dis. 2003 Jul;14(3):189–195.

3. Barbero GJ, Gray A, Scott TF, Kempe CH. Vaccinia gangrenosa treated with
hyperimmune vaccinal gamma globulin. Pediatrics. 1955 Nov;16(5):609–618.
4. Kempe CH. Studies of smallpox and complications of smallpox vaccination.
Pediatrics. 1960 Aug;26;176–189.
5. Ruben FL and Lane JM. Ocular vaccinia. An epidemiologic analysis of 348 cases.
Arch Ophthalmol. 1970 Jul;84(1):45–48.
6. Vora S, Damon I, Fulginiti V, et al. Severe eczema vaccinatum in a household con-
tact of a smallpox vaccinee. Clin Infect Dis. 2008;46(10):1555–1561.
CHAPTER 11

Case
C a e 111g:
1g A 46
1g: 46-Year-Old
-Year-
Y -OlOld
d Man
Man wi
with
ith
h FFev
Fevers,
evers, R
Ras
Rash,
a h, aand
nd
d
Malaise
Mala
Ma laiise

Meenakshi Mehrotra Rana, Michael Mullen, and

Daniel Caplivski
Case Presentation
A 46-year-old man presented to the emergency department with sore throat,
abdominal pain, fever, and a diffuse erythematous rash that began 5 days prior to
286

presentation. He also noted headaches, diffuse myalgias, joint pains, nausea, and
diarrhea that began the previous day. On physical examination he was febrile
(38.8°C), generally ill-appearing, and had enlarged erythematous adenoids, and
cervical lymphadenopathy. The blanching, erythematous maculopapular rash
was not pruritic, and involved his trunk, back, face, and extremities, including his
palms (Figures 11g.1 and 11g.2).
The patient was originally from Beijing, China, and had arrived in New York 2
months prior to presentation. He had no sick contacts at the time of presenta-
tion, and he reported his only sexual partner was his wife in China. His labora-
tory values were notable for thrombocytopenia (99,000 cells/μl) and slightly
elevated liver enzymes (AST 51 units/liter, ALT 42 units/liter). The rapid plasma
regain was nonreactive, and the HIV ELISA test was negative. The HIV viral
load, however, was positive at 8,997,771 copies/ml. The patient later admit-
ted to having recently tried intravenous heroin using a shared needle. He was
referred to a center conducting a clinical trial on acute retroviral syndrome.
Case 11g Discussion: Acute Retroviral Syndrome
Clinical Presentation and Diagnosis
The signs and symptoms associated with acute HIV infection may occur in
40%–90% of patients from 2 to 6 weeks after exposure.1 Typically, patients
present with an infectious mononucleosis-type illness, and symptoms include
fever, pharyngitis, weight loss, myalgias, night sweats, headaches, nausea, and
diarrhea.1,2 Patients may also present with a neurological picture consistent
with aseptic meningitis. On physical exam, a morbilliform rash may be seen in
 Skin and Soft Tissue Infections
287 CHAPTER 11

Figure 11g.1 and 11g.2 The blanching, erythematous maculopapular rash involved the
trunk, back, face, and extremities.

40%–80% of individuals.2 In addition, generalized lymphadenopathy or mucosal

ulcers may be present. Laboratory examination is notable in some cases for
leucopenia, thrombocytopenia, and elevated liver enzymes.
Because symptoms are nonspecific, the diagnosis of acute HIV infection
can be challenging; however, making the diagnosis of acute infection provides
a crucial opportunity for counseling and prevention of further transmission.
There are four generations of HIV screening antibody tests used. The first-
generation IgG sensitive indirect enzyme immunoassay (EIA) detects antibodies
to viral lysate, and the second generation detects antibodies to recombinant
synthetic peptide antigen. The first-generation EIA is no longer available for
use in the United States. The third-generation EIA uses an antigen-antibody
sandwich format, and detects both IgM and IgG antibodies, and is therefore
positive earlier than first- or second-generation tests. A fourth-generation EIA
 combines detection of IgG and IgM antibodies along with p24 antigen, and is
Skin and Soft Tissue Infections

positive even before the third-generation test. The fourth-generation EIA is

not yet approved for use in the United States.3 The western blot is done to
confirm a positive antibody test, but can often be negative or indeterminate in
acute HIV infection.
Because these traditional HIV tests detect antibodies, there is a “window
period” in acute HIV infection where these tests will be negative. These
“window periods” are shorter in the newer-generation EIAs. In patients in
whom acute HIV is suspected, an HIV-1 plasma RNA or viral load should be
sent, in addition to antibody testing. HIV-1 RNA levels will be positive after
9 to 11 days in acute infection, and viremia can reach extremely high lev-
CHAPTER 11

els, up to several million copies, as in the case above.4 HIV-1 RNA tests
are highly sensitive and can have false positive results in up to 1% of cases;
however, the viral load is usually low in these cases and this should prompt
retesting. In the past, p24 antigen has also been used for diagnosis. While it
is highly specific, it is not as sensitive as viral load testing, and false negative
results limit its usefulness.1
While individual viral load testing can be expensive, pooled nucleic acid
amplification testing (NAAT), in which specimens are pooled and then
tested, is a strategy that has been effectively used by blood banks for screen-
ing. NAAT testing is now being adopted widely by many STD and public
health clinics for screening high-risk populations. For example, patients pre-
288

senting to 110 clinics in North Carolina for publicly funded HIV testing were
screened using NAAT. In 8505 consecutive individuals screened, 39 were
positive by traditional antibody screening and an additional five were RNA
positive by pooled NAAT testing (one/five was a false positive result).5 This
strategy increased the diagnostic yield in this population by 10% compared
with traditional antibody testing. Therefore, pooled NAAT may be an effec-
tive way of screening larger populations, and provides a unique opportunity
for prevention.
Management
The treatment of acute HIV infection with highly active antiretroviral therapy
(HAART) remains a controversial topic. Those who advocate for early treat-
ment hypothesize that it may serve as a unique opportunity to modify the host’s
immune response to HIV-1. By preserving the HIV-1 specific cellular immune
response, and decreasing the viral load set point, early initiation of HAART may
delay or prevent decreased immune function and opportunistic infections. In
addition, early therapy may mitigate symptoms of acute retroviral syndrome,
and help prevent transmission by decreasing viremia.1,6
While these are potential advantages, others argue that toxicities of treat-
ment, development of resistance, and cost, remain reasons not to use HAART
in acute HIV infection. In addition, duration of treatment in primary infection
also remains unclear. Lastly, the above potential benefits of early HAART
remain unproven in large randomized, placebo-controlled trials.
One of the initial randomized trials done, was conducted at a time when
monotherapy for HIV was the standard of care. A multicenter, double-blind,
placebo-controlled trial in which 77 patients with primary HIV were randomly

Skin and Soft Tissue Infections

assigned to receive either zidovudine or placebo for 6 months showed sig-
nificant decrease in the number of opportunistic infections and a significant
increase in the CD4 count in the zidovudine group; however, viral loads were
not significantly different.7 In addition, long-term follow-up over a period of 2
years showed that the initial clinical and immunological benefits seen seemed
to wane over time, with differences between the two groups no longer remain-
ing significant.
Subsequent trials have been mainly observational cohorts without much
evidence to support treatment.7,8 Clinical trials are ongoing to assess the
question of whether HAART in primary HIV infection would be beneficial.

CHAPTER 11
Currently, there are three major published guidelines that address this
question. The United States Department of Health and Human Services
(DHHS) guidelines recommend that treatment for patients with acute HIV
is optional, and that the healthcare provider and patient should be aware
that the rationale for treatment in acute HIV remains theoretical. They also
recommend enrollment in a clinical trial. The International AIDS Society
USA (IAS-USA) guidelines suggest that no evidence exists to support the
initiation of antiretroviral therapy in acute HIV infection. The British HIV
Association (BHIVA) guidelines also agree that conflicting evidence exists,
and treatment should only be considered in patients with CD4 less than 200
or with an AIDS-defining illness. Therefore, until a large, placebo-controlled,

289
randomized trial is done, the question of HAART during acute HIV infection
remains controversial. At this time, most guidelines suggest that treatment
is optional in this patient population, and that patients should be enrolled in
a clinical trial.

References
1. Kassutto S and Rosenberg ES. Primary HIV type 1 infection. Clin Infect Dis.
2004;38:1447-1445.
2. Kahn J, Walker B. Acute human immunodeficiency virus type 1 infection. New
Engl J Med. 2004;339(1):33-39
3. Patel P, Mackellar D, Simmons P, et al.; CDC Acute HIV Infection Study Group.
Detecting acute HIV infection using 3 different screening immunoassays and
nucleic acid amplification testing for human immunodeficiency virus RNA, 2006-
2008. Arch Intern Med. 2010;170(1):66-74.
4. Pilcher CD, Eron JJ, Galvin S, Gay C, Cohen MS. “Acute HIV revisited: new
opportunities for treatment and prevention.” The Journal of Clinical Investigation
2004; 113(7): 937-45
5. Pilcher CD, McPherson JT, Leone PA, Smurzynski M, Owen-O’Dowd J, Peace-
Brewer AL, Harris J, Hicks CB, Eron JJ, Fiscus SA. “Real-time, Universal Screening
for Acute HIV Infection in a Routine HIV Counseling and Testing Population.”
JAMA 2002; 288(2): 216-220
6. Apoola A, Ahmad S, Radcliffe K. “Primary HIV Infection.” International Journal
of STD and AIDS 2002; 13: 71-78.
 7. Kinloch-De Loes S, Hirschel BJ, Hoen B, Cooper DA, Tindall B, Carr A, Saurat
Skin and Soft Tissue Infections

JH, Clumeck N, Lazzarin A, Mathiesen L, Raffi F, Antunes F, Overbeck JV, Luthy

R, Glauser M, Hawkins D, Baumberger C, Yerly S, Perneger TV, Perrin L. “A
Controlled Trial of Zidovudine in Primary Human Immunodeficiency Virus
Infection.” NEJM 1995; 333(7): 408-13
8. Smith D, Walker BD, Cooper DA, Rosenberg ES, Kaldor JM. “Is antiretroviral
treatment of primary HIV infection clinically justified on the basis of current evi-
dence?” AIDS 2004; 18:709-718.
290 CHAPTER 11
 Chapter 12

Bone and Joint Infections

Case
C a e 12a:
12a:
2a 51
51-Year-Old
-Year-Ol
Y Olld W
Woman
oman with
ith a P
Painless
aiinle
less FFoot
oott
U
Ul cerr
ce
Ulcer

Keith Sigel
Case Presentation
A 51-year-old woman with insulin dependent diabetes and end-stage renal

291
disease was admitted with pneumonia and was treated with ceftriaxone and
azithromycin. She also had painless, nonhealing left third toe ulcer that had
been present for more than a month. The ulcer had no drainage, and she had
not received any treatment for it previously. She denied any other symptoms,
other than her presenting complaints relating to her pneumonia.
On physical examination, the patient was afebrile, and she had scattered
wheezes in bilateral lung fields. Her extremity exam revealed palpable dorsalis
pedis and posterior tibial artery pulses bilaterally, decreased sensation to fine
touch in both feet, and a nondraining, nonerythematous ulcer at the base of the
left third toe (Figure 12a.1).
Laboratory values were significant for leukocytosis (11 x10³ WBC/μL) and
slightly elevated C-reactive protein (6.25 mg/l, normal <5). A swab of the ulcer
had been sent for culture, and grew methicillin resistant Staphylococcus aureus.
Plain radiography of the patient’s left foot revealed a focal lucency at the third
toe, suggesting bone erosion (Figure 12a.2).
Case 12a Discussion: Diabetic Foot Infections
Clinical Features and Diagnosis
Diabetic foot ulcers are common, and have been observed in up to 5% per year
of patients with diabetes.1 The vascular impairment and peripheral neuropa-
thy of chronic diabetes contribute to both the development and progression
of these lesions. Impairment of neutrophil function by hyperglycemia is also a
contributing factor. The role of infection in diabetic foot ulcers is multifactorial,
and soft tissue infections both in and around the ulceration are often pres-
ent. The determination of whether an ulcer is infected is made clinically, based
Bone and Joint Infections
CHAPTER 12

Figure 12a.1 Ulcer at the base of the left third toe

292

Figure 12a.2 Plain radiograph, left foot showing a focal lucency at the third toe sugges-
tive of osteomyelitis

on the presence of drainage and erythema, as well as systemic signs such as

fever. Laboratory markers of inflammation, such as elevated C-reactive protein
and erythrocyte sedimentation rate, are also supportive of the diagnosis of
infection.2
 Although a variety of organisms may be responsible for infection in diabetic

Bone and Joint Infections

foot ulcers, aerobic Gram-positive cocci, such as Staphylococcus aureus and
Streptococcus species are the most common pathogens.2 Assessing the ulcer
for bone infection is also an important part of the clinical evaluation. The likeli-
hood of bone infection is significantly increased when bone can be probed
within the wound.3 Other imaging studies, such as plain radiography, nuclear
studies (indium-labeled leukocyte scan combined with bone marrow imaging
using technetium-99m–labeled sulfur colloid), or MRI may help to assess for the
integrity of underlying bone when there is a high clinical suspicion of osteomy-

CHAPTER 12
elitis, or if wounds persist.
Treatment
Diabetic foot ulcers should be approached in a multidisciplinary manner with
local wound care, as well as frequent wound surveillance.4 There is little evi-
dence to support the use of antimicrobial agents in ulcers that do not appear
infected clinically. If clinical signs suggest infection in the soft tissue of the ulcer
or surrounding tissues, then an antimicrobial course should be administered,
with a duration based on perceived severity of infection. Broad-spectrum anti-
biotics are usually not necessary unless the infection is severe, although the
presence of methicillin-resistant Staphylococcus aureus should be considered.2
If underlying osteomyelitis is demonstrated or suggested, the wound should be
surgically evaluated, with consideration for deep debridement in concert with

293
extended antimicrobial courses.5

References
1. Cheer K, Shearman C, Jude EB. Managing complications of the diabetic foot. BMJ.
2009;339:b4905
2. Lipsky BA, Berendt AR, Deery HG, et al. Diagnosis and treatment of diabetic foot
infections. Clin Infect Dis. 2004; 39:885–910
3. Miller AO, Henry M. Update in diagnosis and treatment of diabetic foot infec-
tions. Phys Med Rehabil Clin N Am. 2009; 20:611–625
4. Edwards J, Stapley S. Debridement of diabetic foot ulcers. Cochrane Database Syst
Rev. 2010:CD003556
5. Conterno LO, da Silva Filho CR. Antibiotics for treating chronic osteomyelitis in
adults. Cochrane Database Syst Rev. 2009:CD004439

Case
C a e 12b:
12b
2b: N
Non-Healing
on-HHeali
ling Sk
Ski
Skin
in U
Ul
Ulceration
lcerati
tion with
ith aan
n
Asso
As socciated Fistulous
Associated Fistulo
lous
us Traact
Tract

Sean Pawlowski and W. Michael Scheld

Case Presentation
A 54-year-old woman from Pakistan presented with a 16-month history of a
non-healing ulcerative lesion at the base of her thumb, and a 2-month history
of a draining tract at the thenar eminence. The patient recalled that the lesions
 began soon after a book fell on the dorsum of her thumb. It became progres-
Bone and Joint Infections

sively painful, with associated swelling of the thenar eminence and drainage of
fluid. She denied any history of fevers, night sweats, cough, or weight loss.
On physical examination, all her vital signs were normal and her lungs were
clear to auscultation. On the dorsal aspect of the first metacarpal bone on her
right hand, there was evidence of a non-tender ulcerative lesion without associ-
ated erythema. The thenar eminence was slightly tender to palpation, with evi-
dence of a draining sinus (Figure 12b.1). Radiography of the wrist showed bony
erosion of the base of the first metacarpal, base of second metacarpal, and trape-
CHAPTER 12

zium (Figure 12b.2), and chest radiography revealed evidence of apical scarring.
294

Figure 12b.1 The thenar eminence was slightly tender to palpation with evidence of a
draining sinus.

Figure 12b.2 Radiography of the wrist showed bony erosion of the base of the 1st
metacarpal, base of 2nd metacarpal, and trapezium.
 A biopsy and swab of the ulcerative lesion were negative for acid-fast bacilli,

Bone and Joint Infections

but culture of both grew Mycobacteria tuberculosis. The patient was treated with
isoniazid, rifampin, pyrazinamide, ethambutol, and vitamin B6. A subsequent
chest CT scan showed no evidence of active disease, and all sputum samples
were negative. The isolate was pansusceptible after the initial 2-month phase,
and she was continued on isoniazid and rifampin. Because of bony destruc-
tion, slow healing, and an unstable joint, the patient underwent debridement
with placement of a spacer. After 12 months of treatment, her thumb lesion
appeared well healed (Figure 12b.3) and treatment was discontinued.

CHAPTER 12
Case 12b Discussion: Tuberculous Osteomyelitis
Worldwide, extrapulmonary Mycobacterium tuberculosis (MTB) represents
20% of all cases of TB, and infection of the musculoskeletal system represents
1%–5% of all tuberculosis cases.1 It is thought to arise from a foci of bacilli
lodged in bone during the original mycobacteremia of primary infection.2 Any
bone, joint, or bursa can be infected, but the spine, hip, and knee, in order of
frequency, are the most common sites of infection. In addition to MTB infec-
tion, nontuberculous Mycobacteria (NTM) osteomyelitis, and osteoarticular
infections occur, as well. NTM infections are more commonly seen in immuno-
compromised patients, or those that have experienced trauma or surgery; M.
marinum, M. bovis after bCG vaccination, M. avium-intracellulare, M. fortuitum,
M. chelonae, M. ulcerans, M. kansasii, M. xenopi, and M. haemophilum have all

295
been documented as causes of musculoskeletal disease.1,2
Clinical Presentation and Diagnosis
There has been an evolution in the presenting symptoms of osteoarticular TB
within resource rich nations. Newer reports suggest that the majority of cases
now affect an older population who present with more systemic symptoms,

Figure 12b.3 Thumb lesion after 12 months of treatment.

 multiple joint involvement, and periarticular abscess formation, whereas previ-
Bone and Joint Infections

ous literature suggested that it evolved as a chronic, slowly progressive mono-

arthritis, mostly affecting the hip or knee.3 The most common sign is pain and
local swelling at the involved joint, and fever and weight loss are present in only
a minority of patients.2 In chronic cases, cutaneous fistulae, abscesses, and obvi-
ous joint deformity may also be present.
Synovia and periarticular bone are usually involved at the time of diagnosis.
Bony foci result in local demineralization and may destroy the epiphyseal plate,
resulting in deformity to the affected limb.4 Articular cartilage loss occurs as
CHAPTER 12

the infection spreads to subchondral bone and disrupts the nutritional supply
of the cartilage.4 Synovitis develops with resultant joint effusion, granulation
tissue, and development of a pannus and erosions at the margins of the joint.4
Necrotic cartilage and fibrinous material form the classic “rice bodies” found
in synovial fluid.
The weight-bearing articular surfaces are often preserved early in disease,
providing potential for functional recovery if treatment is initiated early.4
Radiographic findings usually evolve weeks to months after symptoms, dem-
onstrating osteopenia, periarticular bony destruction, periosteal thickening,
and destruction of cartilage and bone. In chronic cases, cold abscesses and
fistulous tracts form: 50% of vertebral osteomyelitis cases have paraspinal cold
abscesses.1
Synovial leukocyte counts in tuberculous arthritis are typically lower than
296

those found in bacterial septic arthritis, but biopsy and culture data are needed
to confirm the diagnosis. In articular TB, the synovial fluid culture (sensitivity of
74%) is often nondiagnostic, whereas biopsy and culture of the synovium bone
or deep tissue has a sensitivity approaching 95%.2 Superficial cultures often
demonstrate bacterial contamination and acid-fast smears are rarely positive.
A finding of caseous granulomas on bone biopsy (found in 94% of cases) may
be enough to begin empiric therapy in the right clinical setting.2 The utility of
molecular diagnostic tests in the assessment of smear-negative or culture-neg-
ative patients with suspected extrapulmonary tuberculosis remains unclear.2
Tuberculin skin test results are variable, but chest radiography should be per-
formed to evaluate for pulmonary involvement.
Treatment
Medical therapy for bone and joint tuberculosis does not differ significantly from
pulmonary disease (see Chapter 6). According to the CDC, initial four-drug
combination therapy is recommended until susceptibilities are obtained, with
increasing evidence that 6–9 month regimens that include INH and rifampin are
effective.5 Some experts recommend 12–18 months of therapy, particularly for
poorly vascularized sites, such as bones and joints.4,5 Prolonged therapy should
be considered for patients slow to respond to otherwise adequate treatment.
The treatment of drug-resistant disease follows the same principles for treat-
ment of other sites. Surgical debridement is not needed for cure, but it may
help decrease the load of bacilli. If a joint is unstable or significantly damaged,
fusion or replacement may be necessary. In those cases, prolonged medical
therapy should be used prior to and at times, after, replacement.4
References

Bone and Joint Infections

1. Berbari EF, Stecklenberg JM, Osmon DR. Osteomyelitis. In: Mandell GL, Dolin F,
and Bennett, eds: Principles and Practice of Infectious Diseases. 7th ed. Philadelphia:
Elsevier Churchill Livingston; 2009:1457–1467
2. Gardam M, Lim S. Mycobacterial osteomyelitis and arthritis. Infect Dis Clin North
Am. 2005;19(4):819–830.
3. Fitzgerald DW, Sterling TR, Haas DW. Mycobacterium tuberculosis. In: Mandell
GL, Dolin F, and Bennett, eds: Principles and Practice of Infectious Diseases. 7th
ed. Mandell, G. Bennett, J. Dolin, R. editors. Philadelphia: Elsevier Churchill

CHAPTER 12
Livingston; 2009:3129--3163
4. Tuli SM. General principles of osteoarticular tuberculosis. Clin Orthop Relat Res.
2002 May;398: 11–19.
5. Centers for Disease Control and Prevention. Treatment of tuberculosis.
American Thoracic Society, CDC, Infectious Disease Society of America. 2003;
MMWR 52. 1–77

Ca e 12c:
Case 12c:
2c A P
Painful,
aiinffull, SSwollen
woll
llen Knee
ll K

Michael M. Gaisa and Michael Mullen

Presentation and Case History

297
A 72-year-old woman with a history of hypertension and osteoarthritis under-
went a total knee replacement of the right knee. Six months later she presented
with severe pain, swelling, and warmth of the right knee for 2 days. She also had
shaking chills, subjective fevers and progression of the pain to the point that it
was limiting her ability to stand or ambulate. On physical examination, she was
afebrile, but the right knee was very tender, swollen, and warm (Figure12c.1).

