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Collection Highlights

Equine Behavioral Medicine, First Edition Bonnie V. Beaver

Equine Neonatal Medicine 1st Edition David M. Wong

Equine Pediatric Medicine, Second Edition William V

Bernard(Editor)

Internal Medicine Review Core Curriculum Book 1

Gastroenterology Infectious Disease Robert A. Hannaman
(Ed.)
Internal Medicine 5th Edition Eugene Toy

Equine Clinical Medicine, Surgery and Reproduction 2nd

Edition Graham Munroe

Essentials of Internal Medicine Ardhendu Sinha Ray

Approach to Internal Medicine : a Resource Book for

Clinical Practice 4 ed. Edition Raj Padwal (Editor)

Textbook of Veterinary Internal Medicine Stephen J.

Ettinger
 EQUINE
INTERNAL
MEDICINE
This page intentionally left blank

     
 EQUINE
INTERNAL
MEDICINE
FOURTH EDITION

Stephen M. Reed, DVM, Dipl ACVIM

Rood & Riddle Equine Hospital • Lexington, Kentucky
Professor Emeritus, Department of Veterinary Clinical Sciences • The Ohio
State University • Columbus, Ohio

Warwick M. Bayly, BVSc, MS, PhD, Dipl ACVIM

Professor, Department of Veterinary Clinical Sciences
Washington State University • Pullman, Washington

Debra C. Sellon, DVM, PhD, Dipl ACVIM

Professor, Department of Veterinary Clinical Sciences • College of Veterinary Medicine,
Washington State University • Pullman, Washington
3251 Riverport Lane
St. Louis, Missouri
63043

EQUINE INTERNAL MEDICINE ISBN: 978-0-323-44329-6

Copyright © 2018, Elsevier Inc. All rights reserved.

Previous editions copyrighted 2010, 2005, 1999.

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical,
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This book and the individual contributions contained in it are protected under copyright by the Publisher (other
than as may be noted herein).

Notices

Knowledge and best practice in this field are constantly changing. As new research and experience broaden
our understanding, changes in research methods, professional practices, or medical treatment may become
necessary.
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and
using any information, methods, compounds, or experiments described herein. In using such information or
methods they should be mindful of their own safety and the safety of others, including parties for whom they
have a professional responsibility.
With respect to any drug or pharmaceutical products identified, readers are advised to check the most
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Library of Congress Cataloging-in-Publication Data

Names: Reed, Stephen M., editor. | Bayly, Warwick M., editor. | Sellon, Debra
C., editor.
Title: Equine internal medicine / [edited by] Stephen M. Reed, Warwick M.
Bayly, Debra C. Sellon.
Other titles: Equine internal medicine (Reed)
Description: Fourth edition. | St. Louis, Missouri : Elsevier, [2018] |
Includes bibliographical references and index.
Identifiers: LCCN 2017028516| ISBN 9780323443296 (hardback : alk. paper) |
ISBN 9780323443098 (Ebook)
Subjects: LCSH: Horses--Diseases. | Veterinary internal medicine. | MESH:
Horse Diseases
Classification: LCC SF951 .E565 2018 | NLM SF 951 | DDC 636.1/089--dc23 LC record available at
https://lccn.loc.gov/2017028516

Senior Content Strategist: Jennifer Flynn-Briggs

Content Development Manager: Luke Held
Associate Content Development Specialist: Anna Miller
Publishing Services Manager: Deepthi Unni
Project Manager: Radhika Sivalingam
Design Direction: Amy Buxton

Printed in United States of America

Last digit is the print number: 9 8 7 6 5 4 3 2 1

 Contributors

Monica Aleman, MVZ Cert, PhD, DACVIM Katarzyna Dembek, DVM, PhD, DACVIM
Medicine and Epidemiology Assistant Clinical Professor
University of California Veterinary Clinical Sciences
Davis, California Iowa State University
Ames, Iowa
Warwick M. Bayly, BVSc, MS, PhD, DACVIM
Professor Thomas J. Divers, DVM, DACVIM, DVECCS
Department of Veterinary Clinical Sciences Professor of Medicine
Washington State University Clinical Sciences
Pullman, Washington Cornell University
Ithaca, New York
Michelle Henry Barton, DVM, PhD, DACVIM
Fuller E. Callaway Endowed Chair Bettina Dunkel, DVM, PhD, DACVIM, DECEIM,
Large Animal Medicine Dip ACVECC, FHEA, MRCVS
University of Georgia Senior Lecturer in Equine Medicine
Athens, Georgia Veterinary Clinical Sciences
The Royal Veterinary College
Etta Agan Bradecamp, DVM, DACT, DABVP North Mymms
Theriogenologist Hatfield, UK
Rood and Riddle Equine Hospital
Lexington, Kentucky Katherine S. Garrett, DVM, DACVS
Rood and Riddle Equine Hospital
Teresa Ann Burns, DVM, MS, PhD, DACVIM Lexington, Kentucky
Veterinary Clinical Sciences
Clinical Assistant Professor, Equine Internal Medicine Ray Geor, BVSc, MVSc, PhD, DACVIM
The Ohio State University College of Veterinary Medicine Professor and Pro Vice-Chancellor College of Sciences
Columbus, Ohio Massey University
Palmerston North, New Zealand
Jennifer L. Davis, DVM, MS, PhD
Associate Professor of Clinical Pharmacology Tiffany L. Hall, DVM, DACVIM, DACVECC
Department of Biomedical Sciences and Pathobiology Internal Medicine and Critical Care
Virginia-Maryland College of Veterinary Medicine Associate
Blacksburg, Virginia Equine Medical Center of Ocala
Ocala, Florida
Elizabeth Davis, DVM, PhD, DACVIM
Associate Professor Rachel C. Hector, DVM
Clinical Sciences Resident, Anesthesia and Pain Management
Kansas State University Clinical Sciences
Manhattan, Kansas Colorado State University
Fort Collins, Colorado
Igor F. Canisso, DVM, MSc, PhD, DACT, DECAR
Assistant Professor of Theriogenology
Department of Veterinary Clinical Medicine
College of Veterinary Medicine
University of Illinois Urbana-Champaign
Urbana, IL

v
vi CONTRIBUTORS

Kenneth W. Hinchcliff, BVSc, MS, PhD, DACVIM Francisco J. Mendoza, DVM, PhD, MSc, DECEIM
Journal of Veterinary Internal Medicine Professor of Internal Medicine
Co-Editor-in-Chief Department of Animal Medicine and Surgery
Faculty of Veterinary Science College of Veterinary Medicine
Professor University of Cordoba, Spain
University of Melbourne
Melbourne, Victoria Yvette S. Nout-Lomas, DVM, PhD, DACVIM, DACVECC
Australia Assistant Professor
President and CEO College of Veterinary Medicine and Biomedical Sciences
Trinity College Colorado State University
Parkville, Victoria Fort Collins, Colorado
Australia
Alejandro Perez-Ecija, DVM, MS, PhD, DECVP
Melissa T. Hines, DVM, PhD, DACVIM Associate Professor of Internal Medicine
Professor Department of Animal Medicine and Surgery
Large Animal Clinical Sciences College of Veterinary Medicine
University of Tennessee University of Cordoba, Spain
Knoxville, Tennessee
Ann M. Rashmir-Raven, DVM, MS, DACVS, PGCVE,
Samuel D. Hurcombe, MS, DACVIM, DACVECC FHEA
Associate Professor–Clinical Associate Professor
Cornell Ruffian Equine Specialists Large Animal Clinical Sciences
Cornell University Michigan State University
Elmont, New York East Lansing, Michigan

Mary Lassaline, DVM, PhD, MA, DACVO Stephen M. Reed, DVM, DACVIM
Associate Professor of Clinical Equine Ophthalmology Rood and Riddle Equine Hospital
Surgical and Radiological Sciences Lexington, Kentucky
University of California – Davis Professor Emeritus
Davis, California The Ohio State University,
Columbus, Ohio
Maureen T. Long, DVM, MS, PhD, DACVIM
Associate Professor Chris Sanchez, DVM, PhD, DACVIM
Infectious Diseases and Pathology Associate Professor
University of Florida Department of Large Animal Clinical Sciences
Gainesville, Florida College of Veterinary Medicine, University of Florida
Gainesville, Florida
Khursheed R. Mama, DVM, DACVA
Professor of Anesthesiology Debra C. Sellon, DVM, PhD, DACVIM
Clinical Sciences Professor
Colorado State University Department of Veterinary Clinical Sciences
Fort Collins, Colorado College of Veterinary Medicine
Washington State University
Dianne McFarlane, DVM, PhD, MS, DACVIM, CVSH, Pullman, Washington
OSU
Center of Veterinary Health Sciences Maria R. Schnobrich, VMD, Dip ACT
Professor of Physiological Sciences Leblanc Reproduction Center
Oklahoma State Univeristy Theriogenologist
Stillwater, Oklahoma Rood and Riddle Equine Hospital
Lexington, Kentucky
Harold C. McKenzie III, DVM, MS, DACVIM
Associate Professor Harold C. Schott II, DVM, PhD, DACVIM
Large Animal Clinical Sciences Professor of Internal Medicine
Virginia Maryland College of Veterinary Medicine, Virginia Veterinary Clinical Sciences
Tech Michigan State University,
Blacksburg, Virginia East Lansing, Michigan

Robert H. Mealey, DVM, PhD, DACVIM

Professor
Department of Veterinary Microbiology and Pathology
Washington State University
Pullman, Washington
 CONTRIBUTORS vii

Colin C. Schwarzwald, PhD, DACVIM, DECEIM Ramiro E. Toribio, DVM, MS, PhD, DACVIM
Professor of Equine Internal Medicine Professor
Equine Department Veterinary Clinical Sciences
Vetsuisse Faculty The Ohio State University
University of Zurich Columbus, Ohio
Zurich, Switzerland
Stephanie J. Valberg, DVM, PhD, DACVIM
Charlie Scoggin, DVM, MS, DACT Professor and Mary Anne McPhail Dressage Chair in Equine
LeBlanc Reproduction Center Sports Medicine
Associate Veterinarian College of Veterinary Medicine
Rood and Riddle Equine Hospital Michigan State University
Lexington, Kentucky East Lansing, Michigan
Clinical Sciences
Affiliate Faculty Bryan M. Waldridge, DVM, MS, DABVP, DACVIM
Colorado State University Veterinarian
Fort Collings, Colorado Park Equine Hospital at Woodford
Versailles, Kentucky
Sharon J. Spier, DVM, PhD, DACVIM
Professor
Department of Medicine and Epidemiology
University of California
Davis, California

