Current Clinical Medicine Electronic 2nd Edition

Visit the link below to download the full version of this book:

https://medipdf.com/product/current-clinical-medicine-electronic-2nd-edition/

Click Download Now

 Contributors

Joseph B. Abdelmalak Yvonne Braver Esteban Faith-Fernandez Julie Huang

Abby Abelson Sorin J. Brener Tatiana Falcone M. Elaine Husni
Ahmed Absi Stacy Brethauer Tommaso Falcone Adriana G. Ioachimescu
Edgar Achkar Marie M. Budev Gary W. Falk Octavian C. Ioachimescu
David J. Adelstein Matthew Bunyard Suzanne R. Fanning Harry J. Isaacson
Talal Adhami Carol Burke Richard Fatica Carlos M. Isada
Kamal Adury Saud Butt Omar Fattal Naim Issa
Anjali Advani Leonard Calabrese Michael Faulx Wael A. Jaber
Feyrouz Al-Ashkar Charles Camisa Elizabeth File Ron Jacob
Amjad AlMahameed Darwin L. Caldwell Maria Fleseriu Fredrick J. Jaeger
Antoine Amado John Carey Fetnat Fouad-Tarazi Fred Jaeger
Sheila Armogida William D. Carey Adele Fowler Xian Wen Jin
Wendy S. Armstrong Karin Cesario Robert Fox Georges Juvelekian
Mercedes E. Arroliga Nathaniel Cevasco Kathleen N. Franco Sangeeta Kashyap
Alejandro C. Arroliga Jeffrey T. Chapman Thomas G. Fraser Irene Katzan
Kathleen Ashton Soumya Chatterjee Benjamin J. Freda Gurjit Kaur
Arman Askari Michael C. Chen Katherine Freeman Mani Kavuru
Natasha Atanaskova Neil Cherian John J. FungJorge Garcia Thomas F. Keys
Marjan Attaran Priya Chinnappa Thomas R. Gildea Sami Khalife
Federico Aucejo Anuja Choure Joseph A. Golish Mazen K. Khalil
Joseph Austerman Jeffrey Y. Chung Anil Gopinath Atul Khasnis
Robin Avery Gregory B. Collins Steven Gordon Esther S.H. Kim
H. Nail Aydin Edward C. Covington Lisa Grandinetti Richard Kim
David Barnes Daniel A. Culver Adam Grasso Alice Kim
John R. Bartholomew Ronan Curtin Brian Griffin R. Koelsch
Pelin Batur Mellar Davis Richard Grimm Curry L. Koening
Rachid Baz Steven Deitcher Rula A. Hajj-Ali Ann R. Kooken
Wilma Bergfeld Sevag Demirjian Philip Hall Shakuntala Kothari
Deepak Bhatt Robert Dreicer Amir H. Hamrahian Richard A. Krasuski
Swati Bharadwaj Thomas J. Dresing Shannon Harrison Robert Kunkel
Laura K. Bianchi Raed A. Dweik Teresa Hermida Milton Lakin
Allan Boike Bijan Eghtesad José Hernández-Rodriguez David M. Lang
Michael H. Bolooki Julie A. Elder Robert Heyka Steven P. LaRosa
Brian Bolwell Peter J. Embi Gary S. Hoffman Martin E. Lascano
Corinne Bott-Silverman Kristin Englund Robert Hobbs Bret Lashner
Andrew Boyle Serpil Erzurum Sandra Hong Anthony K. Leung
Linda Bradley Ronan Factora Byron Hoogwerf Harry Lever
William E. Braun Kyrsten Fairbanks Fred Hsieh David S. Lever

vii
viii Contributors

Kerry H. Levin Preetha Muthusamy Nancy Foldvary-Schaefer Rachel M. Taliercio

Alan Lichtin David J. Muzina Philip Schauer Thomas Tallman
Oren H. Lifshitz Dileep Nair Raymond Scheetz Jinny Tavee
Li Ling Lim Joseph Nally Steven Schmitt Anthony Tavill
Daniel Logan Christian Nasr Martin Schrieber David Taylor
Jennifer Lucas Thomas P. Noeller Raul J. Seballos James S. Taylor
Marina Magrey Gian M. Novaro Robert A. Schweikert George E. Tesar
Michael Maier Saul Nurko Mikkael A. Sekeres Holly L. Thacker
Donald Malone Robert S. O’Shea Bo Shen Karl Theil
Judith Manzon Ravindran Padmanabhan Robert W. Shields, Jr. Sharon Longshore Thornton
Anjli Maroo Velma L. Paschall Anita Shivadas Kenneth J. Tomecki
Manu Mathews Lily C. Pien Laura Shoemaker Walton J. Tomford
Steven D. Mawhorter Melissa Piliang Nabin K. Shrestha Rebecca Tung
Mark Mayer Ronnie Pimental Rabin K. Shrestha Marisa Tungsiripat
Ken Mayuga Emilio D. Poggio Bernard J. Silver Allison Vidimos
Peter J. Mazzone Jeannette M. Potts Rishi P. Singh Nicola M. Vogel
Mark S. McAllister Leo Pozuelo Vivek Singh Jamile Wakim-Fleming
Kevin McCarthy Gary W. Procop Mario Skugor Teo Boon Wee
Kathleen Maksimowicz- Mohammed Qadeer Stephen Smith Christopher Whinney
McKinnonn Christine Radojicic Edy Soffer Anna Wieckowska
Adi Mehta Mohammed Rafey Firas Al Solaiman Herbert P. Wiedemann
Atul C. Mehta Justin L. Ranes Apra Sood William Wilke
Tarek Mekhail Russell Raymond Brian R. Stephany Justin G. Woodhouse
Charles M. Miller Feza Remzi Tyler Stevens Bridget Wright
Donald Moffa Thomas Rice Glen H.J. Stevens Mohamad Yamani
Asma Moheet Cristina Rodriguez James K. Stoller Kristine Zanotti
Eamonn Molloy Jess Rowney David Streem Claudia O. Zein
Halle Moore Camille Sabella Patrick Sweeney Robert Zimmerman
Thomas Morledge Ronald M. Sabecks James F. Swiencicki Matthew J. Zirwas
Sherif B. Mossad Mandi Sachdeva Alan Taege
 Acknowledgments

Special thanks to
original authors:

Christopher T. Bajzer (Acute Myocardial Infarction)

David S. Barnes (Primary Biliary Cirrhosis, Primary Sclerosing Cholangitis,

and Other Cholestatic Liver Diseases)

Susan M. Begelman (Venous Thromboembolism)

Divya Singh-Behl (Common Skin Infections)

Robert Dreicer (Prostate Cancer)

Mani Kavuru (Asthma)

Bo Shen (Irritable Bowel Syndrome)

Edy Soffer (Irritable Bowel Syndrome)

David Tschopp (Complications of Acute Myocardial Infarction)

Donald Vidt (Hypertension)

ix
 Preface

Cleveland Clinic Current Clinical Medicine springs from a web-based University School of Medicine. Since publication of the 2009 edition
textbook of medicine that has met with success for more than a of this book, Patrick Sweeney, MD, and Herbert Wiedemann, MD,
decade. Two attributes characterize the chapters in this book: authors have moved to Emeritus Section Editor status. I welcome aboard new
are either current or past members of the Cleveland Clinic staff; Section Editors, Jinny Tavee, MD (Neurology) and Raed Dweik, MD
wherever appropriate, chapters reference, expand, and elaborate on (Pulmonary).
nationally produced clinical practice guidelines. I am extremely The lion’s share of thanks goes to the chapter authors. Each is
pleased with the reception of the book’s first edition. There have been inundated with requests for intellectual contributions—no surprise
many positive reviews, some with helpful suggestions for improve- given their stature in their respective fields. That so many would
ment. And we listened. In this edition are 18 new chapters and 61 agree to support this book is a source of tremendous satisfaction. I
substantially updated ones. More than ever, it covers topics most am beholden to each and every one.
likely to be seen by a generalist. It retains simplicity and practicality, As important as authors and editors, the daunting task of publish-
as well as the beautiful artwork, photographs, tables, and figures. It ing a textbook requires an extended family of publishers, editors, and
seeks to be your daily medical guide. project managers, and a legion of support staff invisible to the Editor-
The book rests on the shoulders of the Section Editors. I owe in-Chief. This book relied on the willingness of Rolla Couchman,
them special gratitude for their commitment to the project. The Acquisitions Editor at Elsevier, to see promise in this work. His
Section Editors are recognized experts with considerable clinical and encouragement and good cheer were invaluable. His successor,
editorial experience. They have assembled the best experts from their Druanne Martin, was a tireless advocate. Rolla and Druanne have
respective specialty areas to produce a work that will be of maximum since left Elsevier to be replaced by the equally capable and encourag-
benefit to the practicing clinician. Although most current Section ing Dolores Meloni. Elsevier’s Developmental Editors, Julia Bartz
Editors have been present since the inauguration of the web-based and Mary Beth Murphy, and Project Managers, Jeffrey Gunning and
virtual textbook, Disease Management Project, some have moved on. Pete Faber, all played major roles in making this work come to life,
Brian Bolwell, MD, a longtime member of the Cleveland Clinic and I thank each of them. At the Cleveland Clinic, Ronna Romano
Taussig Cancer Institute, holds many important posts; he may best deserves special thanks for having ably served as the first manager of
be known for his development of the highly successful bone marrow this work. Donna Miller and her team did a superb job of crafting
transplant program. Brian served as the first Section Editor for the each chapter into a unified website.
Hematology and Oncology Section. Donald Vidt, MD, served as the Finally, it is appropriate to recognize the Cleveland Clinic as an
inaugural Section Editor for the Renal Section. He retired after environment that fosters excellence in medicine and urges its faculty
devoting more than 40 years to an active consulting practice in to be the best. The founding fathers of this organization urged its
hypertension and renal disease, combined with medical education creation more than 90 years ago “… to act as a unit.” More than
and clinical research. David Longworth, MD, was the first Infectious words, the Cleveland Clinic culture provides an environment of
Disease Section Editor. Dr. Longworth served for many years as mutual support for development of best clinical practices and for
Chairman of the Department of Infectious Diseases at the Cleveland education of those within and outside our walls.
Clinic. He has published numerous articles in scientific journals and
book chapters; he has also edited four textbooks. He is currently William D. Carey, MD
Professor and Deputy Chairman, Department of Medicine, Tufts Editor-in-Chief

