Asma Murray

883

S E C T I O N I

OBSTRUCTIVE DISEASES

C H A P T E R 3 8

ASTHMANjira Lugogo, MD • Loretta G. Que, MD • Daniel Fertel, MD

Monica Kraft, MD

INTRODUCTION

DEFINITION

ASTHMA EPIDEMIOLOGY AND RISK FACTORSIntroductionPrevalence of AsthmaRisk Factors

GENETICS OF ASTHMAOverviewLinkage Analysis versus Candidate Gene

ApproachesGenome-Wide Association StudiesFuture Studies

PATHOPHYSIOLOGY OF ASTHMAEtiology of AsthmaCellular Inflammation and AsthmaInflammatory Cytokines and AsthmaBiochemical Mediators of Asthma

AIRWAY REMODELING IN ASTHMAIntroductionEpithelium

Epithelial Basal LaminaExtracellular MatrixAirway Smooth MuscleGoblet Cell Hyperplasia and Mucus

HypersecretionMicrovascular ChangesPhysiologic Manifestations of AsthmaEffects of Treatment on Remodeling

PHYSIOLOGYIntroductionPhysiology of Airflow LimitationPulmonary Function TestingProvocative Challenges and Airway

Hyperresponsiveness

MANAGEMENT OF ASTHMAIntroductionAssessmentTreatmentAdditional Management StrategiesManagement of Acute AsthmaConclusion: Clinician-Patient Partnership

INTRODUCTION

Asthma is one of the oldest known diseases, but it has only been recognized as a major public health problem since the mid 1970s. The prevalence of asthma has increased dramatically and asthma is now recognized as a major cause of disability, medical expense, and pre-ventable death. Asthma has attracted the full spectrum of biomedical investigation, from studies of the preva-lence of asthmatic symptoms in different populations to studies of the effects of substitution of single base pairs in genes in animal models of allergic sensitization of the airways. These studies continue to refine the scientific understanding of asthma and suggest new approaches to diagnosis and treatment. The scope and depth of these studies present significant challenges in reviewing the topic of asthma. This chapter combines the perspectives

of the authors with a “snapshot” of the body of knowl-edge, which is expanding at an explosive pace.

DEFINITION

Although asthma is a clearly recognized clinical entity, agreement on a precise definition of asthma has proved elusive. Asthma has been more often described than defined. The earliest feature described was the labored, rapid breathing typical of asthmatic attacks, because the word “asthma” is derived from the ancient Greek word for “panting.” As knowledge about asthma has grown, the features described as characteristic of asthma have expanded. Measurement of maximal expiratory flow led to recognition of reversible airflow obstruction as a characteristic feature; measurement of changes in airflow

884 OBSTRUCTIVEDISEASES

after inhalation of chemical or physical irritants led to the definition of bronchial hyperresponsiveness. In addi-tion, studies of bronchial biopsies added a description of characteristic pathologic features. This evolution in the understanding of asthma is summarized in the definition offered in the National Heart, Lung, and Blood Institute’s 2007 Update on Asthma Pathophysiology and Treatment Guidelines.1

Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role, including mast cells, eosinophils, T lymphocytes, macrophages, neutrophils, and epithelial cells. In sus-ceptible individuals, inflammation causes recurrent epi-sodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment. The inflamma-tion also causes an associated increase in bronchial hyperresponsiveness to a variety of stimuli.

A feature found even more consistently than eosi-nophilia in bronchial biopsies from patients with asthma is thickening of the lamina reticularis immediately under-neath the subepithelial basement membrane, which is considered a hallmark of airway “remodeling,” however this feature has not yet been incorporated into consen-sus definitions of asthma’s features.

The consensus conference “definition” of asthma serves well as a description of the major features of asthma but does not hold up as a precise definition. No feature is unique to asthma, and no feature is universal in patients with the condition. For example, all tests of airway caliber may be normal between attacks, even in patients whose attacks are sudden and severe. Bronchial responsiveness may be normal over most of the year in patients with seasonal asthma, and bronchial hyperre-sponsiveness is often found in people with allergic rhin-itis but without asthma. Even the association between eosinophilic bronchial inflammation and asthma is incon-stant. Some patients with recurrent episodes of wheez-ing and dyspnea associated with reversible airflow obstruction and bronchial hyperresponsiveness have no evidence of eosinophilic inflammation on bronchial biopsies. Other patients have eosinophilic inflammation of the bronchial mucosa and chronic cough responsive to treatment with an inhaled corticosteroid but have neither airflow obstruction nor bronchial hyperrespon-siveness. Finally, some patients with severe asthma have a predominance of neutrophils, rather than eosinophils, in their bronchial mucosa.

The lack of firm, universally agreed-upon criteria for defining asthma complicates epidemiologic studies of the prevalence of asthma in different populations and of changes in prevalence in the same population over time, but agreement on “working definitions” of asthma has led to many informative studies.

Logically, studies of the genetic basis of asthma should be the most affected by lack of precise diagnostic crite-ria, but the approach developed by genetic researchers has refined concepts of the disease. Geneticists recog-nized that asthma is a complex trait, reflecting variations

in many genes and their interactions with the environ-ment, so they examined the genetic determinants of well-defined phenotypes rather than those of clinically defined asthma. This approach has clarified the role of genes as determinants of atopy, bronchial responsive-ness, and responsiveness to treatment, such as β-agonists. The recognition of asthma as a complex, multifactorial disorder has led to a greater focus on the individual and the varied disturbances in function that contribute to a more or less common clinical expression. Recent advances in science have not necessarily led to a more precise definition of asthma; rather, these advances have made the need for agreement on a definition seem less urgent.

ASTHMA EPIDEMIOLOGY AND RISK FACTORS

IntroductionThe epidemiology of asthma is complex and careful epi-demiologic studies are essential to enhancing our under-standing of a disease that affects millions of people worldwide. The challenges faced when studying asthma epidemiology begin with the lack of a universally accepted definition for the disease. Asthma was defined by the American Thoracic Society in 1962 as a disease characterized by increased hyperresponsiveness of the bronchi and trachea to various stimuli, involving wide-spread narrowing of the airways that changes in severity either spontaneously or as a result of therapy.1a,2 In 1975, the World Health Organization (WHO) described asthma as a chronic condition characterized by recurrent bron-chospasm resulting from a tendency to develop reversi-ble narrowing of airway lumina in response to stimuli of a level or intensity not causing such narrowing in normal individuals.2 The emphasis on bronchoconstriction or bronchospasm as the mechanism of asthma is warranted. However, recent advances in research techniques have shown that asthma is a complicated disease that involves both bronchoconstriction and inflammation.

Epidemiologic studies rely on questionnaire assess-ments of asthma symptoms, physician diagnosis of asthma, and use of asthma medications. Unfortunately, highly sensitive and specific physiologic tests to diag-nose asthma are not available. The methacholine chal-lenge test is highly sensitive but not specific. In 1991, the National Institutes of Health (NIH) and National Heart, Lung, and Blood Institute (NHLBI) described asthma as a chronic inflammatory disorder of the airways in which many cells and cellular elements are involved. The chronic inflammation causes an associated increase in airway hyperresponsiveness that leads to recurrent wheezing, breathlessness, chest tightness, and coughing, particularly at night and in the early morning. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible, either spontaneously or with treatment. The NIH updated the asthma diagnosis and treatment guidelines in 2007.3 Current guidelines emphasize the role of inflammation

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22 countries. The countries covered a wide range of environments including both urban and rural areas. The relationship between atopic sensitization and current wheeze was not significant. However, there was a cor-relation between wheezing and atopy in countries with higher gross national income (typically in the developed world).9 Asthma prevalence rates are higher in affluent countries, an effect that is attributed to differential envi-ronmental exposures in industrialized countries as com-pared with developing countries, in which more people live in rural than in urban areas.10

ISAAC phase III aimed to identify temporal changes in asthma prevalence rates. The prevalence of asthma symptoms increased in Africa, Latin America, and parts of Asia during the observation period, but the overall prevalence of wheezing decreased in English-speaking countries and Western Europe.11

The European Community Respiratory Health Survey (ECRHS)12 was designed to collect data on asthma prev-alence, variation in symptoms, risk factors, and treat-ment patterns in Europe and several centers outside Europe. In 1996, the ECRHS reported a wide variation in the prevalence of asthma symptoms among countries. The lowest prevalence rates occurred in India and Algeria, whereas the highest prevalence rates occurred in the British Isles, New Zealand, Australia, and the United States.13 The increased prevalence of asthma has been substantiated by several large epidemiologic studies.14–18

Death from asthma was previously thought to be very uncommon; however, asthma-related deaths steadily increased in the United States and worldwide between 1980 and the mid-1990s.19–21 There was a sharp rise in asthma-related deaths in Australia and New Zealand in the early 1980s. This increased risk of death was attrib-uted to overuse of the β-agonist fenoterol.22 In 1999, a new diagnostic coding system was initiated, which is thought to have caused the apparent decline in death rates between 1998 and 1999. Although recent death rates have been declining, asthma-related morbidity and mortality continue to be a significant problem. World-wide, approximately 180,000 deaths are attributable to asthma each year, although considerable regional varia-tion exists.18

Approximately 4000 deaths/yr in the United States are attributed to asthma.23 The recent decline in asthma-related deaths is likely related to the increased use of inhaled corticosteroids, improved access to better medical care, and improved recognition and diagnosis of asthma. Disparities exist in asthma-related morbidity and mortality. In the United States, certain populations have a higher burden of asthma-related morbidity and mortality. Deaths from asthma are rare under the age of 18 years. The Morbidity and Mortality Weekly Report (MMWR)23 reported a plateau in asthma related deaths between 2001 and 2003. In 2003, 4055 asthma deaths occurred, suggesting a rate of 1.4/10,000 persons. Higher death rates were noted in persons older than age 65 years and in women (death rate 2.3/10,000 compared with 1.8/10,000 in men).23 Females had a 45% higher risk of dying from asthma than males. Puerto Ricans were the

in asthma and focus on evidence that the patterns and degrees of inflammation are variable, resulting in pheno-typic differences that have important influences on response to therapy.

Prevalence of AsthmaThe prevalence of asthma has been increasing world-wide over the past several decades.4 The etiology of this increase in prevalence is unclear but is likely multifacto-rial. Factors resulting in increased prevalence rates include obesity and exposure to allergens such as house dust mites, mold, and tobacco smoke. Exposure to envi-ronmental triggers results in increased bronchial hyper-responsiveness and asthma. Atopy and allergic rhinitis related to exposure to allergens at an early age likely contribute to the increased incidence of asthma.5 Obesity has also been increasing in prevalence since the mid 1980s.6 Although the available studies cannot address the direction of causality, they indicate that there are impor-tant relationships between environmental and individual factors that warrant further investigation.

In 2006, the National Health Interview Survey (NHIS) estimated that 16.1 million adults (7.3% of the popula-tion) and 6.8 million children (9.4% of the population) in the United States had a diagnosis of asthma.7 The prevalence of asthma in the United States increased from 3.1% in 1980 to 7.7% in 2005. The prevalence of asthma decreases with increasing age. There are important racial differences in the prevalence and morbidity of asthma. In 2005, Puerto Ricans had an asthma prevalence rate 125% higher than non-Hispanic whites and 80% higher than non-Hispanic blacks. Females had a 40% higher prevalence rate than males; however, boys under the age of 18 years old had a higher prevalence than girls.4

The International Study of Asthma and Allergies in Childhood (ISAAC) was performed between June 1996 and November 1997.5 This is the largest study to docu-ment the worldwide prevalence of asthma. The study involved 91 centers in 56 countries and over 6000 sub-jects. The study enrolled two cohorts of subjects: chil-dren aged 6 to 7 years old and 13 to 14 years old. The prevalence of asthma varied widely between countries, ranging from 2.1% to 4.4% in Albania, China, Greece, and Indonesia to 29.1% to 32.2% in Australia, New Zealand, and the United Kingdom. Lower prevalence rates were seen in Asia, Northern Africa, Eastern Europe, and Eastern Mediterranean areas (Fig. 38-1). The prevalence rates in the younger cohort ranged from an average of 4.1% in India, Indonesia, Iran, and Malaysia to 32.1% in Australia, Brazil, New Zealand, and Panama. The results of the ISAAC study indicate that atopy, allergic rhinoc-onjunctivitis, and atopic eczema are highly correlated with the prevalence and symptoms of asthma. Countries with lower rates of atopy had lower prevalence rates of asthma.

The goal of phase II of the ISAAC study was to further investigate the contribution of atopic sensitization to the large international variation in the prevalence of asthma.8 This was a cross-sectional study of random samples obtained from 8- to 12-year-old children in 30 centers in


Risk FactorsHygiene Hypothesis

Several large epidemiologic studies have been designed to identify the risk factors that predispose individuals to developing asthma. In 1989, Strachan25 proposed that exposure to infections early in life results in the develop-ment of a predominately T-helper (Th)1-mediated immune response and down-regulation of the Th2-medi-ated response. The lack of exposure to microbes early in life results in an overactive Th2-mediated response

most likely to die of asthma, with a death rate 3.6 times higher than non-Hispanic whites. Non-Hispanic blacks had an asthma death rate twice as high as non-Hispanic whites.24 The disparate rates of death are attributed to variations in severity of disease, socioeconomic factors such as lack of access to quality health care, increased exposure to exacerbating factors in inner city areas, lack of access to medications, and differences in medications prescribed by medical professionals.20 Health care dis-parities contribute to the major differences in outcomes in different populations.

Republic of Ireland

IndonesiaAlbania

RomaniaGeorgiaGreece

ChinaRussiaTaiwan

IndiaEthiopiaMexico

MoroccoSouth Korea

AlgeriaPolandLatvia

PakistanItaly

OmanUzbekistan

PortugalMalaysia

SingaporeChile

SpainNigeriaEstonia

ArgentinaIran

AustriaBelgium

PhilippinesHong Kong

SwedenThailand

JapanFrance

GermanyKenya

LebanonFinland

MaltaSouth Africa

KuwaitPanamaUruguay

ParaguayUSA

BrazilCosta Rica

PeruCanada

AustraliaNew Zealand

UK

0 5 10 15 20 25 30 35 40

Cou

ntry

Prevalence of asthma symptoms (%)

FIGURE 38-1 n Prevalence of asthma symptoms as reported by written questionnaire. (Redrawn from The International Study of Asthma and Allergies in Childhood [ISAAC] Steering Committee. Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjuncti-vitis and atopic eczema. ISAAC. Lancet 351:1225–1232, 1998; with permission.)