Patricia Talcott, DVM, MS, PhD, DABVT

Professor of Toxicology
Washington Animal Disease Diagnostic Laboratory
Washington State University College of Veterinary Medicine
Pullman, Washington
Veterinary Diagnostic Toxicologist
Washington Animal Disease Diagnostic Laboratory
Pullman, Washington
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Preface

T
his is the fourth edition of Equine Internal Medicine. Like its three predecessors, it has been written
and edited with the aim of promoting a clearer comprehension of the principles of medical disease
and/or problem development by focusing on the basic pathophysiologic mechanisms that underlie
the development of various equine diseases. As with previous editions, basic information is presented and
then related to the clinical characteristics of each disease and its therapy and management.
Most of the chapters that appeared in the previous three editions have been updated, and a number
of them have been extensively revised or rewritten. Although the bulk of the chapters address specific
diseases along systems-based lines, we realize that the practitioner is initially confronted with a specific
problem that may have its origin in one or more of the body’s systems. The first section of the book is
therefore devoted to an in-depth discussion of the basic mechanisms by which problems might develop,
and the principles underlying the treatment of many of them. The reader can build on this foundation by
reading about specific disorders in the second section of the book, which is divided into chapters dealing
with problems of a particular body system or of a specific nature.
Many true experts have contributed to this text. Their depth of knowledge about all aspects of equine
internal medicine is encyclopedic and daunting. We are grateful for their efforts and diligence in help-
ing us to produce what we hope will continue to be regarded as the definitive text on medical diseases of
horses. We are indebted to them for their efforts. We trust that they derive a sense of pride from the part
they have played in producing what we hope represents the gold standard in equine medical textbooks.
In these days of progressive globalization of the world’s societies and associated growth in the inter-
national movement of horses for breeding, recreational, and competitive purposes, there also has been
a worldwide increase in expectations relating to the standard of veterinary care and evaluation of sick
horses. The sophistication of specialist training programs and the increased number of equine internists
also taking advantage of postgraduate doctoral opportunities have resulted in a wealth of new informa-
tion and the maturing of an increasingly complex and challenging discipline—equine internal medicine.
The delivery of superior health care and increased client expectations that have been associated with
the growth of this discipline have led to the appearance of extremely well-informed and astute equine
general practitioners everywhere, and specialist equine internists on most continents. More than ever
before, equine internal medicine now stands as an autonomous specialty in the veterinary profession. We
trust that the fourth edition of Equine Internal Medicine will prove to have as much universal appeal and
application as those editions that preceded it.
Finally, we would be remiss if we did not thank the many people at Elsevier for their persistence and
efforts. Penny Rudolph, Lauren Harms, Radhika Sivalingam and Anna Miller in particular deserve our
gratitude. They and many others have assisted in manuscript preparation, correspondence, and all the
other tasks that must be completed to get a book like this into print. Without them and the generosity
of our colleagues, this book would not have been published. We think that everyone’s efforts have been
worthwhile.
Stephen M. Reed, DVM, Dipl ACVIM
Warwick M. Bayly, BVSc, MS, PhD, Dipl ACVIM
Debra C. Sellon, DVM, PhD, Dipl ACVIM

ix
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Contents

Y PART 1
Mechanisms of Disease and Principles of Treatment
1 Mechanisms of Disease and Immunity, 3
2 Pharmacologic Principles, 79
3 Recognizing and Treating Pain in Horses, 138
4 Critical Care, 158
5 Internal Medicine and Clinical Nutrition, 191
6 Clinical Epidemiology and Evidence-Based Medicine, 218
7 Clinical Approach to Commonly Encountered Problems, 232

Y PART 2
Disorders of Specific Body Systems
8 Disorders of the Respiratory System, 313
9 Disorders of the Cardiovascular System, 387
10 Disorders of the Musculoskeletal System, 542
11 Disorders of the Neurologic System, 580
12 Disorders of the Gastrointestinal System, 709
13 Disorders of the Liver, 843
14 Disorders of the Urinary System, 888
15 Disorders of the Hematopoietic System, 991
16 Disorders of the Endocrine System, 1029
17 Disorders of the Eye and Vision, 1139
18 Disorders of the Skin, 1159
19 Disorders of the Reproductive Tract, 1217
20 Disorders of Foals, 1365
21 Toxicologic Problems, 1460
Appendix I  Aspects of Clinical Relevance in Donkeys, 1513
Index, 1525
xi
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PART 1

Mechanisms of Disease and

Principles of Treatment

1
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 C HA P T E R 1
Mechanisms of Disease
and Immunity
Robert H. Mealey and Maureen T. Long*

nondisrupted skin surfaces. Even though horses inhabit an

The Microbiome environment heavily contaminated with fecal flora, normal
dermal flora in the horse is surprisingly devoid of members
Maureen T. Long of the Enterobacteriaceae.2 Normal inhabitants include mixed
populations of bacteria of species of Acinetobacter, Aerococ-
Dermal and mucosal surfaces provide a life-preserving pro- cus, Aeromonas, Bacillus, Corynebacterium, Flavobacterium,
tective barrier composed of physical, chemical, and microbial Micrococcus, Nocardia, coagulase-negative Staphylococcus,
defenses.1 In the past 5 years, the concept of normal flora has Staphylococcus aureus, Streptomyces, and nonhemolytic Strep-
been broadened to include the whole of “microbiota” that tococcus generae.3 Certain Staphylococcus spp. have been
colonizes skin, gut, and mucosal surfaces. The microbiome associated with skin disease in the horse, and these include
is the science of analyzing the total number of organisms in S. aureus, S. intermedius, and S. hyicus, whereas species such
an ecosystem, which in our case are animals. The practical as S. xylosus and S. sciuri were more associated with normal
application of this science to the clinician is that the microbi- skin. More than 30 species of fungi can inhabit the skin and
ome differs among many niches of the body, varies with indi- Alternaria, Aspergillus, Candida, Fusarium, Rhizopus, and
viduals, and has an interactive role with actual disease states. Trichophyton spp. are commonly present.2 Until recently the
Microbiota is the microbial population within the different presence of Malassezia yeast species has been considered
sites of the body. Commensal bacteria are those living on or pathogenic. Recent fungal culturing of the skin of normal,
within a host in a way such that both derive mutual benefit and healthy horses has confirmed colonization by a species of Mal-
in which interruption of this association results in abnormal assezia yeast that is novel to the horse (tentatively named M.
host development or overt disease. These represent that part equi). Colonized sites include the groin, axilla, and perineal
of the microbiome that has intimately coevolved with the dif- regions.4 To date there are no studies describing the microbi-
ferent niches of the body.1 ome of the skin of horses.
Environment is local, such as within different areas of the
gut, and also external, and these can have either positive or Oral Microbiome
negative effects on the microbiome. For instance, poor ven- The oral and pharyngeal mucosa is richly populated with
tilation in animal housing not only is a direct irritant, but many bacteria, including obligate aerobes, anaerobes, and
changes in pH, metabolism of particulates, and activation of facultative anaerobes.5 By culture, gram-positive and gram-
the immune system will dramatically alter the structure of the negative anaerobes are the predominant flora in the mouth
microbiome. and pharyngeal tonsils of the normal horse, with B. fragilis
Age is also an important factor. Colonization of skin and and Bacteroides spp. most commonly found. Genera consist-
mucosal surfaces occurs at birth and is highly variable in early ing of Fusobacterium spp., Eubacterium spp., Clostridium
life. Changes in management from birth to weaning are accom- spp., Veillonella spp., and Megasphaera spp. are also cul-
panied by changes in diet and husbandry for horses. They create tured. Aerobic and facultative anaerobic populations mostly
a highly dynamic environment that eventually can be used to include S. zooepidemicus, Pasteurella spp., E. coli, Actino-
predict best practices once data on the microbiome in healthy myces spp., and Streptococcus spp. In a 16S metagenomics
horses are obtained in a methodical and scientific manner. analysis of the subgingival sites of the horse, although highly
diverse, many similarities to human and other species were
Skin Microbiome observed.6 The most common bacterial phyla included Gam-
The combination of normal flora and mucosal immunity pro- maproteobacteria, Firmicutes, Bacteroidetes, Betaproteobac-
vides an effective barrier against infectious colonization of teria, Fusobacteria, Actinobacteria, Epsilonproteobacteria,
TM7, Deltaproteobacteria, Synergistetes, GN02, Tenericutes,
Spirochaetes, Chloroflexi, and Alphaproteobacteria. The
* The editors and authors acknowledge and appreciate the contributions of Gammaproteobacteria had the highest population of species,
J. Lindsay Oaks, Thomas R. Klei, D. Paul Lunn, and David W. Horohov as with Moraxella spp. and Pasteurellaceae spp. overrepresent-
previous contributors to this chapter. Some of their original work has been ing the population. In the former, Actinobacillus species and
incorporated into this edition. unclassified Pasteurellaceae were the most common bacteria.
3
4 PART 1 MECHANISMS OF DISEASE AND PRINCIPLES OF TREATMENT