xi
 Asthma
David M. Lang, Serpil C. Erzurum, and Mani Kavuru
ALLERGY AND IMMUNOLOGY

Although much progress has been made in our understanding of reactivity can be regarded as a sine qua non for patients with current
bronchial asthma in recent years, asthma remains a commonly symptoms and active asthma.
encountered condition that challenges physicians in the office setting
as well as in acute care settings.1-3 Although the 1980s were character- EPIDEMIOLOGY AND NATURAL HISTORY
ized by increases in asthma morbidity and mortality in the United
States, these trends reached a plateau in the 1990s, and asthma mor- Several government agencies have been charged with surveillance for
tality rates have declined since 1999. In recent decades, a surge in asthma, including the NHLBI’s National Asthma Education and Pre-
asthma prevalence also occurred in the United States and other vention Program (NAEPP), the Department of Health and Human
Western countries; data suggest this trend may also be reaching a Services (Healthy People 2010), and the Centers for Disease Control
plateau. Tremendous progress has been made in our fundamental and Prevention (CDC). Data published by the CDC indicate that
understanding of asthma pathogenesis by virtue of invasive research approximately 20 million Americans have asthma. Estimates of
tools such as bronchoscopy, bronchoalveolar lavage, airway biopsy, 12-month period prevalence have found that approximately 3.0% of
and measurement of airway gases, although the cause of airway the U.S. population had asthma in 1970; more recent estimates indi-
inflammation remains obscure. cated that the 12-month period prevalence had increased to 5.5% in
The knowledge that asthma is an inflammatory disorder has 1996.6 In association with rising prevalence, patient encounters—via
SECTION 1

become fundamental to our definition of asthma. Evidence-based outpatient visits, emergency department use, and hospitalizations for
practice guidelines have been disseminated with a goal of encourag- asthma—also increased during this period. Asthma surveillance data
ing more frequent use of anti-inflammatory therapy to improve in recent decades have revealed that a disparate burden of asthma
asthma outcomes. To this extent, there has been much emphasis on exists in certain demographic subgroups: in children compared with
early diagnosis and longitudinal care of patients with asthma, along adults, in women compared with men, in blacks compared with
with ensuring adherence to recommended therapies. In this context, whites, and among Hispanics of Puerto Rican heritage compared
there have been advances in our pharmacologic armamentarium in with those of Mexican descent.6 The trend for increasing asthma
both chronic and acute therapy with the development and approval mortality that began in 1978 and continued through the 1980s
of novel medications. Yet, as exciting as this revolution has been reached a plateau in the 1990s, and since 1999 annual rates in the
in asthma research and practice, a number of controversies persist, United States have declined.6 These trends are reassuring, and they
and further fundamental developments in novel therapeutics are have been correlated with increasing rates of dispensed prescriptions
imminent. for inhaled corticosteroids (ICS), implying that improved treatment
This review of asthma for the practicing clinician summarizes of asthma may be responsible for these favorable developments. The
these developments, including an update on the definition of asthma, overall annual economic burden for asthma care in the United States
its epidemiology, natural history, cause, and pathogenesis. In addi- exceeds $11 billion.7
tion, there is a discussion of the appropriate diagnostic evaluation of
asthma and co-occurring conditions, management of asthma, and ETIOLOGY AND PATHOGENESIS
newer therapies for the future.
Clinicians have long known that asthma is not a single disease; it
DEFINITIONS exists in many forms. This heterogeneity has been well established
by a variety of studies that have demonstrated disease risk from early
Asthma is a chronic, episodic disease of the airways that is best environmental factors and susceptibility genes, subsequent disease
viewed as a syndrome. In 1997, the National Heart, Lung, and Blood induction and progression from inflammation, and response to
Institute (NHLBI) included the following features as integral to the therapeutic agents (Fig. 1).
definition of asthma4: recurrent episodes of respiratory symptoms; Asthma is an inflammatory disease and not simply a result of
variable airflow obstruction that is often reversible, either spontane- excessive smooth muscle contraction. Increased airway inflamma-
ously or with treatment; presence of airway hyperreactivity; and, tion follows exposure to inducers such as allergens or viruses, exer-
importantly, chronic airway inflammation in which many cells and cise, or inhalation of nonspecific irritants. Increased inflammation
cellular elements play a role, in particular, mast cells, eosinophils, T leads to exacerbations characterized by dyspnea, wheezing, cough,
lymphocytes, macrophages, neutrophils, and epithelial cells. All of and chest tightness. Abnormal histopathology including edema, epi-
these features need not be present in any given asthmatic patient. thelial cell desquamation, and inflammatory cell infiltration are
The Expert Panel Report (EPR) 3 guidelines,5 issued in 2007, state found not only in autopsy studies of severe asthma cases but even in
that the immunohistopathologic features of asthma include inflam- patients with very mild asthma. Reconstructive lesions, including
matory cell infiltration involving neutrophils (especially in sudden- goblet cell hyperplasia, subepithelial fibrosis, smooth muscle cell
onset, fatal asthma exacerbations; occupational asthma; and patients hyperplasia, and myofibroblast hyperplasia can lead to remodeling
who smoke), eosinophils, and lymphocytes, with activation of mast of the airway wall. Many studies have emphasized the multifactorial
cells and epithelial cell injury. Heterogeneity in the pattern of asthma nature of asthma, with interactions between neural mechanisms,
inflammation has been recognized, consistent with the interpretation inflammatory cells (mast cells, macrophages, eosinophils, neutro-
that phenotypic differences exist that influence treatment response. phils, and lymphocytes), mediators (interleukins, leukotrienes, pros-
The inflammation of asthma leads to an associated increase in the taglandins, and platelet-activating factor), and intrinsic abnormalities
existing bronchial hyperresponsiveness to a variety of stimuli. of the arachidonic acid pathway and smooth muscle cells. Although
Although the absolute minimum criteria to establish a diagnosis of these types of descriptive studies have revealed a composite picture
asthma are not widely agreed on, the presence of airway hyper- of asthma (Fig. 2), they have failed to identify a basic unifying defect.

2 www.expertconsult.com
 Asthma 3

Disease Disease Disease Disease

risk induction consolidation progression

Acute inflammation Mediators

SECTION 1
Allergens
viruses
pollutants Symptoms
Susceptibility genes Cytokines diet Growth
factors
TH2 immune Chronic Tissue
Response
deviation inflammation remodeling

ALLERGY AND IMMUNOLOGY

Cytokines Cytokines
Early-life environment
Maternal programming
Allergens (+)
Infections (–)
Pollutants (±)

Figure 1 Natural history of asthma. (Reproduced from Holgate ST: The cellular and mediator basis of asthma in relation to natural
history. Lancet 1997;350[suppl 2]:5-9. Reprinted in Szefler SJ: The natural history of asthma and early intervention. J Allergy Clin
Immunol 2002;109:S550.)

Antigen Figure 2 Schematic showing airway

inflammation in patients with
IgE asthma. (Reproduced from Spahn J,
Covar R, Stempel DA. Asthma: Addressing
Mast cell T cell B cell consistency in results from basic science,
clinical trials, and observational experience.
Proinflammatory IL-4 Macrophages J Allergy Clin Immunol 2002;109:S492.)

