Asthma
Although much progress has been made in our understanding of bronchial asthma in recent years, asthma remains a commonly encountered condition that challenges physicians in the office setting as well as in acute care settings.1–3 Although the 1980s were characterized by increases in asthma morbidity and mortality in the United States, these trends reached a plateau in the 1990s, and asthma mortality rates have declined since 1999. In recent decades, a surge in asthma prevalence also occurred in the United States and other Western countries; data suggest this trend may also be reaching a plateau. Tremendous progress has been made in our fundamental understanding of asthma pathogenesis by virtue of invasive research tools such as bronchoscopy, bronchoalveolar lavage, airway biopsy, and measurement of airway gases, although the cause of airway inflammation remains obscure.
DEFINITIONS
Asthma is a chronic, episodic disease of the airways that is best viewed as a syndrome. In 1997, the National Heart, Lung, and Blood Institute (NHLBI) included the following features as integral to the definition of asthma4: recurrent episodes of respiratory symptoms; variable airflow obstruction that is often reversible, either spontaneously or with treatment; presence of airway hyperreactivity; and, importantly, chronic airway inflammation in which many cells and cellular elements play a role, in particular, mast cells, eosinophils, T lymphocytes, macrophages, neutrophils, and epithelial cells. All of these features need not be present in any given asthmatic patient. The Expert Panel Report (EPR) 3 guidelines,5 issued in 2007, state that the immunohistopathologic features of asthma include inflammatory cell infiltration involving neutrophils (especially in sudden-onset, fatal asthma exacerbations; occupational asthma; and patients who smoke), eosinophils, and lymphocytes, with activation of mast cells and epithelial cell injury. Heterogeneity in the pattern of asthma inflammation has been recognized, consistent with the interpretation that phenotypic differences exist that influence treatment response. The inflammation of asthma leads to an associated increase in the existing bronchial hyperresponsiveness to a variety of stimuli.Although the absolute minimum criteria to establish a diagnosis of asthma are not widely agreed on, the presence of airway hyper-reactivity can be regarded as a sine qua non for patients with current symptoms and active asthma.
EPIDEMIOLOGY AND NATURAL HISTORY
Several government agencies have been charged with surveillance for asthma, including the NHLBI’s National Asthma Education and Prevention Program (NAEPP), the Department of Health and Human Services (Healthy People 2010), and the Centers for Disease Control and Prevention (CDC). Data published by the CDC indicate that approximately 20 million Americans have asthma. Estimates of 12-month period prevalence have found that approximately 3.0% of the U.S. population had asthma in 1970; more recent estimates indicated that the 12-month period prevalence had increased to 5.5% in 1996.6 In association with rising prevalence, patient encounters—via outpatient visits, emergency department use, and hospitalizations for asthma—also increased during this period. Asthma surveillance data in recent decades have revealed that a disparate burden of asthma exists in certain demographic subgroups: in children compared with adults, in women compared with men, in blacks compared with whites, and among Hispanics of Puerto Rican heritage compared with those of Mexican descent.6 The trend for increasing asthma mortality that began in 1978 and continued through the 1980s reached a plateau in the 1990s, and since 1999 annual rates in the United States have declined.6 These trends are reassuring, and they have been correlated with increasing rates of dispensed prescriptions for inhaled corticosteroids (ICS), implying that improved treatment of asthma may be responsible for these favorable developments. The overall annual economic burden for asthma care in the United States exceeds $11 billion.7
ETIOLOGY AND PATHOGENESIS
Clinicians have long known that asthma is not a single disease; it exists in many forms. This heterogeneity has been well established by a variety of studies that have demonstrated disease risk from early environmental factors and susceptibility genes, subsequent disease induction and progression from inflammation, and response to therapeutic agents (Fig. 1).
Figure 1 Natural history of asthma.