38 ASTHMA 887

might increase or decrease the incidence of asthma, depending on host factors and the timing, location, and type of microbial exposure.31,32 Using a birth cohort, Ramsey and coworkers found that having physician-diag-nosed croup or having two or more physician-diagnosed ear infections in the first year of life was inversely related to atopy at school age. In contrast, bronchiolitis in the first year of life was associated with increased odds of developing asthma at age 7 years.30

Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis and is associated with an increased risk of developing subsequent wheezing or asthma.31,33–43 Recently, rhinovirus has been recognized as an impor-tant risk factor for the development of asthma. Rhinovi-rus infections are common in childhood and occur in the spring and fall. Rhinovirus is a known cause of bronchi-olitis and is the second most common cause of severe bronchiolitis resulting in hospitalizations. Until recently, little was known about the role of moderately severe outpatient lower respiratory tract infections in the devel-opment of asthma. Jackson and colleagues43 performed nasal sinus lavage, culture, and polymerase chain reac-tion (PCR) for microbial RNA on infants and children with outpatient wheezing illnesses. Viral etiologies were responsible for more than 90% of wheezing illnesses during early childhood. From birth to 3 years of age, wheezing with RSV, rhinovirus, or both resulted in odds ratios of 2.6, 9.8, and 10 for developing asthma by the age of 6 years.43 Other studies also support the increased risk of developing asthma following rhinovirus infec-tions.44 Rhinovirus is a very important predictor of asthma if the infection occurs early in life.

Understanding the mechanism by which viruses modify the risk of developing asthma is an area of intense research. In humans, severe viral infections and bronchi-olitis result in alterations in both Th1 and Th2 cytokine levels. RSV invades the respiratory epithelium through attachment and fusion proteins. Rhinovirus binds intrac-ellular adhesion molecule (ICAM)-1 and low-density lipo-protein receptors (LDLPRs) on the respiratory epithelium and is internalized with subsequent receptor upregula-tion. Downstream effects include the induction of inflam-matory chemokines and cytokines, including type 1 interferon (IFN), interleukin (IL)-12 and IL-18.45,46 Addi-tional factors that mediate the effects of acute viral infec-tions in the airways include neuropeptides, growth factors, and leukotrienes.47,48 The secretion of proinflam-matory cytokines causes airway inflammation, whereas growth factors result in airway remodeling, which may eventually increase the risk of wheezing. Although there is substantial knowledge about the mechanisms by which viruses induce acute airway inflammation, little is known about why these changes produce asthma months or years later. Severe respiratory infections may perma-nently alter the innate immune system, and up-regulation of Th2 cytokines49 acutely may cause irreversible changes in the airway that lead to increased airway hyperrespon-siveness (AHR) and asthma at later times.48

Atypical bacterial pathogens are implicated in trigger-ing acute asthma and propagating chronic asthma and airway inflammation.50 The role of these pathogens in

with increased allergic rhinitis and atopy and an increased risk of developing asthma.25,26 Modern environments are more likely to be hygienic, with smaller families, increased access to antibiotics, and decreased exposure to bacterial pathogens and microbes, leading to imbal-ance between the innate and the adaptive immune mechanisms. This maladaptive system increases the risk of developing allergic diseases such as asthma. The pres-ence of a predominantly allergic, Th2-driven milieu results in defective host defense mechanisms that make the host more susceptible to infection (Fig. 38-2).27 The hygiene hypothesis is supported by data obtained from several subsequent epidemiologic studies involving birth cohorts in the United Kingdom, Europe, and prospective studies worldwide.28,29 This association appears to be stronger in Europe than in other countries.10 For instance, the higher incidence of asthma in the inner city is not explained by this hypothesis. Von Mutius10 concluded that the hygiene hypothesis has led to important discov-eries about the etiology of asthma and the interaction between innate and adaptive immune mechanisms, even though it still lacks a unifying etiology. The practical implications of the hygiene hypothesis have not been fully tested.

Infections

The effect of respiratory infections on the incidence of asthma is incompletely understood. Exposure to microbes early in life may be protective against the development of asthma and allergic rhinitis later in life.25 Respiratory infections, particularly from viral pathogens, are especially common in infancy and childhood. The relationship between infection and the development of atopy and asthma is complex and highly dependent on the type of infection.30 Exposure to respiratory illness

• Presence of older siblings• Early exposure to daycare• Viral infection• Farm environment• Tuberculosis

• Widespread use of antibiotics• Western lifestyle• Urban environment• Diet• Aeroallergens

CD4CD4

Protectiveimmunity

Allergic diseasesincluding asthma

Cytokinebalance

Th1 Th2

FIGURE 38-2 n Determinants of the direction of differentiation of precursor T cells in early life. The concept is that environmental factors in early life can have key influences on the direction of differentiation of precursor T cells. Several factors favor devel-opment of a Th1 phenotype, leading to the absence of allergy and asthma.


data demonstrate a significant link, important questions still remain.

Obesity

The role of obesity in the development of asthma is a new area of investigation. The obesity epidemic has been increasing for the past several decades and there are no signs that the trend will change in the near future. The recent Centers for Disease Control and Prevention (CDC) NHIS survey reported that 30% of adults over the age of 18 years are obese and about 68% of United States adults are either obese or overweight. The incidence of obesity has almost doubled since 1990.6 The incidence and prevalence of asthma also have increased, and current prevalence data suggest that asthma affects approximately 5% of the U.S. population. Many studies have examined whether the increased prevalence of obesity has resulted in the increasing incidence of asthma. More than 30 cross-sectional and case-control studies of the relationship between obesity and asthma have appeared since the 1990s.67–71 Almost without exception, these studies report an increased prevalence of asthma in obese and overweight individuals throughout the world. Although such studies do not address the direc-tion of causality, several large epidemiologic studies have found that obese individuals have an increased odds ratio or relative risk of developing asthma (defined as a body mass index [BMI] > 30).72,73 Obesity is associated with multiple comorbidities, including hypertension, hyperc-holesterolemia, diabetes mellitus, obstructive sleep apnea, gastroesophageal reflux disease (GERD), and depression.

The biologic basis for the relationship between obesity and asthma has not been established, but several mecha-nisms have been proposed, including common genetic etiologies, comorbidities, effect of obesity on lung mechanics, and the role of inflammatory mediators secreted by adipose tissue (adipokines). Weiss74 sug-gested that obesity and asthma share common etiologies, for example, common effects of fetal programming or common genetics. Obesity may increase the risk of asthma through its effects on other disease processes such as sleep-disordered breathing (SDB) and GERD. The effect of these disease processes on the development of asthma is controversial. In a community-based cohort study of almost 800 children, Sulit and coworkers75 reported that the association between obesity and asthma was strong even after adjusting for SDB. GERD is associ-ated with increased AHR and wheezing76–78 as a result of vagal nerve stimulation by acid refluxing into the distal esophagus and microaspiration of acid into the bronchi.79,80 Treatment of GERD with medications or sur-gical intervention with Nissen fundoplication improves asthma control and decreases bronchial hyperrespon-siveness.81–85 Whereas GERD and SDB may contribute to the development of bronchial hyperresponsiveness and affect asthma control, these diseases do not entirely account for the association between obesity and asthma.

Recently, there has been interest in the role of adipok-ines in the development and perpetuation of asthma.85a

initiating asthma is poorly defined.50 Johnston and Martin50 reported that with few exceptions, the majority of studies support the presence of a relationship between atypical pathogens and chronic stable asthma.50–55 Chlamydophila pneumoniae and Mycoplasma pneu-moniae are present in the airways of chronic asthmatics and are associated with increased airway inflammation and a more severe asthma phenotype.56–58 The interac-tion between pathogens and asthma is not necessarily causative but rather could indicate an increased suscep-tibility to infections associated with atopy and asthma. Further evidence is required to determine the role of infections in the development of asthma.

Atopy

The incidence of asthma in childhood is strongly and independently associated with hay fever and eczema.59–61 ISAAC phase I involved 155 centers in 56 countries and focused on the prevalence of asthma, allergic rhinitis, and atopic eczema in two childhood cohorts. This study found wide variations in the prevalence of asthma between countries and in different regions within coun-tries.5,7 The prevalence rates differed by more than 20-fold between study centers.5,7,26,60 This variability was likely to be explained by environmental or lifestyle factors.

ISAAC phase II was designed to determine the role of environmental and lifestyle factors on the observed dif-ferences in prevalence rates.8 This study included a smaller cohort of children 9 to 11 years old from 30 study centers in 22 countries and added objective measure-ments of atopy including skin examination, skin prick tests, bronchial challenge testing, and specific immu-noglobulin E (IgE) measurements. Study site selection was based on prevalence rates, and sites with high or low prevalence were included in the second phase of the study.8 Logistic regression modeling revealed no sig-nificant correlation between atopy and wheezing in this cohort of children. Subgroup analysis based on per capita income showed an increase in wheezing associ-ated with atopy and allergy in countries with higher gross national income.9 The association between mater-nal or paternal atopy and the occurrence of asthma in children is controversial. Paternal atopy or asthma is not strongly associated with the incidence of asthma in child-hood9; however, maternal AHR is associated with nonat-opic wheezing in children.62 In contrast, several studies show that a family history of atopy is an important risk factor for atopy in children.63,64

The type of allergen and duration of exposure may be important predictors of asthma in childhood and later life. Torrent and associates65,66 demonstrated that a threshold dose of environmental allergen exposure is required to induce sensitization or asthma, whereas no dose-response relationship existed above this threshold. The determinants of whether one develops allergic rhin-itis/atopy, asthma, or both are unclear. The role of early childhood atopy in the development of asthma contin-ues to be an area on ongoing research, and although the

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increasing evidence that both in utero and childhood exposure to tobacco results in detrimental effects on respiratory health. Studies have demonstrated that in utero and early childhood exposure to tobacco leads to an increased risk of abnormal lung function100,101 and wheezing illnesses in childhood,102–104 an effect that per-sists into adulthood.105 Population-based studies demon-strate that environmental tobacco exposure in childhood also results in an increased risk of asthma.106,107 These effects of tobacco exposure early in life are thought to be mediated by influences on early immune function, specifically alterations in TLR signaling, which result in an increased susceptibility to microbial infections and a decreased ability to activate regulatory pathways that inhibit allergic responses.108 The effect of early tobacco exposure on the development of allergic rhinitis and atopy is controversial; however, there is increasing evi-dence that a strong interaction exists.109 Gene-environ-ment interactions are important mediators of the effects of in utero exposure on the development of asthma.110 Polymorphisms of IL-13111 and β-receptors102 modify the effect of exposure to tobacco smoke on asthma and wheezing in childhood. Tobacco use is also associated with an increased risk of developing asthma.112 Polosa and colleagues113 found that the risk of developing asthma occurs in a dose-response manner in adults with allergic rhinitis. There was an odds ratio of 2.98 (95% confidence interval [CI], 1.81–4.92) of developing asthma in smokers with allergic rhinitis.113 Environmen-tal smoke exposure in adults results in increased morbid-ity and poorer asthma control.

Asthma is a complex disease that is the result of the interaction between genetic predisposition, environ-mental exposures, and responses of the innate and adaptive immune systems. Advances in research have led to the discovery of many possible mechanisms that underlie the development and persistence of asthma. These advances support the conclusion that asthma includes many distinct phenotypes that relate to the underlying pathophysiology and mechanisms of disease. Defining these phenotypes will enhance our ability to tailor therapies and improve outcomes for patients with asthma.

GENETICS OF ASTHMA

OverviewStudies of mono- and dizygotic twins were used initially to estimate the heritability of asthma. These studies showed a higher concordance rate for asthma in monozy-gotic than in dizygotic twins.114 Studies showing an increased prevalence of asthma in first-degree relatives115 lend further support to this hypothesis. Many efforts have been made to study the genetic etiology of asthma in order to better understand its pathogenesis and thereby improve strategies to prevent, diagnose, and treat asthma. Publication of the human genome in 2001 and completion of the International HapMap Project in

One link between obesity and asthma may be the effects of adipokines on airway inflammation. Adipose tissue is metabolically active and participates in energy homeos-tasis. Animal studies of obesity show that adipose tissue secretes biologically active cytokines, including tumor necrosis-α (TNF-α) and IL-6, and adipokines such as leptin, adiponectin, plasminogen activator inhibitor-1 (PAI-1), and resistin.86 Adiponectin, a potent anti-inflam-matory hormone secreted by adipose tissue, is found in low levels in the serum of obese individuals. Adiponectin attenuates allergen-induced airway inflammation and hyperresponsiveness in OVA sensitized and challenged mice.87 In humans, obesity results in systemic inflamma-tion characterized by elevated serum levels of these adi-pokines, chemokines, and acute phase proteins.88 Obesity is associated with increased leptin levels, which may be associated with increased inflammation in the airways of obese asthmatics. Guler and colleagues89 noted that serum leptin was predictive of asthma in boys, even after adjusting for BMI. Other studies reveal higher leptin levels in asthmatic women as compared with normal women; however, adjusting for serum leptin does not affect the association between BMI and asthma.90 The relationship between obesity and asthma does not appear to be mediated via leptin in spite the fact that leptin may be an independent predictor of asthma. The effect of obesity on the development of asthma remains incompletely understood, but these early studies are promising and more work in this area is needed.

Genetics

Genetics play a significant role in the development of asthma and allergic diseases and is discussed in greater detail in the “Genetics of Asthma” section. The interplay between genetic predisposition and environmental exposures underlies the development of asthma. Advances in genomics have led to the discovery of several polymorphisms that are important in the development of asthma91 and the response to therapy. Senthilselvan and associates92 studied a cohort of 915 nonsmoking students and identified an association between Toll-like receptor 4 (TLR4) polymorphisms and atopy in females. TLR4 polymorphisms reduced the odds of having hay fever by 88%.92,93 Conversely, Raby and coworkers94 found no associations between TLR4 polymorphisms and asthma or atopy-related phenotypes. Other polymorphisms of interest in asthma include polymorphisms in IL-4, IL-4 receptor-α, and IL-5 polymorphisms that contribute to susceptibility for bronchial asthma.95–98 The phenotypic and genetic het-erogeneity in asthma poses a challenge to discovering specific genetic mutations that solely increase the risk of asthma.99

Tobacco Use and Environmental Exposure

Exposure to environmental tobacco smoke is common and its role in the development of asthma and abnormal lung function in childhood is controversial. There is


Furthermore, there is greater statistical power in study-ing case-control associations than in family-based linkage studies.

To test genes associated with a specific biologic hypothesis, candidate gene studies use case-control or family-based designs. Case-control designs compare allele frequencies between subjects with and without asthma. Case-control designs have been criticized because the recruitment of study populations can create differences in allele frequencies between cases and con-trols unrelated to disease status and introduce type I error. The family-based design, conversely, avoids issues of population structure and compares the alleles that parents transmit to children with asthma with alleles parents do not transmit. If an allele increases the risk for asthma, it should be more common among the transmit-ted alleles than the nontransmitted alleles.