Cytokines, IL-4

Histamines
Leukotrienes IL-5 IL-5
IL-5 Proinflammatory
Chemokines Cytokines
LTB-4 Tryptase

Bronchospasm

Cytokines
Eosinophil
Macrophages
Neutrophils Activated

Inflammation

Acute Subacute Chronic

Advances have been made in our understanding of asthmatic important differences between animal models of asthma and human
airway inflammation through the use of invasive technology, such as disease, there are few longitudinal studies of human asthma with
bronchoscopy with airway sampling at baseline state,8 and with serial airway sampling, and it is often difficult to determine cause and
experimental provocation (e.g., allergen challenge) and following effect from multiple mediator studies.
administration of interventions, such as anti-inflammatory pharma- Despite the explosion of information about asthma, the nature of
cotherapy. Further insights have been obtained through transgenic its basic pathogenesis has not been established. Studies suggest a
murine models with deletion, or knockout, of specific genes (i.e., genetic basis for airway hyperresponsiveness, including linkage to
those for immunoglobulin E [IgE], CD23, interleukin-4 [IL-4], or chromosomes 5q and 11q. Asthma clearly does not result from a
IL-5) or overexpression of other putative genes. Also, specific mono- single genetic abnormality; rather it is a complex multigenic disease
clonal antibodies or cytokine antagonists have been used in various with a strong environmental contribution. For example, allergic
asthma models. A number of limitations have hindered our under- potential to inhaled allergens (e.g., dust mites, mold spores, cat
standing of asthma obtained from these model systems: There are dander) is found more commonly in asthmatic children or asthmatic

www.expertconsult.com
 4 Asthma

adults whose asthma began in childhood than in those with adult- istic of the Th2 paradigm. In a “cleaner” urban Western society, such
onset asthma. early childhood exposure is lacking, and this encourages a higher
incidence of allergy and asthma. The hygiene hypothesis has become
Immunopathogenesis and the Th2 Phenotype the basis for a number of emerging therapies.
Whether airway hyperresponsiveness is a symptom of airway
Based on animal studies and limited bronchoscopic studies in adults, inflammation or airway remodeling, or whether it is the cause of
the immunologic processes involved in the airway inflammation of long-term loss of lung function, remains controversial. Some inves-
asthma are characterized by the proliferation and activation of helper tigators have hypothesized that aggressive treatment with anti-
ALLERGY AND IMMUNOLOGY

T lymphocytes (CD4+) of the subtype Th2. The Th2 lymphocytes inflammatory therapies improves the long-term course of asthma
mediate allergic inflammation in atopic asthmatics by a cytokine beyond their salutary effects on parameters of asthma control and
profile that involves IL-4 (which directs B lymphocytes to synthesize rates of exacerbation over time.13 This contention has been sup-
IgE), IL-5 (which is essential for the maturation of eosinophils), and ported by an observational study14 that found long-term exposure to
IL-3 and granulocyte-macrophage colony-stimulating factor (GM- ICS was associated with an attenuation of the accelerated decline in
CSF).9 Recent study suggests that mutations in IL-4 receptor alpha lung function previously reported in asthmatics; more studies are
(IL4Rα) are associated with a gain in receptor function and more required to substantiate these findings.
IL-4 functional effect, which is associated with asthma exacerbations,
lower lung function, and tissue inflammation, in particular to mast Concept of Airway Remodeling
cells and IgE.10 Eosinophils are often present in the airways of asth-
matics (more commonly in allergic but also in nonallergic patients), The relation between the several types of airway inflammation (early-
and these cells produce mediators that can exert damaging effects on phase and late-phase events) and the concept of airway remodeling,
the airways. or the chronic nonreversible changes that can happen in the airways,
Knockout studies and anticytokine studies suggest that lipid remains a source of intense research.4 The natural history of airway
mediators are products of arachidonic acid metabolism. They have remodeling is poorly understood, and although airway remodeling
been implicated in the airway inflammation of asthma and have been occurs in some patients with asthma, it does not appear to be a
the target of pharmacologic antagonism by antileukotriene agents. universal finding.
SECTION 1

Prostaglandins are generated by the cyclooxygenation of arachidonic Clinically, airway remodeling may be defined as persistent airflow
acid, and leukotrienes are generated by the lipoxygenation of arachi- obstruction despite aggressive anti-inflammatory therapies, includ-
donic acid. The proinflammatory prostaglandins (prostaglandin ing ICS and systemic corticosteroids. Pathologically, airway remodel-
[PG]D2, PGF2, and TXB2) cause bronchoconstriction, whereas other ing appears to have a variety of features that include increases of
prostaglandins are considered protective and elicit bronchodilation smooth muscle mass, mucous gland hyperplasia, persistence of
(PGE2 and PGI2, or prostacyclin). Leukotrienes C4, D4, and E4 chronic inflammatory cellular infiltrates, release of fibrogenic growth
compose the compound formerly known as slow-reacting substance factors along with collagen deposition, and elastolysis.15 Increased
of anaphylaxis, a potent stimulus of smooth muscle contraction and numbers and size of vessels in the airway wall is a long-recognized
mucus secretion. Ultimately, mediators lead to degranulation of characteristic and one of the most consistent features of asthma
effector or proinflammatory cells in the airways that release other remodeling occurring in mild, moderate and severe asthmatic
mediators and oxidants, a common final pathway that leads to the lungs.16-19 (Fig. 3). Many biopsy studies show these pathologic fea-
chronic injury and inflammation noted in asthma. tures in the airways of patients with chronic asthma. However, there
are many unanswered questions, including whether features of
remodeling are related to an inexorable progression of acute or
The Hygiene Hypothesis, Airway chronic airway inflammation or whether remodeling is a phenom-
Hyperresponsiveness, and Disease Progression enon separate from inflammation altogether (Figs. 4 and 5).
Research has confirmed that the airway epithelium is an active
Most studies of airway inflammation in human asthma have been regulator of local events, and the relation between the airway epithe-
conducted in adults because of safety and convenience. However, lium and the subepithelial mesenchyma is believed to be a key deter-
asthma often occurs in early childhood, and persistence of the asth- minant in the concept of airway remodeling. A hypothesis by Holgate
matic syndrome into later childhood and adulthood has been the and colleagues20 proposes that airway epithelium in asthma functions
subject of much investigation. The hygiene hypothesis has been pro- in an inappropriate repair phenotype in which the epithelial cells
posed to explain the epidemiologic observation that asthma preva- produce proinflammatory mediators as well as transforming growth
lence is much greater in industrialized Western societies than in less factor (TGF)-β to perpetuate remodeling. On the other hand, one of
technologically advanced societies.11,12 This hypothesis maintains the most striking features reported in early detailed histopathologic
that airway infections and early exposure to animal allergens (e.g., studies of asthmatic lungs was the increased amount and size of
farm animals, cats, dogs) is important in affecting the propensity for submucosal vessels, and this has been repeatedly confirmed in other,
persons to become allergic or asthmatic. Specifically, early exposure more recent, reports.17,19,21-24
to the various triggers that can occur with higher frequency in a rural Although understanding of new vessel formation and its genesis
setting might protect against the allergic diathesis that is character- in asthma is still in its early stages, it has been suggested that

Figure 3 Clinical consequences of

Smooth Mucous Inflammatory Fibrogenic
airway remodeling in asthma. RBM,
muscle glands cells growth Elastolysis
mass increase increase persistence factor release respiratory bronchiolar mucosa; ECM,
extracellular mucosa. (Reproduced from
Bousquet J, Jeffery PK, Busse WW, et al:
Asthma: From bronchoconstriction to
Severe Important airways inflammation and remodeling. Am J
Collagen Reduced
bronchospasm mucous secretion Ongoing Respir Crit Care Med 2000;161:1720-1745.)
deposition on elasticity of
during during inflammation
RBM and ECM airway wall
exacerbation exacerbation

www.expertconsult.com
 Asthma 5

vascular remodeling may be a critical component in the pathophys- in the lungs of asthmatic patients by activated inflammatory cells
iology of asthma and a determinant of asthma severity. Asosingh and (i.e., eosinophils, alveolar macrophages, and neutrophils).27 The
colleagues showed that angiogenesis is a very early event, with onset increased ROS production of neutrophils in asthmatic patients cor-
during the initiation of acute airway inflammation in asthma.21 It is relates with the severity of reactivity of airways in these patients;
linked to mobilization of bone marrow–derived endothelial pro- severe asthma is associated with neutrophilic airway infiltrates. Other
genitor cells, which, together with Th1 and Th2 cells, lead to a pro- investigators have measured products of arachidonic acid metabo-
angigogenic lung environment in asthma, which is sustained long lism in exhaled breath condensate.30 Specifically, 8-isoprostane, a
after acute inflammation is resolved.21 The enlarged airway vascular PGF2a analogue that is formed by peroxidation of arachidonic acid,

SECTION 1
bed may contribute to the airflow limitation either through the vas- is increased in patients with asthma of different severities, and leu-
cular tissue’s itself increasing airway wall thickness or through edema kotriene E4 (LTE4)-like immunoreactivity is increased in exhaled
formation. Angiogenesis itself may play a role in the disease progres- breath condensate of steroid-naïve patients who have mild asthma,
sion through recruitment of inflammatory cells, effects that alter with levels about threefold to fourfold higher than those in healthy
airway physiology, or by secretion of proinflammatory mediators. subjects. Concomitant with increased oxidants, antioxidant protec-
tion of the lower airways is decreased in lungs of asthmatic patients.28,29
Exhaled Gases and Oxidative Stress Another reactive species, nitric oxide (NO), is increased in the