The finding of Actinobacillus species is not unexpected; how- ascending colon and cecum, indicating highly specialized
ever, by comparison these taxa are relatively absent from digestive functions associated within the large intestine itself.16
cat and dog oral metagenomes. Of the highly abundant Yeasts and fungi of the order Mucorales have been identified
Firmicutes, many classes of Bacilli were detected; several in the cecum of normal horses and are capable of digesting cel-
Neisseria-like bacteria were detected. Of particular interest lulose and starch.18 By deep sequencing, Firmicutes and Bac-
is the population of oral spirochetes that reside in the equine teroidetes (or in another study, Verruccomicrobia) are the two
mouth because of its relationship to periodontal disease in must abundant phyla.19 The common bovine rumen bacteria
humans, and although there were Treponema, spirochetes, Ruminococcus flavefaciens is one of the most predominant
and leptospires present and abundant, “periodontopatho- cellulolytic bacteria of the equine cecum based on standard
gens” were present in low numbers. When healthy horses microbiologic techniques.15
were compared with horses with oral disease, Actinobacillus Since 2012 several studies have been published investi-
(Gammaproteobacteria) and the Neisseria-like Gemella sp. gating the equine microbiome, and these have been recently
(Firmicutes) predominated compared with Prevotella (Bac- reviewed.17 The techniques employed in each investigation
teroidetes) and Veillonella (Firmicutes).7 could highly bias study results. Fecal samples or samples from
specific gastrointestinal locations have been used. Most stud-
Pharyngeal and Respiratory Microbiome ies had a stated goal of attempting to define the flora of the
Because these same genera are also consistently found in hindgut of the horse.
horses with lower respiratory infections, opportunistic coloni- Routine surveillance demonstrates a relative lack of intesti-
zation by pharyngeal flora is the likely mechanism of disease.5 nal pathogens in the flora of normal horses. In the largest study
Contamination of the trachea of the horse is a frequent occur- to date, fecal shedding of Salmonella enteriditis as detected by
rence, as evidenced by the fact that transtracheal aspiration fecal culture in normal horses from farms without evidence of
yields positive bacterial cultures in approximately 30% of both salmonellosis was 0.8% in resident horses.20 Molecular diag-
normal adult horses and foals.8 As with skin flora, normal nostics, once hoped to provide a tool for understanding the
horses have multiple fungal species inhabiting conjunctival, incidence of Salmonella spp. in the clinically normal horse,
nasal, and oral mucosa.8 Stabling increases the frequency of has provided inconsistent information, and polymerase chain
ocular fungi in normal horses.9 reaction (PCR) is most useful for identification of subclinical
shedders and environmental contamination during an out-
Intestinal Microbiome break.21,22 On the basis of limited investigations, the carriage
In animal models and chronic human conditions, the pres- rates of C. difficile in normal horses and foals appear to be low
ence of normal flora is considered important for intestinal (less than 1.5%).23
maturity and containment of disease. Changes in cecal weight, Intestinal flora in the horse is an important source for
villus:crypt ratio, and volatile fatty acid (VFA) production and extraintestinal pathogens. In studies examining the car-
the development of gut immunoglobulin A (IgA) responses riage rate of Rhodococcus equi, all horses cultured carried
are all affected by suboptimal cecal colonization in germ-free the bacteria regardless of age.24,25 If a farm had endemic R.
animals.10 A relationship between severity of mucosal disease equi and respiratory isolates contain the 90-kDa plasmid
and normal flora has also been demonstrated in models of that is associated with disease, fecal isolates also contained
inflammatory bowel disease of humans.11 this plasmid. In a recent study, there was little difference
Bacteria are present in all parts of the intestinal tract of in the composition of the phyla of fecal bacteria measured
the horse, and the microbial fauna increases in complexity via deep sequencing between normal foals and those with
and density aborally.12 The stomach of the horse is not a ster- either subclinical or clinical R. equi.26 However, a striking
ile environment. A dense population of gram-positive bacte- difference in flora was observed over the first few weeks
rial rods, primarily composed of Lactobacillus spp., colonizes of life among all foals demonstrating the transition from
the nonsquamous portion of the equine stomach. Substantial a juvenile gut to that of the adult. Flora transitioned from
colonization of the duodenum is present with a large popula- equal abundance of Firmicutes to Bacteroidetes over this
tion of proteolytic bacteria, and this colonization increases by short interval.
tenfold in the ileum.13 The right dorsal colon contains the highest numbers
Microbial degradation and fermentation of plant material and the most diversity of protozoal species.17 Four classes
in the large intestine are important components of nutrient of protozoa species, Rhizopoda, Mastigophora, Cliata, and
acquisition in the equid. The consumption of cellulose and Suctoria, have been described based on relative prevalence
starch results in the production of VFAs.14 The major cellulo- in ascending and descending parts of the large colon. The
lytic bacterial strains in the horse produce arrays of fermenta- importance of protozoa for normal gastrointestinal func-
tion products that differ from those of cattle.15 Early genetic tion is debated, but these organisms are presumed to play
techniques also demonstrate that the predominant flora are the an important role in degradation of plant fiber. Despite this
low guanine-cytosine (GC)-content bacteria, which include presumption, one investigation demonstrated little effect of
Cytophaga-Flexibacter-Bacteroides and Clostridium bacteria; protozoa on the digestibility of dry matter with little effect
the actual species are completely novel.16 Standard microbio- on cellulose digestion.27
logic techniques specifically demonstrate Enterobacteriaceae,
Butyrivibrio spp., Streptococcus spp., Bacteroides spp., Lactoba- Urogenital Microbiome
cillus spp., Selenomonas spp., Eubacterium spp., Propionibacte- By far, most of the work that characterizes equine normal
rium spp., and Staphylococcus spp. in residence.17 In addition, flora has focused on urogenital flora to address infertility and
there are completely different compositions of bacteria among fetal loss. Although vaginal and vestibular mucosa of mares
the differing segments of the colon, especially between the should be colonized with normal mucosal flora, the uterus
 CHAPTER 1 Mechanisms of Disease and Immunity 5

is considered sterile. However, typical culturing techniques receptor agonist resting in contraction of antral and duodenal
result in frequent isolation of what could be considered patho- smooth muscles.38 In the horse erythromycin results in a dose-
gens, and cytology and bacterial counts are essential supple- dependent increase in ileocecal emptying.39 Motility-enhanc-
mental tests for detecting true uterine infection. Counts less ing effects have also been observed in human patients treated
than 10 colony-forming units and lack of inflammatory cells with amoxicillin.37
indicate uterine or technical contamination.28 Occurrence of infectious lower respiratory disease in adult
Many bacteria inhabit the external genitalia of stallions, horses is an example of how contamination of a normally
including bacteria considered to be associated with metritis sterile site with several commensal bacteria results in disease.
in mares. The predominant aerobe isolated is coagulase- The tonsillar mucosa of the oropharynx is heavily colonized
negative Staphylococcus spp., followed by Corynebacterium with S. equi subsp. zooepidemicus, and necrosis of this tissue
spp., α-hemolytic Streptococcus spp., and Lactobacillus spp. occurring during viral infection is associated with spread to
Pathogens such as β-hemolytic Streptococcus spp., Pseu- the lower respiratory tract.5 Transport of horses (especially
domonas aeruginosa, and Klebsiella spp. can be frequently for distances greater than 500 miles) is a primary risk factor
found in servicing stallions.29,30 Pregnancy rates appear to for pleuropneumonia as demonstrated in a large retrospective
be the same in mares bred to stallions with P. aeruginosa– study.40 Elevation of the head for an extended period of time
infected semen.31 is likely a contributing factor. Horses normally feed from the
ground for most of the day, and this posture promotes effective
Fungal Microbiome tracheal clearance of inhaled debris and particulate matter.
Essentially the same principles apply regarding normal flora, Pasteurella, Actinobacillus, and Streptococcus spp. are the most
host immunity, and specific virulence factors for the patho- frequent and prolific colonizers of the trachea after prolonged
genesis of fungal infection. Fungal infections can be divided head elevation.41,42
into primary or opportunistic pathogens. True pathogens are Nosocomial infection (health care–associated infections)
less dependent on host status than opportunistic pathogens, is defined by the Centers for Disease Control and Prevention
although even a true pathogen may require some degree of as a localized/systemic condition resulting from an adverse
alteration of normal flora or host immunity to become estab- reaction to the presence of an infectious agent or its toxin.
lished. Long-term antibiotic use, immunosuppression, and There must be no evidence that the infection was present or
compromised organ function (especially involving the pul- incubating at the time of hospital admission.43 Nosocomial
monary or endocrine system) are three primary host factors infections are becoming a major problem for large animal
highly associated with the establishment of opportunistic veterinary teaching and private referral hospitals. Infections
fungal infection. Fungi in particular can adapt to the mam- with Serratia marcescens, Acinetobacter baumannii, S. aureus,
malian environment over a relatively short course in order to methicillin-resistant Staphylococcus spp., Enterococcus spp.,
become established. Establishment usually requires a change and various Salmonella enteritidis serovars have all been
in thermal range, oxygen requirements, and resistance to host reported in association with nosocomial infection in equine
defenses. patients.44,45 Surgical incision infection, joint sepsis, cath-
eter phlebitis, wounds, and diarrhea represent the common
Nosocomial Infections clinical syndromes reported in horses.44-46 When nosocomial
Development of colitis in the horse has been associated with infection involves the acquisition of isolates from the hospital
feed change, antibiotics, surgery, nonsteroidal inflammatory environment, these isolates are more difficult to treat because
drugs, and transport, all events that disrupt flora.32,33 Rapid they frequently undergo high-level antibiotic pressure and
change from a roughage diet to concentrate results in increased attain multiple-drug resistance (MDR). Nosocomially trans-
anaerobes, decreased cellulolytic bacteria, decreased cecal pro- mitted salmonellosis in equine hospital wards is increasingly
tozoa diversity, and decreased pH in the equine cecum.32 Iso- reported, with Salmonella enteritidis serotypes Krefeld, Saint
lation of Clostridium difficile is more likely from horses treated Paul, DT104, and Anatum all demonstrating attainment of
with antibiotics, and clinical disease has been associated with MDR over the course of the outbreak.47,48 Only one study of a
ampicillin, erythromycin, penicillin, and potentiated sulfon- nosocomially transmitted S. enteritidis (serotype Heidelberg)
amide administration in adult horses.34,35 In ponies infected did not demonstrate significant acquisition of MDR over
with Salmonella spp., transport and surgery reactivated infec- time.49
tion and diarrhea, and antibiotics (oxytetracycline) prolonged
shedding but did not induce recrudescence.33 In a case-control
study, use of potentiated sulfonamides was not significantly
associated with the development of diarrhea in hospitalized
Pathogenesis of Bacterial Infections
horses; however, overall antibiotic use was highly associated
with the occurrence of diarrhea.36
Antibiotics disrupt normal gastrointestinal flora and func- The ability of bacteria to gain entry and cause disease results
tion,37 and changes in carbohydrate metabolism are a large from a combination of factors possessed by the agent itself,
intestinal event secondary to reduced microbial reduction environmental conditions, and status of host defenses. Gen-
of carbohydrates to short-chain fatty acids (SCFAs). Because eral mechanisms that are specific to bacteria and enhance
SCFA metabolism and absorption result in fluid and electro- disease are virulence factors that enhance the entry, spread,
lyte absorption, a sudden decrease in SCFA leads to osmotic and damage to host tissues (Table 1.1). Major virulence fac-
diarrhea with an intraluminal accumulation of organic acids, tors are listed for specific equine pathogens. Protein secre-
cations, and carbohydrates. Erythromycin and amoxicillin tion systems (PSSs) are a structurally diverse complex of
directly affect colonic motility.37 Erythromycin is a motilin essential virulence factors for bacteria that allow specialized
6 PART 1 MECHANISMS OF DISEASE AND PRINCIPLES OF TREATMENT