Figure 12c.1 Swollen right knee several months after knee replacement.
 Her laboratory examinations were notable for elevated C-reactive protein
Bone and Joint Infections

(199mg/l, normal <5) and erythrocyte sedimentation rate (78 mm/hour, normal
<20), but her peripheral white blood cell count was not elevated (8x10³ WBC/
μl). Aspiration of the knee revealed cloudy pink fluid with 102,000 WBC/μl,
90% polymorphonuclear cells. No organisms were seen on Gram-stain, but the
fluid culture was positive for Streptococcus intermedius.
During intubation for removal of the prosthesis, the patient was noted by
the anesthesiologist to have gross periodontal disease with a crumbling right
upper molar and a periapical abscess. The prosthetic knee was removed, the
CHAPTER 12

space debrided, and an antibiotic-coated spacer was placed. Cultures from the
operating room also grew Streptococcus intermedius, and the patient revealed
that several of her teeth had been loose, but that she was afraid of dentists.
The remaining necrotic tooth was extracted and she was treated with intrave-
nous ampicillin/sulbactam for 8 weeks. Upon removal of the antibiotic-coated
spacer, excessive bleeding did not allow for a new prosthesis and a new spacer
was placed instead. All cultures from the subsequent surgery were negative,
and a new prosthesis was finally placed 3 months after the removal of the
original prosthesis.
Case 12c Discussion: Prosthetic Joint Infections
Joint replacement surgery (arthroplasty) is a widely performed surgical pro-
cedure in the United States. In 2006, primary total hip and knee arthroplasties
298

alone accounted for close to 800,000 of such cases. Besides infection, a num-
ber of other, noninfectious complications deserve mention; these are mainly
mechanical in nature, and include aseptic loosening of the prosthesis, dislocation,
and fracture of either prosthesis or adjacent bone. Even in the era of periopera-
tive antibiotic prophylaxis, and optimized surgical environments using laminar
airflow technique, prosthetic joint infections occur with infection rates ranging
between 0.5% to 1.0% for hip replacements, 0.5% to 2% for knee replacements,
and less than 1% for shoulder replacements. The frequency with which these
procedures are performed produces significant case numbers, financial strain
on the healthcare system (estimated cost of treating an infected arthroplasty is
in excess of $50,000 per episode), and individual morbidity/disability.1,3
Risk factors for prosthetic joint infections include revision arthroplasty
(either due to a mechanical complication/failure, or infection at the same site),
rheumatoid arthritis, diabetes mellitus, poor nutritional status, obesity, smok-
ing, concurrent immunosuppressive therapy (e.g., corticosteroids), concomitant
malignancy, postoperative surgical site infection or wound healing complica-
tions (hematoma, dehiscence, wound necrosis, etc.), simultaneous bilateral
arthroplasty, and prolonged operative time (>2.5 hours).1,2
Staphylococci (S. aureus and coagulase-negative Staphylococcus species)
account for more than 50% of primary prosthetic hip and knee infections, but
virtually every microorganism can cause prosthetic joint infection. S. aureus is
particularly common in patients with rheumatoid arthritis undergoing arthro-
plasty. Propionibacterium acnes is a rare cause of infection following hip and knee
arthroplasty, but has been described in up to 16% of prosthetic joint infections
following shoulder arthroplasty. Up to 20% of infections are polymicrobial, and

Bone and Joint Infections

up to 10% are culture-negative, commonly in the context of antimicrobial ther-
apy prior to culture acquisition.2,3
The most common presenting symptom is pain. In acute infection, severe
pain, swelling, erythema, and warmth at the site of the infected joint and fever
are common. Chronic infection generally has a more subtle presentation, with
pain alone, and is often accompanied by loosening of the prosthesis at the
bone–cement interface, and sometimes by sinus tract formation with discharge.
The pathogenesis of prosthetic joint infections is determined by a variety of fac-

CHAPTER 12
tors, particularly the inoculum size and virulence of microorganism(s) involved,
as well as host factors (integrity of immune function, impaired wound healing,
etc.). Biofilm formation at the site of prosthetic surfaces is an important phe-
nomenon in the establishment and persistence of microbial infection; it shields
pathogens from the microbicidal effects of the host immune system, and pro-
vides relative resistance to antimicrobial therapy.1
Infections occurring early in the postoperative course (usually within 3
months of joint replacement) are typically acute in presentation and involve
virulent organisms (e.g., S. aureus or Gram-negative bacilli) inoculated at the
time of implantation. Patients who develop postoperative wound complications
(e.g., dehiscence, necrosis, or hematoma) may also develop infection early on,
by contiguous spread of organisms from the superficial wound to deeper soft
tissue structures and prosthetic surfaces. In contrast, infection with less virulent

299
organisms (e.g., coagulase-negative staphylococci and P. acnes) more commonly
presents as chronic infection several months (or years) postoperatively. Acute
hematogenous infection is characterized by the acute onset of symptoms of
infection in a previously well-functioning joint. It can occur at any time following
arthroplasty, even many years postoperatively. Transient staphylococcal bacte-
remia in one report led to secondary prosthetic joint infection in approximately
one-third of cases. The primary focus of infection in such cases is unrelated to
the prosthetic joint; the most common sites are skin and soft tissue, followed
by dental (as is the case in the patient discussed above), and urinary tract. S.
aureus and S. epidermidis are responsible for most infections, except for those
originating in the urinary tract, where E.coli is the most common pathogen.2,3
Serologic inflammatory markers can aid in the diagnosis of prosthetic joint
infection, while leukocytosis has a low sensitivity in detecting infection. In the
absence of concomitant inflammatory conditions, C-reactive protein (CRP)
measurement is a useful tool, with a sensitivity of 73% to 91% and a specific-
ity of 81% to 86% for the diagnosis of prosthetic knee infection (using a cutoff
of t13.5 mg/l). For the diagnosis of prosthetic hip infection, it has a sensitivity
of 95% and a specificity of 62% (using a cutoff of >5 mg/l). While CRP level
and erythrocyte sedimentation rate (ESR) are typically elevated following an
uncomplicated arthroplasty, the CRP level usually returns to the preoperative
level within 2 months; the ESR rate, however, may remain elevated for several
months. CRP levels may be misleadingly normal in patients who have received
antibiotics, or who have infection that is caused by low-virulence organisms
(e.g. P. acnes).1,3
 A synovial fluid leukocyte count of more than 1.7×10³/μl, or a differential
Bone and Joint Infections

count with more than 65% neutrophils, is indicative of an infected knee arthro-
plasty. A synovial fluid leukocyte count of more than 4.2×10³/μl or more than
80% neutrophils suggests an infected hip arthroplasty; these cutoffs are sig-
nificantly lower than those used to diagnose native infectious arthritis. Synovial
fluid cultures have a sensitivity of 56% to 75% and a specificity of 95% to 100%
when directly inoculated into a blood-culture bottle.2,3
A variety of radiologic and nuclear medicine studies are available to assess
the extent of osseous and soft tissue involvement, but in many cases do not
CHAPTER 12

reliably distinguish between infectious and noninfectious etiologies. Computed

tomography (CT) and magnetic resonance imaging (MRI) are the most com-
monly used imaging modalities. The nuclear medicine study considered to be
the modality of choice with the highest specificity (98%) is labeled-leukocyte
imaging (e.g., leukocytes labeled with indium-111) combined with bone marrow
imaging (using technetium-99m–labeled sulfur colloid).1
Treatment of prosthetic joint infections is not standardized, because of the
variable clinical presentations and the lack of data from randomized, controlled
trials. Initial treatment success is often followed by relapse once antibiotics are
discontinued—in part, due to biofilms sequestering the causative microorgan-
ism. Most patients with prosthetic joint infections ultimately require prosthesis
removal for successful eradication of the infection. This can be accomplished in
a one-stage procedure that involves removal of the infected prosthesis, debri-
300

dement of the underlying bone, and placement of a new prosthesis during the
same operation. Due to the risk of recurrent infection, such an approach may
only be suitable in highly selected patients who have satisfactory soft tissue, no
severe coexisting illnesses, and infection with organisms that are highly suscep-
tible to antimicrobial medications.2,3
Two-stage arthroplasty appears to be the treatment modality with the high-
est success rate in patients who can tolerate prolonged periods of immobility.
This procedure involves removal of the infected prosthesis, and debridement
and culture of the underlying bone and periprosthetic tissues. A spacer impreg-
nated with one or more antimicrobial agents may be used to maintain the leg
at its correct length, and aid in controlling the infection. Intravenous antibiot-
ics with activity against the infecting organisms are administered for at least
6 weeks. Reimplantation of a new prosthesis is usually undertaken following the
6-week course of antimicrobial therapy.1
The duration of antimicrobial therapy following implantation of a new pros-
thesis (either in the setting of a 1-staged or 2-staged approach) is not well
defined, but a minimum of 4 to 6 weeks of antimicrobial therapy with proven
efficacy against the isolated pathogen is considered to be the accepted standard
of care. In patients undergoing debridement with retention of the prosthe-
sis, 3-month courses of treatment for infection associated with hip prostheses,
and 6-month courses for infection associated with knee prostheses, are often
used. Oral therapy can be used if the agent has good oral bioavailability (e.g.,
quinolones, trimethoprim–sulfamethoxazole, and tetracyclines). Arthrodesis
and amputation are measures of last resort, and long-term suppressive therapy
alone is sometimes necessary in patients who are elderly, have contraindica-

Bone and Joint Infections

tions to general anesthesia, or refuse to allow removal or debridement of an
infected prosthesis.2,3 IDSA guidelines addressing the issue of prosthetic joint
infections are currently in progress, and expected to be published in the winter
of 2011.

References
1. Lentino JR. Prosthetic joint infections: bane of orthopedists, challenge for infec-
tious disease specialists. Clin Infect Dis. 2003;36:1157–1161.

CHAPTER 12
2. Zimmerli W, Trampuz A, Ochsner PE. Prosthetic-joint infections. N Engl J Med.
2004;351:1645–1654.
3. Del Pozo JL, Patel R. Clinical practice. Infection associated with prosthetic joints.
N Engl J Med. 2009;361:787–794.

Case
C a e 12d:
12d
2d: A 68
68-Year-Old
-Year-
Y -Ol Old
dW Woman
oman with
ith
h Fever
F r and
and
d
Multiple
Mult
Mu i le Inflamed
ltip d Jo
Jointss

Jennifer Jao
Case Presentation

301
A 68-year-old woman from Puerto Rico presented with several days of shaking
chills, weakness, watery diarrhea, arthralgias, and malaise. The pain had been
in prominent in the joints of her fingers, and was accompanied by warmth,
redness, and swelling on the day prior to admission. Her past medical history
included insulin-requiring diabetes mellitus, hypertension, and hypercholester-
olemia. The patient was a smoker, but denied any intravenous drug use, travel,
recent antibiotic use, or sexual activity.
On physical examination, she was ill-appearing with a fever to 38.1º Celsius,
hypotensive (blood pressure 98/50), and tachycardic (heart rate 114 beats per
minute). Examination of her joints revealed erythema, warmth, edema, and
tenderness over her left hand 2nd and 3rd metacarpophalangeal (MCP) joints
and right hand 2nd MCP joints (Figure 12d.1). Full flexion and extension were
impaired in all MCP joints, and there was left wrist pain on active and passive
movement. The remainder of her physical examination was unremarkable.
Her laboratory analyses were notable for leukocytosis 24.5x10³ WBC/μl,
thrombocytopenia (80x10³ platelets/μl), and elevated erythrocyte sedimenta-
tion rate (87mm/hour) and C-reactive protein (186 mg/l). Blood cultures were
positive for Neisseria meningitidis (Figure 12d.2), serogroup Y, and arthrocen-
tesis of the MCP joints was attempted but unsuccessful. She was treated with
14 days of intravenous ceftriaxone followed by oral penicillin for 14 more days.
Case 12d Discussion: Neisseria meningitidis
Neisseria meningitidis is a Gram-negative aerobic diplococcus, first recovered
in meningeal exudate 1887 by Anton Weichselbaum. The serogroups that
Bone and Joint Infections
CHAPTER 12

Figure 12d.1 Erythema, warmth, edema, and tenderness over the left hand 2nd and 3rd
metacarpophalangeal (MCP) joints and right hand 2nd MCP joints.
302

Figure 12d.2 Blood cultures Gram stain with Gram-negative diplococci later identified
as Neisseria meningitidis.

cause the majority of disease are A B, C, Y, and W-135. These serogroups are
based on antigenic variation of the polysaccharide capsule, and vary worldwide
depending on geographic region. In North America, serogroups B, C, and Y are
most common, whereas in Africa, particularly in the “meningitis belt,” sero-
groups A, W-135, C, and X predominate.1
Neisseria grows best on chocolate agar, and exhibits a host of virulence fac-
tors, including its adherence to the microvillus surface of nonciliated columnar
mucosal cells of the nasopharynx, its antiphagocytic polysaccharide capsule,
and its endotoxin release. Major risk factors for infection include asplenia, defi-

Bone and Joint Infections

ciency of terminal complement components, household contacts, black race,
low socioeconomic status, active or passive exposure to tobacco smoke, and
crowded living situations. Several syndromes associated with meningococcal
disease have been reported in the literature: meningitis, bacteremia, menin-
gococcemia (fever, purpura fulminans, hypotension, Waterhouse-Friderichsen
syndrome), pneumonia, epiglottitis, conjunctivitis, urethritis, septic arthritis,
pericarditis, and chronic meningococcemia.1
The clinical syndrome in this particular patient was one of a native joint infec-

CHAPTER 12
tion. In general, these infections are a result of occult bacteremia, but may also
be caused by trauma. Gram-positive organisms are by far the most common
cause, with Staphylococcus aureus being the pathogen in almost half of all native
joint infections.2 This is followed by Streptococcus pyogenes and Streptococcus
pneumoniae. Gram-negative etiologies include H. influenza, E. coli, Salmonella,
N. gonorrhea and N. meningitidis. In young adults, gonococcal arthritis is a lead-
ing cause of septic arthritis behind S. aureus.
Native joint infections commonly involve the knee joints. The classic clinical
presentation of fever, leukocytosis, and joint pain may not always be present,
particularly in immunocompromised patients. Diagnosis is often elusive, since
Gram staining of synovial fluid is only positive in 71% of Gram-positive organ-
isms3 and 40% of Gram-negative organisms. Blood cultures may be helpful, as
up to one-third of patients may have positive blood cultures. WBC counts in

303
synovial fluid may be >50,000 cells/mm,³ though counts as high as these may
also be found in cases of gout and pseudogout. Many cases of septic arthri-
tis have negative synovial fluid cultures, particularly in the case of gonococcal
arthritis.
Our patient had a presumed case of meningococcal arthritis. Though rare,
arthritis in meningococcal infection has been described as early as 1898 by
Osler, when he reported it as “the arthritis of cerebrospinal fever” in a patient
with arthritis and meningococcal meningitis. While our patient did not have
meningococcal meningitis, she did present with arthritis in the setting of menin-
gococcal bacteremia and disease. Typically, arthritis in meningococcal infection
affects the knee joints more than the smaller hand and wrist joints. There is
variation in the time of onset of arthritis from an acute presentation to up to
one month after therapy.4,5
Three clinical types of arthritis have been described in meningococcal disease:
arthritis as a complication of meningococcal disease, primary meningococcal
arthritis, and arthritis as a complication of chronic meningococcemia. In the first
syndrome, the knees and elbows are the most commonly affected, and synovial
fluid is positive in only 15%–20% of patients. In contrast, primary meningococ-
cal arthritis presents as an acute pyogenic arthritis with positive synovial fluid
cultures and no signs of meningitis or meningococcemia. The peak incidence of
this disease is in infancy, and there is a male predominance. Response to antibi-
otics alone is slow, and usually requires surgical drainage. The third syndrome,
which is associated with chronic meningococcemia, presents more often as
arthralgia than arthritis. There may be intermittent fevers for over a week, and
 a migratory rash without systemic toxicity. The pathogenesis is thought to be
Bone and Joint Infections

secondary to immune complex deposition.5,6

Neisseria meningitidis is exquisitely susceptible to beta-lactam antibiotics.
Ceftriaxone 2g IV every 12 hours, or cefotaxime 2g IV every 4–6 hours, is the
recommended first-line therapy for meningitis due to the organism. Alternative
therapies include penicillin G, 4 million units IV every 4 hours.6,7 Primary menin-
gococcal arthritis should be treated with intravenous antibiotics, as well as sur-
gical drainage; however, arthritis as a complication of meningococcal disease
may not require surgical intervention in addition to antibiotic therapy. Because
CHAPTER 12

arthritis as a complication of chronic meningococcemia is thought to be due

to an immune complex deposition, the role for long-term antibiotics remains
unclear.5

References
1. Stephens, DS. “Conquering the meningococcus.” FEMS Microbiol Rev. 2007
Jan;31(1):3–14.
2. Ross, J. Septic arthritis. Infectious Disease Clinics of North America. 2005;
19:799–817.
3. Goldenberg DL, Cohen AS. Acute infectious arthritis. American Journal of
Medicine. 1976;60:369–377.
4. Herrick, W & Parkhurst, G. Meningococcal arthritis. American Journal of the
304

Medical Sciences. 1919;158:473–481.

5. Pinals RS, Ropes MW. Menigococcal arthritis. Arthritis and Rheumatism.
1964;7:241–258.
6. Rosenstein NE, Perkins BA, Stephens DS, Popovic T, Hughes JM. Meningococcal
disease. New England Journal of Medicine. 2001;344:1378–1388.
7. Schaad UB. Arthritis in disease due to Neisseria menigitis. Reviews of Infectious
Diseases. 1980;2:880–887.
 Chapter 13

Vector-Borne Infections

Case
C a e 13a:
13a:
3a A V
Veterinarian
etterina
i aririan
i with
wiith
ith Multiple
Mult
ltiiple
le Skin
SSki
kinn Ul
Ulcers
aafter
af terr Travel to Co
te ost
staa Rica
Costa c

Daniel Caplivski and Robert Phelps

Case Presentation
A 32-year-old man returned from a 14-day vacation to Costa Rica with several

305
ulcerative skin lesions on his left wrist, right and left flanks, and left leg. He also
noted palpable nodules on his left arm proximal to the left wrist lesions. Besides
the ulcers on his wrist (which began as papules), he also noted three ulcers on
his flanks, as well as two on his lower legs. He did not recall any trauma to the
areas, and initially thought the lesions were due to insect bites.
He had no prior medical history and had not traveled to destinations other
than Costa Rica, and his work as a veterinarian mainly exposed him to dogs
and cats. His itinerary included visits to the Arenal volcano region, as well as
overnight stays in the Pacuare jungle lodges where he participated in outdoor
activities including river rafting and ziplining. He had intermittently used insect
repellant, and did not sleep under bed nets. He denied any systemic symptoms
and was afebrile at the time of presentation to our travel medicine practice,
6 weeks after his initial skin lesions appeared. On physical examination, he had
three coalesced ulcers on his wrist (Figure 13a.1), two lesions on his left flank
(Figure 13a.2), one on the right flank, and two on the lower left leg. He also
was noted to have a nodular subcutaneous lesion beneath the left bicep muscle,
suggestive of lymphangitic spread from the wrist site.
Skin scrapings of the base of the lesion and biopsy revealed the presence of
intracellular and extracellular Leishmania amastigotes with typical kinetoplast
structures visible adjacent to the protozoan’s nucleus (Figure 13a.3). Cultures
of the biopsy performed at the Centers for Disease Control subsequently were
positive, and PCR testing confirmed that the species was L. v. panamensis. Prior
to the confirmation of the culture results, the patient began therapy with oral
miltefosine 50 mg orally, twice daily. The medication was obtained under a single-
patient investigational new drug (IND) protocol under the supervision of the Food
and Drug Administration, and imported from the manufacturer in Germany.
Vector-Borne Infections
CHAPTER 13

Figure 13a.1 Cutaneous ulcers on the left wrist with raised erythematous borders.
Proximal to the lesions, several subcutaneous lymph nodes were palpable.
306

Figure 13a.2 Cutaneous ulcer on the left flank.

During the treatment regimen, the patient experienced mild nausea on two
occasions when he did not take the medication with food, but otherwise was
able to complete the 28 days of therapy without adverse events. Several weeks
later, the patient’s lesions showed excellent healing and he experienced no
further recurrences (Figures 13a.4 and 13a.5).
 Vector-Borne Infections
CHAPTER 13
Figure 13a.3 Giemsa stained skin scrapings of the base of the lesion showing intracel-
lular and extracellular Leishmania amastigotes with typical kinetoplast structures visible
adjacent to the protozoan’s nucleus.

307

Figure 13a.4 Wrist lesions several weeks after completion of treatment.

Case 13a Discussion: Leishmaniasis

Clinical Features and Diagnosis
Leishmaniasis is caused by the protozoan parasite Leishmania, and may present
with a variety of clinical symptoms depending on the infecting species and the
immune status of the host. The organism is transmitted to humans via the bite
of a tiny insect vector known as the sandfly, and can cause disease in animal
reservoirs such as dogs, foxes, and rodents in endemic areas. Leishmania is
transmitted in a flagellated promastigote form, and is phagocytosed into tissue
macrophages where it transforms into the amastigote form. The parasite is able
Vector-Borne Infections
CHAPTER 13

Figure 13a.5 Wrist lesions four years after treatment showing complete resolution.

to survive and replicate within immune cells, and lyses the cells as it multiplies.
As the organism replicates in the tissue macrophages of the skin, the inflamma-
tory response leads to a nodular lesion that erodes to become a painless ulcer.
308

There is often a raised erythematous border surrounding the central ulcer-

ation, and proximal lymphadenopathy may be a sign of lymphangitic spread.1
This presentation of the illness has clinical overlap with other infections, such as
sporotrichosis and Mycobacterium marinum infections.
Certain species of the Leishmania genus cause cutaneous disease alone, and
approximately one-third of patients with this form of the infection have ulcers
that heal over time without treatment. In parts of Central and South America,
other species can spread to the mucosal tissues of the oropharynx and nose,
and lead to a highly disfiguring form of the disease called mucocutaneous leish-
maniasis. Visceral leishmaniasis is caused by species found in South America,
Africa, Southern Europe, and India. This potentially fatal form manifests with
fevers, weight loss, hepatosplenomegaly, pancytopenia, and hypergammaglobu-
linemia. Its tendency to cause a darkening of the skin led to the designation,
Kala-Azar, a Hindi term meaning “black sickness.”1
Leishmaniasis is widely distributed throughout the tropics, Middle East,
South Asia, and Southern Europe. An estimated 12 million individuals suffer
from the disease, and an estimated 2 million new cases of Leishmaniasis occur
each year, with an annual estimated mortality of 70,000.1 Leishmaniasis has prin-
cipally been a disease of impoverished nations in the tropics; however, reactiva-
tion illness in patients with AIDS has emerged as an important opportunistic
infection in patients in southern Europe.1
The diagnosis of cutaneous leishmaniasis can be established by visualization
of the intracellular or extracellular amastigotes on smears taken from super-
ficial scrapings or punch biopsies of the ulcer. The kinetoplast is the intracy-
toplasmic body adjacent to the nucleus that distinguishes the amastigotes of
Leishmania from the yeast cells of Histoplasma capsulatum. The organism can

Vector-Borne Infections
also be cultured from the scrapings or biopsied material when incubated on
Novy-MacNeal-Nicolle (NNN) media. The use of polymerase chain reaction
directly on tissue specimens has proven useful in many cases, and is performed
in laboratories at the Centers for Disease Control and Prevention, and at the
Walter Reed Army Institute of Research.2 Serologic assays may have some clini-
cal utility in travelers, but are often falsely negative, especially in cutaneous dis-
ease. Given the protean manifestations of the Leishmania genus, confirmation
of the species can be especially important in decisions regarding treatment.

CHAPTER 13
Management
Standard systemic therapy for leishmaniasis in most parts of the world includes
the intravenous infusion of the heavy metal, pentavalent antimony. The dura-
tion of treatment with this intravenous medication varies from 20–28 days,
and the toxicities include muscle and joint aches, electrolyte abnormalities, and
potential cardiotoxicity. In the United States, it is available only through the
Centers for Disease Control and Prevention’s antiparasitic medication branch.
Amphotericin deoxycholate and lipid preparations of amphotericin have dem-
onstrated efficacy in treating both mucocutaneous and visceral forms of leish-
maniasis.3 Single-dose liposomal amphotericin therapy has been effective in
treating visceral leishmaniasis in the Bihar state of India, where resistance to
antimonial medications remains an important problem.4 The use of lipid prepa-

309
rations of amphotericin for cutaneous leishmaniasis have been extrapolated
from studies in visceral leishmaniasis, and 5–6 doses of 5mg/kg of liposomal
amphotericin B have yielded satisfactory results.1
New World cutaneous leishmaniasis has been an emerging infection among
travelers, as travel to endemic regions has increased. Systemic treatment for
cutaneous leishmaniasis is currently recommended for patients whose infec-
tions may be caused by species with the potential to cause mucocutaneous dis-
ease in the future. Because of the potential toxicities of the currently available
parenteral therapies, oral agents such as miltefosine have generated increased
interest. Miltefosine was originally developed as a chemotherapeutic agent,
but it was discovered to have antiprotozoal activity by inhibiting phospholipid
and sterol biosynthesis.5 Its low toxicity profile and oral formulation make it
an excellent agent to treat many forms of leishmaniasis. Studies of miltefosine
for New World cutaneous leishmaniasis use indicate that it is more effective
against the L. v. panamensis complex than against the L. v. braziliensis and L. m.
mexicana subspecies.5,6 Miltefosine is currently not routinely available in the
United States except when imported via an investigational new drug protocol
under the supervision of the Food and Drug Administration.
Prevention of leishmaniasis in travelers is mainly achieved through the use of
insect precautions with N,N-Diethyl-meta-toluamide (DEET)-based skin repel-
lents and premethrin-based clothing treatments. The usefulness of many bed
nets is limited by the small size of the sandfly, although insecticide-treated nets
can offer some protection against leishmaniasis in areas where the sandflies
are predominantly nocturnal feeders. As leishmaniasis is also a zoonotic illness
that can affect dogs and other small mammals, control of the disease in animal
 reservoirs is another potential intervention to reduce human disease. Dog col-
Vector-Borne Infections

lars treated with deltamethrin have been demonstrated to reduce the rate of
canine disease, as well as human disease in children in areas in which the collars
were used. Efforts to develop an effective vaccine against Leishmania have been
hampered by the organism’s species diversity, and mechanisms for intracellular
survival and immune evasion.1 Killed Leishmania vaccine combined with Bacillus
Calmette-Guérin has had some limited efficacy in South American studies, but
investigation is also ongoing in the development of live attenuated vaccines as
well as novel antigenic targets.1
CHAPTER 13

References
1. Murray HW, Berman JD, Davies CR, Saravia NG. Advances in leishmaniasis.
Lancet. 2005;366(9496):1561–1577.
2. Wortmann G, Hochberg L, Houng HH, et al. Rapid identification of
Leishmania complexes by a real-time PCR assay. Am J Trop Med Hyg. 2005
Dec;73(6):999–1004.
3. Tuon FF, Amato VS, Graf ME, Siqueira AM, Nicodemo AC, Amato Neto V.
Treatment of New World cutaneous leishmaniasis--a systematic review with a
meta-analysis. Int J Dermatol. 2008 Feb;47(2):109–124.
4. Sundar S, Chakravarty J, Agarwal D, Rai M, Murray HW. Single-dose lipo-
somal amphotericin B for visceral leishmaniasis in India. N Engl J Med. 2010 Feb
310

11;362(6):504–512.
5. Soto J, Toledo J, Gutierrez P, et al. Treatment of American cutaneous leishmania-
sis with miltefosine, an oral agent. Clin Infect Dis. 2001 Oct 1;33(7):E57–E61.
6. Soto J, Toledo J, Valda L, et al. Treatment of Bolivian mucosal leishmaniasis with
miltefosine. Clin Infect Dis. 2007 Feb 1;44(3):350–356.