ALLERGY AND IMMUNOLOGY

asthmatic airway.26 Nitric oxide is produced by nitric oxide synthase
Asthma is characterized by specific biomarkers in expired air that (NOS), all isoforms of which—constitutive (neuronal, or type I, and
reflect an altered airway redox chemistry, including lower levels of endothelial, or type III enzymes) and inducible (type II enzymes)—
pH and increased reactive oxygen and nitrogen species during asth- are present in the lung. Abnormalities of NOS I and NOS II genotype
matic exacerbations.25-29 Reactive oxygen species (ROS) such as and expression are associated with asthma. Recent studies have sug-
superoxide, hydrogen peroxide, and hydroxyl radicals cause inflam- gested cytotoxic consequences associated with tyrosine nitration
matory changes in the asthmatic airway. In support of this concept induced by reaction products of NO.31 Based on the high levels of
are the high levels of ROS and oxidatively modified proteins in NO in exhaled breath of asthmatics and the decrease of NO that
airways of patients with asthma.26 High levels of ROS are produced occurs in response to treatment with corticosteroids, measurement
of NO has been proposed as a noninvasive way to detect airway
inflammation, diagnose asthma, and monitor the response to anti-
inflammatory therapy.32-34 The development of NHANES (National
Health and Nutrition Examination Survey) normative levels for the
fractional excretion of NO (FENO) will facilitate more widespread
application of this exhaled gas measure in the clinical care of
Acute Chronic Airway
inflammation inflammation remodeling asthmatics.

The b-Agonist Controversy

Short-Acting b Agonists
Much controversy has surrounded the excessive or regular use of
β-agonist preparations and the contention that this could lead to
Symptoms Exacerbations Persistent worsening of asthma control and pose a risk for untoward outcomes,
(broncho- nonspecific airflow including near-fatal and fatal episodes of asthma.
constriction) hyperreactivity obstruction Several studies from New Zealand suggested that the use of
Figure 4 Links between pathologic mechanisms and clinical inhaled β agonists increases the risk of death in severe asthma.6,35-37
consequences in asthma. (Reproduced from Bousquet J, Jeffery PK, Busse Spitzer and coworkers conducted a matched, case-controlled study
WW, et al: Asthma: From bronchoconstriction to airways inflammation and using a health insurance database from Saskatchewan, Canada, of a
remodeling. Am J Respir Crit Care Med. 2000;161:1720-1745.) cohort of 12,301 patients for whom asthma medications had been

Inflammatory Persistence of Activation of Figure 5 Mechanisms of acute and

cell inflammatory fibroblasts and chronic inflammation in asthma and
recruitment cells macrophages remodeling processes. (Reproduced from
Bousquet J, Jeffery PK, Busse WW, et al:
Asthma: From bronchoconstriction to airways
inflammation and remodeling. Am J Respir
Vascular Inflammatory Tissue Crit Care Med 2000;161:1720-1745.)
Decreased
permeability cell repair and
apoptosis
and edema activation remodeling

Inflammatory Release of Smooth muscle

mediator cytokines and and mucous
release growth factors gland proliferation

Mucus secretion Increased Epilhelial cell

and bronchial activation and
bronchoconstriction hyperreactivity shedding

www.expertconsult.com
 6 Asthma

prescribed.38 Data were based on matching 129 case patients who had determined definitively at this time. Based on findings of SMART,
fatal or near-fatal asthma with 655 controls. The use of a β agonist the U.S. Food and Drug Administration (FDA) issued a black box
administered by a metered-dose inhaler (MDI) was associated with warning, public health advisory, and subsequent label changes for
an increased risk of death from asthma, with an odds ratio of 5.4 per LABA and LABA-containing medications.
canister of fenoterol, 2.4 per canister of albuterol, and 1.0 for back- Data from SMART, combined with other recent reports,42 have
ground risk (e.g., no fenoterol or albuterol). The primary limitation fueled a controversy regarding the role of LABAs in asthma manage-
of these data, and a number of other case-controlled studies, relates ment, such that an honest difference of opinion currently exists
to the comparability of cases and controls in terms of severity of their regarding the appropriate level of asthma severity at which regular
ALLERGY AND IMMUNOLOGY

underlying disease. use of LABA combined with ICS is favorable from a risk-to-benefit
Sears and coworkers conducted a placebo-controlled, crossover standpoint. This will require additional studies to fully clarify;
study in patients with mild stable asthma to evaluate the effects of however, asthma care providers should also be mindful that use of a
regular versus on-demand inhaled fenoterol therapy for 24 weeks.39 LABA in combination with ICS has been associated with a range of
In the 57 patients who did better with one of the two regimens, only favorable outcomes: reduction of symptoms (including nocturnal
30% had better asthma control when receiving regularly adminis- awakening), improvement in lung function, improvement in quality
tered bronchodilators, whereas 70% had better asthma control when of life, reduced use of rescue medication, and reduced rate of exac-
they employed the bronchodilators only as needed. erbations and severe exacerbations compared with ICS at the same
Drazen and coworkers randomly assigned 255 patients with mild or higher dose.43
asthma to inhaled albuterol either on a regular basis (two puffs four Previously published meta-analyses have shown that low-dose
times per day) or on an as-needed basis for 16 weeks.40 There were ICS combined with LABA is associated with superior outcomes com-
no significant differences between the two groups in a variety of pared with higher-dose ICS.44-46 These data led to the recommenda-
outcomes, including morning peak expiratory flow, diurnal peak tion in the EPR-2 update of the NAEPP guidelines to prescribe the
flow variability, forced expiratory volume in 1 second (FEV1), combination of ICS and LABA for patients with moderate persistent
number of puffs of supplemental as-needed albuterol, asthma symp- asthma and severe persistent asthma. The update categorized this
toms, or airway reactivity to methacholine. Because neither benefit management recommendation as based on level A evidence.2 Based
nor harm was seen, it was concluded that inhaled albuterol should on safety concerns, the EPR-3 guidelines5 recommend that medium-
SECTION 1

be prescribed for patients with mild asthma on an as-needed basis. dose ICS be regarded as equivalent to adding LABA to low-dose ICS,
A meta-analysis of pooled results from 22 randomized, placebo- and state “the established, beneficial effects of LABA for the great
controlled trials that studied at least 1 week of a regularly adminis- majority of patients who have asthma that is not sufficiently con-
tered β2 agonist in patients with asthma compared with a placebo trolled with ICS alone should be weighed against the increased risk
group (that did not permit as-needed β2-agonist use) concluded that for severe exacerbations, although uncommon, associated with daily
regular use results in tolerance to bronchodilator and nonbroncho- use of LABA.” At this time, the decision to prescribe, or continue to
dilator effects of the drug and may be associated with poorer disease prescribe, LABA should be based on an individualized determination
control compared with placebo. of risk relative to benefit made by each asthmatic patient in partner-
ship with his or her physician.
Long-Acting b Agonists
Pharmacogenetics
The Salmeterol Multiple-Center Asthma Research Trial (SMART)
was an observational 28-week study comparing salmeterol 42 µg Polymorphisms of the ADRβ2 gene for the β2-adrenergic receptor
metered-dose inhaler twice a day with placebo, in addition to usual can influence clinical response to β agonists. For the ADRB2, single
asthma therapies.41 More than 26,000 subjects were enrolled. nucleotide polymorphisms (SNPs) have been defined at codons 16
SMART found that in the salmeterol group there was a statisti- and 27. The normal, or wild-type, pattern is arginine-16-glycine and
cally significant increase in risk for asthma-related deaths and life- glutamine-27-glutamic acid, but SNPs have been described with
threatening experiences compared with placebo. There were homozygous pairing (e.g., Gly16Gly, Arg16Arg, Glu27Glu, and
statistically significant differences for respiratory-related deaths (rel- Gln27Gln). The frequency of these polymorphisms is the same in the
ative risk [RR], 2.16; 95% confidence interval [CI], 1.06-4.41) and normal population as in asthmatics. Presence of a gene variant itself
asthma-related deaths (RR, 4.37; 95% CI, 1.25-15.34) and in com- does not appear to influence baseline lung function.
bined asthma-related deaths or life-threatening experiences (RR, In the presence of a polymorphism, the acute bronchodilator
1.71; 95% CI, 1.01-2.89) in subjects randomized to salmeterol com- response to a β agonist, or protection from a bronchoconstrictor,
pared with placebo. There were 13 asthma-related deaths and 37 may be affected. Studies indicate that in patients with Arg16Arg
combined asthma-related deaths or life-threatening experiences in variant, the resulting β2-adrenergic receptor is resistant to endoge-
the salmeterol group, compared with 3 and 22, respectively, in those nous circulating catecholamines (i.e., receptor density and integrity
randomized to placebo. are preserved), with a subsequent ability to produce an acute bron-
Of the 16 cases of asthma fatality in subjects enrolled in the study, chodilator response to an agonist. In patients with Gly16Gly, the
13 (81%) occurred in the initial phase of SMART, when subjects were β2-adrenergic receptor is downregulated by endogenous catechol-
recruited via print, radio, and television advertising; following this, amines; therefore, the acute bronchodilator response is reduced or
subjects were recruited directly by investigators. These differences in blunted. In relation to prolonged β-agonist therapy (e.g., >2 weeks)
outcomes occurred largely in African American subjects. In African patients who are homozygous for Arg16 were found to exhibit a
Americans not taking ICS before randomization, salmeterol was decline in lung function and an increase in exacerbation rates in
associated with statistically significant increases in the risk for com- association with regular inhaled short-acting β agonists. These same
bined respiratory-related deaths or life-threatening experiences (RR, patients, when switched to as-needed albuterol, had no decrease in
5.61; 95% CI, 1.25-25.26) and combined asthma-related deaths or lung function, as is the case for homozygous Gly16. Polymorphisms
life-threatening experiences (RR, 10.46; 95% CI, 1.34-81.58). at the 27 loci are of unclear significance. Also, the impact of haplo-
Medication exposures were not tracked during the study, and types (e.g., variant genes linked at >2 loci) is currently unclear. There
allocation to ICS combined with a long-acting β agonist (LABA) was are conflicting data regarding whether Arg/Arg homozygotes are
not randomized, so the effect of concomitant ICS use cannot be prone to experience reflex morbidity with inhaled LABA,43 but the
determined from these data. Whether the statistically significant risk weight of evidence, particularly from more-recent studies,47,48 indi-
in untoward outcomes reflects genetic predisposition, risk associated cates that response to LABA when used in combination with ICS
with LABA monotherapy, or health maintenance behavior cannot be does not vary based on β2-adrenergic genotypes at codon 16.