(Reproduced from Holgate ST: The cellular and mediator basis of asthma in relation to natural history. Lancet 1997;350[suppl 2]:5-9. Reprinted in Szefler SJ: The natural history of asthma and early intervention. J Allergy Clin Immunol 2002;109:S550.)
Asthma is an inflammatory disease and not simply a result of excessive smooth muscle contraction. Increased airway inflammation follows exposure to inducers such as allergens or viruses, exercise, or inhalation of nonspecific irritants. Increased inflammation leads to exacerbations characterized by dyspnea, wheezing, cough, and chest tightness. Abnormal histopathology including edema, epithelial cell desquamation, and inflammatory cell infiltration are found not only in autopsy studies of severe asthma cases but even in patients with very mild asthma. Reconstructive lesions, including goblet cell hyperplasia, subepithelial fibrosis, smooth muscle cell hyperplasia, and myofibroblast hyperplasia can lead to remodeling of the airway wall. Many studies have emphasized the multifactorial nature of asthma, with interactions between neural mechanisms, inflammatory cells (mast cells, macrophages, eosinophils, neutrophils, and lymphocytes), mediators (interleukins, leukotrienes, prostaglandins, and platelet-activating factor), and intrinsic abnormalities of the arachidonic acid pathway and smooth muscle cells. Although these types of descriptive studies have revealed a composite picture of asthma (Fig. 2), they have failed to identify a basic unifying defect.
Figure 2 Schematic showing airway inflammation in patients with asthma.
(Reproduced from Spahn J, Covar R, Stempel DA. Asthma: Addressing consistency in results from basic science, clinical trials, and observational experience. J Allergy Clin Immunol 2002;109:S492.)
Advances have been made in our understanding of asthmatic airway inflammation through the use of invasive technology, such as bronchoscopy with airway sampling at baseline state,8 and with experimental provocation (e.g., allergen challenge) and following administration of interventions, such as anti-inflammatory pharmacotherapy. Further insights have been obtained through transgenic murine models with deletion, or knockout, of specific genes (i.e., those for immunoglobulin E [IgE], CD23, interleukin-4 [IL-4], or IL-5) or overexpression of other putative genes. Also, specific monoclonal antibodies or cytokine antagonists have been used in various asthma models. A number of limitations have hindered our understanding of asthma obtained from these model systems: There are important differences between animal models of asthma and human disease, there are few longitudinal studies of human asthma with serial airway sampling, and it is often difficult to determine cause and effect from multiple mediator studies.
Immunopathogenesis and the Th2 Phenotype
Based on animal studies and limited bronchoscopic studies in adults, the immunologic processes involved in the airway inflammation of asthma are characterized by the proliferation and activation of helper T lymphocytes (CD4+) of the subtype Th2. The Th2 lymphocytes mediate allergic inflammation in atopic asthmatics by a cytokine profile that involves IL-4 (which directs B lymphocytes to synthesize IgE), IL-5 (which is essential for the maturation of eosinophils), and IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF).9 Recent study suggests that mutations in IL-4 receptor alpha (IL4Rα) are associated with a gain in receptor function and more IL-4 functional effect, which is associated with asthma exacerbations, lower lung function, and tissue inflammation, in particular to mast cells and IgE.10 Eosinophils are often present in the airways of asthmatics (more commonly in allergic but also in nonallergic patients), and these cells produce mediators that can exert damaging effects on the airways.
The Hygiene Hypothesis, Airway Hyperresponsiveness, and Disease Progression
Most studies of airway inflammation in human asthma have been conducted in adults because of safety and convenience. However, asthma often occurs in early childhood, and persistence of the asthmatic syndrome into later childhood and adulthood has been the subject of much investigation. The hygiene hypothesis has been proposed to explain the epidemiologic observation that asthma prevalence is much greater in industrialized Western societies than in less technologically advanced societies.11,12 This hypothesis maintains that airway infections and early exposure to animal allergens (e.g., farm animals, cats, dogs) is important in affecting the propensity for persons to become allergic or asthmatic. Specifically, early exposure to the various triggers that can occur with higher frequency in a rural setting might protect against the allergic diathesis that is characteristic of the Th2 paradigm. In a “cleaner” urban Western society, such early childhood exposure is lacking, and this encourages a higher incidence of allergy and asthma. The hygiene hypothesis has become the basis for a number of emerging therapies.