Ca e 113b:
Case 3b: FFever
3b ever iin
n a Returned
Returned
t dTTraveler
raveller

Sean Pawlowski and W. Michael Scheld

Case Presentation
A 30-year-old man from India presented to the emergency department with a
2-day history of fever, shaking chills, mid-epigastric discomfort, and diarrhea.
The patient had lived between India and the United States over the past 2 years,
and his last 6-month stay in India ended 6 weeks prior to admission. While in
India, he presented to a local doctor due to fever and abdominal pain, and was
treated empirically for both malaria and typhoid fever with unknown medica-
tions. He took these medications for 45 days—until within a few weeks of his
departure to the United States.
On physical examination he was febrile (102° Fahrenheit), hypotensive
(85/47), tachycardic (110 bpm,) and tachypneic (22 bpm). He appeared uncom-
fortable, and had abdominal tenderness in the epigastrium and right upper
quadrant without hepatosplenomegaly. Laboratory analyses were significant
for hyperbilirubinemia (total bilirubin 3.2, conjugated bilirubin 1.8) and slightly
elevated liver enzymes (ALT 58 U/L, AST 50 U/L). His electrolytes, creatinine,

Vector-Borne Infections
and complete blood count were normal. Peripheral blood smear revealed ring
and gametocyte forms, within slightly enlarged infected red blood cells, con-
sistent with Plasmodium vivax infection (Figures 13b.1 and 13b.2). The patient’s
parasitemia was low (0.3%) and he was treated with chloroquine for 3 days. He
was subsequently treated with 14 days of primaquine after G6PD testing was
found to be normal.

311 CHAPTER 13
Figure 13b.1 Peripheral blood smear, Wright-Giemsa stain revealing an intraerythro-
cytic ring form.

Figure 13b.2 Peripheral blood smear, Wright-Giemsa stain showing circulating

gametocyte of Plasmodium vivax.
 Case 13b Discussion: Plasmodium vivax Malaria
Vector-Borne Infections

Plasmodium vivax is the most widespread of the four main Plasmodium spe-
cies (P. falciparum, P. vivax, P. malariae and P. ovale) that infect humans, and
occurs throughout most of the temperate zones and parts of the tropics. Non-
falciparum malaria, predominantly P. vivax, accounts for 25%–40% of the global
malaria burden, with between 132 and 391 million cases per year, though this
may be an underestimation.1 Of the total P. vivax cases reported outside Africa,
a60% occur in Southeast Asia and the Western Pacific. Within the South and
Southeast Asian region, India contributes a80% of the total cases.2 P. vivax
CHAPTER 13

malaria (present in 1%–6% of the population in South and Southeast Asia)

makes up the majority of cases in India.2,3 For travelers, P.falciparum is more
prevalent due to its overall greater transmission rate; only 15% of malaria cases
in returning travelers are due to P. vivax.4
Clinical Presentation and Diagnosis
Because it is rarely fatal, P.vivax does not receive the same attention as
P.falciparum; however, P. vivax malaria is a morbid disease in endemic regions,
and because it can remit and recur in up to 20%–80% of cases, it can lead to
significant financial hardships due to work loss.1 In most areas, the burden of
disease is greatest in young children and infants, with immunity usually develop-
ing by 10 to 15 years of age. Differences in parasite virulence, host susceptibility,
age of exposure, as well as parasite factors such as antimalarial drug resistance,
312

may play a crucial role in the clinical presentation.1

Most often, patients present with fever, but it is rarely the classic tertian fever
(every 48 hours) caused by synchronous schizont rupture. High fever and rigors
are more common with P. vivax than with P. falciparum malaria, though P. vivax is
capable of inducing fever at lower levels of parasitemia than P. falciparum, possi-
bly secondary to greater induction of proinflammatory cytokines such as TNF-D.
Pregnant women with P. vivax malaria may give birth to children with lower birth
weight. Patients may present with severe anemia, respiratory distress, and coma,
though P. vivax is rarely fatal and usually only causes death due to splenic rupture
(Figure 13b.3). Cerebral edema, renal failure, and placental malaria, as seen in

Figure 13b.3 CT scan abdomen, axial view showing spontaneous splenic rupture in a
patient with Plasmodium ovale malaria.
P. falciparum infection, do not occur in P. vivax infections, due to low levels of

Vector-Borne Infections
parasite cytoadherence in the postcapillary venules in the latter species.
Diagnosis
Thick and thin peripheral blood smear microscopy is the gold standard for
malaria diagnosis and calculation of percent parasitemia. In cases of severe
malaria (e.g., P. falciparum), follow-up smears are recommended to evaluate for
decreases in parasitemia with treatment. While the BiNaxNow rapid diagnostic
test is approved by the FDA for hospital and commercial laboratories, it cannot

CHAPTER 13
determine the Plasmodium species, and at low levels of parasitemia, it may lead
to false negative results.
Together with Plasmodium ovale, Plasmodium vivax is one of the relapsing
forms of malaria: hypnozoites within the liver may reactivate months or even
years after a patient has been treated for the erythrocytic forms. Both species
tend to infect reticulocytes whose cytoskeletons are poorly developed and,
therefore, infected cells will often appear enlarged on the peripheral blood
smear. P. falciparum infects red cells of any age, and thus leads to higher levels
of parasitemia. P. falciparum is also typified by multiply infected cells, appliqué
forms, and “banana-shaped” gametocytes (Figures 13b.4 and 13b.5). While it is
possible to find schizonts of P. vivax and P. ovale on the peripheral blood smear,
those of P. falciparum are usually attached to the endovascular tissue of small
capillaries, and are rarely seen on the peripheral blood smear. P. malariae and

313
P. knowelsi are similar in appearance on peripheral blood smear, and are charac-
terized by the presence of band forms.5
Treatment
Chloroquine is the mainstay of treatment for acute P. vivax malaria, and is usu-
ally given in 3–4 doses over the course of 2–3 days (600 mg base orally immedi-
ately, followed by 300 mg base PO at 6, 24, and 48 hours). Hydroxychloroquine
is an alternative regimen (620 mg base PO immediately, followed by 310 mg

Figure 13b.4 Peripheral blood smear, Wright-Giemsa stain of a patient with

Plasmodium falciparum malaria.
Vector-Borne Infections
CHAPTER 13

Figure 13b.5 Peripheral blood smear, Wright-Giemsa stain showing the banana-shaped
gametocytes of Plasmodium falciparum.

base PO at 6, 24, and 48 hours). Plasma concentrations of chloroquine are

sustained above the minimum inhibition concentration for at least 28 days, and
thus are capable of suppressing the first relapse, which in tropical zones gen-
314

erally occurs at approximately 21 days. In chloroquine-resistant areas (Papua

New Guinea and Indonesia), quinine sulfate in combination with doxycycline or
tetracycline, or mefloquine or atovaquone-proguanil can be used.6
The previously mentioned antimalarials are active against erythrocytic forms,
but have no activity against the dormant liver hypnozoites. In order to pre-
vent further relapses, primaquine is used eliminate the hypnozoite forms. The
standard recommendation has been 30 mg of primaquine daily over 14 days.
Primaquine resistance is now reported in Papua New Guinea and Indonesia,
and higher doses or longer courses have been advocated for patients returning
from these areas.1 Patients should be evaluated for G6PD deficiency prior to
prescribing primaquine, since it may induce hemolytic anemia in these patients.
Prevalence of the deficiency correlates with the geographic distribution of
malaria, which has led to the theory that carriers of G6PD deficiency may have
partial protection against malarial infection.7 If G6PD deficiency is present,
lower doses of primaquine are used and close monitoring for hemolytic anemia
is recommended.

References
1. Price RN, Tjitra E, Guerra CA, Yeung S, White NJ, Anstey NM Vivax malaria:
neglected and not benign. Am J Trop Med Hyg. 2007 Dec;77(6 Suppl):79–87.
2. Joshi H, Prajapati SK, Verma A, Kang’a S, Carlton JM. Plasmodium vivax in India.
Trends Parasitol. 2008 May;24(5):228–235.
3. Kumar A, Valecha N, Jain T, Dash AP. Burden of malaria in India: retrospective
and prospective view. Am J Trop Med Hyg. 2007 Dec;77(6 Suppl):69–78.
4. Galinski MR, Barnwell JW. Plasmodium vivax: who cares? Malar J. 2008 Dec 11;7

Vector-Borne Infections
Suppl 1:S9
5. Centers for Disease Control. DPDx: Laboratory identification of parasites of
public health concern. Available at: http://www.dpd.cdc.gov/dpdx/HTML/Malaria.
htm
6. Centers for Disease Control. Treatment of malaria, guidelines for clinicians.
Available at: http://www.cdc.gov/malaria/diagnosis_treatment/tx_clinicians.htm
7. Chitnis CE, Sharma A. Targeting the Plasmodium vivax Duffy-binding protein.
Trends Parasitol. 2008 Jan;24(1):29–34.

CHAPTER 13
Case
C a e 113c:
3c A 51
3c: 51-Year-Old
-Year-
Y -OlOld
dWWoman
oman with
ith
h FFever
Fever,
r, R
Rash,
ash,
h
and
an d aan
n Eschar

Luciano Kapelusznik
Case Presentation
A 51-year-old woman presented with 5 days of rash and fever. A day before
her symptoms started, she noticed a small papule on her left calf that quickly
became a blister, and then spontaneously opened and became black and
adherent. By the next day, she developed papulovesicular rash on her face

315
that spread over the next 2 days to her trunk and extremities. Her rash was
not pruritic, but the lesion on her leg was mildly painful. She also developed
fatigue, fevers (103°F), and chills that worsened over the course of the next few
days. Her past medical history included poorly controlled type 2 diabetes mel-
litus and hypertension, for which she was taking insulin, metformin, atenolol,
fosinopril, and aspirin. She immigrated to the United States from Colombia
20 years before presentation, and had always lived in the neighborhood of
Jackson Heights, borough of Queens, in New York City.
She was employed as a commercial cleaner, working in different buildings
across the city, where she occasionally saw mice. On physical examination, she
was in no acute distress, and her vital signs were remarkable for elevated blood
pressure (158/94 mm Hg) and low-grade fever (100.1°F). Several small, rub-
bery, mobile, tender lymph nodes were palpable in the submandibular, supra-
clavicular, and left inguinal regions. The diffuse papular rash involved her scalp,
face, trunk, and extremities, but spared her palms and soles (Figures 13c.1 and
13c.2). Some of the lesions had a clear central vesicle, and there was a 5mm
x 5mm tender black eschar on her left calf that had surrounding erythema,
but had no purulence (Figure 13c.3). The rest of her physical examination was
unremarkable.
Other than mild leukopenia (4.8 x103 WBC/ul), laboratory studies and a
chest radiograph were unrevealing, and she was treated with doxycycline
100 mg twice a day with resolution of the fevers within 24 hours and quick
resolution of the rash. Acute serology for Rickettsia ricketsii, Rickettsia typhi and
Rickettsia akari were all negative, but convalescent Rickettsia akari antibodies
8 weeks later were positive.1 (p. 256)
Vector-Borne Infections
316 CHAPTER 13

Figure 13c.1 and 13c.2 Diffuse papular rash involving scalp, face, trunk and
extremities.

Case 13c Discussion: Rickettsialpox

Clinical Features and Diagnosis
Rickettsialpox is a zoonotic illness caused by the obligate intracellular Gram-
negative coccobacillary bacteria, Rickettsia akari. It was identified in Kew Gardens,
borough of Queens, New York City, in 1946 by Dr. Benjamin Shankman, and
initially named “Shankman’s disease.” It was later renamed “Kew Gardens spot-
ted fever,” only to have its name changed again later to rickettsialpox. The
infection is transmitted to humans via a mite vector (Lyponyssoides sanguineus;
Figure 13c.4), which feeds on the asymptomatic reservoir host, the common
house mouse (Mus musculus). While most cases of rickettsialpox have been
reported from the East Coast of the United States (New York, Connecticut,
Maryland, Massachusetts, Ohio, Pennsylvania and North Carolina), there have
 Vector-Borne Infections
CHAPTER 13
Figure 13c.3 Black eschar on the left with surrounding erythema.

317

Figure 13c.4 The mite vector of Rickettsialpox, Lyponyssoides sanguineus. Adapted

from Saini R, Pui JC, Burgin S. J Am Acad Dermatol. 2004 Nov;51(5 Suppl):S137–42.
 been cases described in Arizona and Utah, as well as Mexico, Turkey, South
Vector-Borne Infections

Africa, Croatia, Ukraine and Korea.2

Rickettsialpox begins with a bite of an infected mite, which forms a black
eschar at the site of inoculation. Three to seven days after the appearance of
the primary lesion, infected patients may develop fever and a papulovesicular
rash that spares palms and soles. Headache (reported in 90%–95% of the cases)
is a very common symptom, and other symptoms such as myalgias, arthralgias,
back pain, sore throat, and gastrointestinal complaints are present in 30% of
the cases. The rash is present in approximately 22% of the cases, and regional
CHAPTER 13

lymphadenopathy at the draining site of the eschar has been reported in 17% of
the cases. Generalized lymphadenopathy, which was commonly reported with
the first case descriptions of the disease, was found to be uncommon in a more
recent case series.1 The number of papulovesicular lesions is highly variable,
having been described from 5 or 6 to as much as a 100; on average, patients
develop between 20 and 40 lesions.2
Laboratory findings are usually nonspecific. About a third of the patients
develop a mild leukopenia with lymphocytic predominance, and cases of acute
hepatitis caused by rickettsialpox have been reported.3 Because of the delay
of the available methods in providing a rapid diagnostic confirmation, the
diagnosis of rickettsialpox often relies on the clinical triad of eschar, rash, and
fever. Since a myriad of conditions can mimic this disease, it is important to
initiate a proper diagnostic evaluation as soon as rickettsialpox is suspected—
318

usually, with paired serum samples for antibody testing. Acute phase antibod-
ies to R. akari by indirect immunofluorescence (IFA) are positive <20% of the
time in confirmed cases.2 An elevated IgM to R. akari is typically indicative of
acute infection, but an elevated IgG may be due to current or past infection.4
Convalescent antibodies are obtained 3–4 weeks after the acute sample (6–8
weeks if the patient was treated with doxycycline) and, if increased fourfold
from baseline, are diagnostic of rickettsialpox infection.
Patients with R. akari infection often have antibodies that cross-react with
other spotted fever group antibodies; their antibodies to R. rickettsii may be
positive, although typically at a lower titer. Immunohistochemical staining (IHC)
of paraffin-embedded skin biopsy specimens is a highly sensitive technique for
confirming the diagnosis. In a study that included 18 patients with laborato-
ry-confirmed rickettsialpox, 16/16 (100%) patients who had an eschar biopsy
and 5/9 (55%) who had a papulovesicular lesion biopsy had a positive result.1
R. akari has also been successfully cultured from fresh eschar biopsies of 5/7
(71%) patients with IHC-confirmed rickettsialpox.5 While R. rickettsii antibodies
can be obtained in commercial laboratories, R. akari IFA and IHC can only be
obtained through the Centers for Disease Control and Prevention (CDC) in
the United States. R. akari culture remains investigational only.
The differential diagnosis of rickettsialpox includes chickenpox, herpes sim-
plex, and brown recluse spider bite, among others. Cutaneous anthrax should
always be considered when evaluating a patient with a fever and an eschar. The
eschar from anthrax, however, tends to be painless and associated with more
edema.1 In patients with the appropriate geographic background, other spotted
fever group rickettsial infections need to be considered. Patients with Rocky
 Vector-Borne Infections
CHAPTER 13
Figure 13c.5 Tache noire in a patient with African tick-bite fever.

Mountain spotted fever tend to be more acutely ill, do not present with an
eschar, and have a rash that involves the palms and soles.
Returned travelers from southern Africa may present with a similar illness,

319
including a black eschar (“tache noire”) at the site of inoculation of the bacteria
(Figure 13c.5). These organisms infect local endothelial cells in the skin, and the
resulting ischemia causes tissue necrosis. African tick-bite fever is caused by
R. africae, and is transmitted by Amblyomma ticks. Another rickettsial disease,
Mediterranean spotted fever (also known as Boutonneuse fever) is endemic in
the Mediterranean coast of Europe, northern Africa, and South Africa. It pres-
ents with an eschar, fever, and a maculopapular rash that often involves palms
and soles. The causative agent, R. conorii is transmitted by the tick Ripichephalus
sanguineus.2
Treatment
Rickettsialpox is a self-limited disease, and without treatment, it usually resolves
within 7 to 10 days. Relapses and reinfections have not been reported, making
it possible that immunity in humans is complete and lifelong. Doxycycline 100
mg twice daily for 5 to 7 days is highly effective, and the fever and rash typically
resolve within 24 to 48 hours after initiation of treatment. Chloramphenicol has
also proven effective, but it is generally avoided because of potential toxicity.2

References
1. Koss T, Carter EL, Grossman M, et al.. Increased detection of rickettsialpox in a
New York City hospital following the anthrax outbreak of 2001: use of immuno-
histochemistry for the rapid confirmation of cases in an era of bioterrorism. Arch
Dermatol. 2003 Dec;139(12):1545–1552.
2. Walker DH, Dumler JS: Emerging and reemerging rickettsial diseases. N Engl J
Med 331:1651–1652,1994.
 3. Madison G, Kim-Schluger L, Braverman S, Nicholson WL, Wormser GP.
Vector-Borne Infections

Hepatitis in association with rickettsialpox. Vector Borne Zoonotic Dis. 2008

Spring;8(1):111–115.
4. Paddock CD, Zaki SR, Koss T, Singleton J Jr, Sumner JW, Comer JA, Eremeeva
ME, Dasch GA, Cherry B, Childs JE. Rickettsialpox in New York City: a persistent
urban zoonosis. Ann N Y Acad Sci. 2003 Jun;990:36–44.
5. Paddock CD, Koss T, Eremeeva ME, Dasch GA, Zaki SR, Sumner JW. Isolation of
Rickettsia akari from eschars of patients with rickettsialpox. Am J Trop Med Hyg.
2006 Oct;75(4):732–738.
CHAPTER 13

Ca e 13d:
Case 13d
3d: A C
Call
all
ll ffrom
m the
th HHematology
emattollogy
gy LLab
ab
b

Meenakshi Mehrotra Rana

Case Presentation
An 82-year-old man presented to the emergency room with nausea, vomiting,
and diarrhea. He also reported intermittent fevers and chills, along with drench-
ing night sweats that required his daughter to change his bedclothes at night for
the past 2 months. His past medical history was significant for diabetes mellitus
complicated by retinopathy, hypertension, hyperlipidemia, coronary artery dis-
ease, pacemaker placement for heart block, gout, gastritis and hepatitis C. He
320

had been hospitalized at an outside institution 2 months prior to admission for

gastrointestinal bleeding, and had been transfused 3 units of packed red blood
cells. He was originally from Puerto Rico, but lived with his daughter in an
apartment in East Harlem for many years and had not recently traveled.
On physical examination, he was an elderly, thin, blind man who was afebrile
at the time of presentation with a normal heart rate (90 beats per minute) and
blood pressure (120/61 mm/Hg). He had scleral icterus but no hepatosple-
nomegaly, and the remainder of his physical examination was unremarkable.
Laboratory examination was significant for leukocytosis (15 x 10³ WBC/μl,
72% neutrophils), anemia (hemoglobin 7.4 g/dl), thrombocytopenia (120 x 103
platelets/μl) and acute renal insufficiency (creatinine 2.5 mg/dl). He had signs
of hemolysis with elevated total and direct bilirubin (6.9 mg/dl and 4.6 mg/dl,
respectively), LDH (837 U/L), and reticulocyte count (10.4%), and low hapto-
globin (<6 mg/dl).
A technologist from the hematology lab noted parasites on a routine periph-
eral blood smear: intraerythrocytic ring forms were seen along with tetrads of
intracellular merozoites consistent with the diagnosis of babesiosis (Figures 13d.1
and 13d.2). He was treated with atovaquone and a macrolide. Babesia microti
serology confirmed the diagnosis (IgG > 1:256, IgM 1:80; Babesia PCR positive).
Given his lack of travel and exposure to the outdoors, an investigation was con-
ducted regarding the blood donors from whom he had received the transfu-
sions. One of the three donors was found to have positive Babesia serology.
Case 13d Discussion: Babesiosis
Human babesiosis is a tick-borne illness caused by protozoa of the genus
Babesia, which are obligate parasites of red blood cells. Historically, the first
 Vector-Borne Infections
CHAPTER 13
Figure 13d.1 Peripheral blood smear, Wright-Giemsa stain with intraerythrocytic ring
forms of Babesia microti.

321

Figure 13d.2 Peripheral blood smear, Wright-Giemsa stain showing tetrads of intracel-
lular merozoites.

account of babesiosis is theorized to occur in the Old Testament, Exodus 9:3,

which describes a plague visited upon the cattle of Pharaoh Rameses II. Later,
Victor Babes, a Hungarian pathologist, first described the microorganism when
investigating the cause of a febrile hemoglobinuria in cattle. Subsequently, Smith
and Kilbourne found a similar organism that infected Texas cattle, and identified
that the parasite was transmitted by a cattle tick; this was the first observa-
tion that an arthropod could transmit an infectious agent to a vertebrate host.
The first human case of babesiosis was not identified until 1957 when a young
asplenic farmer near Croatia, who had been grazing cattle, died of an illness
 in which he presented with fever, anemia, and hemoglobinuria. Around the
Vector-Borne Infections

same time, residents of Nantucket Island were presenting with a febrile illness
dubbed “Nantucket fever.”1
The epidemiology of human babesiosis has changed over the past 50 years
with an increasing number of cases being diagnosed. While there are over a
100 species of Babesia identified, Babesia microti is the most common cause
of human babesiosis in the United States. Endemic areas initially included
Nantucket Island, Martha’s Vineyard, Cape Cod, Block Island (RI), eastern Long
Island, Shelter Island, and Fire Island. This has now expanded to include large
CHAPTER 13

portions of the mainland that extend from Rhode Island and Connecticut down
to New York and New Jersey. More recently, a new species of Babesia termed
WA-1 or B. duncani has been reported to cause human cases in Washington
State and northern California. In Europe, the majority of cases are due to
B. divergens which can cause a more severe infection, especially in asplenic indi-
viduals. A similar species to B. divergens has also been reported in Missouri and
Wisconsin.2
The life cycle of Babesia is complex and involves asexual budding in erythro-
cytes in the mammalian host, and sexual reproduction in the arthropod vector
(Figure 13d.3). Maintenance of the Babesia species is dependent on the pres-
ence of both these hosts. The life cycle of Babesia microti is the most well-
described. The primary tick vector is Ixodes scapularis, well-known because it
322

Transmitted form
Tick takes human-to-human
a blood meal via blood transfusion
(sporozoites Trophozoite
introduced into host)

Merozoite

= Infective Stage
= Diagnostic Stage
Tick takes
Sporozoites a blood meal
(sportozoites intoruded
into host)

Sporogony
Mouse Trophozoite
Tick

Ookinete enters Tick takes

salivary gland a blood meal
(ingests gametes)
Merozoite

Fertilization
in gut

Gamete

Figure 13d.3 Lifecycle of Babesia microti. Source: Centers for Disease Control and
Prevention http://www.dpd.cdc.gov/dpdx
is also the vector for Borrelia burgdorferi and Anaplasma phagocytophilum, the

Vector-Borne Infections
causative agents of Lyme disease and human granulocytic anaplasmosis. The
primary reservoir in the northeastern United States is the white-footed mouse,
or Peromyscus leucopus. The white-tailed deer also serves as an important host
for maintenance and transport of the ticks, although it is not a primary reservoir
for B. microti. The growth of the deer population over the last few decades may
be a contributing factor for the increase in number of Babesia cases.2
The life cycle of Ixodes scapularis takes over two years to complete, and
involves three stages—larva, nymph, and adult. Adult ticks feed on white-tailed

CHAPTER 13
deer and lay eggs that hatch into larvae in the spring; these larvae then feed on
B. microti infected white-footed mice in the late summer. These infected larvae
then molt into nymphs the following spring, and can feed on naïve mice, main-
taining the reservoir. All three stages of the tick can feed on humans, but it is
most commonly nymphs that serve as the primary vector for humans. Based on
their life cycle, the majority of babesial infections occur in the warmer months.
Because of their small size, nymphal ticks may stay attached for up to 72 hours,
and many individuals may not recall ever seeing a tick bite.1,2
After attachment of a tick, B. microti infected erythrocytes accumulate in
the gut of the insect and fuse to form an ookinete that invades the tick sali-
vary glands. The ookinete transforms into dormant sporoblasts until the next
stage of the tick (nymph or adult) takes a blood meal from a vertebrate host.
The sporoblasts are activated and liberate up to 10,000 sporozoites into the

323
skin of the host, and then invade erythrocytes. Once inside the cytoplasm, the
organism is visible as a ring-shaped trophozoite that reproduces by budding in
two planes. The resultant four merozoites form the tetrad most commonly
described as the “Maltese cross”—pathognomonic for Babesia infection. Lysis
of the red blood cells than occurs followed by release of merozoites and infec-
tion of other red blood cells.1,2
Clinical manifestations of babesiosis may range from asymptomatic infection
to severe, fulminant illness. Incubation time varies but symptoms usually appear
one to six weeks after the initial tick bite. The majority of humans infected
with B. microti will experience a mild flu-like illness, including fevers, chills, mal-
aise, headache, anorexia, and myalgias. Other less common symptoms include
cough, sore throat, dyspnea, nausea, vomiting, and diarrhea; some patients
may even experience emotional lability, mild depression, and hyperesthesia.
Healthy individuals may remain completely asymptomatic from babesial infec-
tion for months or years, and may serve as a source of transfusion-transmitted
babesiosis.2
Findings on physical examination may include fever, splenomegaly, and
hepatomegaly. Rash is unusual, and is usually indicative of concurrent Lyme
disease. Laboratory abnormalities may include hemolytic anemia (Coombs test
may be positive), elevated liver enzymes, and thrombocytopenia. Urinalysis is
usually notable for hemoglobinuria or proteinuria. Parasitemia levels are 1%–20%
in the majority of patients; however, in asplenic patients, parasitemia levels can
be as high as 85%. Severe illness is usually seen in asplenic individuals, elderly
patients, and immunocompromised hosts, including those coinfected with HIV.
 Complications of babesiosis include acute respiratory distress syndrome, dis-
Vector-Borne Infections

seminated intravascular coagulation, and congestive heart failure. Renal failure,

hepatic failure, and myocardial infarction have also been described. In patients
who are hospitalized, mortality may be as high as 5%–9%.1
The diagnosis of babesiosis can be challenging because the symptoms are
often nonspecific. Babesiosis is usually detected on Giemsa or Wright stained
thick and thin peripheral blood smears. Babesia microti may be difficult to dif-
ferentiate from Plasmodium falciparum on peripheral blood smear, as both have
intraerythrocytic ring forms; however, extraerythrocytic forms and the pres-
CHAPTER 13

ence of tetrads of merozoites are distinguishing features of Babesia infections.