www.expertconsult.com
 Asthma 7

There are limited data on mutations involving the leukotriene airway hyperreactivity as the cause of symptoms. By far, the most
cascade or corticosteroid metabolism. Polymorphisms of the 5-lipox- commonly used agents are methacholine or histamine, which give
ygenase (5-LO) gene promoter and the LTC4 synthase gene (LTC4S) comparable results. Exercise, cold air, and isocapnic hyperventila-
have been described. Asthmatics with the wild-type allele at 5-LO tion—other approaches that require complex equipment—have a
have a greater response with 5-LO inhibitor therapy compared with lower sensitivity. In a patient with clinical features typical for asthma,
asthmatics with a mutant gene. However, mutations of the 5-LO along with reversible airflow obstruction, there is no need for a
gene promoter occur only in about 5% of asthmatic patients; for this provocation procedure to establish a diagnosis. The use of measures
reason, it is unlikely to play an important role in most patients. An of airway hyperreactivity has been proposed as a tool to guide anti-

SECTION 1
SNP in LTC4S is associated with increased leukotriene production inflammatory therapy, but it is not recommended for routine clinical
and has a lower response to leukotriene-modifying agents. practice. The methacholine challenge test, which is most commonly
Far less is known about genetic variability in the corticosteroid used in the United States, is very sensitive; a positive test result is
pathway. Polymorphisms in the glucocorticoid receptor gene have defined as a 20% decline in FEV1 during incremental methacholine
been identified that appear to affect steroid binding and downstream aerosolization. However, methacholine responsiveness is nonspe-
pathways in various in vitro studies. However, polymorphisms in the cific, and it can occur in a variety of other conditions, including
glucocorticoid pathways have not been associated with the asthma allergic rhinitis, chronic obstructive pulmonary disease, and airway

ALLERGY AND IMMUNOLOGY

phenotype or clinical steroid resistance. infection. For practical purposes, a negative inhalation challenge
with methacholine (or histamine) excludes active, symptomatic
asthma. Measurement of FENO has been associated with a negative
DIAGNOSTIC EVALUATION, COMORBID DISEASE, predictive value of 92%50 for ruling out presence of asthma; however,
AND PEAK EXPIRATORY FLOW MONITORING additional studies are required for this more-convenient and less-
costly test to supplant methacholine challenge, which is still regarded
The history and physical examination are important to confirm a as the gold standard for the diagnosis of asthma.
diagnosis and exclude conditions such as hyperventilation syndrome, PEF monitoring has been advocated as an objective measure of
vocal cord adduction, heart failure, and others that can masquerade airflow obstruction in patients with chronic asthma. Despite a sound
as asthma; to assess the severity of airflow obstruction and the need theoretical rationale for PEF monitoring, as advocated by all pub-
for aggressive intervention including inpatient management; to lished asthma guidelines, clinical trials that examined the use of PEF
identify risk factors for poor outcomes; and to identify comorbid monitoring in ambulatory asthma patients show conflicting results.49
conditions that can make asthma refractory to treatment, includ- Over the past decade, 6 of 10 randomized trials have failed to show
ing sinusitis, gastroesophageal reflux, and ongoing aeroallergen an advantage for the addition of PEF monitoring beyond symptom-
exposure. based intervention for the control group.51 Regular PEF monitoring
The cardinal symptoms of asthma include chest tightness, wheez- allows early detection of worsening airflow obstruction, which may
ing, episodic dyspnea, and cough. Some patients present with atypi- be of particular value in a subset of poor perceivers—persons with a
cal symptoms, such as cough alone (cough-equivalent asthma) or blunted awareness of ventilatory impairment. PEF monitoring also
primarily dyspnea on exertion. The most objective indicator of has value for risk stratification. Excessive diurnal variation and a
asthma severity is the measurement of airflow obstruction by spi- morning dip of PEF imply poor control and a need for careful re-
rometry or peak expiratory flow (PEF). The FEV1 and the PEF yield evaluation of the management plan. PEF alone is never appropriate;
comparable results. For initial diagnostic purposes in most patients, rather, PEF should be part of a comprehensive patient education
spirometry rather than a simple PEF should be performed, although program.
PEF may be a reasonable tool for long-term monitoring.
The NAEPP has set forth the grading of asthma severity into four ASTHMA MANAGEMENT ALGORITHMS
categories based on frequency of daytime and nocturnal symptoms,
peak flows, and as-needed use of inhaled short-acting β agonists: General Concepts Regarding Guidelines
intermittent, mild persistent, moderate persistent, and severe persis-
tent.5 The mildest category, designated mild intermittent in EPR-2, There are many organizational and social barriers to optimal asthma
was changed to intermittent in EPR-3 to emphasize that even patients care. Studies suggest that a small subset of patients uses a large per-
with this level of asthma severity may have serious or even life- centage of health care resources. A major challenge in improving
threatening asthma exacerbations.5 outcomes for asthma is implementing basic asthma management
Hyperinflation, the most common finding on a chest radiograph, principles widely at the community level. Key issues include:
has no diagnostic or therapeutic significance. A chest radiograph
should not be obtained unless complications of pneumonia, pneu- ● Education of primary health care providers
mothorax, or an endobronchial lesion are suspected. The correlation ● Education programs for asthma patients
of severity between acute asthma and arterial blood gases is poor. ● Longitudinal outpatient follow-up with easy access to providers
Mild-to-moderate asthma is typically associated with respiratory ● Emphasis on chronic maintenance therapy rather than acute epi-
alkalosis and mild hypoxemia on the basis of ventilation-perfusion sodic care
mismatching. Severe hypoxemia is quite uncommon in asthma. Nor- ● Emphasis on daily anti-inflammatory therapy
mocapnia and hypercapnia imply severe airflow obstruction, with
FEV1 usually less than 25% of the predicted value. Hypercapnia in Organized approaches to improving care have included dissemina-
the setting of acute asthma does not necessarily mandate intubation tion of clinical practice guidelines, disease state management, and
or suggest a poor prognosis.49 Spirometry in an asthmatic patient case management.52
typically shows obstructive ventilatory impairment with reduced The thesis of disease state management is a global approach to
expiratory flows that improve with bronchodilator therapy. Typi- chronic diseases such as asthma by integrating various components
cally, there is an improvement in either FEV1 or forced vital capacity of the health care delivery system. It is hoped that managing all
(FVC) with acute administration of an inhaled bronchodilator (12% costs of care comprehensively, rather than seeking to minimize the
and 200 mL). However, the absence of a bronchodilator response costs of each component, will improve health outcomes and be cost
does not exclude asthma. The shape of the flow volume loop can beneficial. This approach relies on information technology to iden-
provide insight into the nature and location of airflow obstruction. tify patients, monitor care, and assess outcomes and costs. Asthma
In patients with atypical chest symptoms of unclear etiology is viewed as an ideal disease for the disease management approach
(cough or dyspnea alone), a variety of challenge tests can identify because it is a chronic disease suitable for self-management and