interactions among cells.50 These main systems function to surface components recognizing adhesive matrix molecules.53,54
translocate various sized molecules and are important in the Gram-positive organisms possess afimbrial proteins on their
formation of adhesins on attachment to host cells. Fibrillar surfaces that presumably aid in binding to host cells. The
adhesins (FAs) and nonfibrillar adhesins (NFAs) are the most three most commonly studied afibrillar adhesins are those
important PSS subgroup not used for bacterial conjugation. that bind salivary glycoprotein, bind fibronectin, or are com-
They specifically target host cells and biofilms for enhance- posed of lipoteichoic acid.53,55 Salivary binding proteins are
ment of colonization and invasion. There are multiple types commonly found in pathogens and commensals of the oral
of FAs in both gram-positive and gram-negative bacteria, cavity. Both Streptococcus spp. and Actinomyces spp. possess
with gram-negative types the most well characterized (Table these proteins. Fibronectin binding protein (FBP) is neces-
1.2).51,52 Pili or fimbriae are rod-shaped structures composed sary for S. aureus invasion and binds both fibronectin and
of an orderly array of a single protein usually arranged in collagen to form a bridge between the FBP and the host cell
a helical fashion to form a cylinder. The tip of the fimbria integrin (integrin α5β1).56,57 Heterologs of FBP have been
mediates attachment to carbohydrate moieties on cell sur- demonstrated in S. pneumoniae of humans, S. equi subsp.
faces and is integral to bacterial invasion and colonization. equi, and S. equi subsp. zooepidemicus. Other potential equine
Bacteria can also contain multiple types of pili. Both the bac- pathogens that have FBPs on their surface include Actino-
terial pili themselves and the cellular pathways they use for myces spp., E. fecalis, and L. monocytogenes.55,58 Lipoteichoic
secretion and formation of pili are targets for pharmacologic acid, a common binding factor found in Streptococcus group
intervention, and there are multiple subclasses depending on A bacteria, is important in adhesion of bacteria to cells.59 This
their configuration.51 protein is also important in stimulation of cytokine secretion
Afimbrial adhesins are cell proteins that enhance the bind- from the cells during infection and has been demonstrated in
ing of bacteria to host cells. They are also called microbial group B Streptococcus, including S. equi subsp. equi.60 A less
commonly described afibrillar adhesin is composed of surface
TABLE 1.1 General Mechanisms of Bacterial Pathogenesis polypeptide chains in Corynebacterium that binds to lectin.61
Afibrillar adhesins are also present in gram-negative organ-
Action Mechanism Examples isms; the most commonly studied are conserved high-molec-
Entry of bacteria Adhesion Fibrillar adhesins ular-weight adhesion proteins of Haemophilus influenzae and
Entry Nonfibrillar adhesins Bordetella pertussis.59
Curli fimbriae Bacterial ecology has emphasized the importance of bio-
Lipoteichoic acid film for colonization of both biotic and abiotic surfaces of
Biofilm adhesion proteins bacteria.50 A requirement for biofilm formation is a tight
Membrane ruffling interaction of bacterial adhesins with surface receptors that
promote further bacterial aggregation. The most important
Enhancement of Immune resis- Capsule
family of biofilm adherence proteins is that of Staphylococ-
spread tance Lipopolysaccharide
cus aureus. These proteins have high molecular mass and
Host sub- Anticomplement
repetitive structures whose size and number can be varied
strate Resistance to
during the course of infection, possibly allowing for immune
utilization phagocytosis
evasion.
Phagolysosomal survival
The most common virulence proteins of both gram-pos-
Iron acquisition
itive and gram-negative organisms are bacteria lectins.53-62
Damage to host Toxins Exotoxin Although attachment is thought to be the primary role of
membranes Endotoxin these proteins, attachment itself results in an intracellular
Apoptosis change, including actin rearrangements, cell signaling reg-
  
ulation, or actual secretion of bacterial substances into the

TABLE 1.2 Major Types of Bacterial Adhesins

Adhesin Definition Example
Type 1 fimbriae Cell surface structure primarily on gram-negative bacteria that bind Escherichia coli
to the terminal mannose of glycoproteins on cells
Type 4 pili Cell surface structure primarily on gram-negative bacteria that func- Pseudomonas aeruginosa
tion in adhesion, twitching, and DNA uptake, which bind on CD46
and other glycolipids
Curli fimbriae Coiled aggregative fimbrial structures that bind to fibronectin, lam- Enterohemorrhagic Escherichia
inin, and plasminogen and function in adhesion, aggregation, and coli (EHEC)
biofilm formation Salmonella
Fibrils and flexible rods Short, thin rodlike adhesins that bind to fibronectin for adhesion to Streptococcus species
host tissues
Lipoteichoic acid Part of the peptidoglycan layer of cell walls Gram-positive bacteria
Biofilm Exopolysaccharide produced by bacteria that allows matrix forma- Gram-positive and gram-
tion of embedded material negative bacteria
  
 CHAPTER 1 Mechanisms of Disease and Immunity 7

host cell. These proteins are highly conserved in bacteria and in vitro phagocytosis can be abolished with treatment with
are important targets for immunoprophylaxis. Membrane hyaluronidase and induction of specific immunity against
transformation for uptake of intracellular bacteria such as M-protein of S. equi subsp. equi and S. equi subsp. zooepi-
Yersinia spp., Listeria monocytogenes, Salmonella spp., and demicus.80 The M-proteins of Streptococcus spp. are also essen-
Shigella flexneri can be either zipperlike or triggerlike. Alter- tial for resistance to phagocytosis blocking complement.66,81-83
natively, Salmonella and Shigella bacteria adhere and secrete This mechanism for complement resistance appears to be
proteins that are translocated into the host cell cytoplasm through enhancement of binding of fibrinogen to the bacteria
and trigger actin polymerization.63 In addition to mem- in the presence of M-protein.79,84,85
brane ruffling, Mycobacterium avium and Salmonella spp. Apoptosis is a distinctive morphologic process that results
also rely on activation of intracellular GTPases, leading to in cleavage of nuclear material and scavenging of unwarranted
phagocytosis.64,65 cells without immune activation. Apoptosis or programmed
Once colonization occurs, multiplication and spread of cell death is an important pathway for complex organisms
bacteria are enhanced through virulence factors. These fac- to deal with damaged and diseased tissue. Apoptosis avoids
tors assist bacteria in survival in the hostile host environ- the release of the tissue-damaging enzymes and nonspecific
ment and breakdown of tissue barriers. One of the most elimination of tissue that occurs in cellular necrosis. Several
common and potent strategies for avoidance of phagocytosis bacteria have modulated the host apoptotic pathways for
is the presence of a capsule. Despite the remarkable diver- enhancement of survival.86 Shigella flexneri, S. typhimurium,
sity of bacteria, capsule assembly and structure are remark- and toxins of S. aureus, Pseudomonas spp., and C. diphtheriae
ably similar across species. Early studies with S. equi subsp. have demonstrated programmed cell death as a consequence
equi demonstrated that resistance to phagocytosis was asso- of cellular infection or exposure.87,88 The protein of S. flex-
ciated with an increase in capsule and M-protein,66 and in neri, IpaB, induces apoptosis by binding to and activating the
a model of S. equi subsp. zooepidemicus infection in mice, cellular enzyme caspase 1, which induces apoptosis of mac-
enhancement of virulence was associated with increased rophages.89 Staphylococcus aureus α-toxin, which is similar
amount of capsule, which increased resistance to phagocy- to listeriolysin O, presumably escapes the macrophage after
tosis.67 Although colonization of the guttural pouch occurs engulfment and induces host cell apoptosis.90 The TSST toxin
with nonencapsulated S. equi subsp. equi strains, induction of S. aureus induces B-cell apoptosis and blocks immunoglob-
of lymphadenopathy is associated with capsular strains.68 In ulin production.91
more recent studies of S. equi subsp. equi infection, rapid
colonization in the lingual and pharyngeal tonsil is depen-
dent on genetically associated virulence factors that control
colony morphology, with the mucoid strain having enhanced
Pathogenesis of Fungal Infections
virulence.69 Maureen T. Long
Capsules of anaerobic bacteria are unique, and these
structures may directly account for the formation of Of the 250,000 species of fungi, fewer than 200 are true
abscesses within the host. The capsule of B. fragilis has two pathogens.1 Superficial mycoses affect the hair shaft and the
distinct polysaccharides composed of repeating subunits superficial epidermis. Cutaneous mycoses (dermatophytosis)
with oppositely charged groups (Zwitter ion).70 This poly- infect the epidermis, dermis, hair, and nails of animals, and
saccharide complex injected alone promotes the induction Microsporum, Trichophyton, and Epidermophyton spp. are
of abscess. Infection of rodents with the encapsulated form the most commonly associated pathogenic genera. Subcuta-
of Bacteroides and Fusobacterium spp. results in the forma- neous tissues can become infected with Sporothrix, Conid-
tion of intraperitoneal abscesses, whereas nonencapsulated iobolus, Basidiobolus spp., and members of the Dematiaceae
bacteria do not cause abscessation.71-73 Synergism of capsu- fungi, including the Chromoblastomycosis, Mycetoma, and
lar anaerobes with other bacteria occurs; nonencapsulated Phaeohyphomycosis spp. infections. Most of these infections
bacteria have enhanced survival in abscesses and produce are introduced by penetration through skin or opportunistic
capsule when cultured or inoculated with encapsulated invasion of damaged skin surfaces. Histoplasma capsulatum,
bacteria.72 Coccidioides immitis, Blastomyces dermatitidis, and Para-
Similar to and overlapping with capsule are structural pro- coccidioides brasiliensis are the four most important fungal
teins that block complement. The O side chain of lipopolysac- pathogens that can cause systemic infection. The most com-
charide (LPS) on gram-negative bacteria is an anticomplement mon opportunistic infections include Candida albicans,
factor.74 The longer the side chain, the greater the distance Aspergillus spp., Cryptococcus neoformans, Mucor spp., and
between phagocytes and bacteria. The capsular component, Pneumocystis carinii.
sialic acid, interacts with O antigen to prevent the formation Fungal virulence factors may be more complex than those
of C3 convertase.75 Bacterial enzymes are formed by Strepto- of bacteria because of the higher degree of opportunism that
coccus spp. and other organisms that damage the polymorph occurs with a change in host status. There may be subtle fac-
chemoattractant, C5a.76,77 Production of a protein in Salmo- tors that, combined with host status, result in a certain fungus
nella spp., encoded by the rck gene, prevents insertion of the attaining a virulent state. For instance, the typical fungal wall
C9 fragment of complement into the bacterial membrane.78 is composed of three major polysaccharides: mannose; β-1,3
The M-protein of S. equi subsp. equi appears to decrease depo- and β-1,6 linked glucans; and chitin. Chitin mutants in C.
sition of complement on the surface of bacteria.79 albicans are less virulent when tested in rodent models than
Recent studies of streptococci have shown that when are wild-type fungi.92 Further, a mutant C. albicans that can-
M-protein content is kept constant, the amount of capsule not synthesize complex mannose oligosaccharides does not
is correlated with resistance to phagocytosis.68 Resistance to adhere to other yeast and epithelial cells and has lost virulence
8 PART 1 MECHANISMS OF DISEASE AND PRINCIPLES OF TREATMENT