Multiple blood smears over the course of several days may need to be exam-
ined in cases of low parasitemia. Confirmatory Babesia PCR is highly sensi-
tive and specific, but the delay in obtaining results limits its clinical usefulness.
Serology using an indirect immunofluorescent antibody (IFA) may also be used
for confirmation. A serum IgG titer of 1:64 is diagnostic, and a titer greater than
1:1024 may indicate active infection. Antibody titers usually return to 1:64 or
less, 8 to 12 months after infection.1,2
Symptomatic individuals with babesiosis should be treated. In individuals
with severe disease, a combination of intravenous clindamycin and oral quinine
should be given for 7 to 10 days. Partial or complete red blood cell exchange
transfusion has been used as an adjunctive therapy in cases of severe disease
with high parasitemia. In individuals with mild to moderate disease, an alterna-
324

tive regimen of atovaquone plus a macrolide may be used for 7–10 days. This
combination was found to be as effective as clindamycin and oral quinine in a
prospective, nonblinded, randomized trial of 58 patients with non-life-threat-
ening babesiosis. There was no significant difference in duration of parasitemia,
but adverse reactions were significantly higher in the group treated with clin-
damycin and quinine.3
As described in the case above, babesiosis can be transmitted through blood
transfusion and recent reports suggest that the number of fatalities from trans-
fusion-transmitted babesiosis is increasing.4 Currently, only individuals with a
history of babesiosis are prohibited from donating blood and PCR screening
of blood for Babesia is not yet FDA-approved. As many individuals remain
asymptomatic with babesiosis for months to years and never recall a tick bite, a
potential blood donor may remain infectious for extended periods. In addition,
Babesia microti can survive refrigerated conditions used for blood storage for
21–35 days.5 Given these factors, physicians should have a high clinical suspicion
for babesiosis when patients present with a febrile illness and hemolytic anemia
after recent blood transfusion.

References
1. Vannier E, Gewurz BE, Krause PJ. Human babesiosis. Infect Dis Clin N Am.
2008;22:469–488
2. Mandell, Bennett and Dolin’s Principles and Practice of Infectious Diseases. Chapter
282: Babesia species. 7th ed. Philadelphia: Elsevier Churchill Livingston; 2009.
3. Krause PJ, Lepore T, Sikand VK, et al. Atovaquone and azithromycin for the treat-

Vector-Borne Infections
ment of babesiosis. New Engl J Med. 2000;34:1454–1458
4. Gubernot DM, Lucey CT, Lee KC, Conley GB, Holness LG and Wise RP. Babesia
infection through blood transfusions: reports received by the US Food and Drug
Administration, 1997–2007. Clin Infect Dis. 2009;48:25–30
5. Leiby DA. Babesiosis and blood transfusion: flying under the radar. Vox Sanguinis.
2006;90:157–165.

CHAPTER 13
Case
C a e 113e:
3e Al
3e: Alt
Altered
tered
d Mental
Menttall St
Status,
Stattus, T
Th
Thrombocytopenia
hromb
bocy
cyttopeni
nia
ia
and
an d LLeukopenia
eukopenia iin
n a Hiker
Hike
k r

Rachel Chasan
Clinical Presentation and History
A 71-year-old woman presented to the emergency room in early July with
weakness and fatigue. She reported that the fatigue had begun two days prior,
and had been associated with nausea, vomiting, and diarrhea. She had also
experienced several episodes of shaking chills and near syncope, and had been
unable to get out of bed for the 24 hours prior to admission. The patient’s
medical history included diabetes, hypertension, and hyperlipidemia managed

325
with nateglinide, valsartan, and simvastatin. In the emergency department, she
noted increased thirst and abdominal pain, but denied fevers, rash, myalgias,
arthralgias, headache, or dysuria. Her daughter reported that she had been
slightly confused in the 24 hours before admission. She was an avid hiker and
member of a hiking club; her last hike had been almost 2 weeks prior on Bear
Mountain in upstate New York. She was originally from China, and 3 months
before her presentation she had been hiking in the mountains of Peru.
On physical examination, the patient was febrile (39.6º Celsius) and tachyp-
neic (24 breaths per minute) though her heart rate (64 beats per minute) and
blood pressure (109/62) were normal. She was lethargic but arousable, and
unable to recall the details of recent events. She had dry mucous membranes
and faint rales in the bases of both lungs, but the remainder of her physical
exam was unremarkable. Laboratory values on admission were notable for leu-
kopenia (2.8 x10³ WBC/μl, 84% neutrophils), thrombocytopenia (19x10³ plate-
lets/μl), and elevated liver enzymes (AST 294 U/L, ALT 114 U/L, LDH 856 U/L).
She was also hyperglycemic (295 mg/dl), but the remainder of her laboratory
studies including hemoglobin (14.9 g/dl), creatinine (0.9), alkaline phosphatase
(64 U/L), and GGT(36 U/L) were normal. Her chest radiograph revealed small
bilateral pleural effusions. Her peripheral blood smear and buffy coat smear
were notable for neutrophils with intracytoplasmic morulae (Figures 13e.1 and
13e.2), and intravenous doxycycline was initiated.
The patient’s mental status worsened on the day after admission; she was
increasingly tachypneic, and was transferred to the intensive care unit. Her leu-
kopenia and thrombocytopenia worsened (1.3 x10³ WBC/μl, 15x10³ platelets/
μl), and markers of liver inflammation and cellular destruction peaked on day
Vector-Borne Infections
CHAPTER 13

Figure 13e.1 Peripheral blood smear, Wright-Giemsa stain showing neutrophils with
intracytoplasmic morulae.
326

Figure 13e.2 Peripheral blood smear, Wright-Giemsa stain showing neutrophils with
intracytoplasmic morulae.

four (AST 1205 U/L, ALT 404 U/L, LDH 2461 U/L), but by this time she began
to improve clinically, with return of her normal mental status. One week after
her admission she was discharged home, and her subsequent complete blood
counts and liver enzymes were normal. Her acute serum titer for human mono-
cytic ehrlichiosis (HME) was negative, but the human granulocytic anaplasmo-
sis (HGA) serology was not resulted (insufficient quantity was sent to the lab
for testing). Three months later, the patient’s HGA IgM was negative but the
HGA IgG was positive (1:512). Serology for Lyme disease was negative and no
intraerythrocytic parasites were seen on examination of the peripheral blood
smear. The patient returned to hiking and was advised to use DEET-based

Vector-Borne Infections
skin repellents, long-sleeved clothing, and premethrin clothing treatments for
tick-bite prevention.
Case 13e Discussion: Human Granulocytic Anaplasmosis
Microbiology and Taxonomy
Human ehrlichiosis encompasses five different obligate intracellular bacteria of
the Anaplasmataceae family, three of which have been extensively described in
the literature to cause human disease.1 Human monocytic ehrlichiosis (HME)

CHAPTER 13
is caused by Ehrlichia chaffeensis and targets mainly monocytes. The vector for
this organism is the lone star tick (Amblyomma americanum; Figure 13e.3), and
the animal reservoir is the white-tail deer.2 Most infections occur between May
and July, and the regions with the highest prevalence include the southeastern,
south central, and mid-Atlantic United States.2
Human granulocytic anaplasmosis (HGA) is caused by Anaplasma phagocy-
tophilum, and principally targets granulocytes. The vectors for this organism in
North America are the ticks Ixodes scapularis (Figure 13e.4 and 13e.5; in the
northeastern and upper Midwestern United States) and Ixodes pacificus (in the
western United States).3 Ixodes scapularis is also the vector for Borrelia burg-
dorferi, the agent of Lyme disease, and Babesia microti, the agent of babesiosis.
Since simultaneous infections can occur in a single patient, the diagnosis of
one infection transmitted by I. scapularis should prompt evaluation for the

327
other two. Other animals that serve as reservoirs include white-tailed deer
and white-footed mice, among other small rodents.3 Ehrlichia ewingii is a canine
pathogen now known to cause infections in humans, referred to as Human
ewingii ehrlichiosis; this organism also targets neutrophils.1

Figure 13e.3 The lone star tick (Amblyomma americanum), vector of Ehrlichia
chaffeensis.
Vector-Borne Infections
CHAPTER 13

Figure 13e.4 Ixodes scapularis, the vector of Anaplasma phagocytophilum.

328

Figure 13e.5 Ixodes scapularis, the vector of Anaplasma phagocytophilum.

Infections with human ehrlichiosis are nationally reportable illnesses in the

United States, and prevalence data demonstrate that the number of cases is
steadily increasing, with over 4000 cases of HGA since 19943 and over 2000
cases of HME since 1986.1 Surveillance studies of serum titers for these infec-
tions suggest evidence of infection in endemic areas of greater than 10%, sug-
gesting the case reporting is an underestimation of true incidence of these
diseases.1
Clinical Features and Diagnosis

Vector-Borne Infections
The clinical presentation of all types of human ehrlichiosis is characterized by
similar symptoms and laboratory findings. Most patients report fever, head-
ache and malaise. Confusion occurs in about 20% of patients, and nausea,
vomiting, and diarrhea are also common.1 Laboratory studies are notable for
leukopenia, thrombocytopenia, and elevated transaminases in the majority of
cases.1 Human monocytic ehrlichiosis is associated with the development of
more severe illness (including shock) and higher mortality than patients with
HGA. Immunocompromised hosts are at especially higher risk for compli-

CHAPTER 13
cated HME.1
The most rapid diagnostic test is evaluation of the buffy coat or peripheral
blood smear, for the presence of intracytoplasmic morulae (Latin for mulberry)
in monocytes or neutrophils. The buffy coat is the fraction of centrifuged blood
with the highest concentration of white cells, and examination of this fraction
makes identification of clusters of intracellular bacteria more likely than exami-
nation of the peripheral blood smear alone. Sensitivity is highest during the first
week of infection, and higher in HGA than HME.1 Alternative methods of diag-
nosis include PCR and serology. The sensitivity of PCR ranges from 60%–90%,1
but is not widely available. Serologic testing is more commonly used; diagnosis
is based on the detection of seroconversion or a fourfold change in antibody
titer during the convalescent phase. The sensitivity of serologic testing is high:

329
88%–90% for HME and 82%–100% HGA.1 Culture of the causative organisms is
extremely difficult, usually requiring 2–6 weeks of incubation and a specialized
laboratory.1
Treatment
The literature on treatment of human ehrlichiosis is limited but, based on clini-
cal experience and cell culture, this group of infections is susceptible to the tet-
racyclines. Doxycycline is the drug of choice, and patients generally improved
rapidly, within 24–48 hours of treatment initiation. For pregnant patients and
children, rifamycins have been used successfully. A retrospective cohort study
evaluating timing of initiating therapy found that delayed administration of doxy-
cycline (beyond 24 hours following admission) resulted in significantly more
complications.4 These complications included respiratory failure, prolonged
duration of illness, prolonged hospitalization, and intensive care unit stay.4 Thus,
if the diagnosis of human ehrlichiosis is suspected, therapy should be initiated
promptly before results of confirmatory diagnostic testing are available.

References
1. Dumler JS, Madigan JE, Pusterla N, Bakken JS. Erlichioses in humans: epidemiology,
clinical presentation, diagnosis, and treatment. Clin Infect Dis. 2007;45:S45–S51.
2. Stone JH, Dierberg K, Aram G, Dumler JS. Human monocytic ehrlichiosis. JAMA.
2004; 292(18):2263–2270.
3. Bakken JS, Dumler S. Human granulocytic anaplasmosis. Infect Dis Clin North Am.
2008;22:433–448.
4. Hamburg BJ, Storch GA, Micek ST, Kollef MH. The importance of early treatment
with doxycycline in human ehrlichiosis, Medicine 2008;87(2):53–60.
This page intentionally left blank
 Chapter 14

Noninfectious Syndromes
that Mimic Infections

Ca e 14a:
Case 14a:
4a PProlonged
rolonged
l dPPostpartum
ostpa
t rtum
t Fev
FFever
ver

Lindsey Reese
Case Presentation
A 25-year-old female with no significant medical history was admitted for a
complicated delivery of twins. The first twin was delivered vaginally after a
preterm premature rupture of membranes. The second twin was delivered via

331
cesarean section 21 days later. Shortly after delivery, the patient became febrile
and developed diffuse abdominal pain. She was treated for 5 days with clin-
damycin, gentamicin, and ampicillin for presumed endometritis, but her fevers
persisted.
On physical examination, the patient was febrile but hemodynamically sta-
ble. She had diffuse abdominal tenderness with voluntary guarding. Her incision
site was nontender and had no erythema or discharge. Her laboratory studies
were notable for a leukocytosis of 22 x 103 WBC /μl, but her blood cultures
and chest radiograph were negative.
Differential Diagnosis and Hospital Course
In the setting of a complicated peripartum course culminating in a cesarean sec-
tion, endometritis was initially very high on the differential, so the patient was
treated empirically with antibiotics. The diagnosis of endometritis is often made
clinically when a postpartum patient has fever and uterine tenderness, as labo-
ratory data are nonspecific, blood cultures are often negative, and endometrial
cultures are difficult to collect without contamination from the lower genital
tract. Patients are often started empirically on a standard triple antibiotic regi-
men including clindamycin, gentamicin, and ampicillin, to cover mixed aerobic
and anaerobic pathogens. This regimen has a success rate of nearly 90%, and
most patients’ fevers resolve within 24–48 hrs.1 As in this case, if the patient
fails to defervesce on this regimen, alternative diagnoses should be explored.
Postoperative complications, such as a surgical site infection or thrombosis,
were also on the differential, so a CT scan of the abdomen and pelvis was
recommended (Figure 14a.1).
Noninfectious Syndromes that Mimic Infections

Figure 14a.1 CT scan pelvis, axial view showing dilatation of the right ovarian vein with
a thrombus extending into the inferior vena cava.
CHAPTER 14

The CT scan showed dilatation of the right ovarian vein with a thrombus
extending into the inferior vena cava. The patient was continued on antibiotics
and was started on anticoagulation with heparin. Her fevers resolved over the
332

next 48 hours and antibiotics were discontinued.

Case 14a Discussion: Septic Pelvic Thrombophlebitis
Septic pelvic thrombophlebitis is divided into two entities: postpartum ovarian
vein thrombosis (POVT), and deep septic pelvic thrombophlebitis (DSPT), also
known as enigmatic fever. The entities often occur together, and share the
same pathogenic mechanism, but differ in clinical presentation and diagnostic
findings. POVT presents within the first week postpartum as fever and abdomi-
nal pain refractory to antibiotics, and a thrombosis of the ovarian vein is seen
on imaging. DSPT presents as an unlocalized postpartum fever with no radio-
graphic evidence of thrombosis. The remainder of this discussion will focus on
POVT. These thrombotic complications occur in 1 in 3000 deliveries—one in
9000 vaginal deliveries, and one in 800 cesarean deliveries.2
Vircow’s triad (endothelial damage, hypercoagulability, and venous stasis)
is represented in the pathogenesis of POVT. Endothelial damage occurs from
trauma during delivery, or from preceding infection with endometritis. A clini-
cal diagnosis of endometritis often precedes that of POVT, and cultures from
thrombi yield microorganisms commonly found in endometritis.2 In addition,
pregnancy is a hypercoagulable state, as many of the clotting factors are upregu-
lated, and there is a decrease in fibrinolysis that occurs in the immediate post-
partum period. Lastly, venous stasis occurs in pregnancy due to dilatation of the
ovarian veins that is accompanied by low velocity flow. This leads to retrograde
(left to right) ovarian venous flow, which, along with the dextrotorsion of the
enlarged uterus that causes compression of the right ovarian vein, explains why
POVT occurs on the right side in 90% of cases.2
 POVT presents as fever and abdominal pain within one week postpartum,

Noninfectious Syndromes that Mimic Infections

which does not respond to at least 5 days of appropriate antibiotics. The inci-
dence peaks at postpartum day 2, but 90% of patients will present within 10
days postpartum.3 Patients appear clinically ill, often with abdominal pain over
the affected vein that may radiate to the groin or upper abdomen. Patients can
present with a tender, rope-like abdominal mass that represents the throm-
bosed vessel; this physical sign is diagnostic of POVT but is seen in less than 50%
of cases. Less than 2% of cases present as pulmonary emboli, but they tend to
be small and rarely cause hypoxia.3 The diagnosis of POVT is often made clini-
cally, and when it is suspected, imaging is necessary to confirm the diagnosis and
to guide treatment. CT is the modality of choice, and has a sensitivity of over
90% in detecting a thrombus.3
The treatment of POVT includes antibiotics and anticoagulation; surgical
treatment using pelvic vein ligation is rarely considered for failure of medical
therapy. The antibiotics used for POVT mirror those for endometritis, as infec-
tion often precedes thrombosis. The regimen, known as the triple antibiotic
regimen, includes clindamycin, gentamicin in once daily dosing, and ampicillin.

CHAPTER 14
Other single agent antibiotic regimens, including ampicillin-sulbactam, ticarcil-
lin-clavulanic acid, piperacillin-tazobactam, or third-generation cephalosporins,
were found to be noninferior to the triple antibiotic regimen in individual stud-
ies of endometritis. When synthesizing the data in a meta-analysis, however,
the triple antibiotic regimen was found to have fewer treatment failures and

333
wound infections when compared to other single agent antibiotic regimens.1
Antibiotics are necessary but not sufficient in the treatment POVT, as the
clinical definition of POVT is persistent fever despite antibiotics. In the 1970s, it
was noted in several small case series that the addition of heparin to antibiotics
in the treatment of presumed POVT led to rapid resolution of fever. The reso-
lution of fever with anticoagulation actually became part of the criteria for diag-
nosing POVT; if the addition of heparin was followed by defervescence within
48–72 hours, this was considered pathognomonic for POVT. None of the data
for anticoagulation were based on randomized, prospective trials, however.
Moreover, the diagnosis of POVT was based on the response to heparin and
was often not confirmed by laparotomy or radiology; patients may have defer-
vesced over time, even without anticoagulation.
The utility of heparin was called into question by a prospective, randomized
trial by Brown, et al. in 1999.4 Women with postpartum fever despite 5 days of
triple antibiotic therapy underwent CT scan, wherein 15 women were found to
have POVT and were randomized to continue antibiotics alone or with heparin.
The duration of fever and hospital stay were equivalent between the two groups.
Moreover, no thromboembolic events, and no episodes of reinfection or post-
phlebitis syndrome, were reported for up to 3 months postpartum in either
group. The authors concluded that there was no support for empiric heparin
in postpartum women persistently febrile after 5 days of antibiotics. Only 20%
of patients in their study were found to have a thrombus using modern imag-
ing, and the majority of these patients became afebrile with another 3 days of
antibiotics alone. This study is criticized for its small sample size, however, and
 was powered to assess for fever resolution only. It did not address the poten-
Noninfectious Syndromes that Mimic Infections

tial benefit of anticoagulation with regard to the risk of thrombus extension or

pulmonary embolism. Thus, despite conflicting evidence about the efficacy of
heparin, it is still considered part of the management of POVT.
Current recommendations, based on expert opinion, advocate for pelvic
imaging in postpartum patients with persistent fever despite 5 days of appro-
priate antibiotics. If a thrombus is found on CT scan, heparin should be added
to antibiotics and continued for 7–14 days after fever resolution. Antibiotics
should be stopped within 48–72 hours after defervescence, and long-term
anticoagulation with warfarin should only be considered if there is extensive
thrombus extending into the renal veins or inferior vena cava. Some experts
recommend repeating imaging 3 months following treatment, to demonstrate
clot dissolution prior to stopping anticoagultion.3 Recurrence is uncommon,
and complications such as thrombus extension, septic pulmonary emboli lead-
ing to lung abscesses or empyema, endocarditis, ovarian abscess or infarction,
or ureteral obstruction are extremely rare and have only been reported as
case reports.
CHAPTER 14

References
1. French L, Smaill, FM. Antibiotic regimens for endometritis after delivery. Cochrane
Database of Systematic Reviews. 2004, Issue 4. Art. No.: CD001067. DOI:
334

10.1002/14651858.CD0–01067.pub2.
2. Garcia J, Aboujaoude R, Apuzzio J, Alvarez JR. Septic pelvic thrombophlebitis:
diagnosis and management. Infect Dis in Obstet Gynecol. 2006; 2006:1–4.
3. Klima DA, Snyder TE. Postpartum ovarian vein thrombosis. Am J Obstet Gynecol.
2008; 111(2): 431–435.
4. Brown CE, et al. Puerperal septic pelvic thrombophlebitis: incidence and response
to heparin therapy. Am J Obstet Gynecol. 1999; 181(1): 143–148.

Case
C a e 114b:
4b: W
4b Worsening
orseniingg D
Dyspnea
yspnea and
dPPulmonary
ulmona
lm ary
IInfi
Infilt
ltrates

Michael M. Gaisa, Mary Beth Beasley, and Daniel Caplivski

Presentation and Case History
A 25-year-old woman with no past medical history presented with fever, chills,
nonproductive cough, and dyspnea over the course of two weeks. She had
been treated empirically with azithromycin followed by levofloxacin, but still
had intermittent fevers as high as 102º F and precipitously worsening dyspnea.
On physical examination, she was in mild respiratory distress, tachypneic (respi-
ratory rate 34, saturation 87% on ambient air), tachycardic (heart rate 123 beats
per minute), with slightly increased temperature (37.9 º Celsius) and normal
blood pressure (113/68). Coarse ronchi and bilateral wheezes were noted on
pulmonary examination.
 Laboratory values were significant for leukocytosis (32 x 10³ WBC/ μl),

Noninfectious Syndromes that Mimic Infections

thrombocytosis (647 x 10³ platelets/μl) and elevated lactate dehydrogenase
(293 units/liter), and arterial blood gas analysis revealed hypoxemia and respira-
tory alkalosis (pH 7.52/ pCO2 30 /pAO2 60 mm Hg). Imaging of the lungs with
plain radiography and CT angiography revealed bilateral alveolar infiltrates and
no evidence of pulmonary emboli (Figures 14b.1 and 14b.2).

335 CHAPTER 14
Figure 14b.1 Chest radiograph, anterior posterior view showing diffuse bilateral
alveolar opacification

Figure 14b.2 Chest CT, axial view showing extensive bilateral alveolar infiltrates with
air bronchograms.
 She was empirically treated with vancomycin, cefepime, and azithromy-
Noninfectious Syndromes that Mimic Infections

cin, and eventually underwent bronchoscopy because of persistent dyspnea.