www.expertconsult.com
 8 Asthma

patient education; it can be managed largely on an outpatient basis, tation, with pharmacologic management (see later) then being pre-
thus avoiding costly inpatient care; there is a consensus on what scribed in an evidence-based fashion according to each respective
constitutes optimal care; and optimal care implementation can categorization. In an ideal world, this recommendation, described in
promptly lead to measurable reduction in costs and improved out- EPR-2 would have resulted in patients with asthma receiving phar-
comes. macotherapeutic agents associated with favorable asthma care out-
Although many studies have reported interventions that reduce comes that are also appropriate from both cost and risk-to-benefit
costs and improve outcomes, there are limitations to published standpoints. In the real world, however, this paradigm was imperfect,
asthma disease management studies because a prestudy and post- because it relied on the correct categorization of patients for phar-
ALLERGY AND IMMUNOLOGY

study design has typically been employed, usually with no control macotherapy to be prescribed appropriately. Both health care pro-
group; the choice of outcome measures varies; and several interven- viders and patients are prone to underestimate asthma severity,54 and
tions have often been performed at the same time and it is difficult for this reason, many patients managed based on this paradigm were
to identify the essential components linked with success. These undertreated.
studies have often used proprietary data systems and algorithms that A new paradigm was proposed in EPR-3 guidelines, based on the
make reproducing them difficult. Other design limitations include assessment of asthma control.55 Asthma severity and asthma control
control of cofactors such as severity and season. are not synonymous. Asthma severity is clearly a determinant of
asthma control, but its impact is affected by a variety of factors,
Practice Guidelines including patterns of therapeutic adherence and the degree to which
recommended avoidance measures for clinically relevant aeroaller-
Guidelines for medical practice have been disseminated for a wide gens are pursued. Patterns of health service use, including hospital-
range of conditions. The overall goal of practice guidelines is to ization and emergency department visits, correlate more closely with
improve quality of care, reduce costs, and enhance health care out- asthma control than with asthma severity.55 This follows from the
comes. These guidelines are of interest to many groups including understanding that a patient with severe persistent asthma who is
specialty medical societies, state and federal government, insurers treated appropriately with multiple controllers and who adheres to
and managed care organizations, commercial enterprises, and hos- orders regarding medications and recommended avoidance strate-
pitals. Possible mechanisms by which practice guidelines can improve gies can achieve well-controlled (or totally controlled) asthma. This
SECTION 1

patient care include improved clinician knowledge, encouraging cli- patient will not require hospitalization or emergency department
nicians to agree with and accept the guidelines as standard of care, management, will not miss school or work days, and will not experi-
and influencing clinician asthma care behavior. ence nocturnal awakening or limitation in routine activities because
There is limited evidence, however, that practice guidelines of asthma. This patient has severe persistent asthma that is well con-
achieve favorable clinical outcomes.53 Some clinicians have advo- trolled. In contrast, a patient with mild-persistent to moderate-per-
cated additional strategies to include removing disincentives, adding sistent asthma who either does not receive appropriate instructions
a variety of incentives, and including the guidelines in a broader for avoidance measures and controller medications, or both, or who
program that addresses translation, dissemination, and implementa- is poorly adherent to therapy, will likely have poor control of asthma.
tion in the local community. This patient is more likely to require hospitalization or emergency
department management, miss school or work days, and experience
Asthma Practice Guidelines: Expert Panel Report 3 nocturnal awakening or limitation in routine activities because of
asthma. This patient has mild-to-moderate persistent asthma that is
In 1991, the coordinating committee of NAEPP, along with the poorly controlled.
NHLBI, convened an expert panel to develop extensive and detailed Another limitation of EPR-2 was that the categorization of asthma
guidelines for the diagnosis and management of asthma.1 The EPR-2 severity was proposed at a time before long-term therapy was initi-
was published in 19972 and EPR-3 guidelines were released in 2007.5 ated; however, many patients are already taking controller medica-
Overall, the published guidelines highlight the significant role of tions when they are initially seen. EPR-3 guidelines5 stipulate that the
airway inflammation in the pathogenesis of asthma, an emphasis on asthma severity level can be inferred, based upon response, or lack
the role of anti-inflammatory maintenance therapy for persistent thereof, to asthma pharmacotherapy. This concept, responsiveness, is
asthma, and a focus on establishing risk factors for the development defined as the ease with which asthma control can be achieved by
of asthma and identifying appropriate programs for control and therapy.
prevention. EPR-3 guidelines recommend that asthma should be categorized
The NAEPP outlined four goals of therapy for asthma: maintain based on level of severity at the initial visit, and at subsequent visits
normal activity level, including exercise; maintain near-normal the focus of providers should be on asthma control (Fig. 6). At the
parameters of pulmonary function; prevent chronic and trouble- initial visit, severity is assigned based on assessment of both impair-
some exacerbations of asthma by maintaining a chronic baseline ment and risk domains, as illustrated in Table 1, for patients who are
maintenance therapy; and avoid untoward effects of medications not taking regular controller medication, and for patients on regular
used to treat asthma. To facilitate these goals, the NAEPP outlined a pharmacotherapy for asthma.
number of key components for management. First, patient education For all patients with asthma, regardless of severity classification,
and self-management skills are critical. This education includes the goal of asthma management as described in EPR-35 is the same:
knowledge of the disease, proper use of medications, including to achieve control by reducing both impairment and risk (see Table
appropriate metered-dose inhaler technique, and a written action 2). The impairment domain is focused on the present and entails
plan for managing exacerbations. A second component involves assessments of frequency and intensity of asthma symptoms, func-
measures to minimize or avoid exposure to clinically relevant aeroal- tional limitation, lung function, and meeting expectations of, and
lergens and irritants that can exacerbate asthma. A third component satisfaction with, asthma treatment. The risk domain is focused on the
is pharmacotherapy. future and includes preventing asthma exacerbations and severe
The NAEPP guidelines recommend that asthma should be exacerbations, minimizing the need for using health services (emergency
managed in an algorithmic manner, based on asthma severity; EPR-3 department visits or hospitalization), reducing the tendency for pro-
guidelines introduced the concept of asthma control and its impor- gressive decline in lung function, and providing pharmacotherapy
tance in management. Patients are to be classified as having intermit- that offers minimal or no risk for untoward effects. The impairment
tent, mild persistent, moderate persistent, or severe persistent and risk domains might respond differently to treatment.
asthma, based on assessment of the level of symptoms (day or night), Asthma control is a multidimensional construct. Asthma control
reliance on reliever medication, and lung function at time of presen- can be assessed by use of validated instruments, including the Asthma

www.expertconsult.com
 Asthma 9

Presentation with Figure 6 Revised paradigm for asthma management.

asthma—Classify severity (Modified from Li JT, Oppenheimer J, Bernstein IL, et al:
Attaining optimal asthma control: A practice parameter. J Allergy
Clin Immunol 2005;116: S3-S11.
Serial visits for asthma—Assess control
• Daytime and nighttime symptoms Periodic re-assessment of asthma
• Activity/work/school limitations • Adherence
• PRN use of rescue medication • Psychosocial factors

SECTION 1
• Patient perception of control • Exposures to asthma triggers
• Objective measurements of lung • Co-morbidities
function • ? Alternative diagnosis
• Exacerbations

Asthma
Yes

ALLERGY AND IMMUNOLOGY

well Maintain or step
controlled down therapy

No
• Re-assessment
• Optimize therapy

Table 1 Categorization of Asthma Severity According to Impairment and Risk Domains

Classification of Asthma Severity ≥12 Years of Age

Persistent

Components of Severity Intermittent Mild Moderate Severe

Impairment Symptoms ≤2 days/wk >2 days/wk but not daily Daily Throughout the day

Normal FEV1/FVC: Nighttime awakenings ≤2×/mo 3-4×/mo >1×/wk but not Often 7/wk
8-19 yr: 85% nightly
20-39 yr: 80% Short-acting β2agonist use ≤2 days/wk >2 days/wk but not daily Daily Several times per day
40-59 yr: 75% for symptom control (not and not >1× on any
60-80 yr: 70% prevention of EIB) day
Interference with normal None Minor limitation Some limitation Extremely limited
activity
Lung function Normal FEV1 between
exacerbations
FEV1>80% predicted FEV1>80% predicted FEV1>60% but FEV1<60% predicted
<80% predicted
FEV1/FVC normal FEV1/FVC normal FEV1/FVC FEV1/FVC reduced >5%
reduced 5%

Risk Exacerbations requiring 0-1/yr* ≥2/yr* ≥2/yr* ≥2/yr*

oral systemic
corticosteroids

Recommend Step for initiating treatment Step 1 Step 2 Step 3† Step 4 or 5†

*Consider severity and interval since last exacerbation. Frequency and severity may fluctuate over time for patients in any severity category. Relative annual risk of
exacerbations may be related to FEV1.
†
And consider a short course of oral systemic corticosteroids.
EIB, exercise-induced bronchospasm; FEV1, forced expiratory volume in 1 sec; FVC, forced vital capacity.
Adapted from National Heart, Lung, and Blood Institute: Guidelines for the Diagnosis and Management of Asthma (EPR-3) (available at http://www.nhlbi.nih.gov/
guidelines/asthma/index.htm).