More than 100 genes have been associated with asthma phenotypes. However, few reports of associa-tions between asthma and candidate genes have been replicated across studies. In a review of nearly 500 papers on disease association studies, Ober and Hoffjan130 identified 25 genes that are associated with asthma or atopy in six or more populations and 10 genes that have been associated with asthma or atopy in more than 10 studies (IL-4, IL-13, CD14, adrenergic receptor beta 2 [ADRB2], human leukocyte antigen [HLA]-DRB1, HLA-DQB1, TNF, FCER1B, IL-4Ra, and ADAM 33). These genes in general fall into four broad categories: innate immunity (CD14, HLA-DRB1, HLA-DQB1), Th2 cell signaling (IL-4, IL-13, IL-4Ra), cellular inflammation (TNF, FCEDR1B), and lung development (ADAM 33, ADRB2).

Genome-Wide Association StudiesThe completion of the International HapMap Project in 2005 laid the foundation for the next step in investigat-ing genetics in asthma, genome-wide association studies. In genome-wide association studies (GWAS), high-throughput screening of common genetic variations across the genome is used to genotype a single popula-tion. This unbiased approach has the potential to identify novel susceptibility genes and pathways not previously identified with asthma. The first GWAS for asthma was published in 2007131 and revealed an association between a gene on chromosome 17q21 locus and childhood asthma. This finding led to the identification of ORMDL3 as an asthma susceptibility gene. The potential role of this gene in asthma has not yet been defined, and further studies must be performed to determine its effect on susceptibility to asthma. The second GWAS on asthma was reported by Ober and colleagues132 and showed an association between a promoter variant in the chitinase 3-like 1 gene encoding YKL-40 and asthma, AHR, and decreased lung function. GWAS have also identified the 11p14 locus,133 5q23 locus,134 and chromosome 18135 as potential regions harboring asthma susceptibility loci that warrant further investigation.

2005 produced exponential growth in the field, and over 1 million markers of asthma have been identified. However, asthma is very heterogenous and varies not only in the age of onset, degree of severity, and response to therapy but also in the phenotype, which includes nonspecific AHR, atopy, eosinophilia, and mucus hyper-secretion. Moreover, these phenotypes change during life, which further complicates the search to find genetic risk factors for asthma.

Linkage Analysis versus Candidate Gene ApproachesStudies of asthma susceptibility genes have been carried out using two general approaches: linkage analysis and candidate gene association studies. Linkage analysis is a technique used to systematically scan the entire genome of various family members affected by a disease to iden-tify genetic regions associated or “in linkage” with a disease phenotype. Affected family members are hypoth-esized to share certain alleles located in the identified regions more frequently than would be expected by chance alone. Linkage analysis has been successful in identifying diseases in which the disease penetrance follows simple mendelian genetics but is limited because it has less power than association studies to detect weak genetic effects of loci involved in complex diseases that do not follow mendelian genetics.116,117 This approach, originally called “reverse genetics,” also called positional cloning, does not require a prior hypothesis about which genes cause asthma and has been successful in identify-ing candidate genes for asthma.118–121 ADAM 33 was the first gene identified as an asthma susceptibility gene using a positional cloning approach.120 ADAM 33 belongs to a family of proteins that are membrane-anchored met-alloproteases with diverse functions, including the shed-ding of cell-surface proteins. Increased immunostaining of ADAM33 has been found in the lungs of patients with severe asthma as compared with control subjects or those with mild asthma.122

Several studies also have identified linkage between regions of genes and asthma-associated phenotypes, including atopy, AHR, and elevated IgE levels.123–126 These studies have shown that, although asthma, ele-vated IgE, and AHR are genetically determined,127 no single gene controls inheritance of these phenotypes and heritability of the phenotypes is not the same.128,129

In contrast to linkage analysis, candidate gene asso-ciation studies select specific genes based on a biologic theory about their putative role. The gene of interest is chosen because it is believed to influence the expression of a phenotype because of its biologic role or because of its proximity to a region of linkage or association on a specific chromosome. Association studies are thought to be more powerful than linkage studies in detecting alleles that confer modest risk of disease.116 Furthermore, association studies take advantage of the fact that it is easier to recruit large populations of unrelated individu-als than it is to recruit large numbers of family numbers.

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strate heritability of genetic variations in the two tissues. This approach can be used to determine the effect of disease modifiers on asthma.

GWAS also have the potential to significantly affect medical care in the future by laying the groundwork for personalized medicine. Genetic profiling in subpopula-tions of asthmatics can be used to determine whether genetic polymorphisms predict response to therapy and adverse effects of therapy. The U.S. Food and Drug Administration (FDA) has approved several genetic tests for cytochrome 2D6 and 2C19 variants as part of its efforts to improve patient safety in the treatment of human immunodeficiency virus/acquired immunodefi-ciency syndrome (HIV/AIDS). Pharmacogenetics is also used in the treatment of childhood leukemia; however, tailored therapies for asthma are still under investigation. To date, the most studied genetic variations in asthma are the β2-adrenergic receptor polymorphisms. Three loci at amino acid positions 16, 27, and 164 have been found to significantly alter function.143–145 Genetic asso-ciation studies and linkage analyses in families have further established the importance of these polymor-phisms. Randomized placebo-controlled studies demon-strate that the polymorphism at position 16 may negatively influence response to short acting β2-agonists.146 However, the data with regard to the effect of the polymorphism and response to long-acting β-agonists (LABAs) are controversial147,148 because one small, retrospective study suggested a relationship,149 whereas two other larger retrospective studies did not.147,148 Two prospective, genotype-stratified studies are now in progress that should answer this question.

PATHOPHYSIOLOGY OF ASTHMA

Etiology of AsthmaAsthma is a complex inflammatory disease of the airways that involves many different cells (e.g., neutrophils, basophils, eosinophils, mast cells, macrophages, struc-tural cells) and mediators (e.g., cytokines, chemokines, histamine, leukotrienes, reactive oxygen species, and thromboxanes). The concepts about the pathogenesis of asthma have evolved since the mid 1980s, primarily due to new techniques that have linked various asthma phe-notypes to genotypic patterns. Based on this work, there is a general consensus that airway inflammation and remodeling are critical components of asthma. Further-more, environmental exposures throughout life can modulate the expression of asthma susceptibility genes, making asthma a dynamic disease.

Although asthma is multifactorial in origin, inflamma-tion is believed to be the cornerstone of the disease and is thought to result from inappropriate immune responses to a variety of antigens in genetically susceptible indi-viduals. Evidence from patients with asthma and animal models of bronchial hyperreactivity suggests that recruited CD4 lymphocytes orchestrate and implement immune responses and inflammation that contribute to asthma.

Future StudiesGWAS also have the ability to identify gene-gene interac-tions and gene-environment interactions. Gene-gene interactions identify whether one gene can modify the effect of another in a biologic pathway. Alone the variant has a modest effect; however, when combined with another genetic variant in the signaling pathway, the variant might amplify the impact on the disease.97 By analyzing steps in a pathway, discovery of new genes in an unbiased way can occur.

Gene-environment interactions can be used to study the effect that external factors have on influencing phe-notypic variance. This approach has shown that the influence of susceptibility genes for common diseases, such as asthma, might not become apparent unless the appropriate exposure to the environmental stimulus occurs. Miller and Ho136 listed 20 different reports as identifying specific gene-environment interactions with asthma. As an example, linkage of 5q to bronchial hyper-responsiveness was found in asthmatic children exposed to passive smoking, but not in children from non–smoke-exposed families.137

The future of GWAS also lies in studying the role of epigenetics in the etiology of asthma and the effect of disease modifiers, such as obesity. Epigenetic modifica-tions are defined as a collection of heritable changes in gene expression that do not directly alter DNA sequences. The most common epigenetic modifications of the human genome are DNA methylation and posttransla-tional modification of core histone proteins. DNA meth-ylation involves the covalent addition of a methyl group to a cytosine and usually occurs near CpG sites. Meth-ylation of CpG islands can affect gene expression. Post-translational modification of histones can involve acetylation, methylation, phosphorylation, and ubiquiti-nylation and can alter transcriptional activity. Both of these epigenetic modifications can be heritable and influ-ence gene expression during growth and develop-ment.138 If environmental exposures such as allergens, antibiotics, air pollution, diet, and tobacco exposure can induce epigenetic regulation in vivo, then epigenetics provides an attractive explanation for environmentally regulated alteration of gene expression. Indeed, evi-dence from two large prospective clinical studies indi-cates that prenatal exposure to tobacco smoke is associated with an increased incidence of asthma in young children and adolescents.139,140 Moreover, data also suggest that exposure to tobacco smoke can increase the risk of asthma across generations.141 Determining whether genetic or environmentally triggered epigenetic changes occur in the genome will be important in advancing understanding of the pathogenesis of asthma.

The first study to demonstrate genome-wide linkage and association of gene expression traits in tissues other than lymphoblastoid cell lines was published in 2008.142 Emilsson and associates142 showed that compared with the 10% correlation found in blood, more than 50% of all gene expression traits in adipose tissue correlated strongly with obesity-related traits. They then used genome-wide linkage and association studies to demon-


factor-β (TGF-β) and their regulatory function is due to a TGF-β–dependent mechanism. TR1 cells are inducible and secrete high levels of IL-10, IFN-γ, and TGF-β but no IL-4 or IL-2.159 These cells do not overexpress FoxP3 and appear to be regulated through different pathways.

Epidemiologic studies demonstrate a higher preva-lence of asthma in industrialized Western societies than in less technologically advanced societies.7 These obser-vations are the essence of the “hygiene hypothesis.”160 The hygiene hypothesis proposes that increased hygiene and lack of exposure to environmental antigens, such as animal allergens, may be affecting the immune system by changing the relative balance of the Th1 and Th2 immunologic profile. Early exposures to various triggers that might occur at an increased frequency in a rural setting can tilt the balance to a Th1 dominant response that is protective against the allergic diathesis promoted by Th2 responses. Therefore, in more urban “cleaner” societies where early childhood exposures are less pro-nounced, a shift toward a Th2 immunologic profile occurs, resulting in a higher incidence of asthma and other allergic diseases.

Eosinophils

Eosinophils are prominent cells in the airways of many patients with asthma. Most asthma phenotypes are asso-ciated with increased numbers of eosinophils in blood, bone marrow, and lung, leading to the hypothesis that the eosinophil is a central effector cell in asthma that contributes to ongoing airway inflammation. The secre-tion of eosinophil peroxidase, leukotrienes, reactive oxygen species/reactive nitrogen species (ROS/RNS) by eosinophils can result in epithelial damage, bronchocon-striction, and mucus hypersecretion. Eosinophils also present antigens and secrete cytokines which can further amplify the Th2 response.161 Indeed, the number of eosi-nophils in bronchoalveolar lavage (BAL) and blood cor-relates with severity of disease in humans with asthma. However, whether the eosinophil is causal in the patho-genesis of asthma or an innocent bystander is still debated. Studies in mice blocking IL-5 either by targeted gene deletion or using anti-IL-5 monoclonal antibodies have produced conflicting results.162,163 Further studies in humans confirm that pharmacologic inhibition of IL-5 can result in eosinophil depletion, but this does not provide significant improvement in airway function or disease symptoms in asthma.164 Two published studies165,166 supported the concept that eosinophils are critical in allergic asthma in mice. In one study, Humbles and coworkers165 deleted the high-affinity GATA-1 binding site on the GATA-1 promoter, the transcription factor required for differentiation of immature myeloid cells, and found that despite eosinophil depletion, there was no effect on AHR and mucus production. In an entirely different approach, Lee and colleagues166 used an eosinophil peroxidase promoter to control transgenic expression of diphtheria toxin A chain, to destroy eosi-nophils, and found that eosinophils were essential for AHR and mucus production. The divergent findings in these two studies are difficult to explain and have been

Cellular Inflammation and AsthmaCD4 Lymphocytes

Four distinct subsets of CD4 lymphocytes, Th1, Th2, regulatory T cells (TReg), and T17 cells can differentiate from precursor T cells at the time of antigen presentation and influence cytokine production. The differentiated Th cells are characterized by the specific sets of cytokines they release when stimulated. For many years, it was believed that asthma and other allergic diseases resulted from an imbalance between Th1 and Th2 responses in favor of a Th2 response, promoting an allergic diathesis based on Th2 cell responses. The identification of tran-scription factors controlling Th1 and Th2 differentiation has provided further support for a predominant role of Th2 cells in the pathogenesis of asthma, because Tbet expression is reduced in the asthmatic lung150 and GATA 3 is overexpressed.151,152 However, recent discoveries and an improved understanding of the interaction between Th17 cells and regulatory T cells have shown that the simple Th1/Th2 hypothesis is not sufficient to explain asthma.

Th1 cells drive cell-mediated immune responses and are characterized by the production of IFN-γ, TNF-α, and IL-2 without production of IL-4, IL-5, IL-9, and IL-13. By contrast, Th2 cells mediate humoral responses and are characterized by their secretion of IL-4, IL-5, IL-9, and IL-13 in the absence of IFN-γ and TNF-α. Antigen recog-nition by naive T cells in the presence of IL-12 favors STAT4 and Tbet activation which promote Th1 cell dif-ferentiation. Early IL-4 production favors STAT6 and GATA3 activation, which lead to Th2 cell production. Th17 cells, a newly discovered subset, produce IL-17 and IL-22.153 These T cells are proinflammatory and have been studied primarily in mice. They express a charac-teristic transcription factor, retinoic acid orphan nuclear receptor (ROR-γ).154 In a murine model of allergic asthma, IL-17 was found to be necessary for the induction of allergic asthma. In healthy human subjects with asthma, IL-17 production increases in peripheral blood after aller-gen challenge. In addition to its proinflammatory role in asthma, Th17 cells also have been detected in other inflammatory autoimmune diseases such as Crohn’s disease, rheumatoid arthritis, and multiple sclerosis and have been shown to be important in host defense against bacterial pathogens.155

In contrast to Th1, Th2, and Th17 cells, TReg cells act directly or indirectly to suppress the function of effector T cell responses in allergic asthma. These cells have cytokine profiles that are distinct from Th1 and Th2 cells and appear to control development of autoimmune disease156 and are able to inhibit development of allergic Th2 responses. Several subsets of TReg cells have been identified, including natural CD4+CD25+TReg cells, Th3 cells, and inducible type 1 TReg (TR1) cells.157 A deficiency in CD4+CD25+TReg cells can result in the development of asthma.158 These cells originate in the thymus, require expression of the transcription factor FoxP3 for the devel-opment of the suppressive function, and do not produce cytokines. Th3 cells produce mainly transforming growth

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with the increased oxidants in asthma, the antioxidant activity in the lower airways is reduced, providing further indirect support for the importance of oxidants in asthma.183

Reactive Nitrogen Species

In addition to increased ROS, RNS also may be important in the pathogenesis of asthma. It is well-established that the exhaled breath of asthmatics contains higher concen-trations of nitric oxide (NO) than the exhaled breath of normal individuals.184 NO is produced by nitric oxide synthase (NOS). The three known isoforms of NOS are members of a family of different but related NOS pro-teins: neuronal NOS (NOS1), immunologic NOS (NOS2), and endothelial NOS (NOS3). NOS1 and NOS3 are con-stitutively expressed, although they can be regulated.185 NOS2 was originally described in macrophages and is inducible. All NOS isoforms are expressed in the lung.186 Whereas NOS1 is found primarily in the neuronal plexus; NOS3 is ubiquitous and expressed in respiratory epithe-lium, vascular endothelium, and neurons.187 In contrast, the expression of NOS2 is inducible in respiratory epi-thelium and macrophages.187 NO can react with oxygen or ROS to form oxidation products, NO2

−, NO3−, and per-

oxynitrite,188 which can induce tissue damage. The con-centrations of NO are increased in the exhaled breath of asthmatics, and measurements of expired NO can be used to monitor disease189 and titrate inhaled corticoster-oid therapy.190 Exhaled NO is a summation of airway NO formation, superoxide anion metabolism, changes in airway pH, and metabolism of S-nitrosoglutathione (GSNO), an endogenous bronchodilator present in the lung. GSNO is deficient in the airways of children with acute asthmatic respiratory failure. Mice deficient in GSNO-reductase (GSNOR), an enzyme that metabolizes GSNO, develop allergic airway inflammation, but do not develop AHR,191 which suggests that S-nitrosothiols may play a critical role in reducing bronchoconstriction in allergic asthma.