Immunologic evaluation including HIV testing and gamma globulin levels
revealed no evidence of immunodeficiency. Blood, sputum, and bronchoalveo-
lar lavage cultures were negative for bacteria, mycobacteria, fungi, and viruses,
and Legionella urine antigen testing and direct fluorescence antibody testing
were also negative. Histologic examination of the transbronchial lung biopsy
revealed chronic interstitial and focal organizing pneumonia, with no evidence
of infectious organisms on acid-fast or fungal stains (Figure 14b.3). Given the
absence of inciting factors, such as a concomitant connective tissue disorder,
malignancy, or medication exposure, and based on the histopathologic find-
ings of the transbronchial lung biopsy, the diagnosis of cryptogenic organizing
pneumonia (COP) was established. The patient was treated with oral pred-
nisone and inhaled steroids, with resolution of her symptoms and pulmonary
infiltrates. She had two subsequent relapses of dyspnea and cough that also
responded to oral and inhaled steroids.
CHAPTER 14

Case 14b Discussion: Cryptogenic Organizing Pneumonia

Clinical Presentation and Diagnosis
Cryptogenic organizing pneumonia was previously referred to as idiopathic
bronchiolitis obliterans organizing pneumonia, or BOOP. This disorder is an
idiopathic form of organizing pneumonia in which disease onset is usually within
336

the fifth and sixth decades of life. There is no gender predilection, and cigarette
smoking does not appear to be a predisposing factor. Clinical features initially
may be difficult to distinguish from community-acquired pneumonia—a sub-
acute, flu-like illness is followed by nonproductive cough, dyspnea on exertion,
and weight loss. The majority of patients with COP have a period of 3 months

Figure 14 b.3 Transbronchial biopsy, Hematoxylin and Eosin stain showing mild
chronic inflammatory cell infiltrates within the alveolar septa and organizing pneumonia
within an airspace.
of symptoms before the diagnosis is confirmed, highlighting the subacute nature

Noninfectious Syndromes that Mimic Infections

of this disease.1
Laboratory studies are usually nonspecific, but it is noteworthy that a signifi-
cant portion of COP patients have some degree of leukocytosis, and most have
markedly elevated C-reactive protein levels and erythrocyte sedimentation
rates. On plain radiographs of the chest bilateral, diffuse alveolar opacities in
the presence of normal lung volumes may be seen. Computed tomography of
the chest usually reveals more extensive disease, with patchy air-space consoli-
dation and ground-glass opacities (frequently in the periphery of the lung and in
the lower lung zones) being most common. Small nodular opacities, bronchial
wall thickening, and dilation also occur. Pulmonary function tests commonly
show mild to moderate restriction, and abnormal gas exchange patterns with
reduced diffusion capacity (DLCO) and resting hypoxemia are usually present.
Bronchoalveolar lavage (BAL) findings are nonspecific, but often reveal a lym-
phocytosis with negative microbiologic studies.2,3
Pathology

CHAPTER 14
Organizing pneumonia, as defined by the current American Thoracic Society/
European Respiratory Society consensus classification of interstitial lung disease,
is characterized by intra-alveolar organizing fibroblastic tissue (organizing pneu-
monia) occurring in a patchy distribution centered primarily around airways.
Organizing pneumonia may also be identified within bronchiolar lumens (bron-

337
chiolitis obliterans). The lung parenchyma in the involved areas shows a mild
infiltrate of chronic inflammatory cells associated with pneumocyte hyperplasia.
Intra-alveolar foamy macrophage accumulation may be present due to airway
obstruction. The lung parenchyma in between involved areas is usually unremark-
able. Granulomas, necrosis, and significant neutrophilic or eosinophilic infiltrates
should be absent. The organizing pneumonia pattern may arise secondary to a
variety of potential underlying etiologies (infection, collagen vascular disease, drug
reaction, etc.), which must be excluded clinically. Once disease has been deter-
mined to be idiopathic, then a clinical diagnosis of COP can be made.4
Organizing pneumonia corresponding to clinical COP is best diagnosed on
a wedge lung biopsy, so that the pattern of distribution may be appreciated
and other entities may be excluded. It is important to note that organizing
pneumonia may occur in numerous settings outside of the specific histologic
pattern described above. Organizing pneumonia may occur as a secondary find-
ing or component of a variety of entities, such as hypersensitivity pneumonitis,
Wegener’s granulomatosis, and acute lung injury, among many others. Organizing
pneumonia may also occur as a reactive or reparative phenomenon adjacent to
neoplastic processes, necrotizing granulomas, abscesses, or bronchiectasis. For
this reason, a finding of organizing pneumonia in a small specimen, such as a
needle core or transbronchial biopsy, must be evaluated in the entire context of
the clinical and radiographic findings, and should not automatically be taken as
evidence of COP.5 However, in the presented case, the clinical and radiographic
findings supported a clinical diagnosis of COP in this patient.
Management
While the overall prognosis of COP is better than that of other interstitial lung
diseases, COP is usually not self-limited and requires treatment. The mainstay
 of therapy is glucocorticoids, usually prednisone at 1.0–1.5 mg/kg/d for 4 to 8
Noninfectious Syndromes that Mimic Infections

weeks, followed by a tapering schedule, extending treatment to a total of 3 to 6

months. High-dose parenteral glucocorticoid therapy (methylprednisolone 125
to 250 mg every six hours intravenously for 3 to 5 days) can be considered as
initial treatment in patients with rapidly progressive severe disease. For patients
who progress despite adequate glucocorticoid therapy, or who need a steroid-
sparing agent, cyclophosphamide is used. Empiric antimicrobials are often used
because of the difficulty in distinguishing this diagnosis from infectious etiolo-
gies. Prolonged courses of macrolide antibiotics have successfully been used
in mild cases, presumably related to their anti-inflammatory, rather than their
antimicrobial, properties.1,6
After completion of therapy, patients should be monitored closely with chest
radiographs and pulmonary function tests every 6 to 8 weeks during the first
year. Clinical symptoms often lag behind radiographic findings; therapy should
be resumed if there is any indication of recurrence. Complete remission occurs
in up to two-thirds of patients, and is fairly rapid in onset (usually within 1–2
weeks of therapy); however, recurrence happens quite frequently.2 Patients
CHAPTER 14

with persistent or frequently recurrent disease require prolonged therapy with

prednisone, cyclophosphamide, or both.1,5

References
338

1. Alasaly K, Muller N, Ostrow DN, Champion P, FitzGerald JM. Cryptogenic orga-

nizing pneumonia. A report of 25 cases and a review of the literature. Medicine
(Baltimore). 1995;74:201–211.
2. Cordier JF. Cryptogenic organising pneumonia. Eur Respir J. 2006;28:422–446.
3. Oymak FS, Demirbas HM, Mavili E, et al. Bronchiolitis obliterans organiz-
ing pneumonia. Clinical and roentgenological features in 26 cases. Respiration.
2005;72:254–262.
4. Travis WD, King TE, Bateman ED, et al. American Thoracic Society/European
Respiratory Society international multidisciplinary consensus classification of the
idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2002; 165: 277–304.
5. Drakopanagiotakis F, Polychronopoulos V, Judson MA. Organizing pneumonia.
Am J Med Sci. 2008;335:34–39.
6. Epler GR. Bronchiolitis obliterans organizing pneumonia. Arch Intern Med.
2001;161:158–164.

Case
C a e 114c:
4c FFever,
4c: ever, H
Hyp
Hypotension,
pot
oten
t sion,
i and
dRRash
ash
h in
i aan
n
Immunocompromised
Immu
Im munocompromi mise Patient
sed Pa
P tient with Lymphoma
h Lym
y ph
phooma

Lindsey Reese, Shirish Huprikar, Stephen Mercer, and

Robert Phelps
Case Presentation
A 57-year-old male with a history of angioimmunoblastic T-cell lymphoma was
admitted with 2 days of nausea, vomiting, diarrhea, and fever. After a failed
autologous stem cell transplant (SCT) one year prior to admission, he under-

Noninfectious Syndromes that Mimic Infections

went an allogeneic SCT with a human leukocyte antigen (HLA) identical sister,
2 months prior to admission. The patient’s medications included tacrolimus
and valacyclovir, atovaquone, and voriconazole. On physical examination, the
patient was ill-appearing with fever (39.9°C), hypotension, and tachycardia. He
had a diffuse erythematous rash and a cool, slightly mottled left lower extrem-
ity with decreased pulses (Figure 14c.1).
His admission laboratory studies were significant for pancytopenia (hemo-
globin 10.6 g/dl; white blood cell count 3.6 x 103/μl; platelets 45 x 103/μl),
hypokalemia, and hypomagnesemia. Liver and kidney functions tests were
within normal limits and radiological studies were nondiagnostic.
Hospital Course and Differential Diagnosis
The patient remained hypotensive despite aggressive fluid resuscitation, and
was transferred to the medical intensive care unit (MICU) where he required
blood pressure support with norepinephrine. After obtaining blood cul-
tures, he was started on cefepime, vancomycin, and metronidazole for pre-

CHAPTER 14
sumed sepsis. Voriconazole was continued and intravenous ganciclovir was
substituted for valacyclovir. Dermatology was consulted for a skin biopsy of
the erythematous rash.
In the setting of fever and hemodynamic instability, the patient was started on
broad-spectrum antibiotics for presumed bacterial sepsis. A potential source of

339
Gram-negative bacteremia in this patient was translocation from enteritis due
to Clostridium difficile or cytomegalovirus (CMV), typhlitis, or graft-versus-host
disease (GVHD). Gram-positive sepsis was also possible, as the patient had a
tunneled catheter and, in the setting of hypotension and a diffuse erythematous
rash, toxic shock syndrome (TSS) was considered. Given the appearance of the
diffuse rash, GVHD was strongly considered.

Figure 14c.1 Diffuse erythematous rash on bilateral upper extremity.

 The patient continued to require norepinephrine and high-dose corticos-
Noninfectious Syndromes that Mimic Infections

teroids for hypotension, but blood cultures remained negative. Clindamycin

and intravenous immunoglobulin (IVIG) were added for possible TSS. Over
the next 24 hours, the patient improved dramatically. His fevers resolved and
his blood pressure stabilized, and norepinephrine was discontinued. His left
lower extremity regained circulation and the mottling disappeared. Over the
next day, his rash began to resolve. Blood cultures remained negative, toxin
for Clostridium difficile was negative, and CMV polymerase chain reaction
(PCR) was undetectable; however, the skin biopsy was consistent with GVHD
(Figure 14c.2). Broad-spectrum antimicrobial therapy was discontinued and
prophylaxis was resumed. He continued to improve on high-dose corticoster-
oids and was transferred out of the MICU the following day.
Case 14c Discussion: Graft versus Host Disease
The above case illustrates the potential difficulty in differentiating infectious
from noninfectious complications in immunocompromised hosts. Definitive
diagnosis often requires invasive procedures and comprehensive microbio-
CHAPTER 14

logic techniques to exclude infection. In this case, rapid diagnostics are needed
because immunosuppressive therapy for GVHD could potentially be detrimen-
tal in the setting of active infection.
Acute GVHD is a major complication of allogeneic SCT, and occurs when
the donor T-cells react to host antigens (predominantly the HLAs). The risk
340

of GVHD is related to the degree of mismatch between these antigens (40%

for fully matched patients versus 80% for mismatched patients), so ideally,
the host and donor are matched on as many HLAs as possible, as in the case

Figure 14c.2 Skin biopsy showing an interface dermatitis with marked vacuolization
and necrotic keratinocytes at the dermal-epidermal junction. The interface changes
included prominent follicular extension consistent with the diagnosis of graft versus host
disease.
patient.1 Clinical signs of GVHD include a diffuse maculopapular skin rash

Noninfectious Syndromes that Mimic Infections

(80%); gastrointestinal symptoms such as abdominal pain, nausea, vomiting,
and diarrhea (54%); and evidence of cholestasis on liver function tests (50%).1
The case patient had evidence of skin and gastrointestinal involvement, and
was diagnosed via biopsy, which is the preferred method of diagnosis in these
cases.
Immunomodulators such as calcineurin inhibitors (cyclosporine and tac-
rolimus) and other immunosuppresants such as methotrexate, mycopheno-
late mofetil, and sirolimus are often used in combination to prevent GVHD.
Antibodies against T-cells, such as antithymocyte globulin (ATG), are often
added in high-risk patients. However, when prevention fails in patients, acute
GVHD is treated with high-dose systemic corticosteroids, with complete
remission rates in fewer than 50% of patients.1 As a result, other treatments,
such as ATG, infusion of mesenchymal stem cells, addition of tumor necrosis
factor-D inhibitors, and pulse doses of other immunomodulators are being
studied.
In the case patient, GVHD produced a clinical syndrome that could have

CHAPTER 14
been produced by many possible infectious agents. He was initially treated with
broad-spectrum antibiotics and antivirals for possible sepsis, TSS, or CMV dis-
ease. TSS, a toxin-mediated disease from Staphylococcus aureus or Group A
Streptococcus pyogenes (GAS), presents as fever, rapid-onset hypotension, and
accelerated multisystem organ failure. S. aureus TSS was originally associated

341
with tampon use in the 1980s, but is now more common following disruption
of the skin or mucous membranes or after surgery, and is associated with a
mortality rate of 25%. GAS TSS is often secondary to invasive soft tissue infec-
tions, and is associated with a mortality rate of 50%, particularly in the setting
of necrotizing fasciitis.2
The bacterial toxins in TSS act as superantigens that are able to trigger exces-
sive T-cell activation and downstream cytokine release. Patients initially present
with an influenza-like illness with fever, myalgias, and gastrointestinal symp-
toms. A generalized, erythematous, macular rash occurs early in the syndrome,
followed by desquamation and multiorgan failure in as quickly as 8 hours. In S.
aureus TSS, a focus of infection is often occult, and bacteremia occurs in fewer
than 5%. GAS TSS often arises from clinically evident invasive soft tissue infec-
tions, and bacteremia occurs in 60%.2
Treatment for TSS requires immediate resuscitation, surgical debridement
if necessary, and broad-spectrum antibiotics with activity against GAS and S.
aureus. A combination of E-lactam antibiotics, vancomycin for resistant strains,
and clindamycin to inhibit toxin production, is often used. The case patient also
received IVIG, which has been associated with improved outcomes in GAS TSS.
Administration of IVIG at doses of 1 g/kg on day one, followed by 0.5g/kg on
days 2 and 3, inhibits T-cell activation and in small studies has been associated
with improved 30-day survival.2 This effect is better studied for GAS TSS than
for S. aureus. However, a pathogen may not be detected early or at all, and IVIG
is recommended in all cases of TSS, especially if there is no improvement with
fluid resuscitation and antibiotics.2
 CMV disease was also considered in this patient presenting with fever and
Noninfectious Syndromes that Mimic Infections

gastrointestinal symptoms several months following allogeneic SCT. The risk of

disease is dependent on the CMV serologic status of the donor and the recipi-
ent. Seropositive SCT recipients have the highest risk for CMV reactivation,
and in the pre-prophylactic era, nearly 80% of these patients had a reactivation
and one-third developed disease. The risk of primary disease in a seronegative
recipient with a seropositive donor is approximately 30% in the absence of
prophylaxis.3 The risk of primary CMV disease in a seronegative recipient with
a seronegative donor is low. The most common manifestations of CMV disease
in the SCT population are gastrointestinal disease, as in the case patient, and
pneumonia. Hepatitis, encephalitis, and retinitis are less frequently observed.
Diagnosis can be established with histologic examination for viral inclusions,
immunohistochemical staining, or plasma DNA PCR techniques.3 The case
patient presented with rash (which is an unusual manifestation of CMV dis-
ease); however, GVHD and CMV may coexist, and both diagnoses need to be
considered in such patients.
The case patient was receiving valacyclovir for antiviral prophylaxis, which
CHAPTER 14

is mainly protective against herpes simplex and varicella-zoster viruses.

Valacyclovir prophylaxis has been associated with reduction in CMV viremia,
but data that it prevents disease or prolongs survival is lacking.3 Ganciclovir and
valganciclovir are more effective in the prevention of CMV, but are complicated
by myelosuppressive toxicity. Thus, a preemptive strategy is often used to pre-
342

vent CMV disease in SCT patients. The preemptive strategy is based on weekly
surveillance with CMV DNA PCR. When viremia is detected, valacyclovir is
discontinued in favor of ganciclovir or valganciclovir until viremia is cleared. At
that time, valacyclovir is resumed with continued weekly surveillance. In hos-
pitalized patients, intravenous ganciclovir is the preferred treatment of viremia
(and disease). However, due to similar bioavailability, oral valganciclovir 900 mg
twice daily can be considered in patients without tissue-invasive disease. For
ganciclovir-resistant or refractory disease, or in the setting of profound myelo-
suppression, foscarnet can be used as an alternative therapy.3
In summary, the case illustrates that both infectious and noninfectious causes
of fever and hemodynamic instability need to be considered in the immuno-
compromised host.4 Aggressive supportive care and broad-spectrum antibiotics
should be continued until diagnostic tests confirm the etiologies of decompen-
sation in this vulnerable population.

References
1. Ferrara JL, Levine JE, Reddy P, Holler E. Graft-versus-host disease. Lancet.
2009;373(9674):1550–1561.
2. Lappin E, Ferguson AJ. Gram-positive toxic shock syndromes. Lancet Infect Dis.
2009;9(5):281–290.
3. Boeckh M, Ljungman P. How we treat cytomegalovirus in hematopoietic cell
transplant recipients. Blood. 2009;113(23):5711–5719.
4. Stein PD, Afzal A, Henry JW, Villareal CG. Fever in acute pulmonary embolism.
Chest. 2000;117(1):39–42.
 Case
C a e 14d:
14d
4d: A RRenal
enall Transplant
Transpllantt R
Recipient
Reciipiientt wit
with
ith
ha

Noninfectious Syndromes that Mimic Infections

Medi
Me diaastinal Masss
Mediastinal

Daniel Caplivski and Shirish Huprikar

Case Presentation
A 66-year-old man with a history of end-stage renal disease secondary to diabe-
tes and hypertension underwent successful living, unrelated kidney transplanta-
tion. His post-transplant course had been largely uneventful for 7 years prior
to presentation, and his immunosuppression included cyclosporine, mycophe-
nolate mofetil, and prednisone. For 10 days prior to his admission, he experi-
enced fevers, chills, runny nose, and diffuse bone pain. He also noted that in the
preceding months he had had similar symptoms accompanied by cough, fatigue,
and poor appetite.
On presentation he was febrile (38.6ºC) and his cardiac examination was
notable for an irregular rhythm; an electrocardiogram confirmed new-onset

CHAPTER 14
atrial fibrillation. His laboratory values were significant for leukocytosis (21.3
x 10³ WBC/μl, 80% polymorphonuclear cells), anemia (hemoglobin 12.9 g/dl)
and elevated erythrocyte sedimentation rate (80mm/hour) and lactate dehy-
drogenase (4303 units/liter). Computed tomography of the chest, abdomen,
and pelvis revealed diffuse lymphadenopathy including a 7.7cm mediastinal mass

343
(Figure 14d.1) as well as diffuse soft tissue masses involving the liver, native
kidneys, and transplanted kidneys.
Peripheral blood PCR for Epstein-Barr virus was positive (24,944 copies/
μl), and the bone marrow biopsy revealed patchy infiltrates of medium-sized
lymphoid cells with apoptosis and a “starry sky appearance” (Figure 14d.2).
Flow cytometry confirmed a monoclonal B-cell phenotype consistent with
monomorphic post-transplantation lymphoproliferative disorder/Burkitt’s-like

Figure 14d.1 Chest CT, axial view showing a 7.7 cm mediastinal mass.
Noninfectious Syndromes that Mimic Infections

Figure 14d.2 Bone marrow biopsy, hematoxylin and eosin stain, showing patchy infil-
trates of medium sized lymphoid cells with apoptosis and a “starry sky appearance.”
CHAPTER 14

lymphoma. The patient was treated with reduced immunosuppression and

systemic (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and
prednisone) and intrathecal (methotrexate) chemotherapy. His course was
344

complicated by profound neutropenia, thrombocytopenia, seizures, and respi-

ratory and renal failure. Palliative care measures became the main focus of his
care, and he died three weeks into his hospitalization.
Case 14d Discussion: Post-Transplant Lymphoproliferative Disease
Clinical Presentation and Diagnosis
Malignancies such as lymphoma are often difficult to distinguish clinically from
infectious diseases, since both may produce similar symptoms including fever,
sweats, weight loss, lymphadenopathy, and radiologic and laboratory abnor-
malities. Though the above case appears in the chapter on noninfectious syn-
dromes, it is important to emphasize the essential role that Epstein-Barr Virus
(EBV) plays in post-transplant lymphoproliferative disorder (PTLD). PTLD
ranges in its manifestations from benign post-transplant mononucleosis, to
aggressive malignancies with high mortality rates.1 The EBV genome is found
in >90% of tumors arising from B-cells in PTLD that present within the first
year after transplantation.1 EBV has a latent and lytic phase, and can result in
the immortalization of infected cells.2 Other malignancies linked with EBV have
strong geographic associations, such as Burkitt’s lymphoma in parts of Africa,
and nasopharyngeal carcinoma in Asia.
EBV infection occurs in many immunocompetent hosts during childhood
as a mild febrile illness as the result of exposure to virus in saliva or other
infected body fluids. Young adults with acute infection may present with the
infectious mononucleosis syndrome, characterized by fever, pharyngitis, lymph-
adenopathy, splenomegaly, and atypical lymphocytosis. In immunosuppressed
transplant recipients who are seronegative prior to transplantation, infection
may also occur via the donor organ or blood transfusion.1 Primary infection

Noninfectious Syndromes that Mimic Infections

after transplant confers a much higher risk of PTLD than those patients who
have been exposed prior to transplantation.1 Risk of PTLD also varies with
different organ transplantation, with intestinal transplantation conferring the
highest risk (32%) and renal transplant conferring the lowest risk (1%–2%).1
The most important risk factor, however, is the intensity of immunosuppres-
sion. Antirejection regimens that include antithymocyte globulin are particularly
predisposing towards PTLD, since cytotoxic T lymphocytes are necessary for
surveillance and clearance of EBV-infected cells. Concurrent cytomegalovirus
(CMV) infection may also result in further immunocompromise, and has been
associated with increased risk for PTLD.1
PTLD is often first suspected when routine evaluation of a transplant
recipient with fever and other systemic symptoms does not yield a definitive
cause. Radiographic testing (CT scan or MRI) revealing diffuse or focal lymph-
adenopathy, and tissue biopsy, are the most reliable diagnostic modalities.
Histopathologic characteristics of PTLD lesions range from early plasmacytic
hyperplasia to polymorphic PTLD, monomorphic PTLD, and B-cell or T-cell

CHAPTER 14
neoplasms.1 Confirmatory testing may be performed with detection of EBV-
specific nucleic acids in tissue via in situ hybridization of EBV-encoded small
nuclear RNA (EBER), or in circulating blood samples.1 While the former is
more specific for EBV-associated PTLD, measurements of high levels of circu-
lating EBV DNA may be useful in supporting the diagnosis of PTLD in patients

345
in whom clinical suspicion is high.1 Guidelines and randomized clinical studies
for the interpretation of varying levels of EBV viral loads are still lacking, and
caution must be used in interpreting low-level positive titers.1
Management
A consensus on the optimal management of PTLD based on randomized clinical
trials is challenging, since the disorder comprises such a wide spectrum of clinical
syndromes. First-line management of PTLD includes reduction in immunosup-
pression. In some cases, adjunctive therapies such as antiviral agents, intravenous
immune globulin, monoclonal B-cell antibody therapy, and cytotoxic chemother-
apy are also used.2 The clinical response to reduction of immunosuppression
and the histopathologic grade of the lesion determine the aggressiveness of the
PTLD treatment regimen.2 Antivirals that have been used in the management of
PTLD include ganciclovir and acyclovir, with the former having greater activity
against the lytic phase of EBV in vitro.2 Neither antiviral has been proven to
affect the course of PTLD in the absence of immunosuppression.1,2 Monoclonal
B-cell antibody therapy has become part of the management of PTLD, but its
precise role is yet to be defined. It may be associated with tumor lysis syndrome,
and in cases of PTLD of the bowel, intestinal perforation. For more aggressive
neoplasms (including CNS PTLD), cytotoxic chemotherapy regimens may be
combined with monoclonal B-cell antibody therapy.1 Prognosis for patients with
PTLD varies greatly dependent on the localization of disease, histologic charac-
teristics of the tumor, and the underlying characteristics of the patient. Optimal
strategies for screening, diagnosis, and management are still being defined.
 References
Noninfectious Syndromes that Mimic Infections

1. Allen U, Preiksaitis J; AST Infectious Diseases Community of Practice. Epstein-

Barr virus and posttransplant lymphoproliferative disorder in solid organ trans-
plant recipients. Am J Transplant. 2009 Dec;9(Suppl 4):S87–S96.
2. Preiksaitis JK, Keay S. Diagnosis and management of posttransplant lymphoprolif-
erative disorder in solid-organ transplant recipients. Clin Infect Dis. 2001;33(Suppl
1):S38–46.

Case
C a e 114e:
4e A 23
4e: 23-Year-Old
-Year-
Y -OlOld
d Man
Man with
wiith
hUUne
Unexplained
nexpllain
ined
d Fev
FFevers,
ver
ers,
Diff
Di ffus
use Pains, and
Diffuse dRRas
ah
Rash

Michael M. Gaisa, Stephen Mercer, and Daniel Caplivski

Presentation and Case History
A 23 year-old man from Ecuador presented with a one-month history of sore
CHAPTER 14

throat, diffuse joint pains, chest pain, abdominal pain, fever, and a pruritic ery-
thematous rash. His chest pain was exacerbated by lying flat, and his abdominal
pain was worst in the right upper quadrant. On physical examination, he was
febrile (39.8°C), tachycardic (138 beats/minute), and appeared to be in moder-
ate distress due to the pain. His cardiopulmonary examination revealed distant
346

heart sounds, and slightly decreased breath sounds bilaterally. The rash on his
trunk and legs consisted of erythematous patches with dry scale, and spared the
palms and soles (Figure 14e.1).
The patient’s laboratory examinations were significant for leukocytosis (13.8
WBC per μl, 19% bands), anemia (hemoglobin 9.4 grams/deciliter), elevated
transaminases (AST 120, ALT 71), and lactate dehydrogenase (1139 units/
liter). Markers for systemic lupus erythematosus and rheumatoid arthritis were

Figure 14e.1 Erythematous rash on the trunk consisting of erythematous patches with
dry scale.
negative, as were bacterial and viral cultures. The erythrocyte sedimentation

Noninfectious Syndromes that Mimic Infections

rate was 72mm/hour, the C-reactive protein 232 mg/l, and the ferritin level was
extremely elevated at 46,276 ng/ml (normal 30–400). On admission, the chest
radiograph revealed an enlarged cardiac silhouette, and the EKG was notable
for diffuse T-wave inversions (Figures 14e.2 and 14e.3). CT scan confirmed the
presence of a large pericardial effusion, splenomegaly, and medial, axillary, and
pelvic lymphadenopathy (Figure 14e.4). A skin biopsy revealed spongiosis, skip-
ping mounds of atypical parakeratosis with numerous necrotic keratinocytes in
the upper levels of the epidermis, and a sparse superficial perivascular dermati-
tis (Figure 14e.5). Based on this constellation of findings, the diagnosis of adult
Still’s disease was considered; however, the patient left against medical advice
before further therapy could be offered.

347 CHAPTER 14

Figure 14e.2 Chest radiograph, posterior-anterior view showing an enlarged cardiac

silhouette.

Figure 14e.3 Electrocardiogram with diffuse T-wave inversions.

Noninfectious Syndromes that Mimic Infections

Figure 14e.4 CT scan chest, axial view showing a large pericardial effusion.
348 CHAPTER 14

Figure 14e.5 Skin biopsy showed mounding parakeratosis with prominent necrotic
keratinocytes in the upper epidermis. This reaction pattern has recently been reported
in persistent plaques in adult onset Still’s disease. Also notable were scattered mitoses,
including many in the spinous layer.