in a guinea pig model.93 Both of these mutants can proliferate

in vitro normally, and whether or not this is an actual viru- Pathogenesis of Viral Infections
lence factor is unclear.
As with bacteria, cellular adherence is an important pre-
requisite for infection and colonization of the host. Adhes-
ins have been identified in C. albicans and B. dermatitidis. Viral infections such as equine influenza (Orthomyxoviri-
Two genes have been associated with adhesion in C. albi- dae), rhinopneumonitis and abortion (Herpesviridae), Afri-
cans. The first is a glycoprotein that has sequences consis- can horse sickness (Reoviridae), equine infectious anemia
tent with agglutinating activity. Transformation of this gene (Retroviridae), and various encephalitides (Alphaviridae
into other nonadherent fungal species results in adhesion and Flaviviridae) are responsible for some of the most medi-
of the transformed yeast to cells.94 Candida albicans also cally and economically important diseases of horses. Specific
has integrin-like proteins, the disruption of which results therapy of viral infections remains a significant challenge
in diminished hyphal growth, adhesion to cells, and loss because antiviral drugs are generally ineffective, impractical,
of virulence in mice.95,96 The B. dermatitidis adhesin medi- or prohibitively expensive for the treatment of horses. Treat-
ates binding to human monocyte-macrophages through the ment of most viral infections focuses on supportive care of
CD14 receptor.97 the affected organ systems and control of secondary compli-
Many fungi have polysaccharide capsules that, like bac- cations such as bacterial infection. Currently control of most
teria, help resist phagocytosis and immune activation. The clinically significant viral diseases in horse populations relies
capsule of C. neoformans inhibits leukocyte accumula- on vaccination, quarantine, or even destruction of infected
tion, cytokine secretion, and macrophage phagocytosis.98 animals.
Mutants without capsule are highly infective and avirulent. Despite the great significance of some viral infections,
As indicated earlier, many fungi are engulfed by macro- recognizing that many equine viruses are ubiquitous,
phages, and intracellular survival is mediated by virulence weakly pathogenic, or not associated with any known dis-
factors. Macrophages are decimating cells for C. albicans,99 ease under normal circumstances is also important. Some
H. capsulatum,100 and B. dermatitidis. Histoplasma cap- examples include equine adenovirus, respiratory and
sulatum is primarily a yeast in vivo, and this form infects enteric reoviruses (the term reo is derived from the acro-
macrophages. Phagolysosomal fusion occurs at a normal nym for respiratory enteric orphan, indicating that these
rate,101 but blockage of acidification of the phagolysosome isolates have not been associated with disease), and equine
occurs.102 herpesvirus (EHV) type 2. Some host-virus relationships
Exposure to both pathogenic and saprophytic fungi is an may be mutualistic in that virally derived genetic elements
everyday occurrence. Respiratory contamination and infec- are theorized to benefit the host by facilitating genetic
tion are important for many pulmonary species, but skin pen- variability and evolution.116 Thus many viruses are of no
etration and dissemination from necrotic gut are important practical clinical significance, and no control efforts are
portals for large animals also. Dissemination after the initial warranted. For this reason, the veterinarian should never
infection is dependent on previous damage to host tissues, assume that the recovery of a virus from a clinical specimen
deeper mechanical penetration, or actual invasion of new tis- is significant without proof that the virus can cause the dis-
sues. C. albicans can actually grow through and replace cell ease in question.
membranes.99 True molds invade blood vessels and grow An in-depth discussion of viral structure, taxonomy, and
along the intima of the vessels. Fungi secrete many degradative replication is beyond the scope of this chapter, and the reader
enzymes, including proteinases, phosphatases, and DNAses, is referred to textbooks of veterinary or human virology for
to surmount structural barriers.103 A group of genes called more detailed information.117,118 A brief overview is presented
secreted aspartyl proteinase (SAP) genes allow more persistent to emphasize those features that have clinical relevance.
colonization of host surfaces and deeper penetration.104 The fundamental structure of all viruses is a DNA or RNA
When C. immitis invades the host, the fungi form endo- genome enclosed by a coat of protein called the capsid (Fig.
spores. These endospores secrete a proteinase and a urease 1.1). For viruses that are enveloped, the capsid is enclosed
that likely aid in the breakdown of pulmonary tissues.105-107 further by a host cell–derived lipid membrane into which
The two proteinases of A. fumigatus break down elastin, a viral proteins have been incorporated. In addition to protect-
major component of lung tissues.108,109 Phospholipase activity ing the viral genome, the capsid and other associated struc-
has been demonstrated in C. albicans, C. neoformans, and A. tural proteins (e.g., matrix proteins) are important for virus
fumigatus.110 Strains of Candida spp. with high amounts of this assembly, packaging the viral genome, releasing the genome
enzyme have higher virulence,111 and abolishing this activity into a target cell, and for nonenveloped viruses providing
results in decreased adherence of the organism.112 Host eico- receptors that bind to host cells. For enveloped viruses the
sanoids enhance fungal colonization. Recent evidence dem- receptors are incorporated into the lipid membrane. The pri-
onstrates production of eicosanoids by both dermatophytosis mary clinical significance of these features is that enveloped
and systemic fungi.113 viruses, because of their fragile lipid membrane, are highly
Fungi induce apoptosis, which may be due either to the susceptible to inactivation by heat, desiccation, or deter-
direct effect of a fungal toxin or secondary to host cell cyto- gents, and transmission typically requires direct exchange of
skeleton rearrangements.114 The gliotoxin of A. fumigatus can body fluids, short distance aerosols, or arthropod vectors. In
induce DNA fragmentation and apoptosis in macrophages.115 contrast, nonenveloped viruses (e.g., equine rotavirus) are
This toxin also has many other immunosuppressive qualities, resistant to physical inactivation, and environmental con-
which include inhibition of the neutrophil respiratory burst tamination is more likely to be a significant factor in their
and T-cell activation. transmission.
 CHAPTER 1 Mechanisms of Disease and Immunity 9

Herpesvirus Lipid envelope mutations are neutral or even deleterious, in the face of selective
(host cell derived) pressures such as the host immune response or antiviral drugs,
Capsid this genetic plasticity allows rapid development of resistant
(icosahedral) virus populations.120 Secondary structures or certain sequences
Genome in the viral genome may facilitate polymerase errors further at
Tegument
selected regions that are important for immune evasion, such as
in sequences that code for neutralizing epitopes.119 The genome
Surface viral of some viruses, such as influenza, comprise separate segments,
glycoproteins which allows reassortment of entire gene segments and sudden
(with receptors) and dramatic changes in antigenicity.121
All viruses are obligate intracellular parasites. Viral replica-
tion can occur only within living cells, and all viruses to some
extent depend on the host cell synthetic machinery. The life cycle
Rotavirus of all viruses includes the following steps: attachment to the tar-
get cell, entry into the cell, uncoating and release of the viral
genome, transcription and translation of viral proteins, replica-
Genome
tion of the viral genome, assembly of new virions, and release
(11 segments) of progeny virions117,118 (Fig. 1.4). Although the biochemistry of
these steps is beyond the scope of this discussion, recognizing
Capsid that they are all specific, energy-requiring interactions between
(2 layers of protein) the virus and the host cell is important. The inability of the virus
to interact appropriately with a cell at any of these steps prevents
Outer capsid proteins replication in that cell type and defines the tropism of the virus.
(with receptors) All of these steps are also important potential targets for antivi-
ral drugs and host immune responses.
Once the viral nucleocapsid gains entry to the cytosol of
FIG. 1.1 Schematic representations of basic viral structure. The basic struc- the cell, the viral genome is released through the process of
ture of an enveloped virus is shown by the drawing of a herpesvirus. The ba-
uncoating. After uncoating, the viral genome localizes to the
sic structure of a nonenveloped virus is shown by the drawing of a rotavirus.
appropriate regions of the cell for replication and mRNA tran-
scription. DNA viruses typically replicate genomes and tran-
scribe mRNA in the nucleus and then transport the mRNA to
the cytoplasm for translation. RNA viruses typically replicate,
The composition of the viral genome is an important basis transcribe mRNA, and translate viral proteins in the cyto-
for virus classification (Fig. 1.2). The type of viral genome also plasm. These sites of replication account, respectively, for the
determines the strategies required to replicate the genome and location of viral inclusion bodies that are diagnostically useful
transcribe messenger ribonucleic acid (mRNA; Fig. 1.3). Viral in histopathologic sections.
genomes may be single-stranded RNA, double-stranded RNA, Cells that replicate virus often are killed as a direct con-
single-stranded deoxyribonucleic acid (DNA), or double- sequence of infection. One mechanism by which viruses kill
stranded DNA. The genomes of single-stranded RNA viruses cells is lysis, often associated with the release of progeny viri-
may have positive polarity, in which the genome also serves ons. Insertion of viral proteins into cell membranes, budding,
directly as mRNA for translation of viral proteins. To replicate direct toxicity of viral proteins, and diversion of normal host
genomes, these viruses must first synthesize a strand of com- cell homeostatic processes to viral replication may result in
plementary RNA that can be used as a template to replicate death of the cell.117,118,122 Viruses also may activate the cellular
genomes and transcribe new mRNA. Retroviruses are a subset self-destruct mechanism of programmed cell death (apopto-
of single-stranded, positive-polarity RNA viruses that use their sis). Although cells may induce apoptosis in an attempt to pre-
RNA genomes as templates to produce double-stranded DNA, vent completion of the virus life cycle, viruses also may use this
which in turn is used for the transcription of mRNA and new mechanism to kill the cell and facilitate release of virions.123
viral genomes. Single-stranded RNA viruses may also have Viral infection can cause neoplastic transformation of
negative polarity, in which the genome is antisense to mRNA, infected cells. The most common examples in horses include
and synthesis of a complementary RNA strand is required to warts (equine papillomavirus) and sarcoids (bovine papillo-
serve as mRNA and as a template for new genomes. The clini- mavirus). Virally induced invasive neoplastic diseases such
cal significance of these types of replication strategies is that as leukemia or lymphosarcoma have not been recognized in
they require polymerases and other enzymes not normally the horse. Viral proteins that activate the cell cycle into the
found in eukaryotic host cells. These unique viral enzymes are growth and division phases may lead to neoplastic transfor-
important targets for antiviral drugs because they can be used mation if expressed in a cell that is not killed by the infection.
selectively to inhibit viral replication. Papillomavirus infections induce epithelial neoplasms (fibro-
Viral RNA polymerases are low fidelity and lack proofread- papillomata) using a virally encoded protein (E5 oncoprotein)
ing functions and thus randomly introduce errors into new that induces proliferation of normally quiescent cells and that
RNA at an average rate of about one nucleotide mismatch per presumably is needed for viral replication.124 Oncogenic retro-
10,000 bases copied.119 In a population of viruses, therefore, viruses, including leukemia and sarcoma viruses, induce neo-
virtually every individual virus differs slightly, and this popula- plastic transformation by integration into the host cell genome
tion is referred to as a quasi-species. Although many of these and activation of cellular oncogenes.125
10 PART 1 MECHANISMS OF DISEASE AND PRINCIPLES OF TREATMENT