Arginase

Recent evidence indicates that arginine metabolism may also contribute to the development of AHR in allergic asthma. Increased arginase activity in allergic asthma was first described in a guinea pig model whereby administra-tion of an arginase inhibitor, N-hydroxy-nor-L-arginine (NOHA), reduced AHR and restored NO production.192 Arginase expression is also increased in BAL cells, inflam-matory cells, and airway epithelium obtained from bron-chial biopsies of asthmatic subjects.193 Furthermore, genetic polymorphisms in arginase have been identified, supporting a role for arginase in asthma and atopy in children.194

Arachidonic Acid Metabolism

Products of arachidonic acid metabolism are also increased in the exhaled breath of patients with asthma.195 Cysteinyl leukotrienes and other products of the 5-

attributed to background strain variability, controversy about the IL-5 antibody used in the studies, and indirect effects of diphtheria toxin A.167

Inflammatory Cytokines and AsthmaAtopic asthmatics have increased expression of Th2 cytokines in airway biopsies and BAL compared with healthy volunteers.168 Th2 cells regulate allergic inflam-mation via production of IL-3, IL-4, IL-5, IL-9, IL-10, and IL-13. IL-5 has an essential role in regulating eosinophilic inflammation in asthma and subsequent AHR.169 IL-9 appears to augment Th2-driven inflammation and be involved in mast cell release, IgE production, and mucus hypersecretion.170 IL-10 is an anti-inflammatory cytokine and acts to inhibit inflammatory cytokine expression, chemokines, IL-5171 and granulocyte-macrophage colony-stimulating factor (GM-CSF) production172 in asthma.

Although all Th2 cytokines contribute to the patho-genesis of asthma, IL-4 and IL-13 are particularly relevant. IL-4 is critical for the synthesis of IgE and is involved in eosinophil recruitment to the airways.173 Because IL-4 also acts to promote Th2 cell differentiation, it acts at a critical proximal site in the allergic response and is an attractive target for inhibition. This concept is supported by studies in IL-4–deficient mice, which show that IL-4 is essential for the development of allergic symptoms, because allergen-challenged IL-4–deficient mice do not develop an asthma phenotype.174

IL-13 has a similar structure to IL-4 and shares a func-tional receptor, IL-4Rα. A substantial body of evidence supports IL-13 as necessary and sufficient to induce aller-gic asthma.175,176 Acute administration of IL-13 to mice recapitulates many of the features of allergic asthma, including AHR, eosinophilia, mucus hypersecretion,175,176 and subepithelial fibrosis.177 Genetic evidence in humans further supports a role for IL-13 dysregulation in allergic asthma. Polymorphisms in the promoter region and coding regions of the gene are associated with increased risk of developing asthma.178,179

Biochemical Mediators of AsthmaReactive Oxygen Species

Asthma is characterized by altered airway redox chemis-try and increased oxidative stress in the airways.180 Lung inflammatory cells, including eosinophils, macrophages, and neutrophils, are increased in the asthmatic airway and able to release large quantifies of ROS and RNS.181 Furthermore, eosinophils, macrophages, and neutrophils isolated from asthmatics produce increased concentra-tions of ROS compared with normal subjects.182 Mye-loperoxidase and eosinophil peroxidase produced by these granulocytes are increased in BAL and peripheral blood in asthmatics and can produce large amounts of the potent ROS, hydroxyl radical,182 resulting in epithe-lial damage and increased AHR in asthmatic individuals. The observation that lung eosinophils in BAL and blood correlate with AHR in asthma provides further support for a proinflammatory role of ROS in asthma. Concurrent


ASM cells, have been shown to produce mediators asso-ciated with remodeling in vitro and, to a lesser extent, in vivo.213,214 The precise relationship between remode-ling and inflammation is unclear.

EpitheliumNormal airway epithelium contains ciliated columnar, mucus-secreting goblet, and surfactant-secreting Clara cells that form a highly regulated and impermeable barrier made possible by tight junctions located on the apical surface of the columnar cells.215,216 The airway epithelium is altered in the airways of mild and severe asthmatics, because epithelial changes have been identified in biop-sies of airways of adults and children.217 Although initial pathologic studies in asthma attributed epithelial abnor-malities to bronchoscopy-related injury,218,219 recent studies have revealed that the airway epithelium is abnor-mal both in vitro and in vivo. The finding that damaged asthmatic epithelium is associated with up-regulated epi-dermal growth factor receptors and impaired prolifera-tion suggests a pattern of chronic injury and aberrant repair.220 This is hypothesized to lead to increased epithe-lial permeability due to dysfunction of the airway tight junctions221 and may in part be responsible for the increased susceptibility of asthmatic epithelium to oxidant injury.222

A great deal of evidence suggests that the airway epithelium is a central participant in innate and adap-tive immune responses.223 Disruption of the tight junc-tions allows easy entry of microparticles, allergens, and microbes into the subepithelial space with resultant activation of inflammatory cells, leading to the produc-tion of cytokines and chemokines and propagation of inflammation.215,224 Subsequent production of growth factors is thought to lead to subepithelial fibrosis and airway remodeling. Holgate225 proposed the concept of the epithelial mesenchymal trophic unit (EMTU) (Fig. 38-3), which is analogous to the “soil” that allows the “seed” of Th2 inflammation to persist. The activated EMTU is hypothesized to propagate Th2 inflammation through interactions with resident airway immune cells via proinflammatory mediators derived from the acti-vated structural cells of the EMTU.226 The cytokines produced by immune cells are proposed to feed back to the EMTU, contributing to a cycle of persistent chronic inflammation, with propagation of myofibrob-lasts, proliferation of smooth muscle, and alterations in microvasculature.

Epithelial Basal LaminaA characteristic feature of asthma in adults and children is the hyalinization and thickening of the basal lamina beneath a normal-appearing epithelial basement mem-brane.216 Accompanying this unique change in airway structure is an increased number of myofibroblasts capable of laying down matrix,227 including increased amounts of type III and V collagens, fibronectin, and tenascin.228,229 Asthma is not associated with basement membrane thickening but rather subepithelial fibrosis

lipoxygenase pathway are potent inflammatory media-tors implicated in the pathogenesis of asthma. Elevated concentrations of cysteinyl leukotrienes are produced in the airway of asthmatics196 and have been recovered from the urine of patients with allergen-induced asthma,197 exercise-induced asthma,198 and aspirin-induced asthma.199 Leukotrienes act by binding to receptors on the surface of structural and inflammatory cells. These receptors activate G protein–coupled receptors in the cytoplasm and increase intracellular calcium, resulting in bronchoconstriction and mucus secretion.200 Inhibitors of the 5-lipoxygenase pathway and cysteinyl leukotriene receptor 1 are used to treat asthmatics who remain symptomatic despite using inhaled corticosteroids.

AIRWAY REMODELING IN ASTHMA

IntroductionAirway remodeling is one of the cardinal pathologic fea-tures of chronic asthma and is defined as structural alter-ation of the airway with characteristic changes in the nature, content, and distribution of airway elements.201 The degree of remodeling is a function of disease sever-ity over time, because the degree of structural changes on biopsy and imaging studies correlates with the clini-cal severity of asthma.202–204 The major pathologic changes include increased deposition of subepithelial collagen, airway smooth muscle (ASM) hyperplasia, pro-liferation and hyperplasia of goblet cells and submucosal glands, and microvascular changes.205 These structural changes result in thickening of airway walls and decreased diameter of the airway lumen, which have been observed in pathologic and radiographic studies.206,207 Ultimately, remodeling contributes to the characteristic physiologic changes of asthma discussed previously, including airflow limitation, AHR, and mucus hypersecretion.

The primary hypothesis about the pathogenesis of airway remodeling is that remodeling is caused by exag-gerated airway inflammation in response to environmen-tal stimuli. The experimental support for this hypothesis includes animal data linking allergen-driven Th2 inflam-matory responses with extensive airway remodeling in mice.208,209 For example, overexpression of the Th2 cytokine IL-13 in transgenic mice leads to the character-istic changes of airway remodeling, including increased subepithelial collagen deposition, epithelial hyperpla-sia, enhanced mucus production, and microvascular changes.210 Similarly, in an ovalbumin challenge model of allergic asthma, inhibition of leukotriene formation substantially reduced airway remodeling and reduced the expression of Th2 cytokines.211 Nevertheless, the limited efficacy of anti-inflammatory treatment in pre-venting remodeling suggests that remodeling may not be entirely due to inflammation. Some evidence sug-gests that remodeling may occur independently of the recruitment of inflammatory cells.212 Native airway con-stituents, including epithelial cells, fibroblasts, and

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Extracellular MatrixExtracellular matrix (ECM) is increased in the airway walls of humans with asthma and is seen in experimental models. In ovalbumin challenge models, airway wall collagen, fibronectin, and proteoglycan deposition are increased.239,240 Loss of elastic fiber content in the small airway adventitial layer has been demonstrated in studies of severe and fatal asthma.241–243 Airway elastin, the matrix component whose degradation is central to emphysema, is also decreased in biopsy specimens from asthmatic patients.244–246 These changes appear to be mediated, at least in part, by exposure to Th2 cytokines. For example, IL-5 exposure increases allergen-induced collagen deposition, whereas allergen-chal-lenged IL-5 knockout mice have decreased collagen deposition.247,248 Mice with a knockout of Tbet, a Th1-specific transcription factor, have profound defects in the production of Th1 cytokines and increased produc-tion of Th2 cytokines. As a result, the mice develop a remodeled asthmatic phenotype, with high levels of Th2 cytokines and increased subepithelial collagen deposi-tion. The central role of IL-13 is illustrated by the amel-ioration of airway remodeling that occurs when IL-13 is neutralized.249

with deposition of collagen beneath the basement membrane.230 These changes have been reported in early asthma close to the beginning of the disease, suggesting that the changes in matrix deposition are not the result of chronic inflammation.216,225,231,232 Both the Tucson Children’s Respiratory Study and the Childhood Asthma Management Program demonstrated that reduced lung function can occur early in life and is unabated by conventional therapies.233,234 The mechanisms involved in remodeling of the basal lamina are unknown. However, murine models of asthma have suggested roles for plate-let-derived growth factor (PDGF), TGF-β, and IL-13.235 TGF-β promotes the differentiation of fibroblasts into myofibroblasts, which form collagen and secrete growth factors.236 In humans, PDGF has been implicated in airway remodeling by inducing airway fibroblasts to produce collagen and increase matrix formation. The PDGF-BB isoform enhances fibroblast procollagen I formation in subjects with severe asthma as compared to those with mild to moderate asthma.237,238 Additionally, PDGF and TGF-β have been shown to modulate expression of matrix metalloproteinases and regulation of migratory function of human airway smooth muscle cells.238a Further research is required to determine the mechanisms of airway fibrosis and to guide more specific therapy in asthma.

Dendritic cell

Mucus

Initiation

(Myo) fibroblasts Amplification

Propagation

Smooth muscle

Blood vessels

Environmental agentsInflammatory cell products

Th-2 and Th1cytokines

Chemoattractants eg IL-8,proinflammatory mediators

THE EPITHELIAL-MESENCHYMAL TROPHIC UNITIN ASTHMA

Th-2 cell

Neutrophil

EosinophilMast cell

TNF

IL-3,IL-5

GM-CSF

IL-9,IL-3, IL-4

FIGURE 38-3 n Schematic representation of the interaction between immune, inflammatory, and structural cells through the epithelial-mesenchymal trophic unit (EMTU) in the pathogenesis of asthma. (Adapted from Holgate ST: The airway epithelium is central to the pathogenesis of asthma. Allergol Int 57:1–10, 2008.)


diameter associated with more severe asthma.259 Taken together, it seems likely that both hypertrophy and hyperplasia contribute to the increased smooth muscle mass characteristically seen in remodeled airways of patients with asthma.