Case 14e Discussion: Still’s Disease

Clinical Presentation and Diagnosis
Adult onset Still’s disease (ASD) is a rare systemic inflammatory disorder of
unknown etiology, characterized by fever, evanescent rash, arthritis, and mul-
tiorgan involvement. It was first described in children by the English pediatri-
cian George Still in 1897, and is now called systemic onset juvenile inflammatory
arthritis when it occurs in children < 16 years of age. In 1971, a series of cases
with disease presentations similar to those in children were described in adults,
giving rise to the term, “adult onset Still’s disease.”1
 The etiology of ASD is poorly understood. Many studies have suggested a

Noninfectious Syndromes that Mimic Infections

genetic component, linking the disease to a variety of HLA antigens; however,
familial cases are uncommon and reports of cases in twins are extremely rare. It
has also been hypothesized that ASD may be a reactive syndrome, where vari-
ous infectious agents may act as disease triggers in the genetically predisposed
host. Viruses, such as rubella, mumps, CMV, EBV, parainfluenza, coxsackie B4,
adenovirus, influenza A, HHV-6, parvovirus B19, and even hepatitis B and C
viruses have all been implicated in case reports and small series. Other reports
suggest bacterial triggers, including Mycoplasma pneumoniae, Chlamydia pneu-
moniae, Yersinia enterocolitica, Brucella abortus, and Borrelia burgdoferi. There
remains no conclusive evidence for an infectious etiology, and there have been
emerging reports of cytokine dysregulation as a potential pathophysiological
contributor.2
While there have been case reports of ASD in the elderly, the disease char-
acteristically affects younger individuals, with most patients reporting disease
onset between 16 and 35 years of age. There seems to be no clear gender
preference. A number of classification criteria have been derived from ret-

CHAPTER 14
rospective data, and include major and minor criteria. The Yamaguchi criteria
have been shown to be most sensitive, emphasizing the main clinical features
of this disease. The presence of five criteria, two of them major, is required to
establish a diagnosis with a sensitivity of 93.5%.
The four major Yamaguchi criteria are:

349
• Fever of at least 39ºC lasting at least one week
• Arthralgias or arthritis lasting t 2 weeks
• A nonpruritic macular or maculopapular, evanescent skin rash
• Leukocytosis (t 10,000/μl), with at least 80% neutrophils.
The five minor Yamaguchi criteria include:
• Sore throat
• Lymphadenopathy
• Hepatomegaly or splenomegaly
• Transaminitis, particularly elevations in aspartate and alanine aminotrans-
ferase, and lactate dehydrogenase concentrations
• Negative tests for antinuclear antibody and rheumatoid factor.
Fever is almost universally present and follows a quotidian (daily spikes) or
double quotidian (two spikes/day) pattern. Temperatures generally exceed
39°C and the fever curve can shift quite dramatically, but most patients do not
completely defervesce in the intervals between spikes.3
Arthralgias and arthritis occur in the majority of cases and may initially
present as an asymmetric, transient oligoarthritis. As the disease pro-
gresses, arthritic changes typically become symmetric, more severe, and
destructive. Most patients develop polyarthritis and joint pain associated
with fever spikes. Ankylosis of the wrist may occur in some patients, and
helps to differentiate ASD from rheumatoid arthritis, but it is a late mani-
festation of the disease. The most frequently affected joints are the knees,
 wrists and ankles; although involvement of the elbow, shoulder, proximal
Noninfectious Syndromes that Mimic Infections

and distal interphalangeal joints, metacarpophalangeal and metatarsopha-

langeal joints, temporomandibular joints, and hip have been described.
Arthrocentesis often demonstrates marked leukocytosis with a neutrophil
predominance.
The exanthem associated with both the juvenile and adult forms of Still’s dis-
ease is characteristically evanescent, salmon-colored, nonpruritic, macular or
maculopapular, and tends to coincide with febrile episodes. It usually involves
the proximal extremities and trunk, but can spread more distally and involve
the face. The rash can easily be mistaken for a drug reaction. Mechanical irrita-
tion of the skin may trigger an eruption (Koebner phenomenon). Histology usu-
ally shows lymphocytic, perivascular inflammation of the superficial dermis, but
is largely nonspecific. Several recent reports indicate that a subset of adult Still’s
disease patients may present with a rash including persistent scaly papules and
plaques, in addition to the typical nonspecific evanescent rash found in younger
populations. This persistent component is unique histologically, in that there
are prominent necrotic keratinocytes in the upper half of the epidermis as seen
CHAPTER 14

in our patient (Figure 14e.5).4 Serositis can occur, and manifests as pleural or
pericardial effusions; cardiac tamponade and involvement of the myocardium
have also been described.
The laboratory profile generally reflects systemic inflammation and acti-
vation of the inflammatory cytokine cascade. While rheumatoid factor and
350

antinuclear antibodies are typically negative, C-reactive protein and ESR are
markedly elevated. Ferritin is an acute phase reactant, produced by the his-
tiocyte-macrophage system under the influence of inflammatory cytokines
(IL-1, IL-6, IL-18 and TNFD) and possibly released by damaged hepatocytes.
Ferritin levels are usually markedly increased and typically higher than in other
autoimmune and inflammatory conditions. A fivefold increase of ferritin levels
(normal 40–200 ng/ml) to t 1000 ng/ml is felt to be suggestive of, yet by no
means specific for, ASD. Extremely elevated levels as high as 250,000 ng/ml
have been described. Ferritin levels correlate with disease activity, and are used
as markers for monitoring treatment success and relapses. Leukocytosis with
neutrophil predominance is present in the majority of cases. Anemia of chronic
disease is common, as is reactive thrombocytosis. Pancytopenia should alert
the provider to the possibility of reactive hemophagocytic syndrome, which
can occur in the setting of ASD and is characterized by the presence of well-
differentiated macrophages in the bone marrow engaging in phagocytosis of
hematopoietic cells. Hepatomegaly and mild to moderate elevation in aspartate
and alanine aminotransferase and lactate dehydrogenase levels are common
(50%–75% of cases). Clinical presentations range from subclinical hepatitis to
fulminant hepatic failure (very rare). Liver biopsy typically shows mild periportal
inflammation with monocytic infiltration. Severe, nonsuppurative pharyngitis
occurs frequently in ASD. Lymphadenopathy (often involving cervical lymph
nodes) and splenomegaly may be appreciated and are due to benign, reac-
tive, polyclonal B-cell expansion. The polyclonal nature of the proliferation
distinguishes ASD histopathologically from lymphoma which, in the setting of
fever and leukocytosis, may be a confounding consideration in the differential

Noninfectious Syndromes that Mimic Infections

diagnosis.2
Since there is no specific diagnostic test, and the clinical spectrum of ASD is
quite heterogeneous, it is pivotal to exclude a variety of differential diagnoses
that can closely mimic features of the disease. Certain neoplastic disorders
have been confused with ASD, including leukemia, lymphoma, and angioblastic
lymphadenopathy; lymph node and bone marrow biopsies can be useful in rul-
ing out these entities. Other considerations in the differential diagnosis include
reactive arthritis and other spondyloarthropathies, hemophagocytic syndrome,
dermatomyositis, Kikuchi’s syndrome, Sweet’s syndrome, granulomatous dis-
eases, and vasculitides, as well as periodic fever syndromes, such as familial
Mediterranean fever.2
The clinical course usually follows one of three patterns, each accounting for
approximately one-third of patients:
• Monocyclic pattern: predominance of systemic symptoms (fever, rash, serosi-
tis, and organomegaly); single disease episode; most patients achieve remis-
sion within 1 year (median time is 9 months).

CHAPTER 14
• Intermittent or polycyclic systemic pattern: recurrent flares, with or without
arthropathy; there is complete remission between flares, which may be years
apart and tend to be milder than the initial episode.
• Chronic articular pattern: predominant arthropathy that can be severe and

351
lead to joint destruction.
Management
Treatment options include NSAIDs for mild disease; most patients, however,
will require glucocorticoids at some point during therapy. High-dose oral
prednisone at 0.5–1 mg/kg/d is recommended for more severe presentations
at the onset of disease, and pulse-dose methylprednisolone (1000 mg/day for
3 days) is used for life-threatening disease due to severe hepatic involvement,
cardiac tamponade, etc. Disease-modifying antirheumatic drugs (DMARDs)
such as methotrexate and cyclosporine have been used successfully in some
case series, but now merely play an adjunctive role. Biological agents, such
as the TNFD-antagonists, etanercept and infliximab; the IL-1 receptor antag-
onist, anakinra; and monoclonal B-cell antibody therapy, are reserved for
refractory cases. 2

References
1. Bywaters EG. Still’s disease in the adult. Ann Rheum Dis. 1971;30:121–133.
2. Efthimiou P, Paik PK, Bielory L. Diagnosis and management of adult onset Still’s
disease. Ann Rheum Dis. 2006;65:564–572.
3. Yamaguchi M, Ohta A, Tsunematsu T, et al. Preliminary criteria for classification
of adult Still’s disease. J Rheumatol. 1992;19:424–430.
4. Lee JL, Yang C, Hsu MM. Histopathology of persistent papules and plaques in
adult-onset Still’s disease. J Am Acad Dermatol. 2005;52:1003–1008.
Noninfectious Syndromes that Mimic Infections

Ca e 114f:
Case 4f: A 45
4f 45-Year-Old
-Year-O
Y Old M
Old
Ol Man
an with
ith B
Bullae
ulllae
la an
and
nd V
Vesicles
esiicl
cles
les

Amy Mathers, Stephen Mercer, and William Michael Scheld

Case Presentation
A 45-year-old male with a history of obesity and hypertension had a motor
vehicle accident requiring open reduction/internal fixation of the left forearm.
He subsequently developed osteomyelitis and septic arthritis of the left elbow,
in the setting of methicillin-resistant Staphylococcus aureus (MRSA) bacter-
emia. The patient underwent surgical irrigation and debridement with com-
plete removal of the internal fixation device, and was treated with vancomycin
15 mg/kg IV every 12 hours. He was on day 16 of home intravenous therapy
when he developed a pruritic vesiculobullous eruption, mostly involving his
chest and upper arms, and painless mouth ulcers (Figure 14f.1).
Over a 24-hour period, the severity of the vesiculation progressed, raising
concerns of possible Stevens-Johnson syndrome; therefore, the patient was
CHAPTER 14

admitted. The serum vancomycin concentration on admission was 13.7 μg/ml,

and all subsequent doses were held. He denied odynophagia, gastrointestinal
bleeding, fever, or chills. One day after admission, there were no new lesions
but the vesicles and bullae present were evolving to become unroofed ulcers
(Figure 14f.2). He did not develop leukocytosis or eosinophilia, and hepatic and
352

metabolic panels were within normal limits. Pruritus persisted for several days,
and the lesions remained mostly restricted to the chest, extremities, and mouth
(Figure 14f.3). Daptomycin was used for the remainder of the patient’s treat-
ment for MRSA bacteremia and osteomyelitis.
A punch biopsy of a bullous lesion of the right arm demonstrated subepider-
mal vesiculation, further characterized by marked papillary dermal edema and
an intraepidermal vesicle containing, and surrounded by, a mixed inflammatory
infiltrate comprised mostly of neutrophils, but also with a significant number

Figure 14f.1 Oral ulcers on the hard palate.

 Noninfectious Syndromes that Mimic Infections
Figure 14f.2 Right arm skin lesions: the vesicles and bullae were evolving to become
unroofed ulcers.

353 CHAPTER 14

Figure 14f.3 Chest skin lesions: erosions that had evolved from vesicles and bullae.

of eosinophils (Figure 14f.4). Fibrin deposition was present within the dermis
and the blister cavity, and direct immunofluorescence for IgA was positive for
linear segmental deposits along the dermal–epidermal junction (Figure 14f.5).
Immunofluorescence for IgG, IgM, and C3 were negative. The eruption com-
pletely resolved over two weeks, and the patient’s infection responded to dap-
tomycin without further complication.
Noninfectious Syndromes that Mimic Infections

Figure 14f.4 Skin biopsy, hematoxylin and eosin stain showing a supepidermal cleft
with a prominent neutrophilic infiltrate in the papillary dermis consistent with a linear
CHAPTER 14

IgA immune reaction.

354

Figure 14f.5 Skin biopsy, direct immunofluorescence stain showing a linear band of IgA
at the dermal epidermal junction.

Case 14f Discussion: Vancomycin-associated Linear IgA

Bullous Dermatosis
Vancomycin drug reactions are frequent, but true allergic reactions are rare. As
vancomycin use has increased over the last decade, it can be anticipated that
reactions to this drug may become more frequent. We discuss below several
types of vancomycin reactions, with a focus on linear IgA deposition.
“Red Man Syndrome”
The most common reaction to vancomycin is “red man syndrome.” This
response is generally believed to be caused by direct action on mast cells,
resulting in histamine release. Red man syndrome is best classified as an idio-
pathic infusion reaction, which resembles IgE-mediated anaphylaxis but does
not involve drug-specific IgE. In vitro studies indicate that vancomycin directly

Noninfectious Syndromes that Mimic Infections

activates mast cells, resulting in release of vasoactive mediators, including hista-
mine.1 Red man syndrome is characterized by flushing, erythema, angioedema,
and pruritus, usually affecting the upper body, neck, and face, predominantly.
Myalgias, muscle spasms, dyspnea, and hypotension may also occur. Although
clinically it resembles an anaphylactic reaction, it does not require prior sensiti-
zation and is often largely dependent on the rate of administration of the drug.
An infusion rate of 33 mg/min (1 gram over 30 minutes) has been used in
the majority of patients symptomatic with red man syndrome, whereas rates
of 10 mg/min (corresponding to 1 gram over 1.67 hours or less) rarely cause
symptoms (package insert). Premedication with antihistamines may prevent a
reaction. A small, randomized double blind trial of 33 patients found that pre-
treatment with diphenhydramine (50 mg orally), along with the first dose of 1
gram of vancomycin over 60 minutes, prevented red man syndrome. Reactions
occurred in 8 of 17 (47%) of the placebo group, compared to none in the
diphenhydramine group (p=0.003).2
IgE-Mediated Vancomycin Reaction

CHAPTER 14
True allergy to vancomycin is rare, and requires prior exposure to vancomycin.
Patients may initially appear to have red man syndrome, but their symptoms
do not improve with slower infusion rates or antihistamines. There are two
case reports of patients with true anaphylaxis with positive skin testing, who

355
underwent desensitization and then tolerated a course of vancomycin by main-
taining constant detectable drug levels.3 There are no validated skin testing pro-
cedures, and predictive values are unknown; however, intradermal skin tests
were positive at 0.1 mcg/ml, whereas control subjects reacted at >10 mcg/ml.3
Rare Severe Skin Reactions
Stevens-Johnson syndrome (SJS), exfoliative dermatitis, and toxic epidermal
necrolysis (TEN) have all been described in case reports in response to van-
comycin.4 Early recognition and discontinuation of the medication are critical.
Desensitization should never be performed following these reactions, as re-
exposure to the drug could result in a more severe or fatal recurrence of the
reaction.
Linear IgA Bullous Dermatosis
Linear IgA bullous dermatosis (LABD) was first described as an autoimmune
disease characterized by bullous lesions from deposition of IgA along basement
membranes. This entity can be idiopathic (associated with malignancy and con-
nective tissue diseases, such as rheumatoid arthritis and systemic lupus erythe-
matosus), or drug-induced. There are several case reports in the literature of
this reaction to vancomycin, and the initial presentation is often confused with
TEN or SJS (as was seen in our case).
LABD may present from one day to one month following initiation of vanco-
mycin treatment. The reaction appears to be idiosyncratic and unrelated to peak
or trough serum vancomycin concentrations. The medication history is impor-
tant, as these subepidermal bullous lesions are often difficult to distinguish from
bullous pemphigoid, erythema multiforme, or dermatitis herpetiformis, both on
 clinical and histopathologic grounds. The histopathology is characterized by a
Noninfectious Syndromes that Mimic Infections

subepidermal blister with a predominately neutrophilic infiltrate and perivascu-

lar inflammation. The definitive finding of linear IgA bullous dermatitis is linear
IgA deposition at the dermal–epidermal junction, with direct immunofluores-
cence studies. The distinction between idiopathic and drug-induced LABD is
made by removal of the offending medication, which results in resolution of
drug-induced lesions, whereas in idiopathic settings they persist.
Patients with drug-induced LABD tend to be older and lack mucosal or
conjunctival lesions, whereas up to 40% of patients with the idiopathic vari-
ety have mucosal involvement.5 The drug-induced variant usually responds
partially to systemic immunosuppressive treatment, and tends to be localized
more to pressure-bearing areas. Circulating anti-basement membrane zone IgA
antibodies are usually not detectable in drug-induced LABD, but are found in
13%–30% of patients with idiopathic linear IgA.5 Vancomycin-induced LABD has
been reported to resolve after the cessation of vancomycin in all of the pre-
viously reported cases.5,6 Although vancomycin is most frequently associated
with LABD, other drugs have been reported to cause this reaction, including
CHAPTER 14

ampicillin, rifampin, and sulfamethoxazole ⁄ trimethoprim.5 When compared to

LABD, SJS has more consistent mucous membrane involvement, less pruritus,
more confluent erythema, and widely disseminated purpuric macules and pap-
ules, including typical or atypical target lesions.7 Histologically, SJS is notable
for extensive epidermal necrosis and only sparse inflammation. Early biopsy is
356

needed to distinguish between the two entities, as this has an impact on prog-
nosis and management.7

References
1. Veien M, Szlam F, Holden JT, Yamaguchi K, Denson DD, Levy JH. Mechanisms of
nonimmunological histamine and tryptase release from human cutaneous mast
cells. Anesthesiology. 2000;92(4):1074–1081.
2. Wallace, MR, Mascola, JR, Oldfield, EC. Red man syndrome: Incidence, etiology,
and prophylaxis. J Infect Dis. 1991;164:1180.
3. Chopra N, Oppenheimer J, Derimanov GS, Fine PL. Vancomycin anaphylaxis
and successful desensitization in a patient with end stage renal disease on hemo-
dialysis by maintaining steady antibiotic levels. Ann Allergy Asthma Immunol. 2000;
84:633.
4. Alexander II, Greenberger PA. Vancomycin-induced Stevens-Johnson syndrome.
Allergy Asthma Proc. 1996;17(2):75–78.
5. Khan I, Hughes R, Curran S, Marren P. Drug-associated linear IgA disease mimick-
ing toxic epidermal necrolysis. Clin Exp Dermatol. 2008; 34(6):715–717.
6. Senanayake SN, Hardman DT, Miller AC. Case of vancomycin-induced linear
immunoglobulin A bullous dermatosis. Intern Med J. 2008;38(7):607.
7. Jones DH, Todd M, Craig TJ. Early diagnosis is key in vancomycin-induced linear
IgA bullous dermatosis and Stevens-Johnson syndrome. J Am Osteopath Assoc.
2004;104(4):157–163.
 Index

A patient with blurry vision, for Pseudomonas

99–104 aeruginosa, 166
Acanthamoeba encephalitis, PML and, 62, 65 for pulmonary
32–36 Pneumocystis jiroveci with, nocardiosis, 184
case presentation, 32 178–179 in S. intermedius brain
diagnosis, clinical features, prostatic abscess with, abscess, 46
33, 34, 34, 35 258 Amoxicillin
differential diagnosis, 33 Streptococcus pyogenes for infective endocarditis,
Acinetobacter haemolyticus, patient, 111–115 199
20 Treponema pallidum for Mycobacterium
Actinobacillus uveitis, 72 tuberculosis, 17
actinomycetemcomitans, Aids Clinical Trial Group for Streptococcus
201–202 (ACTG), 64 pneumoniae, 129
Acute bacterial prostatitis, Albendazole for typhoid fever, 227
257 for hydatid cysts, 232 Amoxicillin-clavulanate,
Acute myelogenous for neurocysticercosis, 59 for Nocardia farcinica
leukemia (AML), 50–53, for racemose epidural abscess, 17
94–99, 167–170 neurocysticercosis, 60 Amphotericin
Acute respiratory distress Altered mental status for GAE, 36
syndrome (ARDS), 130, in Acanthamoeba intravenous, for

357
149, 156, 217, 236, 324 encephalitis, 32–36 pulmonary
Acute retroviral syndrome, in Cryptococcus neoformans histoplasmosis, 159
286–289 meningitis, 12 for rhinocerebral
case presentation, 286 in Mycobacterium mucormycosis, 126
clinical presentation, tuberculosis meningitis, Amphotericin B. See also
diagnosis, 286–288, 16 liposomal amphotericin B
287 in Neisseria meningitidis for cutaneous
management, 288–289 meningitis, 1–3 alternariosis, 282
Acyclovir in Streptococcus for HIV-negative patients
adverse effects, 30t intermedius brain with Cryptococcus, 12
for HSV encephalitis, 25 abscess, 43–46 plus flucytosine, 12
intravenous in Strongyloides stercoralis, intravitreal, for
for HSV meningitis, 26 233–238 endophthalmitis, 96
for RBLM, 24 Alternaria, 279–282 liposomal, for
for PTSD, 345 case presentation, endophthalmitis, 99
for varicella zoster virus 279–280, 280 Amphotericin deoxycholate,
encephalitis, 30t, 31 clinical manifestations for Leishmaniasis, 309
Adult T-cell lymphoma/ cutaneous, subcutaneous Ampicillin
leukemia, 38, 40t infections, 281 with aminoglycoside, for
Advisory Committee on oculomycosis, 281 Group B streptococci,
Immunization Practices rhinosinusitis, 281 268
(ACIP), 3 treatment, 282 with gentamicin,
AIDS Amblyomma ticks, 319 clindamycin, for POVT,
altered mental status in, Amikacin 333
32–36 for endophthalmitis, 93 for typhoid fever,
Cryptococcus for Mycobacterium 227, 229
meningoencephalitis abscessus, 276 Ampicillin/sulbactam
and, 9 for Mycobacterium for Cardiobacterium
cytomegalovirus retinitis fortuitum, 276 hominis, 203
with, 76–83 for Mycobacterium for Lemierre’s syndrome,
disseminated tuberculosis, 14, 17 119
histoplasmosis with, Aminoglycosides, 17. See for liver abscess, 225
155–156, 158 also amikacin; kanamycin; for Ludwig’s angina, 111
Leishmaniasis with, 308 streptomycin for POVT, 203
nocardiosis as risk factor, for B. henselae retinitis, 89 Anakinra, for Still’s disease,
53 for KPC-E infections, 253 351
 Anaplasma phagocytophilum, for diabetic foot Ataxia. See Streptococcus
INDEX

323, 327. See also infections, 293 intermedius brain abscess

human granulocytic for prosthetic joint Atovaquone
anaplasmosis (HGA) infections, 300 for AML, 50
Anti-CD20 (monoclonal Antiparasitic therapy for Pneumocystic
B-cell antibody therapy) with corticosteroids, for pneumonia, 179t
for PTLD, 345 neurocysticercosis, 59 with proguanil and quinine
for Still’s disease, 351 for hydatid cysts from sulfate, for P. vivax
Anti-staphylococcal agents. Echinococcus granulosis, malaria, 314
See daptomycin; linezolid 231 Azacitidine, for acute
Antibiotics. See also for Leishmaniasis, 309 myelogenous leukemia,
macrolide antibiotics for T. cruzi infection, 214 167
broad-spectrum Antiretroviral therapy Azathioprine, 8, 180
for GVHD, 341 (ARVs). See also Azithromycin
for toxic shock HAART (highly active for atypical pneumonia,
syndrome, 341 antiretroviral therapy) 137
intravenous CNS Cryptococcus and, 11 for B. henselae retinitis,
for Nocardia infections, HIV-positive PML patients 89
53, 180 and, 64 for Balamuthia mandrillaris
for primary Antithymocyte globulin infection, 33
meningococcal (ATG) for infective endocarditis,
arthritis, 304 for CMV colitis, 242 199
for prosthetic joint for GVHD, 341 for Legionella pneumophila,
infections, 300 for PTLD, 345 189
for Streptococcus Antiviral therapy. See also for Mycoplasma
agalactiae necrotizing acyclovir; famciclovir; pneumoniae, 136
fascitis, 180 ST-246; valacyclovir for Streptococcus
for Streptococcus bovis for GVHD, 341 pneumoniae, 127
endophthalmitis, 93 for herpes zoster for typhoid fever, 229
for Streptococcus ophthalmicus, 28 Aztreonam
358

pneumoniae for H1N1 influenza, 151 for KPC-producing

meningitis, 5 for PTLD, 345 Klebsiella pneumoniae,
intravitreal for varicella zoster virus 253
for endogenous encephalitis, 29, 30t, 31 for Pseudomonas
endophthalmitis, 93 Arthritis aeruginosa, 166
oral meningococcal arthritis,
for chronic prostatitis, 303–304
256, 257 rheumatoid arthritis, 8, B
for liver abscesses, 225 26, 156, 298, 346–347, Babesia microti, 320–324
for Mycobacterium 349, 355 Babesiosis, 320–324
fortuitum, 274 septic arthritis, 1, 118, case presentation, 320
for typhoid fever, 229 268, 296, 303, 352 clinical presentation,
for uncomplicated systemic onset juvenile 323–324
typhoid fever, 229 inflammatory arthritis, diagnosis, 324
systemic 348–351 differential diagnosis, 324
for endocarditis, 93 Arthrodesis, for prosthetic epidemiology, 321–322,
for liver abscess, 225 joint infections, 300 321–323
triple antibiotic regimen Arthroplasty. See prosthetic treatment, 324
for POVT, 333 joint infections Bacillary angiomatosis (BA),
Antibiotics with Aspergillus fumigatus, in 84, 87
antipseudomonal activity. immunocompromised Bacillary peliosis (BP), 84
See aminoglycosides; hosts, 170–176 Back pain. See
aztreonam; carbapenems; case presentation, Staphylococcus aureus
cefepime; ceftazidime; 170–172, 171–173 epidural abscess
ciprofloxacin; clinical presentation, Bacterial meningitis, 6,
levofloxacin; piperacillin; diagnosis, 172–175 16, 20
ticarcillin management, 175–176 Bacteroides, 46
Antiepileptic medications, Aspergillus fumigatus Balamuthia mandrillaris
in S. intermedius brain endophthalmitis, 94–99 infection, 33
abscess, 46 clinical features, diagnosis, Bartonella bacilliformis, 84
Antihistamines prior 97–98 Bartonella henselae retinitis,
to vancomycin, for presentation, case history, 84–89
“red man syndrome” 94–96, 94–96 case history, 84, 84
prevention, 355 treatment, 98–99 clinical presentation,
Antimicrobial treatment Asplenia, 8, 303 diagnosis, 84, 87–88
for Cryptococcus Asymptomatic inflammatory differential diagnosis, 88
neoformans, 12 prostatitis, 257, 259 management, 89
Bartonella quintana, 84 Carbapenems. See also for pneumococcal