Control Questionnaire (ACQ), Asthma Therapy Assessment Ques- the ACT entails a patient’s accurately responding to five questions
tionnaire (ATAQ), and the Asthma Control Test (ACT). These (using a 1-5 scale) pertaining to the previous 4 weeks: activity restric-
instruments include assessment of asthma symptoms, frequency of tion at work, school, or home; frequency of shortness of breath
use of as-needed rescue medication, the impact of asthma on every- episodes; frequency of nocturnal awakening; as-needed use of rescue
day functioning, and, in the case of the ACQ, the impact of asthma bronchodilator; and overall assessment of asthma control. The lowest
on lung function. The ACT is highlighted herein as an example of a possible score is 5 and the highest possible is 25. The higher the score,
validated instrument that can be used in routine asthma manage- the better the control of asthma; however, using a cut point of 19
ment as a gauge of asthma control. The ACT is reliable and respon- yields the best balance of sensitivity (71%) and specificity (71%) for
sive to asthma control over time.56,57 The process of accomplishing classifying asthma as poorly controlled or well controlled.57 Use of

www.expertconsult.com
 10 Asthma

Table 2 Classification of Asthma Control by Impairment and Risk Domains

Classification of Asthma Control ≥12 Years of Age

Components of Control Well Controlled Not Well Controlled Very Poorly Controlled

Impairment Symptoms ≤2 days/wk >2 days/wk Throughout the day

Nighttime awakenings ≤2×/mo 1-3×/wk ≥4×
Short-acting β2 agonist use for symptom ≤2 days/wk >2 days/wk Several times per day
ALLERGY AND IMMUNOLOGY

control (not prevention of EIB)

Interference with normal activity None Some limitation Extremely limited
FEV1 or peak flow >80% predicted 60%-80% predicted <60% predicted/personal best
Validated Questionnaires*
ATAQ 0 1-2 3-4
ACQ ≤0.75 ≥1.5 N/A
ACT ≥20 16-19 ≤5

Risk Exacerbations requiring oral systemic 0-1/yr ≥2/yr† ≥2/yr†

steroids
Progessive loss of lung function Evaluation requires long-term follow-up care.
Treatment-related adverse effects Medication side effects can vary in intensity from none to very troublesome and
worrisome. The level of intensity does not correlate to specific levels of control
but should be considered in the overall assessment of risk.

*ATAQ = Asthma Therapy Assessment Questionnaire; ACQ = Asthma control Questionnaire; ACT = Asthma Control Test.
†
Consider severity and interval since last exacerbation.
Adapted from National Heart, Lung, and Blood Institute: Guidelines for the Diagnosis and Management of Asthma (EPR-3) (available at http://www.nhlbi.nih.gov/
guidelines/asthma/index.htm).
SECTION 1

serial ACT scores in asthma management can objectify the degree to Box 1 Inhalant Allergens
which the goals of management as described in NAEPP guidelines
are being achieved, which can encourage optimal asthma care out- ● Dust mites
● Trees
comes. A randomized, controlled trial demonstrated that asthma ● Cockroaches
management guided by assessment of asthma control leads to ● Grass
improved control of asthma over time.58 ● Pets (cats, dogs, etc.)
The current paradigm for asthma management (see Fig 6), rec- ● Ragweed and other weeds
ommends that asthma care providers categorize asthma severity at ● Mold spores
the initial visit based on the criteria mentioned earlier, and subse-
quent visits should proceed with assessment of asthma control. If
asthma is well controlled (ACT = 20), the provider, in collaboration
with the patient, may consider maintaining current management or
a step down. If asthma is not well controlled, it is appropriate to step Clinical relevance of inhalant allergens can be demonstrated by
up management or carry out an assessment to determine whether immediate hypersensitivity skin testing or radioallergosorbent
factors such as poor adherence or a comorbid condition is present (RAST) assay. Of these, skin testing is more sensitive, is less costly,
that is complicating response to therapy. If asthma is not well- and entails no delay in yielding results; for these reasons, skin testing
controlled, data indicate that such patients are at elevated risk for is preferred. The information that these diagnostic tests provide,
exacerbation of asthma, and on this basis they are clearly candidates whether the asthmatic patient exhibits IgE-mediated (allergic)
for intervention.59 potential to inhalant allergens, and which allergens the patient can
Although the concept of expert practice guidelines that have be said to be allergic to, is used to direct relevant avoidance measures.
become increasingly evidence based merits widespread support, spe- EPR-35 also recommends that diagnostic allergy testing may be indi-
cific treatment regimens must be determined by the physician and cated for “selected patients who have asthma at any level of severity
patient based on consideration of risk relative to benefit and tailored … as a basis for education about the role of allergens for avoidance
to individual patient needs. Because asthma research is rapidly evolv- and for immunotherapy.” Avoidance of clinically relevant allergens
ing and new pharmacotherapeutics are anticipated, continued peri- can lead to substantial reduction of symptoms and medication reli-
odic revision of guidelines for asthma can be anticipated. ance, and for some patients this can be the most important element
of asthma management. The inhalant allergens that can provoke and
Allergy, Allergen Avoidance, and perpetuate asthma symptoms are listed in Box 1. Persons with
Allergen Immunotherapy asthma are usually sensitized to more than one allergen.
Air conditioning can be associated with a dramatic reduction in
Sensitization to inhalant allergens such as dust mites; mold spores; exposures to outdoor pollens and mold spores while indoors. Because
cat, dog, or other animal proteins; cockroach and other insect aller- we now spend the majority of our time indoors,60 the usefulness of
gens; and outdoor pollens is common among asthmatic patients. The air conditioning for improving asthma symptoms should not be
1997 Expert Panel Report 2: Guidelines for the Diagnosis and Man- underestimated.
agement of Asthma differed from the 1991 Expert Panel Report in Dust mites are microscopic, and they rely on heat and humidity
recommending cutaneous or in vitro testing “for at least those to survive and proliferate.61 Allergy to dust mites is common in
patients with persistent asthma exposed to perennial indoor aller- patients with asthma. Recommended avoidance measures to reduce
gens.”1,2 EPR-3 guidelines5 point out that “sensitivity to a perennial exposures to dust mite allergen include encasing the mattress,
indoor allergen is usually not possible with a patient’s medical history box spring, and pillows in impermeable covers; reducing indoor
alone.” relative humidity; washing bedding weekly in the hot cycle (130°F);

www.expertconsult.com
 Asthma 11

and, if possible, removing carpets in favor of tiled or hardwood asthma (steps 2-4) and who have a clinically relevant component of
flooring.61 allergic potential to inhalant allergens. Allergen immunotherapy
For patients who are allergic to cat or dog dander and who own entails the incremental administration of inhalant allergens for the
pets, no avoidance strategy can rival the benefit that will occur purpose of inducing immune system changes in the host response
with eliminating the pet from the home. If a cat or dog is removed with natural exposure to these allergens. Numerous studies carried
from the home, however, the allergen can persist for several months. out since 1954 have shown statistically and clinically significant dose-
For this reason, clinical benefit cannot be expected promptly.62 dependent benefits with administration of allergen immunotherapy
When it is not possible to eliminate pets from the homee, second- in properly selected patients with asthma.64

SECTION 1
best measures include restricting the pet from the bedroom, The immunologic changes that develop with administration of
using high-efficiency particulate or electrostatic air cleaners, and allergen immunotherapy are complex. Successful immunotherapy
removing carpets and other furnishings that otherwise serve as an results in generation of a population of CD4+/CD25+ T lympho-
allergen reservoir. Washing the cat or dog, if recommended as an cytes producing IL-10 and/or TGF-β. Allergen immunotherapy
avoidance strategy, needs to be carried out frequently—at least twice has been shown to block the immediate and late-phase allergic
a week.63 response; decrease recruitment of mast cells, basophils, and eosino-
When a regimen of avoidance measures combined with appropri- phils upon provocation or natural exposure to allergens in the

ALLERGY AND IMMUNOLOGY

ate pharmacotherapy is undesirable, not feasible, or ineffective to skin, nose, eye, and bronchial mucosa; blunt the seasonal rise in
achieve optimal asthma control, administration of allergen immu- specific IgE; and suppress late-phase inflammatory responses in
notherapy vaccines (allergy shots) can be considered.64,65 As shown the skin and respiratory tract.66 However, the efficacy of immuno-
in Figure 7, the EPR-3 guidelines recommend considering allergen therapy in relation to these immunologic changes is not completely
immunotherapy for patients who have mild or moderate persistent understood.

Persistent asthma: Daily medication

Intermittent
asthma Consult with asthma specialist if step 4 care or higher is required.
Consider consultation at step 3.