Whether airway hyperresponsiveness is a symptom of airway inflammation or airway remodeling, or whether it is the cause of long-term loss of lung function, remains controversial. Some investigators have hypothesized that aggressive treatment with anti-inflammatory therapies improves the long-term course of asthma beyond their salutary effects on parameters of asthma control and rates of exacerbation over time.13 This contention has been supported by an observational study14 that found long-term exposure to ICS was associated with an attenuation of the accelerated decline in lung function previously reported in asthmatics; more studies are required to substantiate these findings.
Concept of Airway Remodeling
The relation between the several types of airway inflammation (early-phase and late-phase events) and the concept of airway remodeling, or the chronic nonreversible changes that can happen in the airways, remains a source of intense research.4 The natural history of airway remodeling is poorly understood, and although airway remodeling occurs in some patients with asthma, it does not appear to be a universal finding.
Clinically, airway remodeling may be defined as persistent airflow obstruction despite aggressive anti-inflammatory therapies, including ICS and systemic corticosteroids. Pathologically, airway remodeling appears to have a variety of features that include increases of smooth muscle mass, mucous gland hyperplasia, persistence of chronic inflammatory cellular infiltrates, release of fibrogenic growth factors along with collagen deposition, and elastolysis.15 Increased numbers and size of vessels in the airway wall is a long-recognized characteristic and one of the most consistent features of asthma remodeling occurring in mild, moderate and severe asthmatic lungs.16–19 (Fig. 3). Many biopsy studies show these pathologic features in the airways of patients with chronic asthma. However, there are many unanswered questions, including whether features of remodeling are related to an inexorable progression of acute or chronic airway inflammation or whether remodeling is a phenomenon separate from inflammation altogether (Figs. 4 and 5).
Figure 3 Clinical consequences of airway remodeling in asthma.
RBM, respiratory bronchiolar mucosa; ECM, extracellular mucosa.
(Reproduced from Bousquet J, Jeffery PK, Busse WW, et al: Asthma: From bronchoconstriction to airways inflammation and remodeling. Am J Respir Crit Care Med 2000;161:1720-1745.)
Figure 4 Links between pathologic mechanisms and clinical consequences in asthma.
(Reproduced from Bousquet J, Jeffery PK, Busse WW, et al: Asthma: From bronchoconstriction to airways inflammation and remodeling. Am J Respir Crit Care Med. 2000;161:1720-1745.)
Figure 5 Mechanisms of acute and chronic inflammation in asthma and remodeling processes.
(Reproduced from Bousquet J, Jeffery PK, Busse WW, et al: Asthma: From bronchoconstriction to airways inflammation and remodeling. Am J Respir Crit Care Med 2000;161:1720-1745.)
Research has confirmed that the airway epithelium is an active regulator of local events, and the relation between the airway epithelium and the subepithelial mesenchyma is believed to be a key determinant in the concept of airway remodeling. A hypothesis by Holgate and colleagues20 proposes that airway epithelium in asthma functions in an inappropriate repair phenotype in which the epithelial cells produce proinflammatory mediators as well as transforming growth factor (TGF)-β to perpetuate remodeling. On the other hand, one of the most striking features reported in early detailed histopathologic studies of asthmatic lungs was the increased amount and size of submucosal vessels, and this has been repeatedly confirmed in other, more recent, reports.17,19,21–24
Although understanding of new vessel formation and its genesis in asthma is still in its early stages, it has been suggested that vascular remodeling may be a critical component in the pathophysiology of asthma and a determinant of asthma severity. Asosingh and colleagues showed that angiogenesis is a very early event, with onset during the initiation of acute airway inflammation in asthma.21 It is linked to mobilization of bone marrow–derived endothelial progenitor cells, which, together with Th1 and Th2 cells, lead to a proangigogenic lung environment in asthma, which is sustained long after acute inflammation is resolved.21 The enlarged airway vascular bed may contribute to the airflow limitation either through the vascular tissue’s itself increasing airway wall thickness or through edema formation. Angiogenesis itself may play a role in the disease progression through recruitment of inflammatory cells, effects that alter airway physiology, or by secretion of proinflammatory mediators.