INDEX
Benznidazole, for Chagas ertapenem; imipenem; meningitis, 7
disease, 214 meropenem for recurrent meningitis,
Beta-lactam antibiotics for Group B streptococci, 23
for B. henselae retinitis, 89 268 for Streptococcus
for Cardiobacterium for liver abscess, 225 constellatus
hominis, 203 for Ludwig’s angina, 111 endocarditis, 194
for Lemierre’s syndrome, for Pseudomonas for Streptococcus
119 aeruginosa, 166 pneumoniae, 127,
for liver abscess, 225 in S. intermedius brain 129, 131
for Ludwig’s angina, 111 abscess, 46 with vancomycin, 131
for Neisseria meningitidis, Cardiac infections, 191–215 Cellulitis, 110, 112, 114, 209,
304 Cardiobacterium 262, 268, 270
for Pseudomonas hominis endocarditis, Cephalexin, for infective
aeruginosa, 166 200–203 endocarditis, 199
for TSS, 341 Chagas’ disease, 208–214 Cephalosporins. See
BK virus hemorrhagic Streptococcus constellatus fourth-generation
cystitis, 249–251 endocarditis, 191–199 cephalosporins;
case presentation, 249, tubercular pericarditis, third-generation
249–250 204–208 cephalosporins
clinical presentation, Cardiobacterium hominis Cerebrospinal fluid (CSF)
diagnosis, 250–251 endocarditis, 200–203 analysis
management, 251 case presentation, 200 for C. neoformans, 9
Bone and joint infections, clinical features, diagnosis, for HTLV-1, 40t
291–304 203 for Klebsiella pneumoniae
diabetic foot infections, treatment, 203 meningitis, 19f
291–293 Cat scratch disease (CSD), for Mycobacterium
Mycobacteria tuberculosis, 87–89 tuberculosis, 16
293–296 Cefazolin for N. meningitidis, 1
Neisseria meningitidis, for perioperative for RBLM, 23

359
301–304 prophylaxis, 217 for S. pneumoniae, 4f, 5f
prosthetic joint infections, for Pseudomonas keratitis, for Streptococcus
297–301 70 intermedius, 44–45
Borrelia burgdorferi, with tobramycin, for varicella zoster virus
323, 327 cyclopentolate encephalitis, 26
Brain abscesses hydrochloride, 67 Chagas disease, 208–214
methods of acquisition, Cefepime, 148 case presentation,
46, 48 for febrile neutropenia, 208–210, 209–210
Staphylococcus aureus 167 epidemiology,
management, 49 for Pseudomonas parasitology, 210–211,
presentation, diagnosis, aeruginosa, 166 211, 212
48–49 with vancomycin for Chickenpox, 27, 318
Streptococcus intermedius Klebsiella pneumoniae Children
presentation, diagnosis, meningitis, 21 Acanthamoeba in, 34
43–46, 44, 45 Cefotaxime bacterial meningitis in,
treatment, 46 for Neisseria meningitidis, 6, 8
Brivudin, for varicella zoster 304 Bartonella henselae in, 87
virus encephalitis, 30t for pneumococcal human ehrlichiosis in, 329
Bronchiolitis, 150, 150, meningitis, 7 influenza vaccination
151, 169 Cefoxitin, for Mycobacterium for, 152
Bronchiolitis obliterans, 242, abscessus, 276 P. vivax malaria in, 312
336, 337 Ceftazidime respiratory syncytial virus
Bullous myringitis, 135 for Pseudomonas in, 168–169
Bullous pemphigoid, aeruginosa, 166 S. pneumoniae in, 131
355–356 with vancomycin for Sporothrix schenckii in, 279
Klebsiella pneumoniae Streptococcus pyogenes
meningitis, 21 in, 115
C Ceftriaxone systemic onset juvenile
Calcineurin inhibitors. with clindamycin, for inflammatory arthritis
See cyclosporine; Lemierre’s syndrome, in, 348–351
tacrolimus 119 typhoid fever in, 228, 229
Candida albicans, 97 (IV) for infective vector-borne infections in,
Carbapenem resistance endocarditis, 197 213, 214
by Enterobacteriaceae, with metronidazole, for Chloramphenicol
252–253 liver abscess, 225 for B. henselae retinitis, 89
by Klebsiella pneumoniae, for Neisseria meningitidis, for Rickettsialpox, 319
252–253 304 for typhoid fever, 229
 Chloroquine case presentation, 217, pathology, 337
INDEX

for Entamoeba histolytica, 218–219 presentation, case history,

226 diagnosis, 220 334–336, 335
for P. vivax malaria, epidemiology, clinical Cutaneous leishmaniasis,
313–314 presentation, 217, 309
Cholestyramine, for 219–220 Cyclopentolate
Clostridium difficile colitis, prevention, 221 hydrochloride, 67
221 treatment, 220–221 Cyclophosphamide
Chronic bacterial prostatitis, CMVR (cytomegalovirus for cryptogenic organizing
257 retinitis), 100, 103–104 pneumonia, 338
Chronic prostatitis/chronic Co-trimoxazole, for B. for transfusion-dependent
pelvic pain syndrome, henselae retinitis, 89 aplastic anemia, 249
257, 258 Colitis Cycloserine, for
Cidofovir Clostridium difficile colitis, Mycobacterium
for PML, 64 217–2221 tuberculosis, 14, 17
with probenecid, for cytomegalovirus colitis, Cyclosporine
CMVR, 82 81, 239–245 for graft versus host
resistance to, 78 ulcerative colitis, 28 disease, 341
for vaccinia virus infection, Community-acquired for Still’s disease, 351
285 pneumonia (CAP), Cysticercus cellulosae, 59
Ciprofloxacin 130–131, 136, 164 Cysticidal agents.
for AML, 50 Congestive heart failure See albendazole;
with metronidazole, for (CHF), 135, 197, 217, mebendazole
liver abscess, 225 255, 324 Cystoid macular edema
for Mycobacterium Conjunctival infection. See (CME), 103
fortuitum, 276 Treponema pallidum Cytarabine (IV) therapy, for
for Pseudomonas uveitis HIV-negative patients
aeruginosa, 166 Contact lenses. See with PML, 65
for Pseudomonas keratitis, Pseudomonas keratitis Cytomegalovirus colitis,
70 Coronary artery disease, 47 239–245
360

Clarithromycin Corticosteroids case presentation,

for infective endocarditis, for AML, 94 239–242, 240–241
199 with antiparasitic therapy, discussion, 242
for Legionella pneumophila, for neurocysticercosis, prevention, 242–244,
189 59 244t
for M. chelonae/ for GVHD, 341 treatment, 244–245
M. abscessus isolates, for Mycobacterium Cytomegalovirus retinitis
276 tuberculosis, 14, 17 (CMVR), 76–83, 100,
for M. marinum infections, for neurosyphilis, 72 103–104
275 oral, for B. henselae case presentation, 76,
for Mycobacterium retinitis, 89 77–78, 79–81
abscessus, 276 oral/IV for Treponema clinical features, diagnosis,
for Mycobacterium pallidum uveitis, 75 81–82
tuberculosis, 17 in S. intermedius brain diseases caused by, 81
Clavulanate abscess, 46 treatment, 82–83
for Mycobacterium for Streptococcus pyogenes, Cytotoxic chemotherapy,
tuberculosis, 17 115 for PTLD, 345
Clindamycin for tuberculous
with cephalosporins + pericarditis, 206, 208
metronidazole for Coxiella burnetti, 201 D
Ludwig’s angina, 111 Coxsackievirus, 24 Dapsone
with gentamicin, ampicillin Cranial epidural abscesses, for Nocardia farcinica
for POVT, 333 49 epidural abscess, 53
for graft versus host Crohn’s disease, 28 for Pneumocystis
disease, 340 Cryoglobulinemia, 40t pneumonia, 179t
for infective endocarditis, Cryptococcus neoformans Daptomycin
199 meningitis, 8–13 for brain abscesses, 49
with oral quinine, for case presentation, 8–9 for MRSA, 262, 264, 277
babesiosis, 324 clinical features, 9f, 11–12 Decitabine, for acute
with primaquine, diagnosis, 10f, 11f myelogenous leukemia,
for Pneumocystic treatment, 12–13 167
pneumonia, 179t Cryptogenic organizing Deep septic pelvic
for toxic shock syndrome, pneumonia, 334–338 thrombophlebitis
340 clinical presentation, (DSPT), 331–334
for TSS, 341 diagnosis, 336, Deltamethrin (in dog
Clostridium difficile colitis, 336–337 collars) for Leishmaniasis
217–2221 management, 337–338 prevention, 310
Dermatitis herpetiformis, Echoviruses, 24 for persistent cough, 137

INDEX
355 Ehrlichia chaffeensis, 327 for tuberculous
Diabetes, 47 Ehrlichia ewingii, 327 pericarditis, 206
risk factor, for spinal Eikenella corrodens, 200, 202 Ethionamide, for
epidural abscesses, 48 Empiric antimicrobial Mycobacterium
23-valent polysaccharide medications. See tuberculosis, 17
vaccine for, 8 cephalosporin; Exfoliative dermatitis, 355
Diabetic foot infections, vancomycin
291–293 Encephalitis and myelopathy
clinical features, diagnosis, (case studies), 23–41 F
291–293, 292 Acanthamoeba Famciclovir
treatment, 293 encephalitis, 32–36 adverse effects, 30t
Differential diagnosis human T-lymphotropic for RBLM, 24
of Acanthamoeba virus-1 myelopathy, for varicella zoster virus
encephalitis, 33 36–40 encephalitis, 30t
of CSD, 88 recurrent benign Fever and confusion after
of graft versus host lymphocytic meningitis, neurosurgery. See
disease, 339 23–25 Klebsiella pneumoniae
of Nocardia asteroides, 183 varicella zoster virus meningitis
of PML, 64 encephalitis, 25–31 First-generation
of rickettsialpox, 318 Endocarditis, 45, 48 cephalosporins. See
of spinal lesions, 48 Cardiobacterium hominis azithromycin; cephalexin;
of Still’s disease, 351 endocarditis, 200–203 clarithromycin;
of syphilitic uveitis, 75 culture-negative in HIV- clindamycin
of Treponema pallidum infected patients, 84 Fluconazole
uveitis, 72 Group B streptococcal for Balamuthia mandrillaris
of unilateral infection and, 268 infection, 33
granulomatous S. bovis and, 92 high dose, with
conjunctivitis and Streptococcus constellatus amphotericin,
POS, 88 endocarditis, 191–199 for immuno-

361
Diffuse alveolar damage systemic antibiotics, 93 compromised
(DAD), 150, 150, 151 Endogenous HIV-negative patients
Diloxanide furoate, for endophthalmitis. See with Cryptococcus, 12
Entamoeba histolytica, Streptococcus bovis for lymphocutaneous/
226 endophthalmitis cutaneous
Diphenhydramine with Endophthalmitis sporotrichosis,
vancomycin, for “red Aspergillus fumigatus 278–279
man syndrome” endophthalmitis, 94–99 suppressive, for HIV-
prevention, 355 Streptococcus bovis negative patients with
Disseminated MRSA endophthalmitis, 90–93 Cryptococcus, with
infections, 47 Entamoeba histolytica, renal impairment, 12
Dizziness. See 225–226 Fluconazole consolidation
Streptococcus intermedius Epstein-Barr virus (EBV), 24, therapy
brain abscess 343, 344 for HIV-negative patients
DMARDS (disease- ERM (epiretinal membrane), with Cryptococcus, with
modifying antirheumatic 103 renal impairment, 12
drugs). See cyclosporine; Ertapenem with liposomal
methotrexate for Enterobacteriaceae- amphotericin B for
Doxycycline producing KPCs, 253 immunocompromised
for human ehrlichiosis, for liver abscess, 225 HIV-negative patients
329 Erysipelas, 114 with Cryptococcus, 12
for M. marinum infections, Erythema multiforme (EM)/ Flucytosine
275 EM major, 133, 136, 355 with amphotericin B, for
with quinine sulfate, for P. Erythromycin, for HIV-negative patients
vivax malaria, 314 Mycoplasma pneumoniae, with Cryptococcus, 12
for Rickettsialpox, 319 136 for Balamuthia mandrillaris
Escherichia coli, 20 infection, 33
Etanercept, 155–156, 188, 351 Fluoroquinolone,
E for Legionella pneumophila, pyrazinamide,
Echinocandins 188 ethambutol (plus an
for neutropenic fever, 126 for Still’s disease, 351 aminoglycoside)
in vitro/in vivo efficacy, Ethambutol for isoniazid/
for Aspergillus for M. marinum infections, rifampin resistant
fumigatus, 176 275 Mycobacterium
Echinococcus granulosus. for Mycobacterium tuberculosis, 14, 17
See hydatid cysts from tuberculosis, 14, 17, with/without second
Echinococcus granulosus 144, 145t agent, 17
 Fluoroquinolones. See intravitreal administration, HIV-related therapeutic
INDEX

also ciprofloxacin; for CMVR, 82–83 controversy, 288–289

gatifloxacin; levofloxacin; for PTSD, 345 for retinal lesions, 104
moxifloxacin resistance to, 78, 83 HACEK group of gram-
for B. henselae retinitis, 89 Gastrointestinal infections, negative bacteria, 195,
for Chlamydia pneumoniae, 217–245 196t, 200–201, 202t, 203
136 Clostridium difficile colitis, Haemophilus influenzae
for Clostridium difficile 217–2221 infection, 2–3, 164,
colitis, 220 cytomegalovirus colitis, 200, 263
for community-acquired 239–245 HAM/TSP (HTLV-1
pneumonia, 136 Entamoeba histolytica, associated myelopathy/
extended-spectrum, for 225–226 tropical spastic
epidural abscess, 53 Gemella morbillorum liver paraparesis), 39t–40t
for Legionella pneumophila, abscess, 222–226 HAP/TSP (hospital
189 hydatid cysts from associated pneumonia/
for Legionella spp., 136 Echinococcus tropical spastic
with metronidazole, for granulosus, 230–232 paraparesis), 40
liver abscess, 225 Strongyloides stercoralis, Hematopoietic stem cell
for prostatic abscess, 233–238 transplant (HSCT)
257–258 typhoid fever, 226–229 recipients, 168–170
for Pseudomonas keratitis, Gatifloxacin, for Legionella Hemorrhagic cystitis. See BK
70 pneumophila, 189 virus hemorrhagic cystitis
for S. intermedius brain Gemella morbillorum liver Heptavalent pneumococcal
abscess, 46 abscess, 222–226. conjugate (PCV-7), 7, 131
for typhoid fever, 229 See also Entamoeba Heptavalent pneumococcal
Focal central nervous histolytica conjugate (PCV-7)
system infections clinical features, diagnosis, vaccine, 7
Neurocysticercosis, 223–225 Herpes simplex virus
54–60 presentation, case history, meningoencephalitis,
Nocardia farcinica epidural 222–223 23–25
362

abscess, 50–53 treatment, 225–226 Herpes zoster ophthalmicus,

progressive multifocal Gentamicin 28
leukoencephalopathy, with clindamycin, Histoplasma capsulatum,
60–65 ampicillin for POVT, in immunocompetent
Staphylococcus aureus 333 hosts, 153–159
epidural abscess, for infective endocarditis, case presentation, 153
47–49 197 diagnosis, clinical features,
Streptococcus intermedius for Pseudomonas keratitis, 153, 154–158, 155–159
brain abscess, 43–46 70 management, 159
Focal retinochoroiditis, 88 Glomerulonephritis, 4, 36, HIV/AIDS patients. See also
Foot infections. See diabetic 110, 115, 196t immunocompromised
foot infections Glucocorticoids patients
Foscarnet for cryptogenic organizing cytomegalovirus retinitis
for CMV colitis, 240, pneumonia, 338 in, 81–82
241, 246 for Still’s disease, 351 immune reconstitution
for CMV retinitis, 76, 78, Graft versus host disease uveitis in, 102–104
82–83 (GVHD), 94, 170, 174, prostatic abscess
for graft versus host 338–342 vulnerability in, 259
disease, 342 case presentation, HIV-negative patients with
intravitreal administration, 338–339, 339 Cryptococcus
for CMVR, 82–83 clinical presentation, amphotericin B treatment,
Fourth-generation 340–341 12
cephalosporins hospital course, immunocompromised
with metronidazole, for differential diagnosis, patients
brain abscesses, 46 339–340 amphotericin with high
with metronidazole, for treatment, 341–342 dose fluconazole, 12
Ludwig’s angina, 111 Granulomatous amebic consolidated fluconazole
Fusobacterium necrophorum, encephalitis (GAE), 34 therapy, 12
118, 119–120 Group B streptococcus. See with renal impairment,
Streptococcus agalactiae liposomal amphotericin
necrotizing fasciitis B treatment, 12
G HIV-negative patients with
Ganciclovir Cryptococcus, with renal
for CMV prophylaxis, 342 H impairment
intravenous, for HAART (highly active fluconazole consolidation
cytomegalovirus colitis, antiretroviral therapy) therapy, 12
244–245, 244t CMVR and, 82–83 suppressive fluconazole, 12
HIV-negative patients with for Mycobacterium Infectious Disease Society of

INDEX
PML, IV cytarabine (IV) fortuitum, 276 America (IDSA)
therapy, 65 for pulmonary CNS cryptococcosis
HIV-positive patients nocardiosis, 184 treatment goals, 12
with PML, antiretroviral Immune globulin Klebsiella pneumoniae
therapy for, 65 for heart transplant, 244t meningitis
Pneumocystis jiroveci and, intravenous (IV) recommendations, 21
179, 180 for Clostridium difficile Infective dermatitis, 39
H1N1 influenza, in colitis, 221 Infective endocarditis (IE).
immunocompetent for PTLD, 345 See Cardiobacterium
hosts, 147–152 vaccine (VIG), for vaccinia hominis endocarditis;
case presentation, virus infection, 285 Streptococcus constellatus
147–148 Immune reconstitution endocarditis
diagnosis, 149–150 uveitis (IRU), 99–104 Infliximab, 155–156,
epidemiology, clinical clinical features, diagnosis, 188, 351
presentation, 149 102–104 for Legionella pneumophila,
pathology, 150–151 clinical presentation, 188
prevention, 152 99–102, 100–102, 104 for Still’s disease, 351
treatment, 151–152 treatment, 104 Interferon alpha-2, for
HSV encephalitis Immunocompetent patients. PML, 64
acyclovir treatment, 25 See pulmonary infections Interleukin-2, for PML, 64
types 1 and 2, 24 in immunocompetent Intravenous immunoglobulin
Human ewingii ehrlichiosis, hosts (IVG), for graft versus
327–328 Immunocompromised host disease with
Human granulocytic patients. See also possible TSS, 340
anaplasmosis (HGA), pulmonary infections in Invasive aspergillosis,
325–329 immunocompromised 174–176
clinical presentation, hosts Iodoquinol, for Entamoeba
history, 325–327, 326 Acanthamoeba disease histolytica, 226
microbiology, taxonomy, association in, 34 Isoniazid

363
327–328, 327–328 azithromycin for B. for Mycobacterium
Human T-lymphotropic henselae retinitis, 89 tuberculosis, 14, 17,
virus-1 myelopathy cytomegalovirus retinitis 144, 145t
(HTLV-1), 36–40 in, 81 for persistent cough, 137
clinical presentation, with herpes zoster, for tuberculous
36–37, 38–39 valacyclovir treatment pericarditis, 206
diagnosis/WHO for, 48t Itraconazole
diagnostic criteria, with Mycobacterium for cutaneous
39–40, 39t–40t tuberculosis, 141 alternariosis, 282
donor-derived, in organ prostatic abscess for lymphocutaneous/
transplantation, 38 vulnerability in, 259 cutaneous
epidemiology, 37–38 S. anginosus infections sporotrichosis,
management, prognosis, association in, 45, 46 278–279
40 Immunosuppression oral, for pulmonary
Hydatid cysts from reduction histoplasmosis, 159
Echinococcus granulosus, for Alternaria, 282 Ivermectin/thiabendazole,
230–232 for BK virus hemorrhagic for Strongyloides
case presentation, 230, cystitis, 251 stercoralis, 235, 238
230–231 for PML (HIV-negative Ixodes scapularis, 322–323,
clinical presentation, patients), 65 328
diagnosis, 231, 232 for PTLD, 345
management, 232 Impetigo, 114
Hydroxychloroquine, Infants J
for P. vivax malaria, Chagas disease in, 214
313–314 Group B streptococcal JC virus, 61–65, 251
Hyper-IgE syndrome (HIES), infections in, 267–268, Job’s syndrome
261, 263–264 269 (hyper-IgE syndrome),
HTLV-1 risk factors, 38 261, 263–264
meningococcal disease in, 2
I P. vivax malaria in, 312
Ichthyosis, 40t PCV-7 vaccination for, K
IgE-mediated vancomycin 7–8, 131 Kanamycin, for
reaction, 355 progressive vaccinia Mycobacterium
Imipenem in, 284 tuberculosis, 17
for liver abscess, 225 respiratory syncytial virus Ketoconazole, for cutaneous
for Mycobacterium in, 170 alternariosis, 282
abscessus, 276 S. pneumoniae in, 131 Kingella kingae, 200, 202
 Klebsiella pneumoniae Liposomal amphotericin B from Cryptococcus
INDEX

meningitis, 18–21 for Aspergillus fumigatus, neoformans, 9, 11

clinical presentation, 175 herpes simplex virus and,
diagnosis, 20 for Cryptococcus with 23–25, 28, 31
history, 18–19 HIV-negative, 12 Mycoplasma pneumoniae
treatment, 21 for Cryptococcus with and, 135
KPC-producing Klebsiella immunocompromised VZ meningoencephalitis,
pneumoniae, 251–254 HIV-negative 28–29
case presentation, 251, 252 fluconazole consolidation Meropenem
epidemiology, therapy, 12 for liver abscess, 225
microbiology, 252–253 suppressive fluconazole, with vancomycin, for
management, 253–254 12 Klebsiella pneumoniae
with flucytosine/ meningitis, 21
fluconazole, for Methicillin-resistant
Cryptococcus with renal Staphylococcus aureus
L impairment, 12 infection (MRSA), 47,
Late complement-deficient for Leishmaniasis, 309 111, 149, 164, 165t,
(LCCD) patients for pulmonary 283, 352
risk factors, 2–3 histoplasmosis, 159 clinical features, diagnosis,
vaccine interval for, 3 Ludwig’s angina, 107–111 263–264
Legionella pneumophila, in case presentation, 107, clinical presentation,
immunocompromised 108–109 history, 261–262,
hosts, 184–189 clinical presentation, 262–263
case presentation, diagnosis, 110 therapy, 166, 261, 262,
184–185, 185–187, 187 management, 110–111 264, 277
clinical features, diagnosis, Lyme disease, 75, 88, 323, Methotrexate
188–189 326, 327 for GVHD, 341
microbiology, Lyponyssoides sanguineus, for Still’s disease, 351
epidemiology, 187–188 316 Methylprednisone
treatment, 189 for cryptogenic organizing
364