ENVELOPED NONENVELOPED

dsDNA dsDNA

DNA Polyomaviridae
Iridoviridae Adenoviridae
Hepadnaviridae
Herpesviridae ssDNA
Poxviridae, Chordopoxviridae
Parvoviridae

ssRNA dsRNA

Reoviridae

Coronaviridae Paramyxoviridae Bunyaviridae Toroviridae

Birnaviridae

RNA Orthomyxoviridae Arenaviridae Togaviridae Flaviridae ssRNA

Piconaviridae
Retroviridae Rhabdoviridae

Caliviridae

Filoviridae

FIG. 1.2 Virus family classification based on genome composition and presence of envelope or absence
of envelope. The relative size of the viruses to each other is also shown.

At the host level viruses may use several mechanisms to infected animals serve as the reservoir of the virus.127-129 On
establish persistent infections and avoid immune clearance. reactivation viral nucleic acids are translocated across syn-
Virologic latency is defined as the presence of a viral genome apses to epithelial cells of the nasopharynx, which produce
that is not producing infectious virus.126 The genomes of infectious virus. The stimuli that induce reactivation are
latent viruses are transcriptionally suppressed and trans- poorly defined, but reactivation can be induced by immuno-
lationally silent so that no viral proteins are expressed that suppression (e.g., corticosteroids) and presumably by other
may identify the cell to the immune system as infected. The stressors, such as pregnancy, transport, and social stress.128,130
definition of latency also stipulates that on reactivation, viral The severity of disease in a virus-infected horse, or whether
gene expression and the production of infectious progeny infection even results in clinical disease at all, is the result
virions can be resumed, differentiating latently infected cells of a complex interaction among the triad of virus, host, and
from cells infected with defective viruses. In contrast, some environment. Critical factors include viral virulence, viral
persistent viral infections are characterized by continual rep- spread within the animal, the intensity of direct and immune-
lication despite the presence of antiviral immune responses. mediated pathologic response elicited by the virus, and the
Even in the absence of recognizable clinical signs, such infec- ability of the virus to avoid clearance by the host. Other than
tions are not truly latent. The classic latent infection is that the virulence of the virus, which is strictly a property of the
of the herpesviruses. For the α-herpesviruses, such as EHV1 virus, the other virus-host interactions can be influenced by
and EHV4, latent infections are established in the nuclei of the age and genetics of the host and by environmental fac-
sensory neurons and can be maintained indefinitely, and tors such as stress and nutrition. These factors account for
 CHAPTER 1 Mechanisms of Disease and Immunity 11

Protein Synthetic Replicative New Viral

Expression Intermediates Viral Genome Intermediates Genome

dsDNA
Adenoviridae
Asfarviridae
Herpesviridae
(+) mRNA Iridoviridae dsDNA
Papillomaviridae
Polyomaviridae
Poxviridae

ssDNA
(+) mRNA dsDNA Circoviridae (– or +) dsDNA ssDNA
Parvoviridae (– or +)

dsRNA
(+) mRNA Birnaviridae dsRNA
Reoviridae

ssRNA (+)

Arteriviridae
Astroviridae
Caliciviridae
(+) mRNA ssRNA (–) Coronaviridae ssRNA (–) ssRNA (+)
Flaviviridae
Picornaviridae
Togaviridae

dsDNA Retroviridae dsDNA

ssRNA (–)
Arenaviridae
Bornaviridae
Bunyaviridae
(+) mRNA Filoviridae ssRNA (+) ssRNA (–)
Orthomyxoviridae
Paramyxoviridae
Rhabdoviridae

FIG. 1.3 Summary of the main virus families that infect vertebrates and general strategies employed by
these viruses to produce mRNA for protein expression and to replicate genomes. Required intermediate mol-
ecules are indicated. White arrows indicate the need for unique viral polymerases, including RNA-dependent
RNA polymerase and RNA-dependent DNA polymerase (reverse transcriptase). Dark arrows indicate the use
of cellular polymerases or viral homologs of cellular polymerases. ds, Double-stranded; ss, single-stranded;
(+) for RNA = positive polarity, polarity of RNA used for protein translation; (+) for DNA = coding strand,
sequence same as for (+) RNA; (− or +) DNA = contains single strands of DNA of both polarities. (Modified
from Baltimore D: Expression of animal virus genomes, Bacteriol Rev. 35:235-241, 1971.)

the observation that considerable variation in disease signs in virulence, presumably because of the greater number of
can occur among a group of animals infected with the same infected cells and amount of tissue damage. The virulence
viral strain. of equine infectious anemia virus strains can be correlated
Certain strains of a virus may cause more severe disease directly to plasma virus titers and numbers of infected cells,
than other strains. The main properties of a virus that may without any changes in tropism.131,132 The molecular basis
affect virulence include host cell tropism and replication for the increased replication rate is not clear but most likely
rate. A tropism change that leads to involvement of addi- is caused by variation in viral regulatory sequences and
tional tissues or facilitates virus spread generally results in proteins.133,134
more severe disease. Outbreaks of EHV1 abortion or neu- Viral infections generally are regarded as localized or sys-
rologic disease strongly suggest that EHV1 strains exist temic. Localized viral infections are those that are restricted
that have a tropism for these tissues compared with EHV1 to a single organ system, often at the site of entry. Because
strains that cause respiratory disease. An increase in the infection of the tissue is direct, the incubation period for
viral replication rate is usually associated with an increase localized viral infections is usually short, often only a few
12 PART 1 MECHANISMS OF DISEASE AND PRINCIPLES OF TREATMENT

1 (Fig. 1.5). Localized viral replication first occurs at the site of

entry and in regional lymph nodes. Depending on the level
of replication, clinical disease may be present. The virus then
Cytoplasm enters the blood or lymphatics and spreads to other tissues,
2
such as spleen and liver, in which clinical disease may occur.
Virus is amplified and then released again for a second, usually
9 higher-titered, viremia that further disseminates the virus to
3 Nucleus
other organs. Each viremic episode is associated with a febrile
response and is the basis for the biphasic fever response asso-
4 6 ciated with some viral infections. Because systemic infections
6 4
require multiple steps, the incubation periods are longer than
5 for localized infections, typically 1 to several weeks. Infec-
10 tions in the horse by eastern, western, or Venezuelan equine
encephalitis virus closely follow this paradigm. Localized viral
7
7 11 replication occurs at the site of entry (mosquito bite) followed
by viremia and dissemination to the central nervous system.139
8 For most horses, even nonvaccinated horses, dissemination is
8 controlled before infection of the brain, and neurologic dis-
ease is a rare outcome of infection. A variation on the theme
is infection of horses with EHV1. The most common clini-
cal disease associated with EHV1 infection is rhinopneumo-
FIG. 1.4 Schematic representation of the general virus life cycle. Both nitis caused by a localized infection of the nasopharyngeal
RNA and DNA viruses share the initial steps, including attachment (1); entry/
mucosa.140 In almost all cases, a cell-associated viremia also
fusion (2); and uncoating and release of viral genome into the cell (3). Solid
occurs in lymphocytes, but in most infected horses this does
arrows indicate remaining steps for RNA viruses, which all occur in the cyto-
not result in disease. However, in some cases, viremia is asso-
plasm, including transcription of mRNA (4); translation of viral proteins (5);
ciated with infection of endothelial cells, and in the pregnant
replication of the viral genome (6); assembly of new virions (7); and release
mare vascular damage to the uterus and placenta may lead to
of progeny virions (8). Dashed arrows indicate steps for a DNA virus. The life
abortion.140,141 Similarly, infection of the vascular endothelium
cycle is similar except that the DNA genome is translocated to the nucleus (9)
in the central nervous system results in neurologic disease.142
for transcription (4) and replication of viral genomes (6). Viral mRNA is then
Some viruses also may spread in the host through nerves.
translocated back to the cytoplasm for translation (10), and newly synthesized
In the horse rabies is the best-known infection that relies on
viral proteins are translocated back to the nucleus (11) for assembly (7); new
neural spread. Following local replication in myocytes at the
virions are then released from both nuclear and cytoplasmic membranes (8).
site of entry, usually a bite wound, rabies virus ascends periph-
eral nerves into the central nervous system, where it repli-
cates in neurons and then egresses by way of cranial nerves
days. Many infections of the skin or mucosal surfaces are to the salivary gland.143 EHV1 and EHV4 establish latency in
localized, and examples in the horse include infections with the nuclei of sensory neurons that innervate the nasopharynx
enteric rotavirus and influenza. For influenza, virus is inhaled and reach the nucleus by ascending nerve axons. Similarly, on
into the nasopharynx and replicates in epithelial cells of the reactivation these viruses egress back down the axon to infect
upper respiratory tract and trachea. Virus is not present in epithelial cells.127,144
the blood or tissues outside of the respiratory tract. In gen- Once a virus reaches a target organ, virally mediated cell
eral, viruses remain localized because they lack the recep- death is the fundamental source of pathologic response,
tors to infect cells of other tissues or circulating cells, such as disease, and clinical signs observed by the veterinarian.
monocytes or lymphocytes, that can disseminate the virus. Despite the great complexity of virus-host interactions
Some viruses are temperature sensitive and remain local- and the many factors that influence the expression of clini-
ized because they are unable to replicate efficiently at core cal disease, in actuality viruses have a limited number of
body temperatures. EHV3, the cause of coital exanthema, is ways by which to cause pathology. Cells and tissues may be
restricted to the surface of the genitalia in horses because of destroyed directly by cytolytic viral infections or by infec-
its temperature sensitivity.135 EHV1 and EHV4 are not tem- tions that affect the differentiated function of target cells
perature sensitive, however, and systemic infection may occur (e.g., neoplasms and immunodeficiencies). Viral infections
with these viruses. Temperature sensitivity is also a means of organ systems with bacterial flora (e.g., intestinal and
by which some viruses, such as equine influenza and infec- respiratory tracts) can disrupt the normal barrier functions
tious bovine rhinotracheitis virus, may be attenuated for use of these organs and result in secondary bacterial infections
as modified-live intranasal vaccines. Infection by the vaccine and toxemia that may contribute significantly to the patho-
strain is limited to the cooler mucosal surfaces; the inability logic response. Cell death and pathologic response also may
to spread systemically prevents sequelae such as abortion and be caused by host immune responses specifically directed
pneumonia.136,137 against virally infected cells or by indiscriminate inflam-
Systemic infections are those in which virus is dissemi- matory responses. Virally induced autoimmune diseases
nated to multiple tissues by blood or lymph. This viremia may have not been described in horses but are another potential
exist in the form of cell-free virions in the plasma or lymph source of pathologic response that may be identified in the
or may be cell associated in circulating blood cells, usually future.
monocytes or lymphocytes. The classic paradigm for a sys- For most of the clinically important viral diseases of horses,
temic infection is infection of mice with ectromelia virus138 disease manifestation results from some combination of
 CHAPTER 1 Mechanisms of Disease and Immunity 13