Exhaled Gases and Oxidative Stress
Asthma is characterized by specific biomarkers in expired air that reflect an altered airway redox chemistry, including lower levels of pH and increased reactive oxygen and nitrogen species during asthmatic exacerbations.25–29 Reactive oxygen species (ROS) such as superoxide, hydrogen peroxide, and hydroxyl radicals cause inflammatory changes in the asthmatic airway. In support of this concept are the high levels of ROS and oxidatively modified proteins in airways of patients with asthma.26 High levels of ROS are produced in the lungs of asthmatic patients by activated inflammatory cells (i.e., eosinophils, alveolar macrophages, and neutrophils).27 The increased ROS production of neutrophils in asthmatic patients correlates with the severity of reactivity of airways in these patients; severe asthma is associated with neutrophilic airway infiltrates. Other investigators have measured products of arachidonic acid metabolism in exhaled breath condensate.30 Specifically, 8-isoprostane, a PGF2a analogue that is formed by peroxidation of arachidonic acid, is increased in patients with asthma of different severities, and leukotriene E4 (LTE4)-like immunoreactivity is increased in exhaled breath condensate of steroid-naïve patients who have mild asthma, with levels about threefold to fourfold higher than those in healthy subjects. Concomitant with increased oxidants, antioxidant protection of the lower airways is decreased in lungs of asthmatic patients.28,29
Another reactive species, nitric oxide (NO), is increased in the asthmatic airway.26 Nitric oxide is produced by nitric oxide synthase (NOS), all isoforms of which—constitutive (neuronal, or type I, and endothelial, or type III enzymes) and inducible (type II enzymes)—are present in the lung. Abnormalities of NOS I and NOS II genotype and expression are associated with asthma. Recent studies have suggested cytotoxic consequences associated with tyrosine nitration induced by reaction products of NO.31 Based on the high levels of NO in exhaled breath of asthmatics and the decrease of NO that occurs in response to treatment with corticosteroids, measurement of NO has been proposed as a noninvasive way to detect airway inflammation, diagnose asthma, and monitor the response to anti-inflammatory therapy.32–34 The development of NHANES (National Health and Nutrition Examination Survey) normative levels for the fractional excretion of NO (FENO) will facilitate more widespread application of this exhaled gas measure in the clinical care of asthmatics.
The β-Agonist Controversy
Short-Acting β Agonists
Several studies from New Zealand suggested that the use of inhaled β agonists increases the risk of death in severe asthma.6,35–37 Spitzer and coworkers conducted a matched, case-controlled study using a health insurance database from Saskatchewan, Canada, of a cohort of 12,301 patients for whom asthma medications had been prescribed.38 Data were based on matching 129 case patients who had fatal or near-fatal asthma with 655 controls. The use of a β agonist administered by a metered-dose inhaler (MDI) was associated with an increased risk of death from asthma, with an odds ratio of 5.4 per canister of fenoterol, 2.4 per canister of albuterol, and 1.0 for background risk (e.g., no fenoterol or albuterol). The primary limitation of these data, and a number of other case-controlled studies, relates to the comparability of cases and controls in terms of severity of their underlying disease.