Step 6 Step up if
Step 5 needed
Preferred:
Preferred: (first, check
Step 4 High-dose adherence,
High-dose ICS + LABA + environmental
Preferred:
ICS + LABA oral control, and
Step 3
corticosteroid comorbid
Medium-dose
Preferred: ICS + LABA AND conditions)
AND
Step 2
Low-dose Alternative: Consider
Preferred: ICS + LABA Omalizumab Consider Assess
Step 1 OR for patients Omalizumab control
Medium-dose
Low-dose ICS Medium-dose who have for patients
ICS + either
Preferred: ICS allergies who have
LTRA, Step down
Alternative: allergies
Theophylline, if possible
SABA PRN Alternative: or Zileuton
Cromolyn,
LTRA, Low-dose ICS (and asthma is
Nedocromil, or + either LTRA, well controlled
Theophylline Theophylline, at least
or Zileuton 3 months)

Each step: Patient education, environmental control, and management of comorbidities.

Steps 2–4: Consider subcutaneous allergen immunotherapy for patients who have allergic asthma
(see notes).

Quick-relief medication for all patients

• SABA as needed for symptoms. Intensity of treatment depends on severity of symptoms: up to 3

treatments at 20-minute intervals as needed. Short course of oral systemic corticosteroids may
be needed.
• Use of SABA >2 days a week for symptom relief (not prevention of EIB) generally indicates
inadequate control and the need to step up treatment.

Figure 7 Stepwise treatment approach for managing asthma in adults and children older than 12 years. EIB,
exercise-induced bronchospasm; ICS, inhaled corticosteroids; LABA, long-acting β agonists; LTRA, leukotriene receptor
antagonists; SABA,short-acting β agonists. (Adapted from National Heart, Lung, and Blood Institute: Guidelines for the
Diagnosis and Management of Asthma (EPR-3). Available at http://www.nhlbi.nih.gov/guidelines/asthma/index.htm.)

www.expertconsult.com
 12 Asthma

In contrast to medication that affects only symptoms, immuno- Desensitization can be performed for patients who require
therapy can favorably affect the disease process that underlies administration of ASA or ASA-like drugs for management of co-
asthma symptoms. Numerous randomized, double-blind, placebo- occurring conditions (e.g., arthritis, thromboembolism, or coronary
controlled trials have shown that allergen immunotherapy is associ- artery disease). Clinical benefit in patients with AERD—particularly
ated with benefit for reducing symptoms and reducing reliance on for polypoid rhinosinusitis—was observed in 87% of patients who
medication.66 A meta-analysis of 75 randomized, placebo-controlled were desensitized and then took ASA regularly for more than 1 year.75
studies confirmed the effectiveness of immunotherapy in asthma, Improvement included reduced level of symptoms, lower reliance on
with a significant reduction in asthma symptoms and medication, medication, and less morbidity (as reflected in fewer annual episodes
ALLERGY AND IMMUNOLOGY

and with improvement in bronchial hyperreactivity.67This meta- of upper respiratory infection or sinusitis and reduced rates of sinus
analysis included 36 trials for dust mites, 20 for pollens, and 10 for surgery procedures). Based on these findings and previous experi-
animal dander. Immunotherapy is efficacious for pollen, mold, dust ence with ASA desensitization50 this intervention can also be consid-
mite, cockroach, and animal allergens; however, its effectiveness is ered for patients with corticosteroid dependency, poorly controlled
more established for dust mite, animal dander, and pollen allergens, asthma, or refractory rhinosinusitis who require repeated sinus
because fewer studies have been published demonstrating efficacy surgery procedures. Because of potentially serious bronchospastic
using mold and cockroach allergens. reaction that can occur during desensitization, this procedure should
In the United States, 7 to 10 million immunotherapy injections only be carried out in settings with experienced physicians and
are administered annually. Because systemic reactions are not appropriate equipment to treat such reactions.
uncommon, immunotherapy should be given only in a setting in
which adequate precautions are taken and life-threatening anaphy- Pharmacotherapy
laxis can be treated.55 The decision to begin allergen immunotherapy
should be individualized and based on severity of symptoms, relative The pharmacotherapy for asthma, as recommended by current
benefit with pharmacotherapy, and whether the patient has comor- NAEPP guidelines, is summarized in Figure 7 and Tables 3 through
bid conditions such as cardiovascular conditions or is using beta 5. The overall strategy is a stepwise approach based on level of sever-
blockers.68 These factors increase the risk for (serious) anaphylaxis, ity. Inhaled short-acting β agonists (relievers) used on an as-needed
which is the major risk of allergen immunotherapy. basis are recommended for patients who have intermittent asthma
SECTION 1

and who are asymptomatic between episodes. Patients with persis-

Aspirin Intolerance and Desensitization tent asthma, with more frequent symptoms, are treated with the
addition of an anti-inflammatory agent (controller) used on a sched-
Aspirin (ASA) and nonsteroidal anti-inflammatory drugs (NSAIDs) uled basis in addition to an inhaled short-acting β agonist on an
can provoke bronchospasm (with or without nasal and ocular con- as-needed basis. For patients with more-severe disease and during
gestion or flushing) in a subgroup of asthmatic patients.69 In patients acute exacerbations, addition of oral corticosteroids as a short-term
with aspirin-exacerbated respiratory disease (AERD), potentially burst is appropriate.
serious bronchospastic reaction occurs up to several hours after
exposure to ASA or an ASA-like drug; even a subtherapeutic dosage Inhaled Corticosteroids. With the current paradigm of asthma
of ASA in this setting can lead to potentially life-threatening bron- as a chronic inflammatory disorder of the airways, ICS have become
chospasm. ASA and NSAIDs, including ibuprofen, naproxen, sulin- the preferred therapy for all patients with persistent asthma—mild,
dac, indomethacin, and etodolac, inhibit cyclooxygenases 1 and 2 moderate, and severe. Recent data indicate that ICS do not cure
(COX-1 and COX-2) and are 100% cross-reactive in ASA-sensitive asthma, and cessation of therapy often results in prompt relapse.
asthmatic patients. In AERD patients, cross-reaction can also occur Inhaled steroids are cost effective in the management of asthma, with
with higher doses of salsalate or acetaminophen, which are weak an incremental cost-effectiveness ratio for a symptom-free day of
inhibitors of COX-1 and COX-2. Selective inhibitors of COX-2 (e.g., approximately $5.00 to $6.00.76 Regular use of ICS can reduce rates
celecoxib) do not cross-react with ASA and can be tolerated without of asthma exacerbation77 and prevent increases in bronchial hyper-
bronchospastic reaction.69 responsiveness78 and accelerated loss of lung function.14 A large ret-
COX inhibition downregulates the enzyme PGE2, leading, in rospective case-control study from Canada associated regular use of
turn, to excessive production of sulfidopeptide leukotrienes (LTC4, ICS with statistically significant reductions in rates of mortality from
LTD4, and LTE4). These mediators participate in acute broncho- asthma.79
spastic reaction provoked by ASA ingestion and also contribute to Evidence indicates that patients with moderate persistent asthma
the ongoing airways obstruction and inflammation that persist in who remain symptomatic on low-dose ICS monotherapy experience
AERD patients despite avoidance of ASA and other COX-inhibiting greater benefit from LABA added to low-dose ICS compared with
drugs.69 Administration of antileukotriene agents, which either selec- doubling the dose of ICS.43 Several studies have examined the useful-
tively block leukotriene receptors or inhibit leukotriene synthesis by ness of ICS taken in combination with other agents such as theoph-
blocking 5-LO or its activator, 5-LO activating protein (FLAP), are ylline80 and leukotriene antagonists.81 These agents are also a rational
efficacious in the management of chronic persistent asthma in alternative, taken in combination with ICS, to doubling the dose of
patients with AERD. Added benefit has been reported in double- ICS in patients who remain symptomatic on low-dose ICS mono-
blind, placebo-controlled studies in AERD patients receiving therapy. The benefits of combination therapy—as measured by
inhaled (and oral) corticosteroids treated with montelukast70 or symptom scores, as-needed use of β agonists, lung function, and
zileuton.71 exacerbation rates—with these other agents are not as dramatic as
Antileukotriene agents also attenuate bronchospastic reaction with the addition of LABA.82 A study from the Asthma Clinical
provoked by ASA challenge in AERD.72,73 For this reason, antileukot- Research Network found that monotherapy with salmeterol is not
riene drugs are useful for reducing severity of reaction in patients adequate replacement therapy for asthma controlled on triamcino-
undergoing desensitization, although respiratory reaction is not lone 400 µg twice a day.83 As noted earlier, LABA monotherapy can
blocked completely.69 Biosynthesis of leukotrienes is upregulated in improve symptoms and lung function, but has no effect on airways
AERD; a key enzyme, LTC4 synthase, is overexpressed in bronchial inflammation.43
mucosa.69 AERD patients have increased expression of the Cys-LT1 The molecular mechanism of action of glucocorticoids involves
receptor on inflammatory leukocytes,74 thereby enhancing their binding to a specific intracellular glucocorticoid receptor (GCR).
ability to respond to leukotrienes. Downregulation of Cys-LT1 recep- This binding dissociates heat-shock proteins and creates an active
tor expression might explain the mechanism for benefit with ASA glucocorticoid and receptor (GC-GCR) complex. The GC-GCR
desensitization treatment.74 complex translocates to the nucleus and binds to specific GCR-

www.expertconsult.com