Asthmatic ASM may be phenotypically different from ASM in nonasthmatic airways, with altered proliferative or contractile capacities. Smooth muscle cells exhibit phenotypic plasticity in vitro, with the ability to switch between a hyperproliferative and a hyperfunctional phe-notype, depending on culture conditions. This phenom-enon could theoretically explain the variable presence of both ASM hyperplasia and hypertrophy in asthma. To date, gene expression studies addressing this possibility are intriguing but inconclusive.266

In addition to alterations in quantity and function, asthmatic ASM appears to have an altered anatomic rela-tionship with inflammatory cells. Data demonstrate that smooth airway infiltration by mast cells is an important feature of asthmatic airway remodeling.267 Notably, this colocalization of mast cells and ASM is present in a cross section of asthma phenotypes and degrees of severity.268 Several mast cell products have the potential to adversely affect the growth and function of smooth muscle, and their localization in the smooth muscle may facilitate this interaction. For example, the mast cell–derived media-tors histamine, prostaglandin D2, and the cysteinyl leu-kotrienes are potent constrictors of airway smooth muscle.269 Human ASM promotes human lung mast cell (HLMC) survival in vitro, induces rapid HLMC prolifera-tion, and enhances constitutive HLMC degranulation, suggesting a smooth muscle–driven allergen-independ-ent mechanism of chronic mast cell activation.270

Goblet Cell Hyperplasia and Mucus HypersecretionGoblet cell hyperplasia is a hallmark of the pathology of asthma in mild, moderate, and severe disease. Mucin is secreted by goblet cells in the airway epithelium and mucus glands in the submucosal space. Airway mucus is a viscoelastic gel composed of cells, secreted polypep-tides, and cellular debris, which forms a thin film lining the airway surface.271 Under normal circumstances, airway mucus serves a protective function, trapping foreign debris, bacteria, and viruses, then working in concert with the ciliated epithelium to clear captured material. In asthma, excessive production of mucus con-tributes to airway obstruction. Secreted mucin levels in induced sputum are higher in patients with lower forced expiratory volume in 1 second (FEV1) values, indicating that mucus hypersecretion plays an important role in airway obstruction in asthma.272 Accumulation of intra-luminal mucus plays a significant role in fatal or near-fatal asthma, and widespread occlusion of airways by mucus is a common finding in autopsy studies of fatal asthma.273,274 Mucin is the major protein component of these plugs, which is a high-molecular-weight glycopro-tein produced by goblet cells in the epithelium and glands in the submucosa.275,276 Secreted and oligimerized

TGF-β, derived from eosinophils, macrophages, and other cells, is also strongly implicated in ECM remodel-ing. Mice treated with anti-TGF-β antibody have decreased ECM deposition,250 whereas treatment of asthmatics with anti-IL-5 antibody decreases ECM deposition and reduces BAL concentrations of TGF-β.251 In addition, the gene for TGF-β is up-regulated in allergen-challenged mice252 and Tbet/IFN-γ–deficient mice have elevated levels of TGF-β.249

Changes in the ECM appear to correspond with phys-iologic changes seen in asthma.253 Increased submucosal matrix protein deposition, in addition to contributing to luminal narrowing, changes the mechanical properties of the airway wall. Stiffening of the airway wall reduces forces exerted on lung parenchyma, leading to reduced distensibility. There are also data to suggest loss of elastic recoil in asthma, and early data suggest that loss of elastin may play a role.241,246,254

Airway Smooth MuscleAirway smooth muscle (ASM) mass is increased in humans with asthma and experimental animal models. The increased smooth muscle mass in airway walls con-tributes to airway luminal narrowing by occupying space and increasing the extent of narrowing for each degree of smooth muscle contraction.255,256 In animal models, increased ASM mass accounts for a significant percent-age of AHR257 and correlates with methacholine sensitiv-ity.258 In pathologic studies, increased ASM mass in large airways is linked with both severe and fatal asthma.259,260

In addition to the effects of increased smooth muscle mass on airway physiology, ASM cells have been shown to play a central role in the molecular events that initiate and propagate airway remodeling. The relationship of smooth muscle to the ECM is complex, with smooth muscle cells elaborating matrix proteins, as well as matrix metalloproteinases (MMPs) and their tissue inhib-itors (TIMPs), possibly via signaling between the ECM and cell surface receptors.261 Proof of this relationship comes from the ability of ASM cells to secrete ECM pro-teins in response to asthmatic sera, suggesting autocrine regulation of airway remodeling.262 Furthermore, ASM obtained from asthmatic airways secretes more ECM protein than nonasthmatic ASM and ECM from asthmat-ics induces a greater degree of cell proliferation.262

The relative contributions of smooth muscle hyper-trophy versus hyperplasia in increasing smooth muscle mass is not clear. Data from a Norway rat ovalbumin-challenge model shows that increases in ASM mass are associated with increased DNA synthesis, suggesting smooth muscle hyperplasia.263 More recent human biopsy data demonstrate that muscle mass increases along with the number of nuclei, providing additional support for the role of hyperplasia in smooth muscle remodeling.264 However, a second ovalbumin-challenge model showed increased muscle mass without a con-comitant increase in the number of smooth muscle cell nuclei.265 Furthermore, human biopsy studies support hypertrophy as the cause of increased smooth muscle mass in asthma, with greater smooth muscle cellular

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Physiologic Manifestations of AsthmaAirway Hyperresponsiveness

AHR is a characteristic feature of asthma. Hyperrespon-siveness can occur in response to a number of nonspe-cific environmental irritants, pharmacologic agonists, and inflammatory mediators. In the past, the predomi-nant view was that airway inflammation was the mecha-nism causing AHR. This concept has been criticized, because a number of studies have shown dissociation between AHR and inflammation,191,293 highlighting the fact that inflammation alone is insufficient as a mecha-nism of disease. Evidence suggests that a number of inflammatory Th2 cytokines, CD4 cells, and biochemical mediators contribute to the development of AHR in asthma. Exposure to Th2 cytokines in asthmatic airways can increase the isometric constrictor response of ASM by increasing calcium release from intracellular stores.294,295 In addition to the airway inflammation, factors contributing to mechanical airway obstruction have also been implicated in the pathogenesis of AHR, including epithelial permeability, smooth muscle hyper-trophy, mucus hypersecretion, and airway remodeling.

Epithelial Permeability

The airway epithelium is the source of many of the cytokines and inflammatory mediators contributing to airway inflammation and increased AHR in asthma. The airway epithelium serves several different functions within the lung. The airway epithelium is in a unique position, because it is exposed to the environment and is the primary target of viruses and inhaled agents known to cause or exacerbate asthma. In addition to barrier protection and mucociliary clearance of unwanted path-ogens, the epithelium can regulate the response of other lung cells involved in the inflammatory and fibrotic response of the lung to external stimuli.

In asthma, there is evidence that airway epithelial barrier function is impaired and epithelial tight junctions are disrupted. These cells show reduced transepithelial resistance indicating epithelial permeability, which is associated with AHR. Confocal microscopy with antibod-ies directed at adapter proteins (ZO-1) and tight junction proteins (occludin) support the concept that tight junc-tions are poorly developed in asthmatic epithelium. In addition to disruption of the tight junctions, epithelial desquamation has been described as a pathologic feature in patients with asthma who die from acute respiratory failure.296 Furthermore, markers of apoptosis indicating programmed cell death have also been noted in airway tissue of subjects with asthma and correlate with disease severity and chronicity.222

Smooth Muscle Hypercontractility

Hypercontractility of ASM is believed to be a key deter-minant of the development of AHR in asthma. It is still unclear whether contractile force is enhanced in the asthmatic airway, where inflammatory mediators accu-

mucins have an important role in determining the prop-erties of the extracellular mucus layer.

In patients with asthma, the number of mucus-secret-ing goblet and submucosal cells in the airway is increased compared with that in normal individuals.277 Although 19 human mucin genes (MUC) have been described, the major secreted mucus proteins include the gene prod-ucts MUC5AC and MUC5B. MUC5AC is the predominant gel-forming mucin and is disproportionately increased in asthma.278 In addition to quantitative differences in mucus gene products in asthma, asthmatic mucus may be functionally different. The increased viscosity seen in asthmatic mucus may be accounted for by variations in oligimerization and by incomplete release of mucins from goblet cells.279 The latter may lead to “tethering” of luminal mucins to the airway epithelium and increased adherence of mucus to airway walls.280

The increase in mucus production seen in asthma may be attributed to increased mucin production, increased exocytosis of previously formed mucus from airway cells, or both. The migration of mucus from preformed granules to the apical surface of epithelial cells is depend-ent on the presence of myristolated alanine-rich C kinase substrate (MARCKS protein), and activation of the MARCKS protein requires phosphorylation by protein kinase C.281 The strength of this relationship is bolstered by the observation that protein kinase C is up-regulated together with mucin production after stimulation of airway epithelial cells with neutrophil elastase.282 Binding of mycoplasma to TLR and subsequent expression of Th2 cytokines has also been shown to lead to increased mucus production in a murine model of asthma, possibly mediated by a nuclear factor-κB (NF-κB) binding site on the MUC5AC promoter.283 However, TLR2 knockout mice have increased mucus production, possibly due to decreased levels of IFN-γ and subsequently increased TGF-β levels.284

Microvascular ChangesBronchial neovascularization is a recognized feature of airway remodeling, with dilated and tortuous mucosal blood vessels present even in mild asthma.285 Function-ally, the airway microvasculature is more permeable, with leakage of plasma proteins into the extravascular space associated with mucosal edema.286 Mucosal edema results in airway narrowing, which may have a pro-nounced effect on airway function.286

Vascular endothelial growth factor (VEGF) appears to be a key mediator of the pathogenesis of airway vascular abnormalities in asthma. VEGF levels are increased in the asthmatic airway,287 with levels of VEGF staining corre-sponding to increasing bronchial vascularity.288 A number of different stimuli for VEGF expression are present in asthma. Th2 cytokine exposure prompts the release of VEGF from ASM cells,289,290 as does increased mechanical strain as seen in symptomatic airway obstruction.291 Trans-genic induction of VEGF in murine airway epithelial cells leads to increased pulmonary angiogenesis and increased expression of Th2 cytokines, suggesting the presence of a feedback loop increasing vascular remodeling.292


toms suggest new therapeutic avenues targeting the underlying pathogenesis of airway remodeling in asthma.130

PHYSIOLOGY

IntroductionAs understanding of the pathogenesis of asthma improves and strategies for treatment evolve, it is important to recognize that the link between the pathophysiology and the treatment of asthma is functional, involving var-iable limitation of air flow. These two cardinal manifesta-tions of asthma, variability of symptoms in response to environmental factors and limitation of air flow, are crucial to making the diagnosis of asthma and distin-guishing asthma from other obstructive lung diseases.

Physiology of Airflow LimitationDuring asthma exacerbations, diffuse narrowing of the airways results in profound physiologic consequences. This narrowing has been thought to occur disproportion-ately in the small bronchi,307 although recent studies suggest a prominent role for large and medium airways.308 As a result, lung function tests are abnormal, with an increase in airway resistance and a decline in maximal expiratory flow. Airway narrowing also prevents the lungs from completely emptying (“air trapping”) due to resistance to expiratory flow and to bronchial closure at higher than normal lung volumes. The breath-to-breath variability of asthmatic obstruction and air trapping led to the concept of dynamic hyperinflation.309 As a result of dynamic hyperinflation, asthmatics breathe at higher total lung volumes, detectable as increased residual volume.310 Despite elevated total lung volumes, asthmat-ics typically have reduced tidal ventilation. Decreasing forced vital capacity (FVC) suggests worsening air trap-ping, whereas worsening of the FEV1/FVC ratio indicates increasing airway narrowing.311

At high lung volumes, flow limitation due to bronchial narrowing is offset by increased circumferential traction on the bronchial airways due to “tethering” of airways to inflated alveoli.312 This response may be less effective in asthma, because the altered mechanical properties of the ECM in asthmatic airways reduce the mechanical forces opposing ASM contraction.313 The net effect is that the work of breathing increases significantly, due in part to decreased lung and chest wall compliance at higher thoracic volumes and in part to the greater effort required to overcome the resistance of narrowed airways. The diaphragm and intercostal muscles are overloaded due to thoracic hyperinflation and mechanically disad-vantaged due to suboptimal positioning on their length-tension curves.314 As a result, accessory muscles of respiration, including the abdominal muscles and sterno-cleidomastoids, are required.315 A large proportion of the subjective dyspnea associated with asthma exacer-bations has been attributed to respiratory muscle fatigue.316

mulate, or whether smooth muscle is abnormal in asthma. Numerous reports have identified increased ASM mass in fatal and nonfatal asthma. The cellular mechanism of increased ASM mass in asthma represents a balance between smooth muscle hypertrophy and pro-liferation.297 Benayoun and associates259 found that patients with mild asthma had larger smooth muscle cell diameter in their airways than control subjects. The increase in ASM mass correlated with asthma severity, suggesting a causal role for smooth muscle hypertrophy in the development of AHR. Conversely, Woodruff and colleagues264 found that hyperplasia of smooth muscle occurs in mild to moderate asthma without changes in cell size or gene expression.

Excessive shortening of ASM also can result in exces-sive narrowing of the airways, and several different mechanisms have been proposed. One proposal sug-gests that exposure to chronic inflammatory mediators in the local asthmatic environment results in chronic shortening of ASM, so that further shortening occurs during activation.298 A second proposal suggests that the ECM surrounding ASM alters the ASM phenotype by increasing ASM mass and decreasing its secretory proper-ties.299 A third scenario suggests that abnormal relaxation of ASM occurs in asthma, which can contribute to increased bronchospasm,300 whereas a fourth scenario suggests that there is a change in the interdependence between the airway wall and the surrounding lung.300,300a

Effects of Treatment on RemodelingBecause of the importance of airway remodeling in the pathogenesis of asthma, efforts have been devoted to reversing airway remodeling. One hypothesis is that treatment of the inflammatory component of asthma may lessen airway remodeling. In a murine model of asthma, administration of corticosteroids in combination with allergen avoidance reduced airway fibrosis and smooth muscle mass.301 In another study comparing a leukotriene antagonist and a corticosteroid in an allergy-driven mouse model of asthma, the leukotriene inhibitor decreased ASM mass and subepithelial collagen deposition, whereas corticosteroids had no effect on remodeling.302

An alternative approach is to mechanically reduce smooth muscle mass in order to improve physiologic function. The application of controlled thermal energy via a radiofrequency catheter in order to reduce smooth muscle mass has been shown to reduce methacholine responsiveness in dogs.303 Early clinical trials in human subjects have shown beneficial effects on asthma symp-toms via reduction in smooth muscle mass, with results that were sustained for 1 year.304

With an increased understanding of the molecular mechanisms of asthma pathophysiology and airway remodeling, more focused therapeutic strategies can be explored.304a In vitro studies of compounds targeting putative mediators involved in remodeling suggest a promising role for novel agents in the treatment of asthma.253,305,306 Recent studies highlighting novel genes associated with airway remodeling and asthmatic symp-

38 ASTHMA 899

compared with an individual patient’s baseline measure-ment obtained when asymptomatic and well-control-led.327,328 Evaluation of peak flow measurements obtained during a trial of long- versus short-acting β-agonists suggests that individual peak flow is highly variable and that the variability in PEF has a greater predictive value for asthma exacerbations than the absolute PEF measurement.329,330

Spirometry

The best and most standardized test of airflow obstruc-tion is the FEV1. The FEV1 has the advantage of being an objective, non–patient-reported measurement of lung function. Improvement in FEV1 of more than 12% and 200 mL after bronchodilator treatment indicates revers-ible airflow obstruction and is suggestive, but not diag-nostic, of asthma.331 Prebronchodilator FEV1 is a strong predictor of decline in asthma control whereas postbron-chodilator FEV1 is a marker of future risk.332,333 However, accurate measurement requires stopping LABAs for at least 12 hours and short-acting bronchodilators for at least 6 hours. Furthermore, because the FEV1 may be normal or near-normal between asthma flares, it is a poor marker of response to bronchodilators in mild asthma. The absolute value of the FEV1 is dependent on FVC and also reflects the small airways. Interpretation of FEV1 therefore requires simultaneous FVC measurement. In asthma, the relative reduction in FEV1 is typically greater than the reduction in the FVC. As a result, the FEV1/FVC ratio in asthma is usually less than 70%. A characteristic flow-volume loop is created with scoop-ing of the expiratory loop consistent with airflow limita-tion (Fig. 38-4). However, in severe asthma, this ratio may actually increase as profound air trapping increases residual volume and reduces the FVC. This reversible restriction due to air trapping has been reported in asthma.311,334