Sears and coworkers conducted a placebo-controlled, crossover study in patients with mild stable asthma to evaluate the effects of regular versus on-demand inhaled fenoterol therapy for 24 weeks.39 In the 57 patients who did better with one of the two regimens, only 30% had better asthma control when receiving regularly administered bronchodilators, whereas 70% had better asthma control when they employed the bronchodilators only as needed.
Drazen and coworkers randomly assigned 255 patients with mild asthma to inhaled albuterol either on a regular basis (two puffs four times per day) or on an as-needed basis for 16 weeks.40 There were no significant differences between the two groups in a variety of outcomes, including morning peak expiratory flow, diurnal peak flow variability, forced expiratory volume in 1 second (FEV1), number of puffs of supplemental as-needed albuterol, asthma symptoms, or airway reactivity to methacholine. Because neither benefit nor harm was seen, it was concluded that inhaled albuterol should be prescribed for patients with mild asthma on an as-needed basis.
Long-Acting β Agonists
The Salmeterol Multiple-Center Asthma Research Trial (SMART) was an observational 28-week study comparing salmeterol 42 µg metered-dose inhaler twice a day with placebo, in addition to usual asthma therapies.41 More than 26,000 subjects were enrolled.
Data from SMART, combined with other recent reports,42 have fueled a controversy regarding the role of LABAs in asthma management, such that an honest difference of opinion currently exists regarding the appropriate level of asthma severity at which regular use of LABA combined with ICS is favorable from a risk-to-benefit standpoint. This will require additional studies to fully clarify; however, asthma care providers should also be mindful that use of a LABA in combination with ICS has been associated with a range of favorable outcomes: reduction of symptoms (including nocturnal awakening), improvement in lung function, improvement in quality of life, reduced use of rescue medication, and reduced rate of exacerbations and severe exacerbations compared with ICS at the same or higher dose.43
Previously published meta-analyses have shown that low-dose ICS combined with LABA is associated with superior outcomes compared with higher-dose ICS.44–46 These data led to the recommendation in the EPR-2 update of the NAEPP guidelines to prescribe the combination of ICS and LABA for patients with moderate persistent asthma and severe persistent asthma. The update categorized this management recommendation as based on level A evidence.2 Based on safety concerns, the EPR-3 guidelines5 recommend that medium-dose ICS be regarded as equivalent to adding LABA to low-dose ICS, and state “the established, beneficial effects of LABA for the great majority of patients who have asthma that is not sufficiently controlled with ICS alone should be weighed against the increased risk for severe exacerbations, although uncommon, associated with daily use of LABA.” At this time, the decision to prescribe, or continue to prescribe, LABA should be based on an individualized determination of risk relative to benefit made by each asthmatic patient in partnership with his or her physician.
Pharmacogenetics
In the presence of a polymorphism, the acute bronchodilator response to a β agonist, or protection from a bronchoconstrictor, may be affected. Studies indicate that in patients with Arg16Arg variant, the resulting β2-adrenergic receptor is resistant to endogenous circulating catecholamines (i.e., receptor density and integrity are preserved), with a subsequent ability to produce an acute bronchodilator response to an agonist. In patients with Gly16Gly, the β2-adrenergic receptor is downregulated by endogenous catecholamines; therefore, the acute bronchodilator response is reduced or blunted. In relation to prolonged β-agonist therapy (e.g., >2 weeks) patients who are homozygous for Arg16 were found to exhibit a decline in lung function and an increase in exacerbation rates in association with regular inhaled short-acting β agonists. These same patients, when switched to as-needed albuterol, had no decrease in lung function, as is the case for homozygous Gly16. Polymorphisms at the 27 loci are of unclear significance. Also, the impact of haplotypes (e.g., variant genes linked at >2 loci) is currently unclear. There are conflicting data regarding whether Arg/Arg homozygotes are prone to experience reflex morbidity with inhaled LABA,43 but the weight of evidence, particularly from more-recent studies,47,48 indicates that response to LABA when used in combination with ICS does not vary based on β2-adrenergic genotypes at codon 16.