DAY
Skin: Invasion
Multiplication

1 Regional lymph node:

Multiplication

2
Bloodstream:
Primary viremia

3
Incubation Spleen and liver:
period Multiplication necrosis
4

Bloodstream:
5 Viremia

Skin: Focal infection

6 Multiplication

Swelling of foot
(Primary lesion)
8

Early rash
Papules
Disease 9

10

Severe rash
Ulceration
11

FIG. 1.5 Schematic representation of the pathogenesis of mousepox (ectromelia), illustrating the classic
paradigm for the events in a systemic infection. (From Fenner F: The pathogenesis of the acute exanthems,
Lancet. 252:915, 1948.)

cytolytic infection and immune-mediated tissue destruction. apparent. EHV1 infections of the respiratory epithelium,
The relative contribution of these mechanisms is primarily a which has a large number of cells with a high turnover rate,
function of viral virulence and host factors that influence the produce mild clinical disease even with a high rate of infec-
type and intensity of immune responses. The predominant tion. On the other hand, much more significant clinical
mechanism of pathologic response also can vary with differ- manifestations of EHV1 infection such as abortion and neu-
ent stages of the same disease, as seen in acute versus chronic rologic disease are caused by infection of a few endothelial
equine infectious anemia. In acute disease most of the disease cells because minimal vascular damage can lead to thrombo-
manifestation is caused by direct viral damage and cytokines, sis, ischemic necrosis, and damage to large amounts of tissue.
whereas in chronic disease immune complex–mediated ane- If viral infection results in neoplastic transformation of a cell
mia and glomerulonephritis become more significant. type, disease may progress according to the characteristics of
The disease associated with a given viral infection is the neoplasm, whether or not the virus remains associated
related to the affected organ system(s), the number of cells with the tumor.
destroyed, and the sensitivity of the affected organ system to In most viral infections immune-mediated pathologic
dysfunction. If the number of infected cells is not sufficient response contributes significantly to disease and in some
to lead to clinically significant organ dysfunction, the result cases may be the predominant cause of disease manifestation.
is a subclinical infection. When enough cells are infected to Equine immune and inflammatory responses are covered else-
lead to overt organ dysfunction, clinical disease becomes where in this chapter.
14 PART 1 MECHANISMS OF DISEASE AND PRINCIPLES OF TREATMENT

Although not described in horses, viral infections in other in disease conditions. Immune responses leading to protective
species can induce immune-mediated responses to host cell resistance against reinfection occur, but the level of this resis-
antigens and autoimmune diseases. The best documented tance is most often incomplete. Mechanisms associated with
human autoimmune disease suspected to be initiated by viral these responses have not been investigated extensively in the
infections is Guillain-Barré syndrome, in which infection with horse, but information is available from other host-parasite
cytomegalovirus or Epstein-Barr herpesvirus elicits antinerve systems that may be relevant to equids. The purpose of this
ganglioside immune responses and demyelinating disease.145 section is to acquaint the reader with contemporary thoughts
Postinfluenza myocarditis is an occasional sequela in horses on host-parasite interactions. Because of their prevalence,
and human beings and is a potential autoimmune disease. major importance to equids, and information available, cover-
Although no direct evidence supports this theory, influenza age is limited to helminth parasites that occur in most devel-
virus is not identified consistently in affected heart muscle, oped and nontropical countries.
and the pathogenesis is not known.146 Infection with most metazoan parasites results in inflam-
A key requirement for viruses to be maintained in nature mation and structural and functional changes of the organs
is to persist successfully in a reservoir host (if the reservoir is invaded. The outcome of these changes is an alteration of the
an infected animal) and to be transmitted to another suscep- host’s physiologic state. The degree of alteration depends on
tible host. One of the most important obstacles to persistence the existing physiologic condition of the animal, which is dic-
and transmission is detection and elimination by the host tated to a great degree by its age, nutritional status, and previ-
immune system. Within the host rapidly replicating viruses ous immunologic experience with the parasite. The numbers
such as influenza may shed and transmit virus before the host of parasites introduced and the specific parasite also affect the
can mount specific antiviral immune responses. Herpesvi- degree of physiologic change that occurs. When these fac-
ruses avoid detection during latency by not expressing any tors favor major alterations, the results are readily identifiable
viral proteins. Immunodeficiency viruses may cripple antivi- clinical signs of infection. Subclinical infections, although less
ral immune responses by directly infecting immunoregulatory apparent, are potentially important to the general health of the
CD4+ T lymphocytes. One of the most important mechanisms animal and continued transmission of the agent. The patho-
of immunologic avoidance is antigenic variation in which neu- physiologic effects of infection by ectoparasites, helminths, and
tralizing viral antigens are altered so that they are no longer microorganisms are in many cases similar.150,151 Abnormalities
recognized or accessible by host immune responses. Antigenic in weight gain, skeletal growth, reproduction, and lactation may
variation is generated by nucleotide errors during transcrip- result from infections with any of these agents. These changes
tion or replication, which result in amino acid substitutions are often directly related to parasite-induced anorexia, disrup-
in the relevant epitopes. Other mechanisms by which some tion of metabolic processes, and anemia. An understanding of
viruses may modify their antigenicity is through intramolecu- the morphologic and biochemical lesions produced by specific
lar recombination/duplication or reassortment of segmented parasites clarifies the role of these agents in clinical and sub-
genomes (e.g., influenza and African horse sickness).120,121 For clinical conditions associated with the infections. Most detailed
reassortment, coinfection of a single cell with genetically dif- studies of the pathophysiology of parasitic infections have been
ferent virions may result in a progeny virion with segments conducted in laboratory animal models and domestic animal
derived from both virions and a major change in antigenicity. species other than the horse.151 However, the classical pathol-
In influenza these are called antigenic shifts, and the radical ogy of parasitic infections of the horse has been reviewed.149,152
change in the antigenicity of the virus may render preexisting The following discussion outlines some recent observations on
immunity in the host population ineffective at preventing out- host-parasite interactions that may be of significance to equine
breaks of disease with high morbidity and mortality rates.121 medicine. Examples of host-parasite interactions responsible
Genetic differences in susceptibility to disease have been for alterations in host homeostasis are presented as they relate
well documented. In an outbred population of animals, the to the gastrointestinal tract, lungs, and skin.
considerable variation in the type or severity of clinical dis-
ease is well recognized, even when animals are infected with Y GASTROINTESTINAL TRACT
the same virus strain and have no recognizable differences
in other factors such as age, challenge dose, nutrition, and Internal parasites are most important to equine health as
general health status. Conversely, highly inbred populations mediators of gastrointestinal problems, including colic and
may be more uniformly susceptible to a viral disease.147 Thus diarrhea. Although almost all internal parasites have been
inbreeding can pose problems for endangered species, such as inferentially implicated as causative agents of colic at some
Przewalski’s horse, or other populations with limited genetic time, significant evidence-based experimental or field obser-
variability, which may incur high rates of morbidity or mortal- vations have emerged to support this contention for some
ity if the animals are infected with a virulent virus. Host genet- parasites. The helminth parasites include large strongyles,
ics may affect the tropism of the virus and influence the type principally Strongylus vulgaris, Parascaris spp., Anoplocephala
and intensity of immune responses to a viral infection. perfoliata, and as a group the cyathostomins.
The pathogenesis of colic associated with migration of
Strongylus vulgaris through the mesenteric arteries and the
resultant thrombosis, infarctions, and necrosis of the intes-
Pathogenesis of Parasitic Infections tine have been described in detail elsewhere.149,152,153 Large
strongyles are easily controlled with currently available mac-
rocyclic lactone anthelmintics and are rare in horses kept on
Horses serve as hosts for numerous parasites, which induce well-managed farms in developed countries. Histologic stud-
a wide range of pathologic and immunologic responses.148,149 ies of experimentally infected parasite-free pony foals dur-
Many of the latter are of a hypersensitive nature and also result ing the initial stages of infection indicate that the severity of
 CHAPTER 1 Mechanisms of Disease and Immunity 15