The performance of the forced expiratory maneuver requires inhalation to total lung capacity prior to exhala-tion. In normal patients, the resultant stretch of intrapul-monary airways causes reflex bronchodilation and a shift

The airway obstruction and closure in asthma is non-uniform, with significant regional variability that may not be completely reflected by decreases in peak flow.317,318 Although pulmonary blood flow is reduced in areas of alveolar hypoventilation, the magnitude of this response in insufficient to offset more than moderate or severe airflow obstruction. Ventilation-perfusion mismatching leads to a widened alveolar-arterial oxygen difference that tracks with increasing asthma severity; the arterial oxygen tension in acute severe asthma typically falls below 70 mm Hg.319,320 Arterial carbon dioxide tension initially falls as alveolar ventilation increases, because CO2 elimination is less impaired than O2 uptake by ven-tilation-perfusion mismatching.321 As respiratory muscles fatigue, carbon dioxide tension increases, so that a normal or elevated PCO2 during an asthma exacerbation suggests impending respiratory failure.322 Worsening of airflow obstruction or any factor that decreases respira-tory drive (such as sedation) can drop alveolar ventila-tion precipitously; the resultant rise in PCO2 further inhibits respiratory drive and muscle performance and hastens respiratory failure.323

Pulmonary Function TestingEven between asthma exacerbations, pulmonary func-tion testing shows characteristic changes reflecting the reduced flow and air trapping of dynamic hyperinflation. Decreased expiratory flow can be easily and reproduci-bly detected with a peak flowmeter in ambulatory patients, and peak expiratory flow (PEF) measurement is an accepted method to correlate physiologic function with the clinical severity of asthma. However, peak flow measurements are not standardized and cannot be cor-related with other measures of lung function.324 PEF as a percentage of the predicted value is 10% higher than FEV1 on average, with a great deal of variability between measurements.325 PEF measurements tend to underesti-mate less severe obstruction and overestimate more severe obstruction.326 Currently, the recommended use of PEF measurement is for the daily monitoring of ambu-latory patients. In this situation, the values should be

Lung volume (L)

Flo

w r

ate

(L/s

ec)

A B C

FIGURE 38-4 n Flow-volume loops in asthma. A, The typical scooped appearance of the flow-volume loop in asthma is shown as the solid blue line. The predicted normal flow-volume loop is shown by the dashed line. B, The scooped appearance of the initial flow-volume loop (blue line) may show complete reversal following use of a bronchodilator (brown line). C, In some cases, the reversal of the scooped appearance following use of a bronchodilator is incomplete (brown line). (A-C, Adapted from Sameer KM: Asthma: Diagnosis and management. Med Clin North Am 90:39–60, 2006.)


pected finding of an increase in diffusing capacity should raise the possibility of undiagnosed asthma, whereas decreased diffusing capacity in a suspected asthmatic is suggestive of an alternate diagnosis or coexisting condition.347

Provocative Challenges and Airway HyperresponsivenessAHR to environmental stimuli is a hallmark of asthma. Patients suspected of having asthma despite normal lung function testing usually develop bronchoconstric-tion in response to a provocative stimulus. Direct stim-ulation, during which a substance known to induce bronchoconstriction via direct action on smooth muscle is inhaled into the airways, is the most widely used method of assessing bronchial hyperresponsiveness. Nebulized methacholine, delivered in doubling con-centrations until FEV1 falls by more than 20%, is the most commonly used agent. The concentration that causes a 20% fall is labeled the PC20 (provocative concentra-tion resulting in 20% fall in the FEV1) and can be used to measure the degree of AHR. A PC20 less than 16 mg/mL is consistent with mild AHR, less than 4 mg/mL is consistent with moderate AHR, and less than 1 mg/mL with severe AHR,348 with lower PC20 levels generally corresponding to more severe asthma.349 Bronchial hyperresponsiveness also has been associated with increased risk of developing persistent asthma and airway remodeling.350

Indirect stimuli, such as cold air exposure, exercise, inhalation of hypertonic saline, mannitol, and adenosine monophosphate, may also induce bronchoconstriction. Rather than working directly on smooth muscle, indirect stimuli cause the release of inflammatory mediators from airway cells that then interact with ASM to induce bron-choconstriction. Although the dose response is more difficult to assess with indirect stimuli, the results have direct applicability to daily asthma symptoms. For example, direct challenge of athletes suspected of having exercise-induced bronchospasm is less likely to uncover bronchospasm than indirect challenge using a surrogate for physical activity.351 There also may be differences between direct and indirect stimuli in the evaluation of response to treatment, with indirect challenge providing a better idea about response to therapy.352

MANAGEMENT OF ASTHMA

IntroductionThe inherent complexities in evaluating and treating asthma are evident from studies in the 1970s and 1980s documenting a significant number of asthma deaths that were attributable to failure of clinicians to recognize the clinical severity of asthma, leading to inadequate management. For example, a study of asthma deaths in the West Midland and Mersey regions of England in 1979 led to the conclusion that failure to recognize the

in the pressure-volume curve. This alteration in lung mechanics is generally attributed to a transient decrease in ASM tone.335 However, some asthmatics have the opposite response, developing bronchoconstriction during deep inspiration. The mechanism of this “spirom-etry-induced bronchoconstriction” is unknown, but some evidence suggests that it may be partly due to increased inflammation and remodeling of asthmatic airways.336

An alternative method for assessing airflow obstruc-tion is to evaluate midexpiratory flow, measured between 25% and 75% of the FVC (FEF25%–75%). Obtained at lower lung volumes, reductions in the FEF25%–75% may be more sensitive for identifying obstruction in small airways.337 Studies in patients at high risk for asthma based on atopic symptoms have shown that this index is valuable in pre-dicting AHR.338 Similarly, in childhood asthmatics who have become asymptomatic, the FEF25%–75% is a sensitive marker of residual physiologic abnormalities.339 The clin-ical utility of the FEF25%–75% is limited by the lack of acceptable standardized values. High numbers of false-positive and false-negative results occur when 80% of predicted FEF25%–75% is used for classification.340

The limitations of the FEF25%–75% are in part due to large variation in the duration of FVC maneuvers. To address this issue, measurement of the forced expiratory volume over the first 6 seconds (FEV6) has been proposed as an alternative to the FVC. The advantages of this maneuver over the FVC include ease of measurement, a more explicit end-of-test definition, and reduced risk of syncope.341 Data are available suggesting parameters that may be used for disease classification, although the sen-sitivity and specificity of the FEV1/FEV6 in comparison to the FEV1/FVC ratio remain controversial.342,343

Lung Volumes and Diffusing Capacity

As a result of dynamic hyperinflation and consequent air trapping, residual volume, functional residual capacity, and total lung capacity may be elevated in asthma. Exhaled gas dilution measures only the communicating volume of gas and may underestimate these volumes due to regional heterogeneity in the distribution of ventilation.344 For this reason, body plethysmography is often considered the method of choice for lung volume evaluation in severe asthma. However, because plethysmography measures the total volume of compressible gas within the thorax and abdomen, the inclusion of intra-abdominal gas may lead to overestimation of total lung capacity, particularly in severely obstructed asthmatics.345

Single-breath diffusing capacity is a marker of carbon monoxide gas transfer in the lungs and is reduced in most chronic lung diseases because of altered alveolar capillary surface area and/or maldistribution of inspired gas due to airflow obstruction. In asthma, the diffusing capacity is normal or elevated if airflow obstruction is not severe, and this can be useful in distinguishing asthma from other obstructive lung diseases.346 Elevated diffusing capacity in asthma has been attributed to improved perfusion of well-ventilated upper lung zones and is associated with large lung volumes. The unex-

38 ASTHMA 901

AssessmentAsthma Control

The assessment of patients with asthma involves five essential features: the current degree of control, based on symptoms, reliever medication use, recent exacerba-tions, and clinical lung function; and the risk of future adverse outcomes. With this in mind, the NHLBI recently updated guidelines, and the Global Initiative for Asthma (GINA) proposed a parallel scheme for asthma control based on expert opinion328 (Table 38-1). The NHLBI and GINA categorizations represent categorical interval vari-ables with threshold values. For example, the GINA guidelines accept some daytime symptoms (≤2 times/wk) in the definition of “controlled” asthma, whereas nocturnal symptoms move a patient to the “partially controlled” category. The importance of control indices is underscored by the relationship between poor asthma control and substantial degrees of physical impairment and diminished quality of life, even after taking the base-line severity of asthma into account.356

Several different validated instruments exist for assess-ing asthma, including the Asthma Control Questionnaire, Asthma Control Test, Asthma Therapy Assessment Ques-tionnaire, and Asthma Control Scoring System.357–360 All are useful because they direct history taking, provide

severity of asthma delayed treatment, that routine asthma management was unsatisfactory, and that 86% of the deaths might have been preventable.353 A similar study in 1988 included the observation that a large number of asthmatics admitted to the hospital for observation were discharged with no escalation in the management of their asthma.354 This ultimately led the NHLBI to convene the first expert panel to develop guidelines for the diagnosis and treatment of asthma, and the resulting recommendations were published in 1991.355 Other guidelines soon followed, extending the NHLBI’s initial recommendations. Subsequent revisions have provided clinicians with a reliable framework for evi-dence-based management of patients with asthma. These guidelines emphasize maintaining long-term control of symptoms through attention to environmental and social components of asthma and using treatment regi-mens tailored to the severity of each patient’s symptoms. Crucial components of management include initial eval-uation of severity and ongoing assessment of control; appropriate pharmacologic therapy to reverse bron-choconstriction and ameliorate inflammation; identifica-tion and control of environmental factors that worsen symptoms or trigger exacerbations; and creation of a partnership between the patient and the health care professional to ensure that therapy is tailored to symptoms.

TABLE 38-1. Classification of Asthma Control in Adults and Children Older than 12 Years of Age

Components of Control

CLASSIFICATION OF ASTHMA CONTROL (YOUTHS ≥ 12 YR OF AGE AND ADULTS)

Well-Controlled Not-Well-Controlled Very Poorly Controlled

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

Nighttime awakening ≤2 times/mo 1-3 times/wk ≥4 times/wk

Interference with normal activity None Some limitation Extremely limited

Short-acting β-agonist use for symptom control (not prevention of EIB)

≤2 days/wk >2 days/wk Several times/day

FEV1 or peak flow >80% predicted/personal best

60%–80% predicted/personal best

<60% predicted/personal best

Validated questionnaires

ATAQ 0 1–2 3–4

ACQ ≤0.75* ≥1.5 N/A

ACT ≥20 16–19 ≤15

RISK Exacerbations 0-1/yr ≥2/yr†

Consider severity and interval since last exacerbation

Progressive 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

*ACQ values of 0.76–1.4 are indeterminate regarding well-controlled asthma.†(1) The level of control is based on the most severe impairment or risk category. Assess impairment domain by patient’s recall of previous 2–4 wk and by spirom-

etry or peak flow measures. Symptom assessement for longer periods should reflect a global assessment, such as inquiring whether the patient’s asthma is better or worse since the last visit. (2) At present, there are inadequate data to correspond frequencies of exacerbations with different levels of asthma control. In general, more frequent and intense exacerbations (e.g., requiring urgent, unscheduled care, hospitalization, or intensive care unit admission) indicate poorer disease control. For treatment purposes, patients who had two or more exacerbations requiring oral systemic corticosteroids in the past year may be considered the same as patients who have not-well-controlled asthma, even in the absence of impairment levels consistent with not-well-controlled asthma.

ACQ, Asthma Control Questionnaire; ACT, Asthma Control Test; ATAQ, Asthma Therapy Assessment Questionnaire; EIB, exercise-induced bronchospasm; FEV1, forced expiratory volume in 1 second; N/A, not applicable.

Adapted from National Heart, Lung, and Blood Institute as a part of the National Institutes of Health and the U.S. Department of Health and Human Services, 2007.


in normal, nonasthmatic patients.367,368 FeNO falls in a dose-dependent manner with steroid use, making FeNO less useful as an ongoing biomarker in patients using steroid therapy.369,370 A recent trial showed that an FeNO of more than 45 parts/billion excludes well-controlled asthma with a negative predictive value of nearly 90%. High FeNO suggests a severe, steroid-responsive pheno-type. A decline in FeNO of more than 40% between visits is a sign of improved control, and low levels of FeNO predicted lower risk of acute exacerbation.371 Measuring the FeNO during a period of good control can provide a baseline for comparing trends over time when following symptoms and response to treatment. Although the FeNO is a promising biomarker in asthma, the cost/benefit ratio of using FeNO to assess asthma control requires more study.

TreatmentOverview

Pharmacologic therapy for asthma is subdivided into acute, short-term “reliever” medications and chronic “controller” medications. Reliever medications target bronchoconstriction by relaxing ASM. The β-agonists such as inhaled albuterol are the most effective reliever medications. Other reliever medications include methyl-xanthines (e.g., theophylline) and short-acting anti-cholinergics such as inhaled ipatropium bromide. The most widely used controller medications are inhaled cor-ticosteroids, which have a localized anti-inflammatory effect. There is overlap in the use and mechanism of action of reliever and controller medications. LABAs, used in conjunction with an inhaled corticosteroid, provide additional control of symptoms. Theophylline, although primarily a bronchodilator, also has a sustained anti-inflammatory effect at low doses, whereas inhaled corticosteroids such as budesonide have been used in the acute treatment of asthma exacerbations.372,373 The introduction of omalizumab, a specific anti-IgE antibody, provided the first opportunity to treat and control asthma based on specific pathophysiologic characteristics. Tai-loring biologic therapy based on pathophysiologic mech-anisms in individual patients is an area of active clinical investigation, and additional agents addressing the aller-gic and nonallergic phenotypes of asthma are under investigation.

Specific Pharmacologic Agents

Current guidelines recommend adjusting therapy in a stepwise fashion to reduce daily symptoms and risk of exacerbations, while minimizing the use of medica-tions.374,375 The hierarchy of treatment recommendations is based on the available literature about efficacy and safety and provides a prominent role for controller med-ications at all levels of asthma treatment. In general, the strategy and recommendations in adults and children are similar. However, the increased risk of adverse effects and/or the lack of safety data in pediatric patients for theophylline, omalizumab, and the 5-lipoxygenase inhib-

goals for the management of symptoms, and guide adjust-ments in treatment.