DIAGNOSTIC EVALUATION, COMORBID DISEASE, AND PEAK EXPIRATORY FLOW MONITORING
The NAEPP has set forth the grading of asthma severity into four categories based on frequency of daytime and nocturnal symptoms, peak flows, and as-needed use of inhaled short-acting β agonists: intermittent, mild persistent, moderate persistent, and severe persistent.5 The mildest category, designated mild intermittent in EPR-2, was changed to intermittent in EPR-3 to emphasize that even patients with this level of asthma severity may have serious or even life-threatening asthma exacerbations.5
Hyperinflation, the most common finding on a chest radiograph, has no diagnostic or therapeutic significance. A chest radiograph should not be obtained unless complications of pneumonia, pneumothorax, or an endobronchial lesion are suspected. The correlation of severity between acute asthma and arterial blood gases is poor. Mild-to-moderate asthma is typically associated with respiratory alkalosis and mild hypoxemia on the basis of ventilation-perfusion mismatching. Severe hypoxemia is quite uncommon in asthma. Normocapnia and hypercapnia imply severe airflow obstruction, with FEV1 usually less than 25% of the predicted value. Hypercapnia in the setting of acute asthma does not necessarily mandate intubation or suggest a poor prognosis.49 Spirometry in an asthmatic patient typically shows obstructive ventilatory impairment with reduced expiratory flows that improve with bronchodilator therapy. Typically, there is an improvement in either FEV1 or forced vital capacity (FVC) with acute administration of an inhaled bronchodilator (12% and 200 mL). However, the absence of a bronchodilator response does not exclude asthma. The shape of the flow volume loop can provide insight into the nature and location of airflow obstruction.
In patients with atypical chest symptoms of unclear etiology (cough or dyspnea alone), a variety of challenge tests can identify airway hyperreactivity as the cause of symptoms. By far, the most commonly used agents are methacholine or histamine, which give comparable results. Exercise, cold air, and isocapnic hyperventilation—other approaches that require complex equipment—have a lower sensitivity. In a patient with clinical features typical for asthma, along with reversible airflow obstruction, there is no need for a provocation procedure to establish a diagnosis. The use of measures of airway hyperreactivity has been proposed as a tool to guide anti-inflammatory therapy, but it is not recommended for routine clinical practice. The methacholine challenge test, which is most commonly used in the United States, is very sensitive; a positive test result is defined as a 20% decline in FEV1 during incremental methacholine aerosolization. However, methacholine responsiveness is nonspecific, and it can occur in a variety of other conditions, including allergic rhinitis, chronic obstructive pulmonary disease, and airway infection. For practical purposes, a negative inhalation challenge with methacholine (or histamine) excludes active, symptomatic asthma. Measurement of FENO has been associated with a negative predictive value of 92%50 for ruling out presence of asthma; however, additional studies are required for this more-convenient and less-costly test to supplant methacholine challenge, which is still regarded as the gold standard for the diagnosis of asthma.
PEF monitoring has been advocated as an objective measure of airflow obstruction in patients with chronic asthma. Despite a sound theoretical rationale for PEF monitoring, as advocated by all published asthma guidelines, clinical trials that examined the use of PEF monitoring in ambulatory asthma patients show conflicting results.49 Over the past decade, 6 of 10 randomized trials have failed to show an advantage for the addition of PEF monitoring beyond symptom-based intervention for the control group.51 Regular PEF monitoring allows early detection of worsening airflow obstruction, which may be of particular value in a subset of poor perceivers—persons with a blunted awareness of ventilatory impairment. PEF monitoring also has value for risk stratification. Excessive diurnal variation and a morning dip of PEF imply poor control and a need for careful re-evaluation of the management plan. PEF alone is never appropriate; rather, PEF should be part of a comprehensive patient education program.
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