Leishmaniasis, 305–310 pneumonia, 338

case presentation, M pulse-dose, for Still’s
305–306, 306–307 Macrolide antibiotics. disease, 351
clinical features, diagnosis, See also azithromycin; Metronidazole
307–309 clarithromycin with cephalosporin, for
management, 309–310 for B. henselae retinitis, 89 brain abscesses, 46
Lemierre’s syndrome, for Legionella pneumophila, for Entamoeba histolytica,
116–120 189 226
case presentation, for M. chelonae/M. for F. necrophorum, 46
116–118, 117–118 abscessus, 276 oral, for Clostridium
clinical features, 118 for prostatic abscess, difficile colitis, 220–221
diagnosis and treatment, 257–258 for Streptococcus
119–120 Mebendazole, for hydatid pneumoniae, 127
Levofloxacin, 148 cysts, 232 Miltefosine
for AML, 94 Mefloquine for GAE, 36
for febrile neutropenia, 167 for JC virus, 65 for Leishmaniasis, 305, 309
for Legionella pneumophila, with quinine sulfate, for Minocycline, for Nocardia
189 P. vivax malaria, 314 farcinica epidural abscess,
with metronidazole, for Meningitis (case studies), 53
liver abscess, 225 1–21 Mirtazapine, for PML, 65
for Mycoplasma Cryptococcus neoformans Mollaret, Pierre, 23–24
pneumoniae, 136 meningitis, 8–13 Monoclonal B-cell antibody
for Pseudomonas Klebsiella pneumoniae therapy (anti-CD20)
aeruginosa, 166 meningitis, 20–21 for PTLD, 345
Linear IgA bullous dermatitis Mycobacterium tuberculosis for Still’s disease, 351
(LABD), 355–356 meningitis, 13–17 Monoclonal gammopathy,
Linezolid Neisseria meningitidis 40t
for brain abscesses, 49 meningitis, 1–3 Moraxella catarrhalis, 164
for MRSA, 166, 264 Streptococcus pneumoniae Moxifloxacin
for Mycobacterium meningitis, 4–8 for epidural abscess, 53
tuberculosis, 17 Meningococcal arthritis, for Mycobacterium
for Nocardia farcinica 303–304 tuberculosis, 14
epidural abscess, 53 Meningococcal meningitis, for Mycoplasma
for Pseudomonas 3, 303 pneumoniae, 136
aeruginosa, 166 Meningococcemia, 303–304 MRSA infections, 47
for pulmonary Meningoencephalitis Mucocutaneous leishmaniasis,
nocardiosis, 184 Chagas disease and, 213 308
Mucormycosis. See Mycophenolate mofetil, 120, N,N-Diethyl-

INDEX
rhinocerebral 170, 233, 239, 242, 249, meta-toluamide (DEET)-
mucormycosis 251, 341, 343 based skin repellent, for
Mus musculus, 316 Mycoplasma pneumoniae, Leishmaniasis prevention,
Myasthenia gravis, 8, 180 in immunocompetent 309
Mycobacterium africanum, hosts, 132–136 Nocardia asteroides, in
140 case presentation, immunocompromised
Mycobacterium avium- 132–133, 132–133 hosts, 180–184
intracellulare, 295 clinical features, 134–136, case presentation,
Mycobacterium bovis, 140 135 180–181, 182
Mycobacterium canetti, 140 diagnosis, 136 clinical manifestations,
Mycobacterium caprae, 140 microbiology, 181–183
Mycobacterium chelonae/ epidemiology, 134 laboratory diagnosis,
abscessus group, 274, treatment, 136 183–184
275, 295 management, prognosis,
Mycobacterium fortuitum, 184
271–276, 295 Nocardia farcinica epidural
case presentation, 271, N abscess, 50–53
271–274, 274 Naegleria fowleri, 33 case presentation, 50–52
clinical presentation, Neck swelling clinical features, diagnosis,
274–275, 274–276 and sore throat 50, 51–52, 52–53
microbiology, 274 (case) (See Ludwig’s management, 53
treatment, 276 angina) risk factors for, 53
Mycobacterium gordonae, and stridor (case) Non-Hodgkin’s lymphoma,
274 (See Ludwig’s angina) 167, 170, 263
Mycobacterium haemophilum, Necrotizing bronchiolitis, Noninfectious syndromes
295 151 that mimic infections,
Mycobacterium kansasii, 295 Necrotizing cellulitis, 107 331–356
Mycobacterium marinum, Necrotizing fasciitis, cryptogenic organizing
274–275, 295, 308 114–115, 265–270, 341 pneumonia, 334–338

365
Mycobacterium microti, 140 Necrotizing graft versus host disease,
Mycobacterium mucogenicum tracheobronchitis, 150, 338–342
group, 274 150 post-transplant
Mycobacterium pinnipedii, Neisseria meningitidis, in joint lymphoproliferative
140 infection disease, 343–345
Mycobacterium smegmatis case presentation, 301, septic pelvic
group, 274 302 thrombophlebitis,
Mycobacterium tuberculosis, microbiology, 303 331–334
in immunocompetent treatment, 303–304 Still’s disease, 346–351
hosts, 137–147 Neisseria meningitidis vancomycin-associated
case presentation, 137, meningitis, 1–3 reactions, 352–356
138–140, 140 in complement-deficient Nontuberculous
clinical features, 142–143 patients, 2–3 mycobacteria (NTM),
diagnosis, 143–144 vaccination interval for 263, 274–275, 278, 295
microbiology, LCCD patients, 3 Nosocomial pulmonary
epidemiology, Neonates and Group B infections, 144, 161–166.
140–142, 141, 143 streptococcal disease, See also Pseudomonas
treatment, 144, 145t–146t, 267–268 aeruginosa, in
147 Neovascular membrane immunocompromised
Mycobacterium tuberculosis, formation (NVE), 103 hosts
thumb lesion, 293–296 Neuraminidase inhibitors. NSAIDs, for Still’s disease,
case presentation, See oseltamivir; 351
293–295, 294 peramivir; zanamivir
clinical presentation, Neurocysticercosis
diagnosis, 295–296 case presentation, 54, O
treatment, 296 55, 56 Oculomycosis, 281
Mycobacterium tuberculosis diagnosis, 58–59 Ophthalmologic infections,
complex, 274 epidemiology, clinical 67–105
Mycobacterium tuberculosis presentation, 57 Aspergillus fumigatus
meningitis, 13–17 management of, 59–60 endophthalmitis,
clinical features, diagnosis, Neuroretinitis, 88 94–99
14f, 15f, 16 New World cutaneous Bartonella henselae
TB, HIV coinfection, 17 leishmaniasis, 309 retinitis, 84–89
treatment, 17 Nifurtimox, for Chagas cytomegalovirus retinitis,
Mycobacterium ulcerans, disease, 214 76–83
275, 295 Nitazoxanide, for Clostridium immune reconstitution
Mycobacterium xenopi, 295 difficile colitis, 221 uveitis, 99–104
 Pseudomonas keratitis, for vancomycin allergic Polymyxins, for KPC-E
INDEX

67–70 patients, 268 infections, 253–255

Streptococcus bovis Penicillin G Polysaccharide diphtheria
endophthalmitis, for antibiotic prophylaxis, toxoid conjugate
90–93 270 vaccine, 3
Treponema pallidum for Group B streptococci, Posaconazole
uveitis, 70–76 268, 270 for cutaneous
Oropharyngeal and sinus (IV), for E-lactamase alternariosis, 282
infections, 107–126 negative (in vitro efficacy)
Lemierre’s syndrome, F. necrophorum, 120 for pulmonary
116–120 for Neisseria meningitidis, histoplasmosis, 159
Ludwig’s angina, 107–111 304 for lymphocutaneous/
rhinocerebral Pentamidine cutaneous sporo-
mucormycosis, for Balamuthia mandrillaris trichosis, 278–279
120–126 infection, 33 oral, for Aspergillus
Streptococcus pyogenes, for GAE, 36 fumigatus, 175
111–115 for Pneumocystic for rhinocerebral
Oroya fever, 84 pneumonia, 179t mucormycosis, 126
Orthopoxviruses. See Pentavalent antimony, for Post-herpetic neuralgia
vaccinia virus infection Leishmaniasis, 309 (PHN), 27, 28
Oseltamivir, 148, 152 Peptostreptococcus, 46 Post-transplant
Osteomyelitis Peramivir, for H1N1 lymphoproliferative
daptomycin treatment, influenza, 152 disease (PTLD), 242,
352 Pericardial infections, 109, 343–345
in diabetic foot infections, 205. See also tubercular case presentation,
292, 293 pericarditis 333–334, 343–344
Group B streptococcal Peromyscus leucopus, 323 clinical presentation,
infections and, 268 Phenylbutazone, for RBLM, diagnosis, 344–345
tuberculous osteomyelitis, 24–25 management, 345
295–296 Piperacillin, for Pseudomonas Postpartum ovarian vein
366

vertebral osteomyelitis, aeruginosa, 166 thrombosis (POVT),

48, 53, 110, 248, 296 Piperacillin/tazobactam 332–334
for liver abscess, 225 Praziquantel
for Ludwig’s angina, 111 for adult tapeworm, 59
P for POVT, 333 for liver cysts, 230
P-aminosalicylic acid, Placoid chorioretinitis, for neurocysticercosis, 59
for Mycobacterium 74–75 Prednisone, 8
tuberculosis, 17 Plasmodium falciparum, 312, for AML, 94
PAIR (percutaneous 313, 324 for cryptogenic organizing
aspiration, installation, Plasmodium knowelsi, 313 pneumonia, 338
and respiration) Plasmodium malariae, 313 high-dose/oral, for Still’s
procedure, 230, 232 Plasmodium ovale, 313 disease, 351
Palivizumab, for respiratory Plasmodium vivax malaria, oral, for erythema
syncytial virus, 169, 170 310–314 multiforme major
Parinaud’s oculoglandular case presentation, with Mycoplasma
syndrome (POS), 88 310–311, 312 pneumoniae, 133
Paromomycin, for clinical presentation, for Pneumocystis
Entamoeba histolytica, diagnosis, 312–313 pneumonia, 94
226 diagnosis, 313, 313–314 Premethrin-based
Pediatric infections. See treatment, 313–314 clothing treatment, for
children; infants; Pneumocystis carinii. See Leishmaniasis prevention,
neonates Pneumocystis jiroveci, in 309
Penicillin immunocompromised Prevotella, 46
for Group B streptococci hosts Primaquine
infection, 269 Pneumocystis jiroveci with clindamycin,
for infective endocarditis, (Pneumocystis pneumonia), for Pneumocystis
197 in immunocompromised pneumonia, 179t
intravenous (IV) hosts, 176–179 for P. vivax malaria, 314
for neurosyphilis, 72 case presentation, Probenecid, with cidofovir,
for Treponema pallidum 176–177, 177–178 for CMVR, 82
uveitis, 75 epidemiology, diagnosis, Probiotics, for Clostridium
for pneumococcal 178 difficile colitis, 221
pneumonia, 131 in non-HIV-infected Progressive multifocal
for Streptococcus bovis patients, 178–179 leukoencephalopathy
endophthalmitis, 93 treatment, 178–179 (PML), 60–65
for Streptococcus pyogenes, Pneumonia severity index AIDS-associated PML,
115 (PSI), 130–131 62, 65
 case history, presentation, Legionella pneumophila, clinical presentation,

INDEX
60–61, 61, 62 184–189 diagnosis, 168–169
clinical presentation, Nocardia asteroides, management, 169–170
diagnosis, 62–64 180–184 Rheumatoid arthritis, 8,
JC virus association, 61–65 Pneumocystis jiroveci, 26, 27–28, 156, 298,
management of, 64–65 176–179 346–347, 349, 355
Prophylactic mold-active Pseudomonas aeruginosa, Rhinocerebral
oral triazoles, for 161–166 mucormycosis, 120–126
Aspergillus fumigatus, in respiratory syncytial virus case presentation,
immunocompromised (RSV), 167–170 120–121, 121–124
patients, 175 Pulmonary nocardiosis. See clinical features, diagnosis,
Propionibacterium acnes, 20 Nocardia asteroides, in 125–126
Prostatic abscess, 255–259 immunocompromised epidemiology, 121,
case presentation, hosts 124–125
255–256, 255–256 Pyrazinamide management of, 126
clinical presentation, 257 for Mycobacterium Rhinosinusitis, 281
diagnosis, 257–259 tuberculosis, 14, 17, Rhodococcus equi infections,
epidemiology, 256–257 144, 145t, 148, 295 183
treatment, 257–258 for persistent cough, 137 Ribavirin
Prosthetic joint infections, for tuberculous aerosolized, for
297–301 pericarditis, 206 respiratory syncytial
clinical presentation, virus, 169
299–300 intravenous, for
microbiology, 298–299 Q respiratory syncytial
presentation, case history, Quinine sulfate for P. vivax virus, 169
297, 297–298 malaria Rickettsia africae, 319
risk factors, 298 with atovaquone- Rickettsia akari, 315–316,
treatment, 300–301 proguanil, 314 318
Proteus mirabilis, 20 with doxycycline, 314 Rickettsia conorii, 319
Pseudomonas aeruginosa, with mefloquine, 314 Rickettsialpox, 315–319

367
20, 68, 69 with tetracycline, 314 case presentation, 315, 316
Pseudomonas aeruginosa, in Quinine (oral) with clinical features, diagnosis,
immunocompromised clindamycin, for 316, 317, 318–319, 319
hosts, 161–166 babesiosis, 324 differential diagnosis, 318
case presentation, 161, Quinolones, for prosthetic treatment, 319
162–164 joint infections, 300 Rifampin
clinical presentation, for B. henselae retinitis, 89
diagnosis, 164–165 for GAE, 36
management, 166 R for human ehrlichiosis, in
pathology, 161, 164 Racemose pregnancy, 329
Pseudomonas keratitis, neurocysticercosis, 60 for Legionella pneumophila,
67–70 Ramoplanin, for Clostridium 189
case presentation, 67–68 difficile colitis, 221 for M. marinum infections,
clinical features, diagnosis, Ramsey-Hunt syndrome, 28 275
68–70 RBLM. See recurrent benign for Mycobacterium
organisms associated lymphocytic meningitis tuberculosis, 14, 17,
with, 69 Recurrent benign lymphocytic 144, 145t
risk factors, 68–69 meningitis (RBLM), 23–25 for persistent cough, 137
treatment, 70 case presentation, 23 for tuberculous
Pulmonary alveolitis, 40t clinical manifestations, pericarditis, 206
Pulmonary infections in diagnosis, 23–24 Rifamycins
immunocompetent treatment, 24–25 for Clostridium difficile
hosts, 128–159 Recurrent meningitis. colitis, 221
Histoplasma capsulatum, See recurrent benign for human ehrlichiosis,
153–159 lymphocytic meningitis 329
H1N1 influenza, 147–152 (RBLM) Rifapentine (long
Mycobacterium Red man syndrome, 48, acting rifamycin),
tuberculosis, 137–147 354–355 for Mycobacterium
Mycoplasma pneumoniae, Respiratory fluoroquinolones. tuberculosis, 144, 146t,
132–136 See gatifloxacin; 148
Streptococcus pneumoniae, levofloxacin; moxifloxacin Ripichephalus sanguineus,
127–131 Respiratory syncytial 319
Pulmonary infections in virus (RSV), in Rituximab
immunocompromised immunocompromised for PTLD, 345
hosts, 161–190 hosts, 167–170 for Still’s disease, 351
Aspergillus fumigatus, case presentation, Rocky Mountain spotted
170–176 167–168, 167–168 fever, 318–319
 S Spontaneous aerobic diagnosis, 195–196, 196t
INDEX

Gram-negative bacillary management, 196–197

Salicylates, for Streptococcus meningitis, 20 prevention, 198–199
pyogenes, 115 Sporothrix schenckii, 277–279 Streptococcus gallolyticus, 92
Salmonella enterica serotype case presentation, 277, Streptococcus intermedius
Typhi. See typhoid fever 277–278 brain abscess, 43–46
Salvage therapy clinical manifestations, 278 case presentation, 43
of invasive aspergillosis, diagnosis, 278 clinical presentation,
176 treatment, 278–279 diagnosis, 43–46,
of rhinocerebral ST-246 (experimental 44, 45
mucormycosis, 126 antiviral), for vaccinia Streptococcus macedonicus,
Sarcoidosis. See virus infection, 285 92
progressive multifocal Staphylococcus aureus Streptococcus pasteurianus,
leukoencephalopathy bacteremia (SAB), 92
Saturated solution of 247–248 Streptococcus pneumoniae,
potassium iodide (SSKI), Staphylococcus aureus in immunocompetent
for lymphocutaneous/ bacteriuria (SABU), hosts, 127–131. See also
cutaneous sporotrichosis, 247–248 community-acquired
279 Staphylococcus aureus pneumonia (CAP)
Seizures epidural abscess, 47–49 case presentation,
in Herpes simplex virus case presentation, 47–48 127–129, 128–130
meningitis, 24 clinical presentation, diagnosis, clinical features,
in Mycobacterium diagnosis, 48–49 130–131
tuberculosis meningitis, differential diagnosis, 48 treatment, prevention,
16 management, 49 131
in Streptococcus Staphylococcus aureus Streptococcus pneumoniae
intermedius brain pyelonephritis, 247–248, meningitis, 4–8
abscess, 45, 46 248 clinical features, 6–7
Septic arthritis, 1, 118, 268, Staphylococcus epidermis, diagnosis, 4f, 5f, 6f, 7
296, 303, 352 46, 69 treatment, prevention,
368

Septic jugular Stevens-Johnson syndrome 7–8

thrombophlebitis, 118 (SJS), 136, 352, 355 Streptococcus pyogenes,
Septic pelvic Still’s disease, 346–351 111–115
thrombophlebitis, clinical presentation, case presentation,
331–334 diagnosis, 348–351 111–113, 112–114
case presentation, 331, presentation, case history, clinical features, diagnosis,
332 346–347, 346–348 114–115
differential diagnosis, treatment, 351 management, 115
hospital course, Streptococcal pharyngitis, Strongyloides hyperinfection
331–332 115, 135 syndrome (SHS),
presentation, 332–333 Streptococcus agalactiae 236–238
treatment, 333–334 necrotizing fasciitis, Strongyloides stercoralis,
Sirolimus 265–270 233–238
for GVHD, 341 case presentation, 265, case presentation,
for invasive aspergillosis, 266–267 233–235, 233–236
175 clinical presentation, clinical features, diagnosis,
Sjögren’s syndrome, 40t diagnosis, 268 236, 236–237
Skin and soft tissue management, prevention, management, 238
infections, 261–290 268, 269, 270 pretransplant evaluation,
acute retroviral syndrome, microbiology, 238
286–289 epidemiology, 265, Strongyloidiasis, 39
Alternaria, 279–282 266–267, 267–268 Sulfadiazine, for Balamuthia
methicillin-resistant Streptococcus anginosus mandrillaris infection, 33
Staphylococcus group, 45 Sulfonamides. See
aureus infection, Streptococcus bovis also trimethoprim-
261–264 endophthalmitis, 90–93 sulfamethoxazole
Mycobacterium fortuitum, case presentation, 90–91, for brain abscesses with
271–276 90–91 nocardiosis, 46
Sporothrix schenckii, clinical features, diagnosis, in combination for
277–279 92–93 immunocompromised
Streptococcus agalactiae management, 93 patients, 46
necrotizing fascitis, Streptococcus constellatus for Nocardia farcinica
265–270 endocarditis, 191–199 epidural abscess, 53
vaccinia virus infection, case presentation, for prostatic abscess,
282–285 191–192, 193–194, 257–258
Spinal epidural abscesses, 194–195 for pulmonary
48–49 complications, 197–198 nocardiosis, 184
Surgical intervention for typhoid fever, 229 for MRSA, 262, 264, 277

INDEX
for endocarditis, 93 Ticarcillin, for Pseudomonas for Nocardia farcinica
for endophthalmitis, 99 aeruginosa, 166 epidural abscess, 53
for fulminant Clostridium Ticarcillin/clavulanate for Pneumocystic
difficile colitis, 221 for liver abscess, 225 pneumonia, 179t
for hydatid cysts, 232 for POVT, 333 for prosthetic joint
for pneumococcal Tigecycline infections, 300
meningitis, 7 for community-acquired for pulmonary
for prosthetic joint pneumonia, 254 nocardiosis, 184
infections, 300 for intra-abdominal for typhoid fever, 229
for rhinocerebral infections, 254 Trypanosoma cruzi, 209–214.
mucormycosis, 126 for KPC-E infections, See also Chagas disease
for spinal/cranial epidural 253–254 Tuberculous pericarditis,
abscesses, 49 for KPC-producing 204–208
for toxic shock syndrome, Klebsiella pneumoniae, case presentation, 204–205
341 251 clinical manifestations,
for vaccinia virus infection, for MRSA, 264 diagnosis, 205–206,
285 for Nocardia farcinica 206–207
Syphilitic chorioretinitis, 74 epidural abscess, 53 epidemiology, 205
Syphilitic iridocyclitis, 74 for skin/soft tissue management, 206, 207
Syphilitic uveitis, 74–75 infections, 254 23-valent pneumococcal
Systemic antiviral therapy. Tinidazole, for Entamoeba polysaccharide vaccine,
See acyclovir histolytica, 226 7–8
Systemic lupus erythe- TNF-D antagonists. See Typhoid fever, 226–229
matosus, 27, 346, 355 etanercept; infliximab case presentation,
Tobramycin, 67 226–227, 227
for M. chelonae/M. clinical presentation,
T abscessus isolates, 276 diagnosis, 228–229
Tacrolimus for Pseudomonas keratitis, epidemiology, 228
for AML, 94 70 management, prevention,

369
for graft versus host Tolevamer, for Clostridium 229
disease, 341 difficile colitis, 221
Tactile hyperesthesia, 28 Toxic-binding agents.
Taenia solium (tapeworm, See cholestyramine; U
larval form), 57, 58, 59 tolevamer Ulcerative colitis, 28
Terbinafine, for Toxic epidermal necrolysis United Network for Organ
lymphocutaneous/ (TEN), 355 Sharing (UNOS), 38
cutaneous sporotrichosis, Toxic shock syndrome, 115, Urinary tract infections,
279 339–341 247–259
Tetracyclines Treponema pallidum uveitis, BK virus hemorrhagic
for B. henselae retinitis, 89 70–76 cystitis, 249–251
for human ehrlichiosis, 329 case presentation, 70–72, KPC-producing Klebsiella
for Legionella pneumophila, 71–72 pneumoniae, 251–254
189 clinical features, 74–75 prostatic abscess, 255–259
for Mycoplasma diagnosis, 75 Staphylococcus aureus
pneumoniae, 136 treatment, 75–76 pyelonephritis,
for prosthetic joint uvea anatomy, 72–74 247–248
infections, 300 Triatoma infestans (“kissing
Third-generation bug”), 210–211. See
cephalosporins. See also also Chagas disease; V
cefotaxime; ceftriaxone Trypanosoma cruzi Vaccinations
for community-acquired Triazoles (prophylactic heptavalent
pneumonia, 131 mold-active oral), pneumococcal
for liver abscess for Aspergillus fumigatus, conjugate (PCV-7), 7
with metronidazole, 225 175 for S. pneumoniae
plus metronidazole/ Trifluorothymidine (topical), prevention, 131
aminoglycoside, 225 for vaccinia virus H1N1 influenza, 152
for Ludwig’s angina, 111 infection, 285 interval for LCCD
for Nocardia infections, 53 Trimethoprim-dapsone, for N. meningitidis
for pneumococcal Pneumocystic pneumonia, meningitis, 3
meningitis, 7 179t polysaccharide diphtheria
for POVT, 333 Trimethoprim- toxoid conjugate, 3
for Staphylococcus aureus, sulfamethoxazole Russia vaccine study, 3
49 (TMP-SMX) 23-valent pneumococcal
for Streptococcus for GAE, 36 polysaccharide vaccine
intermedius brain for M. marinum infections, for S. pneumoniae
abscess, 46 275 prevention, 131
 Vaccine immune globulin for pneumococcal Leishmaniasis, 305–310
INDEX

(VIG), for vaccinia virus meningitis, 7 Plasmodium vivax malaria,

infection, 285 for Pseudomonas 310–314
Vaccinia virus infection aeruginosa, 166 Rickettsialpox, 315–319
clinical features, 284–285 for Pseudomonas keratitis, Verruga peruana lesions,
diagnosis, treatment, 285 70 84
presentation, 282–283, for recurrent meningitis, Vertebral osteomyelitis, 48,
283–284 23 53, 110, 248
Valacyclovir for TSS, 341 Vidarabine (topical)
adverse effects, 30t Vancomycin-associated for vaccinia virus infection,
for AML, 50, 94 reactions, 352–356 285
for immunocompromised case presentation, Vircow’s triad, in
patients with herpes 352–353, 352–354 deep septic pelvic
zoster, 48t IgE-mediated vancomycin thrombophlebitis, 332
for RBLM, 24 reaction, 355 Visceral leishmaniasis,
for varicella zoster virus Linear IgA bullous 309
encephalitis, 30t, 31 dermatitis, 355–356 Vitreoretinal traction (VRT),
Valganciclovir rare severe skin reactions, 103
for CMV prophylaxis, 342 355 Voriconazole
for CMVR, 82 “red man syndrome,” 48, for AML, 50, 94
oral, for cytomegalovirus 354–355 for Balamuthia mandrillaris
colitis, 244–245, 244t Varicella zoster virus infection, 33
Vancomycin, 148 encephalitis, 25–31 for cutaneous
for B. henselae retinitis, clinical features, 28–29 alternariosis, 282
89 diagnosis, 29 for endophthalmitis, 98
for brain abscesses, 46, 49 presentation/case history, (in vitro efficacy),
with ceftriaxone, 25–26, 26, 29 for pulmonary
for Streptococcus prevention, 31 histoplasmosis, 159
pneumoniae, 131 rate of zoster/postherpetic (IV), for Aspergillus
for febrile neutropenia, neuralgia, 27 fumigatus, 175
370

167 treatment, 29, 30t, 31 VZV meningoencephalitis,

for infective endocarditis, virology, epidemiology, 28–29
197 26–28
intravitreous, for Vasculitis, 40t
endophthalmitis, 93 Vasopressors, 1, 148 W
for Ludwig’s angina, 111 Vector-borne infections,
for MRSA, 166, 261, 264 305–329 Wegener’s granulomatosis,
oral, for Clostridium Anaplasma 28
difficile colitis, 220–221 phagocytophilum, West Nile virus, 29
plus cefepime or 322–323, 328
ceftazidime or Babesiosis, 320–324
meropenem for Borrelia burgdorferi, 323 Z
Klebsiella pneumoniae human granulocytic Zanamivir, for 2009 H1N1
meningitis, 21 anaplasmosis, 325–329 influenza, 152