Lung Function

Lung function testing is an important part of assessing asthma, both for making the initial diagnosis and as a means of evaluating the response to therapy. A recent study from the Genetics in Asthma Network361 suggested that FEV1 and FVC are useful components of a standard-ized scheme for identifying the contribution of genes and environments to disease expression. Further proof of the importance of lung function testing was provided by a recent finding that asthmatic patients with lower FEV1 values were at significantly higher risk of needing acute care.362 Although the FEV1, the FEV1/FVC ratio, and PEF are useful in the diagnosis and monitoring of asthma, the utility of these measurements in improving the outcome of asthma remains incompletely defined. FEV1 is an objective measurement of lung function. The pre-bronchodilator FEV1 is related to asthma control, whereas postbronchodilator FEV1 is related to future risk of exac-erbations. Accurate measurement requires stopping LABAs for 12 hours and short-acting bronchodilators for 6 hours. Because FEV1 is often normal or near-normal in mild asthma, FEV1 may be poorly responsive to bron-chodilators in mild asthma.

PEF measurement is a standard method to correlate physiologic function with asthma severity, and has been used as a marker of asthma control in many clinical trials. However, individual peak flow measurements are highly variable and the variability in peak flow has a greater predictive value for future exacerbations than individual PEF measurements themselves.329,330 The clinical useful-ness of peak flow measurements is also limited by patient resistance to home monitoring and difficulty with con-sistently maintaining peak flow records.

Biomarkers

The presence of sputum eosinophilia provides useful information about the asthma phenotype. Low sputum eosinophil counts predict response to inhaled corticos-teroids and decreased risk of exacerbations, whereas elevated sputum eosinophil counts (>10%) put the subject at high risk for future exacerbations.363,364 A change of 50% in sputum eosinophil counts is consid-ered to be clinically significant, whereas a decline in absolute eosinophil count predicts deterioration when inhaled corticosteroids are withdrawn.365,366 However, induced sputum eosinophils may be difficult to obtain in clinical practice. Furthermore, the lag between speci-men collection and processing may lead to delays in adjusting treatment.

Fractional excretion of nitric oxide (FeNO) has some advantages over counting the number of sputum eosi-nophils. Measurement of FeNO can be performed rapidly in a primary care setting, requires less technical exper-tise, and provides real-time objective physiologic data. However, the FeNO in stable, mild asthma after use of inhaled corticosteroids is often in the same range as that

38 ASTHMA 903

action than salmeterol, whereas salmeterol has a longer duration of action. Each has been shown to improve lung function, reduce symptoms, and reduce the frequency of exacerbations.382

Adverse events associated with the use of β2-agonists are primarily due to unwanted activation of β2-receptors on nonpulmonary tissue. Cardiac stimulation causes tachycardia and arrhythmias, whereas skeletal muscle stimulation causes tremors and hypokalemia. Since the introduction of β-agonists, there has been concern about the clinical implications of receptor desensitization. The short-acting β-agonist fenoterol was implicated in two epidemiologic studies of increased asthma deaths in the 1960s and 1970s383,384; later analysis suggested that this might have been due to excessive use, rebound bron-choconstriction due to short duration of action, or tach-yphylaxis. After fenoterol was withdrawn, mortality declined,385 and the safety profile of subsequent short-acting β2-agonists has been good. Clinical data suggest that “as-needed” versus scheduled short-acting β2-agonist treatment is associated with improved physiology386 and fewer, less severe exacerbations.387

Adverse events with long-acting β2-agonists also are of concern, particularly because of their long duration of action. In the Salmeterol Multicenter Asthma Research Trial (SMART),388 patients were randomized to salme-terol or placebo plus usual care, with approximately 13,000 patients in each arm. There was no significant difference in risk of death in either group, but subgroup analysis identified a small but increased risk of death that was more prominent in African American subjects in the salmeterol arm of the trial. However, the African Ameri-can patients also had poorer control of symptoms at baseline (with more exacerbations and hospitalizations) and a lower rate of inhaled corticosteroid use than the white patients.388 Importantly, the use of LABAs with inhaled corticosteroids in the same metered-dose inhaler has been shown to be safe and effective.389

Several studies have explored the relationship between polymorphisms in the β2-receptor and responses to β-agonist therapy. Specifically, the presence of the Arg/Arg mutation at the B16 locus has been associated with lower PEF, FEV1, symptoms, rescue inhaler use, and increased rate of exacerbations in patients treated with scheduled albuterol as compared with patients who lack the Arg/Arg mutation. All of these symptoms improve when regular albuterol is withdrawn.146,390,391 Use of LABAs (with and without inhaled corticosteroids) has been shown to worsen physiologic markers of respira-tory function in Arg/Arg patients in some studies, although these findings are not consistent.149,392 Two large randomized trials are currently underway that should shed light on this issue.

Other Bronchodilators. Anticholinergic agents act as bronchodilators via competition with acetylcholine at neuromuscular junctions, thereby blocking transmission of bronchoconstrictor reflexes.393 The short-acting anticholinergic ipratropium bromide is effective in patients with chronic obstructive pulmonary disease (COPD) but is considered a second-line agent for treating asthma, most likely because cholinergic tone contributes

itor zileuton, lead to their exclusion from current pedi-atric treatment guidelines.374

β2-Agonists. β2-Agonists have been used for thou-sands of years in the form of the ephedrine-containing herbal preparation ma huang.376 However, it was not until the 1940s, when the nonselective β-agonist isopro-terenol was introduced, that β-agonists became the standard of care for treating airway disease. The subse-quent development of the β2-selective agents albuterol and terbutaline, with improved side effect profiles, led to their current role as the cornerstone of asthma therapy.377

β2-Agonist activity is primarily mediated by binding to a specific G-coupled transmembrane receptor found in high abundance on ASM. Receptor binding leads to increased intracellular cyclic adenosine monophosphate (AMP) and relaxation of ASM.378 Notably, β2-receptors are also found on other resident airway cells, including airway epithelial cells and circulating immune cells, and binding to these sites may reduce vascular permeability and inflammatory mediator release.379 One concern raised about the chronic use of β2-agonists is that of receptor desensitization.380 As with most signaling recep-tors, repeated exposure to β2-agonists can lead to decreased responsiveness of membrane receptors through receptor down-regulation via receptor endocy-tosis and uncoupling of receptor from downstream trans-duction pathways. This response appears to be self-limited in ASM.

β2-Selective agonists are usually administered by aerosol, which maximizes delivery to target tissue (ASM), while minimizing the exposure of nontarget tissues. Both short-acting and long-acting agents are available, and the onset and duration of action are primarily related to lipophilicity.16 Short-acting agents are used for rescue or emergent treatment, whereas LABAs are used in combination with inhaled corticosteroids for chronic management.

A number of highly selective short-acting β2-agonists are now available, and all have a rapid onset of action with peak action between 60 and 90 minutes. Because they are inhaled directly into the airways, systemic side effects are minimal, even at high doses. A β2-agonist preparation containing only the active isomer of albuterol was developed in an attempt to minimize side effects. However, clinical trials have not shown significant dif-ferences in outcome or tolerability.381 Based on current guidelines, these medications should be used to treat symptoms not adequately controlled on a regimen of long-acting agents. Increased frequency of short-acting β2-agonist use is a sign of inadequate control of symp-toms or overreliance on rescue medication. Patients using more than one canister a month or requiring exces-sive doses of rescue inhalers (defined as >2 doses/wk) should be considered for a step-up in therapy.374,375

LABAs have minimal utility for treating acute asth-matic symptoms because of their delayed onset of action. However, in patients with inadequately controlled asthma, they can be added to an inhaled corticosteroid to improve symptoms. Formoterol and salmeterol are the two LABAs available. Formoterol has a shorter onset of


ICS; although a small observational study suggested increased risk,408 a meta-analysis of several randomized controlled trials did not corroborate this finding.409 The risks of cataract formation410 and glaucoma411 are slightly increased, whereas hypothalamic-pituitary axis suppres-sion, gastrointestinal bleeding, and other complications of systemic steroids are not associated with inhaled prep-arations. The Towards a Revolution in COPD Health (TORCH) trial of the use of inhaled corticosteroids for COPD showed an increased risk of pneumonia, but this has not been demonstrated in patients with asthma.412 The use of inhaled corticosteroids in the pediatric popu-lation has raised concerns about growth suppression. However, available data show only a small and transient decrease in growth trajectory that does not translate into a reduction in adult height.404,413,414

Leukotriene Modifiers. Leukotrienes (LTs) are derived from cell membrane arachadonic acid metabo-lism. LT receptors on ASM and macrophages mediate bronchoconstriction, mucus hypersecretion, and mucosal edema.415 As a result, the LT pathway is a primary target for the development of novel asthma con-troller medications. Commercially available leukotriene modifiers (LTMs) work in one of two places in the LT pathway. Zileuton blocks 5-lipoxygenase, the enzyme that converts arachadonic acid to LTA4, which is the first step in LT synthesis. Montelukast, zafirlukast, and pran-lukast all inhibit LT receptors, blocking the final step in the LT pathway. All are taken orally as either once-daily or twice-daily doses.

LTMs have a modest bronchodilator effect and may improve asthma symptoms and exacerbation rates.416 Physiologic benefits have also been seen, with improve-ments in spirometry and measures of airway inflamma-tion.417 Whereas the subpopulation of patients with aspirin-sensitive asthma may derive great benefit from LTMs,418 data also suggest that LTMs are adequate as single agents in mild persistent asthma.419,420 Although LTMs treat multiple asthma symptoms, they are less effi-cacious than low-dose ICS. As a result, patients who require ICS for asthma control cannot be safely switched to LTM monotherapy. Therefore, the primary role of LTMs is as an adjunct to ICS, and the addition of LTMs typically leads to a reduction in the corticosteroid dose or an improvement in asthma control.421,422 Recent data suggest that the substitution of LTMs for ICS in smokers with asthma leads to similar symptomatic benefits, pos-sibly due to impaired therapeutic responses to ICS in this population. However, it is not clear whether this benefit would persist with the addition of LTMs to ICS in patients who smoke cigarettes.423 Overall, LTMs are less effective than LABAs as adjunctive therapy and do not seem to confer added benefits when added to a regimen that includes an ICS and an LABA.424,425

Overall, LTMs are well tolerated. Initial reports sug-gested a link between LTMs and Churg-Strauss syndrome, but this is now thought more likely to be due to an unmasking of the syndrome by a reduction in corticos-teroid dose with the introduction of an LTM.426 Zileuton is metabolized by the cytochrome P-450 system and has been associated with reports of hepatotoxicity. As a

less to bronchoconstriction in asthma. Although no trials have compared short-acting anticholinergics with short-acting β-agonists, randomized trials studying the addition of anticholinergics to β-agonists do not show any addi-tional benefit in patients with chronic asthma. However, specific asthma phenotypes might be more likely to respond to anticholinergic treatment, including patients with fixed airflow obstruction, advanced age,394 or longer duration of disease.395 Furthermore, anticholinergics may be an acceptable alternative for certain subgroups of patients who do not tolerate β-agonist treatment or for patients with the Arg/Arg-16 genotype, although this has not been studied directly.

Tiotropium, a long-acting anticholinergic agent, has been shown to be beneficial for treating the symptoms of COPD. The value of tiotropium in patients with asthma is not clear, but a randomized trial is in progress. Spiro-metric improvement has been demonstrated in case series of asthmatics who do not have sputum eosi-nophilia396 and asthmatics with concomitant COPD.397 Animal data suggest that tiotropium may have an antire-modeling effect comparable with that of budesonide.398

Inhaled Corticosteroids. With recognition of the central role of inflammation in the pathophysiology of asthma, contemporary treatment strategies now emphasize corticosteroids for long-term control of symp-toms. Corticosteroids suppress inflammatory responses through a broad influence on signal transduction and gene expression pathways. Corticosteroids bind to a specific cytoplasmic receptor that translocates to the nucleus, where it modulates expression of inflamma-tory genes through inhibition of histone acetyltrans-ferases and recruitment of histone deacetylases.399,400 Airway inflammatory cell influx and markers of airway inflammation in asthma are reduced by corticosteroid administration.401,402

Systemic corticosteroids have been used in the treat-ment of asthma since the 1940s and continue to be a cornerstone of the management of acute exacerbations. However, systemically administered corticosteroids are associated with a variety of undesirable side effects. The introduction of inhaled corticosteroids (ICS) in the 1970s ushered in a new era in the treatment of asthma. As with bronchodilators, delivery of drug directly into the lungs through the use of inhaled preparations minimizes sys-temic toxicity and improves therapeutic benefit.

The use of ICS improves all aspects of asthma control. ICS reduce asthmatic symptoms, improve lung function, decrease airway inflammation, and control AHR.403,404 A large meta-analysis showed that inhaled corticosteroids reduce asthma exacerbations by 55% as compared with placebo405 and reduce the risk of hospitalization by 50% as compared with use of as-needed β-agonists alone.406 Furthermore, risk of death from asthma is reduced in a dose-response manner with the use of ICS.407 As a result, ICS are considered to be first-line therapy for all patients requiring more than twice-weekly β-agonist use.375

The risk of systemic toxicity is diminished but not absent with the use of ICS, particularly at doses less than 400 µg budesonide daily or the equivalent. Data are conflicting about the risk of bone demineralization from

38 ASTHMA 905

Additional Management StrategiesControl of Triggers

Environmental factors have been shown to contribute to the pathogenesis of asthma, including occupational exposures, tobacco smoke, pollutants, respiratory infec-tions, allergen exposures, and comorbid conditions. Cigarette smoking decreases asthma control and reduces the efficacy of corticosteroids. All patients with asthma who smoke cigarettes should be strongly encouraged to quit.434 Certain comorbid conditions, including GERD and rhinosinusitis, may worsen asthma symptoms and severity. Because treatment of GERD and sinusitis often improves the control of asthma, all difficult-to-treat patients with asthma should be evaluated for these underlying conditions.435,436

Reduction of allergen exposure and provision of aller-gen immunotherapy are common strategies for treating asthma. Allergic asthmatics improve when removed from their domestic environment, but environmental control is often difficult to achieve.437 The most common allergens include dust mites and cat dander. Whereas avoiding environmental allergens is ideal, most patients do not like the idea of avoiding or giving away their pets. Although overall data are mixed, several studies have shown clinical benefits from dust mite control measures (i.e., impermeable mattress covers, frequent vacuuming, cockroach control).438,439 For patients with an allergic asthma phenotype, allergen-specific immunotherapy may reduce asthma symptoms and improve bronchial hyperreactivity.440,441 However, administration must take place under careful conditions owing to the risk of ana-phylaxis, and the optimal duration of treatment is not completely clear.