lesions produced in the intestine cannot be attributed solely ruptures and intussusceptions of the cecum and colon asso-
to mechanical disruption caused by larval migrations and that ciated with these infections.160,161 Several case-control studies
these larval stages induce some biologic amplification system have documented an association between colics in the ileal
within the mucosa, which results in the degree of inflamma- region and A. perfoliata infection.162 These parasites inhabit
tion observed.154 Although the mechanisms involved in this the region of the ileocecal junction and produce ulcerated
response have not been investigated, the histologic nature of lesions of the mucosa and submucosal inflammation. Detailed
the lesion is characteristic of an Arthus reaction, suggesting experimental investigations of these infections have not been
an involvement of the immune response. Other experimental conducted, and thus specific details on the pathogenesis and
studies using the parasite-free pony–S. vulgaris system have relevance of these lesions are lacking. An association between
implicated a role for the immune response in the mediation severity of observed lesions and tapeworm burden has been
and regulation of the arterial lesions produced by this para- observed.163,164
site. Passive transfer of immune serum but not normal serum Cyathostomins (cyathostomes or small strongyles) have
reduced the severity of arteritis seen and clinical signs asso- not generally been considered to be of major importance,
ciated with experimental infections without reducing the particularly as causative agents of colic. In this regard,
numbers of parasites that develop in these ponies.155 However, Uhlinger’s field studies are of particular importance.165,166 In
treatment with immune serum also induced an anamnestic these controlled experiments different anthelmintic treatment
eosinophilia and marked perivascular infiltration of eosino- regimens were used to test their efficacy in reducing the inci-
phils in the cecum. The reduction in intravascular lesions may dence of colic. The more efficacious treatment programs sig-
have been associated with an inactivation of parasite-secreted nificantly reduced the incidence of colic by 2 to 13 times that
inflammatory factors either by antibody or serum enzymes seen in the same herds before implementation of the more
or circulating cytokines. This serum may also have contained efficacious treatment. Because of the management programs
nonspecific host-derived antiinflammatory substances. The used before the initiation of this study and the results of fecal
exacerbation of the eosinophil response may have been asso- cultures, it can be assumed that the primary parasites pres-
ciated with the formation of immune complexes. Although the ent in these horses were cyathostomins. These data strongly
mechanisms are unknown, the results suggest that the immune implicate a role for cyathostomins in a substantial proportion
response may simultaneously modulate and potentiate inflam- of colics observed under field conditions. The parasite or host
mation. It has been postulated that larvicidal treatment of S. factors involved in these colic cases are unknown but may be
vulgaris–infected horses and killing of intravascular larvae the dynamic turnover of parasites during the life cycle in the
may release a bolus of antigenic factors from these larvae mucosa and the related inflammatory responses seen that they
within the mesenteric vasculature, resulting in an exacerba- induce.
tion of arterial and intestinal lesions and colic. Experimen- Cyathostomins have been implicated in numerous case
tal testing of this hypothesis indicates that this phenomenon reports with seasonal diarrhea in adult horses, which is a con-
does not occur and further that viable larvae are necessary to dition called larval cyathostominiasis. These cases are charac-
maintain the arteritis and eosinophilia seen.156 Experimental terized by a sudden onset of diarrhea during the late winter
studies using parasite-free ponies that were immunized with or spring. Horses younger than 5 years of age are particularly
crude adult worm antigens and subsequently challenged with at risk, but mature horses can be affected as well, and a case-
S. vulgaris larvae showed an exacerbation of the pathologic fatality rate of 50% has been reported.167 These are difficult
responses seen in the mesenteric vasculature and including to diagnose, and the only consistent signs are weight loss,
an anamnestic eosinophilia, further suggesting a role for the hypoproteinemia, and diarrhea.166 Large numbers of larval
immune response in the development of these lesions.157 cyathostomins can be found in the feces or in intestinal con-
Colic associated with Parascaris spp. infection in foals has tents and within the mucosa of these horses. These symptoms
been related to intestinal impaction and rupture and is not are related to the synchronous emergence of fourth-stage
considered to be of major significance in adult horses.158 These larvae of these parasites from the mucosa. These larvae build
conditions in foals may become more important with the to potentially large numbers within the mucosa owing to the
widespread identification of Parascaris spp. resistance to iver- arrested development of infective larvae. The seasonality of
mectin.159 However, ascarid nematodes are particularly potent the occurrence of this condition at present does not appear
sources of allergens, and it is not inconceivable that the hyper- to vary in different climatic regions as does the analogous
sensitized mature horse may respond to low-level infections bovine condition of type II ostertagiasis. Specific parasite or
with this parasite. Observations made in the author’s labora- host factors associated with the regulation of the hypobiotic
tory are noteworthy in this regard. Two mature Parascaris-free state of the larvae or the inflammatory response initiated at
adult horses were inoculated intradermally with less than 90 parasite emergence have not been described. Other clinical
μg of saline-soluble somatic extract of adult Parascaris spp. reports have suggested that cyathostomin-related diarrhea
to test for immediate hypersensitivity to this antigen. Both and weight loss are not related to the seasonal presentation
horses experienced an immediate systemic response and colic. described previously.168 This is supported by experimental
One of the horses died within 3 hours of intradermal inocula- studies demonstrating that pathophysiologic effects occur as
tion. Necropsy results were consistent with the diagnosis of large numbers of parasites enter the intestine, as well as when
acute severe colitis. Because of the allergic potential of ascarid they leave.169
nematodes and the sensitivity of the equine gut to immediate In view of the paucity of specific mechanistic information
hypersensitivity reactions, this potential is worthy of further on the pathophysiologic effects of equine gastrointestinal par-
characterization and consideration. asites, a synopsis of relevant information gathered from other
Clinical observations have maintained an interest and model systems is warranted, particularly for nematodes.151,170
concern over the pathogenic potential of Anoplocephala per- Parasitic organisms may induce changes in gastrointestinal
foliata infections. Earlier case reports have described cecal function directly by mechanical disruption of tissues and cells
16 PART 1 MECHANISMS OF DISEASE AND PRINCIPLES OF TREATMENT

or by the release of factors that directly alter cell function. Parascaris spp. larval migrations in the lungs of yearling
Induction of the immune response serves as an anamnestic horses produce more severe clinical signs and inflammatory
amplification system. The result of these changes is an altera- responses than in foals that are reared parasite free. These
tion in function of the smooth muscle and epithelium of the infections in yearlings are accompanied by focal accumula-
bowel. tions of lymphoid tissue, indicating an induction of an active
A number of helminth parasites, including Parascaris local immune response. It is suggested that this is an age-
spp., stimulate intestinal smooth muscle hyperplasia. This related phenomenon.178 However, it is likely that more severe
response may be induced by intestinal inflammation or ste- reactions could be the result of previous sensitization to Par-
nosis associated with parasitism. Contractility of these mus- ascaris spp. antigens. Increased responses of this nature have
cles can be induced in a Schultz-Dale reaction by stimulation been described in the livers of pigs immunized with Ascaris
with parasite antigens. This response is mediated in rats suum antigens following challenge infections.
by mast-cell–derived 5-hydroxytryptamine (5-HT) and in Dictyocalus arnfieldi infections of donkeys rarely produce
guinea pigs by histamine. A regulatory relationship of myen- clinical signs, and it has been suggested that these equids are
teric neurons to these antigen-induced changes has also the natural host for this parasite. Infections of horses produce a
been demonstrated in this model system. These latter experi- more severe and prolonged bronchial inflammatory response
ments suggest that antigen-induced stimulation of smooth similar to Dictyocalus sp. infection in other hosts. The mecha-
muscle contractility may be correspondingly blocked by nisms associated with this differential response have not been
γ-aminobutyric acid similarly stimulated by mast cell prod- defined but are not uncommon in unadapted host-parasite
ucts. This complex system may be an adaptation by the host associations. It is possible that the more marked inflammatory
to maintain homeostasis in the face of continued antigenic reaction of the horse to these parasites is due to the absence of
stimulus. It is noteworthy that strongyle-induced altera- downregulatory mechanisms that are established in the more
tions in myoelectric activity of the equine small intestine and adapted natural host, the donkey.
colon have been demonstrated in vivo.171,172 In some of these
experiments, dead S. vulgaris larvae evoked an alteration of Y SKIN
the smooth muscle response in previously exposed ponies,
suggesting a role for the immune response in the stimulation Whereas Onchocerca cervicalis infections in horses are rare
of the hyperactivity.173 where macrocyclic lactone anthelmintics are regularly used,
There is a rapidly growing literature on the host-parasite reactions to the filarial nematode illustrate variations seen in
interactions of a number of mouse models of gastrointestinal responses to chronic parasite infection. Focal, alopecic, depig-
nematode infections.174-177 The mouse models include infec- mented, pruritic lesions are often seen in infected horses. Not
tions of Trichinella spiralis, Nippostrongylus brasiliensis, Helig- all infected horses react to this infection, and the appearance
mosomoides polygyrus, and Trichuris muris. Because of the of clinical signs is often seasonal. Detailed studies have not
use of the mouse the most contemporary of immunologic, been conducted on the pathogenesis of these lesions in horses.
genetic, molecular, and cell biologic techniques are available However, similar conditions occur in human onchocercia-
and may provide useful insights into potential explanations of sis,179 and it is likely that the host-parasite responses active in
immunologic and pathophysiologic responses of the horse to humans are also present in the horse. Lesion development is
nematode parasites, particularly the cyathostomins. Although associated with immune-mediated killing of microfilariae in
differences in specifics exist among these murine models, it is the skin. Parasites appear to be killed in an antibody-depen-
clear that these worms induce a type 2 T-helper cell cytokine dent cell-mediated reaction. In this response antimicrofilar-
response consisting of interleukins (ILs) IL-4, IL-5, IL-9, and ial surface IgG and IgE antibodies mediated adherence and
IL-13. IL-4 and IL-13 induction of the Stat6 pathway is cen- degranulation of granulocytes, which are predominantly
tral to most of the resulting responses. There is a consistent eosinophils. Major basic protein of eosinophils has been dem-
mastocytosis and eosinophil infiltration of the intestine. The onstrated in the tissues of patients with dermal lesions, and
resulting responses also involve goblet cells, the enteric ner- it has been suggested that eosinophil toxic enzymes and pro-
vous system, epithelial cells, and alternately activated macro- teins are responsible for many of the changes seen. The rea-
phages as effector cells. Cell junctions are disrupted, smooth son for the absence of these lesions in most horses is unclear.
muscle hypercontractility is stimulated, epithelial cell secre- Human onchocerciasis and filariasis are spectral diseases.
tion increased, and goblet cell production of mucus is stim- In these diseases regulation of immune responses has been
ulated. Although these mechanisms are used most often to associated with the lack of pathologic responses to the para-
explain expulsion of the nematodes in question, they could be sites.180,181 Immune regulatory mechanisms associated with
equally important in the disruption of the homeostasis seen in these infections include immune tolerance, anergy, induction
the parasitized equine intestine. of immune regulation involving Treg cells or macrophages,
and the production of IL-10 and transforming growth factor
Y RESPIRATORY SYSTEM beta (TGF-β)–altering Th-cell subsets and the production of
specific cytokines during different phases of the infections.
Several nematode parasites infect the equine lung. These Recent studies have also focused on the role of an intracellular
include migrating stages of Strongyloides westeri and Paras- commensal microorganism, Wolbachia, which is a parasite of
caris spp. en route to the small intestine. Migrating stages of Onchocerca and other filarial nematodes. These bacteria have
aberrant parasites, such as Habronema sp., Draschia megas- been shown to mediate type 1 inflammatory lesions in humans
toma, and Strongylus spp., which induce granulomatous foci in and mouse models.180
the lung parenchyma, and adults and larvae of the lungworm The presence of these types of parasite-associated immune
Dictyocalus arnfieldi, which inhabit the bronchi, also occur. regulatory events has yet to be critically studied in the horse.
Host responses to two of these are noted. However, the seasonal variability in skin responses to the
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