Medication Adjustment Based on Asthma Control

The definition of asthma severity is based on the severity of symptoms at the time of diagnosis. More recent defini-tions take into account the degree of treatment neces-sary to maintain control and the frequency of exacerbations. Asthma control, defined as the degree of symptoms present while on appropriate therapy, is more fluid. Depending on the extent of control, a more or less aggressive approach to symptom management may be needed. Recent studies support the importance of focus-ing on asthma control as a means of reducing exacerba-tions and morbidity.441a Published guidelines provide an up-to-date framework for medication choices when “stepping up” therapy to improve asthma control and “stepping down” therapy when control has been achieved (Fig. 38-5). For patients with mild, intermittent asthma, with symptoms that return to baseline between episodes, as-needed use of a short-acting bronchodilator is usually sufficient to maintain control of symptoms. For patients with chronic asthma (symptoms that occur >2 times/wk, nocturnal symptoms, or symptoms that affect activity), the addition of a controller medication is needed, and an ICS is the initial agent of choice.404,442,443

result, liver function should be monitored during its use. The availability of a sustained-release preparation of zileuton has made it a better option as adjunctive therapy. At present, zileuton is reserved for patients with refrac-tory asthma or who have an asthmatic phenotype sug-gesting benefit from the use of an LTM.427

Phosphodiesterase 4 Inhibitors (Theophylline). Theophylline is a well-established phosphodiesterase inhibitor that has mild anti-inflammatory properties. Because of its narrow therapeutic index, theophylline is not widely used in treating asthma. However, the discov-ery of additional anti-inflammatory properties, likely mediated by histone deacetylation, has led to a resur-gence of interest.428 Although no longer a first-line therapy, theophylline is currently used in low doses as adjunctive treatment for asthma that is difficult to control with steroids alone.429 The addition of theophylline to an existing drug regimen for poorly controlled asthma improves markers of control (rescue inhaler use, lung function) to a greater extent than LTMs.423 Dose-related side effects, such as anorexia, palpitations, dysrhythmias, and seizures, require careful clinical and laboratory monitoring.

Anti-Immunoglobulin E Treatment. The introduc-tion of omalizumab, a monoclonal antibody to IgE, rep-resents a new era of therapy targeted to specific asthma phenotypes. Omalizumab targets the receptor-binding portion of IgE, preventing it from interacting with immune cells to cause degranulation.430 The addition of omalizumab to ICS in poorly controlled allergic asthmat-ics is associated with improved asthma control and fewer exacerbations.431 Omalizumab is generally well tolerated, but rare reports of anaphylaxis have led to recommenda-tions that patients be observed for 2 hours after each of the first three injections to ensure safety.304 High cost, the requirement for monitoring during treatment, and the need to carefully select patients likely to benefit have limited the use of omalizumab. However, cost analysis suggests that anti-IgE therapy in patients with severe allergic asthma results in a cost-per-quality-adjusted life year that compares favorably with other uses of expen-sive health care resources.432

Nonpharmacologic Treatment

Bronchial thermoplasty is a novel intervention for asthma that is based on the observation that increased ASM mass is a characteristic feature of asthma. During thermo-plasty, controlled thermal energy is delivered to the airway wall, resulting in reduction of ASM mass. In patients with moderately severe asthma, thermoplasty been shown to reduce airway responsiveness to an inhaled constrictor and improve lung function.433 Treat-ment leads to improvements in symptoms and quality of life and reduction in the use of rescue medication in patients with moderate or severe asthma.304 However, treatment requires a series of three bronchoscopies, exposing patients to the concomitant procedural risk, and long-term outcome data are lacking. Nevertheless, the specific targeting of ASM in asthma remains an area of investigation.


Prevention Program (NAEPP) guidelines give the options of increasing the dose of ICS or adding an LABA. This is also the preferred approach for pediatric patients. A third option is the addition of LTMs to low-dose ICS.422

If symptoms are still not controlled on one of the regimens just discussed, the next medication added depends on previous medication choices. For patients on increased doses of ICS, the recommended next step is the combination of a moderate- to high-dose ICS with an LABA. However, increasing the ICS dose for a patient already on an ICS/LABA combination is less likely to be effective.450,451 Other options include the addition of an LTM or sustained-release theophylline to an ICS.452 If symptoms remain uncontrolled on a full complement of standard medications, options include the addition of systemic corticosteroids or specific anti-IgE therapy for patients with allergic asthma.431

Once symptoms are controlled for a protracted period of time, therapy can be stepped down. Strategies for de-

As mentioned previously, when used properly, ICS amel-iorate all asthma symptoms, improve airway physiology, and reduce hospitalizations and asthma mortality. Failure to respond to ICS suggests nonadherence to medica-tions, uncontrolled trigger exposures and/or comorbidi-ties, or a steroid-nonresponsive phenotype. Approximately 30% of asthmatics fall into the last category. These patients typically have less airway inflammation and obtain their maximum response to a low-dose of ICS.444,445 LTMs are an alternative for patients who do not tolerate ICS and are the preferred agent for patients with con-comitant allergic rhinitis.416,417

For patients with persistent asthmatic symptoms despite the appropriate use of a controller medication, clinicians have several different options for “stepping-up” therapy. Some guidelines recommend the addition of an LABA to low-dose ICS (often in a combination inhaler) based on a large amount of efficacy data.446–449 However, because of concerns over the potential side effects of LABAs, the National Asthma Education and

Persistent asthma: daily medication

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

Intermittentasthma

Step 1

Preferred:SABA PRN

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.

Step 2

Preferred:Low-dose ICS

Alternative:Cromolyn,

LTRA,Nedocromil,orTheophylline

Step 3

Preferred:Low-dose

ICS + LABAOR

Medium-doseICS

Alternative:Low-dose ICS+ either LTRA,Theophylline,

or Zileuton

Step 4

Preferred:Medium-doseICS + LABA

Alternative:Medium-doseICS + either

LTRA,Theophylline,

or Zileuton

Step 5

Preferred:High-dose

ICS + LABA

AND

ConsiderOmalizumabfor patientswho haveallergies

Step 6

Preferred:High-dose

ICS + LABA + oral

corticosteroid

AND

ConsiderOmalizumabfor patientswho haveallergies

Step up ifneeded

(first, checkadherence,

environmentalcontrol, andcomorbid

conditions)

Step down ifpossible

(and asthmais well

controlled at least

3 months)

Assesscontrol

Key: Alphabetical order is used when more than one treatment option is listed within either preferred or alternative therapy.EIB, exercise-induced bronchospasm; ICS, inhaled corticosteroid; LABA, long-acting inhaled beta2-agonist; LTRA, leukotrienereceptor antagonist; SABA, inhaled short-acting beta2-agonist.

FIGURE 38-5 n Medication recommendations for control of asthma in adults and children older than 12 years of age. (Adapted from the National Heart, Lung, and Blood Institute as a part of the National Institutes of Health and the U.S. Department of Health and Human Services, 2007.)

38 ASTHMA 907

suggests impending respiratory failure. Anion gap meta-bolic acidosis may also be present, which is usually due to elevated lactate levels. Patients who fail to respond to albuterol administration within 30 to 60 minutes, with persistent dyspnea and peak flow less than 70% of base-line, require hospital admission.374

Key pharmacologic components of treatment include repeated or continuous short-acting bronchodilator administration (via nebulizer or metered-dose inhaler with a spacer) and systemic glucocorticoids.457 The com-bination of short-acting β-agonists and ipratropium at the initiation of treatment is associated with physiologic improvements and reduced rate of hospitalization, but the benefits do not persist after hospitalization.458 Systemic corticosteroids are unequivocally associated with more rapid return to baseline function and are considered the first-line therapy for acute asthma. The initial dosing range for adult hospitalized patients is from 1.5 to 2.0 mg/kg of intravenous methylprednisolone or the equivalent.459 ICS are typically not used acutely, although some data suggest that the addition of inhaled budesonide to systemic corticosteroids following an emergency department visit leads to improved symp-toms and a decreased relapse rate.460,461 Intravenous mag-nesium sulfate, usually given as a 2-g bolus, may act as a smooth muscle relaxant and has been shown to reduce hospital admission rates.462 Supplemental oxygen to keep saturations above 90% helps maintain oxygen delivery to peripheral tissues and minimizes hypoxemic vasoconstriction.

Severe exacerbations of asthma are characterized by persistent reductions in peak expiratory flow of less than 40% predicted with poor response to initial treatment. These patients may demonstrate progressive hypercap-nia, fatigue, altered sensorium, and dysrhythmias and are at high risk for respiratory arrest. Low-level noninvasive positive-pressure ventilation without positive end-expira-troy pressure (PEEP) has been shown to reduce the rate of hospitalization and may be considered in alert, coop-erative patients who are not in immediate need of intuba-tion.463 Helium/oxygen mixtures increase flow through the airways and may be a useful adjunct in patients with severe exacerbations that do not respond to initial emer-gency treatment.464,465

Oral intubation and mechanical ventilation are manda-tory for patients in respiratory arrest or impending res-piratory arrest. Mechanical ventilation in patients with severe asthma exacerbations may be complicated by immediate postintubation worsening of gas exchange and hemodynamic instability due to increased airway and intrathoracic pressures from dynamic lung hyperin-flation. Provided that the patient is adequately oxygen-ated, briefly decreasing the mandatory respiratory rate to allow an extended expiratory phase is often success-ful. Initial ventilator settings should be focused on mini-mizing dynamic hyperinflation by using a relatively low minute ventilation (with respiratory rate between 12 and 14/min and tidal volumes in the 6-8 mL/kg range), a high inspiratory flow rate, and minimal to no PEEP.466 Aggres-sive sedation should be given to improve comfort and patient-ventilator synchrony. Short-term paralysis may be

escalation of therapy are determined by a patient’s con-troller regimen. Patients on an ICS alone can be considered for a decrease in dose or dosing interval. Some data suggest that conversion to as-needed com-bined short-acting β2-agonists/ICS may be effective with a lower total steroid dose.453,454 However, an as-needed regimen is not yet part of NHLBI guidelines. Similarly, for patients on a combined ICS/LABA regimen or LTM/ICS regimen, clinicians should focus first on reducing the ICS component.

Management of Acute AsthmaAsthma is a common cause of emergency room visits and hospital admissions. In 2004, asthma accounted for 1.8 million visits to emergency departments, or 64/10,000 people, with 497,000 asthma hospitalizations, or 17/10,000 people.24 The treatment of acute asthma is based on the cornerstones of chronic asthma therapy but typically requires greater attention to patient monitoring and an escalation in the aggressiveness of asthma care.

Asthma exacerbations are characterized by increased shortness of breath, coughing, and/or chest tightness, and airflow limitation (as measured by decreased peak flow or FEV1) is a cardinal feature. Increased symptoms typically precede a detectable decrease in air flow,455 although a subset of patients are at high risk of exacerba-tions due to poor perception of airflow limitations. In the outpatient setting, increased requirement for rescue inhalers, especially in a patient previously on a stable regimen, suggests an asthma flare.

Patients with asthma exacerbations require prompt evaluation and treatment in order to limit morbidity and mortality. Goals include relief of airflow obstruction and amelioration of respiratory symptoms. Patients with milder symptoms (with peak flow decrease <20%) may be evaluated in an outpatient setting but should be referred to an acute care facility if they fail to respond promptly to aggressive treatment with bronchodilators and systemic glucocorticoids.374 Conversely, certain patients are at high risk of asthma-related death and should be evaluated in the emergency department as soon as possible when their symptoms worsen. This includes patients with a history of recent exacerbation or previous near-fatal asthma, overutilization of short-acting β2-agonists or underutilization of ICS, recent oral glucocorticoid use, poor compliance with asthma action plans, or concomitant psychiatric disease.456

In the acute care setting, the severity of an asthma exacerbation should be assessed by physical examina-tion, including oximetry and measurement of peak expir-atory flow. Use of accessory muscles, ability to complete sentences, and arterial oxygen tension all should be eval-uated. Patients require close monitoring during the early stages of treatment, because it may take several hours for symptoms to resolve. Chest radiography is useful if pneumothorax is suspected but does not usually provide clues as to the etiology of an exacerbation. Arterial blood gas measurement typically reflects mild hypoxemia and respiratory alkalosis; the normalization of PaCO2 in the absence of significant symptomatic improvement


allowing patients to titrate their own treatment based on changes in symptoms and peak expiratory flow with some degree of independence. The use of such guided self-management reduces asthma morbidity in different patient populations and patient care settings.467

Crucial components of self-management plans include education, self-monitoring with symptoms and/or peak flow, regular review, and patient directed self-manage-ment using a written action plan. Effective patient educa-tion is central to this approach. Better communication by health care providers translates into measurably better outcomes with no additional physician time commit-ment.468 Even for patients unable to engage in guided self-management, regular follow-up and medication review is beneficial, because approximately 50% of patients on long-term therapy fail to take medications as directed some of the time.469

necessary in patients for whom ventilator synchrony cannot be achieved with sedation alone. Bronchodilator administration should be continued until airway resist-ance decreases.

Conclusion: Clinician-Patient PartnershipFor chronic asthma, treatment should balance the best symptom control with the lowest possible dosage of medication.374 Effective management requires that the patients form a partnership with the health care provid-ers in order to ensure an appropriate flow of information, with the patients assuming a major role in the assessment and treatment of their disease. Through collaborative effort, a guided self-management plan can be developed,

KEY POINTS

• Asthma is an important cause of disability, death, and economic cost.

• Asthma is increasing in developed countries and appears to be increasing to epidemic proportions in non-Western societies that have adopted features of Western culture.

• On a fundamental level, asthma is a disease of misdirected immunity, with the direction of immune function being influenced by many genes and probably also by airway infections, especially with viruses, but established in the first few years of life. The cells most important in orchestrating this “misdirected” immune response in the airways are dendritic cells and CD4 Th2 lymphocytes.

• The cytokines produced by these lymphocytes, particularly IL-13, alter the function of immunological and structural cells in the airways, either directly through activation of specific receptors on the cells or indirectly through their effects on other cells, such as B lymphocytes, mast cells, eosinophils, and polymorphonuclear leukocytes. Repeated release of these cytokines alters the function and structure of the airways.

• The structural changes, often referred to as “remodeling,” are now recognized as potentially irreversible.

• The approach to the diagnosis, assessment, and treatment of asthma has changed in response to the recognition of asthma as a chronic inflammatory disease punctuated by intermittent exacerbations.

• The therapies available are effective in controlling asthma, but their efficacy depends on engaging the patient as a full partner in care.

• Before the most economical and effective approach for preventing asthma can be undertaken, more information is needed about the interplay between individual genotypes and environmental stimuli that are responsible for initiating and perpetuating the disease.

• Until a curative treatment is developed, only the combined use of anti-inflammatory and bronchodilator therapies, coupled with measures to reduce environmental exposures, can reduce the costs of asthma for the individuals affected. Applied widely, these measures can also reduce the consequences and costs for the health care system.

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