Asthma.docx

Asthma Asthma is a disease characterized by episodic airway obstruction and airway hyperresponsiveness usually accompanied by airway inflammation. In most cases, the airway obstruction is reversible, but in a subset of asthmatics, a component of the obstruction may become irreversible. In a large proportion of patients, the airway inflammation is eosinophilic, but some patients may present with differing types of airway inflammation, and in some cases, there is no obvious evidence of airway inflammation. MANIFESTATIONS Asthma most frequently presents as episodic shortness of breath, wheezing, and cough, which can occur in relation to triggers but may also occur spontaneously. These symptoms can occur in combination or separately. Other symptoms can include chest tightness and/or mucus production. These symptoms can resolve spontaneously or with therapy. In some patients, wheezing and/or dyspnea can be persistent. Episodes of acute bronchospasm, known as exacerbations, may be severe enough to require emergency medical care or hospitalization and may result in death. EPIDEMIOLOGY Asthma is the most common chronic disease associated with significant morbidity and mortality, with ~241 million people affected globally. Cross-sectional studies suggest that 7.9% of the population in the United States suffers from asthma as compared to ~4.3% prevalence worldwide. Prevalence continues to increase (starting at 7.3% in 2001 in the United States) and is associated with transition from rural to urban living. Asthma is more prevalent among children (8.4%) than adults (7.7%). In children, the prevalence is greatest among boys (2:1 male-to-female ratio), with a trend toward greater prevalence in women in adulthood. In some patients, asthma resolves as they enter adulthood only to “recur” later in life. In the United States in 2016, 1.8 million people visited an emergency department for asthma, and 189,000 were hospitalized. The total economic cost in the United States in 2007 was estimated at $56 billion. In the United States, asthma is more prevalent in blacks than Caucasians, and black race is associated with greater case morbidity. The ethnicity with the greatest prevalence in the United States is the Puerto Rican population. Asthma mortality increased worldwide in the 1960s, apparently related to overuse of inhaled β2-agonists. Reduction in mortality since then has been attributed to increased use of inhaled corticosteroids. Asthma mortality declined globally from 0.44 per 100,000 people in 1993 to 0.19 in 2006, but further reduction in mortality has not occurred since that time. TABLE 287-1 Exposures and Risk Factors Related to the Development of Asthma 1. Allergen exposure in those with a predisposition to atopy 2. Occupational exposure 3. Air pollution 4. Infections (viral and Mycoplasma) 5. Tobacco 6. Obesity 7. Diet 8. Fungi in allergic airway mycoses 9. Acute irritants and reactive airway dysfunction syndrome (RADS) 10. High-intensity exercise in elite athletes THE PATHWAY TO THE DEVELOPMENT OF ASTHMA The pathway to development of asthma can be varied. As illustrated in Fig. 287-1, there is an interplay between genetic susceptibility (see below) and environmental exposure and endogenous developmental factors (e.g., aging and menopause [see “Etiologic Mechanisms and Risk Factors” and Table 287-1]) that can lead to the development of asthma. Continued or additional exposures and triggers (Table 287-2) can affect the progression of disease and the degree of impairment. PATHOPHYSIOLOGY ■■MECHANISMS LEADING TO ACUTE AND CHRONIC AIRWAY OBSTRUCTION The pathobiologic processes in the airways that lead to episodic and chronic airway obstruction of asthma are discussed below. Their pathologic correlates are highlighted in Fig. 287-2, illustrating the pathologic changes that can occur in asthmatic airways. These processes can occur individually or simultaneously. There can be temporal variation of these processes in an individual based on exogenous factors, discussed later in this chapter, as well as the aging process itself. These processes can involve the entire airway (but not the parenchyma), but there can be significant spatial heterogeneity, as has now been demonstrated using hyperpolarized gas ventilation studies and high-resolution computed tomography (CT) of the thorax. TABLE 287-2 Triggers of Airway Narrowing 1. Allergens 2. Irritants 3. Viral infections 4. Exercise and cold, dry air 5. Air pollution 6. Drugs 7. Occupational exposures 8. Hormonal changes 9. Pregnancy Airway Hyperresponsiveness Airway hyperresponsiveness is a hallmark of asthma. It is defined as an acute narrowing response of the airways in reaction to agents that do not elicit airway responses in nonaffected individuals or an excess narrowing response to inhaled agents as compared to that which would occur in nonaffected individuals. A component of the hyperresponsiveness occurs at the level of the airway smooth muscle itself as demonstrated by hyperresponsiveness to direct smooth-muscle–acting agents such as histamine or methacholine. In many patients, the apparent hyperresponsiveness is due to indirect activation of airway narrowing mechanisms as a result of stimulation of inflammatory cells (which release direct bronchoconstrictors and mediators that cause airway edema and/or mucus secretion) and/ or stimulation of sensory nerves that can act on the smooth muscle or inflammatory cells. Agents and physical stimuli that elicit such responses are discussed later. The apparent increased responsiveness of the airways in asthma may also have a structural etiology. In asthma, airway wall thickness is associated with disease severity and duration. This thickening, which may result from a combination of smooth-muscle hypertrophy and hyperplasia, subepithelial collagen deposition, airway edema, and mucosal inflammation, can result in a tendency for the airway to narrow disproportionately in response to stimuli that elicit increased airway muscle tension. A major therapeutic objective in asthma is to decrease the degree of airway hyperresponsiveness. Inflammatory Cells While airway inflammation can be precipitated by acute exposure to inhalants, most asthmatics have evidence of chronic inflammation in the airways. Most commonly, this inflammation is eosinophilic in nature. In some patients, neutrophilic inflammation may be predominant, especially in those with more severe asthma. Mast cells are also more frequent. Many inflammatory cells are present in an activated state, as will be discussed in the section on inflammation. Airway Smooth Muscle Airway smooth muscle can contribute to asthma in three ways. First, it can be hyperresponsive to stimuli, as noted above. Second, hypertrophy and hyperplasia can lead to airway wall thickening with consequences for hyperresponsiveness, as noted above. Lastly, airway smooth-muscle cells can produce chemokines and cytokines that promote airway inflammation and promote the survival of inflammatory cells, particularly mast cells. Subepithelial Collagen Deposition and Matrix Deposition Thickening of the subepithelial basement membrane occurs as a result of deposition of repair-type collagens and tenascin, periostin, fibronectin, and osteopontin primarily from myofibroblasts under the epithelium. The deposition of collagen and matrix stiffens the airway and can result in exaggerated responses to increased circumferential tension exerted by the smooth muscle. Such deposition can also narrow the airway lumen and decrease its ability to relax and thus can contribute to chronic airway obstruction. Airway Epithelium Airway epithelium disruption takes the form of separation of columnar cells from the basal cells. The damaged epithelium is hypothesized to form a trophic unit with the underlying mesenchyme. This unit elaborates multiple growth factors thought to contribute to airway remodeling as well as multiple cytokines and mediators that promote asthmatic airway inflammation. Vascular Proliferation In a subset of asthmatics, there is a significant degree of angiogenesis thought to be secondary to elaboration of angiogenic factors in the context of airway inflammation. Inflammatory mediators can result in leakage from postcapillary venules, which can contribute to the acute and chronic edema of the airways. Airway Edema Submucosal edema can be present as an acute response in asthma and as a chronic contributor to airway wall thickening. Epithelial Goblet Cell Metaplasia and Mucus Hypersecretion Chronic inflammation can result in the appearance and proliferation of mucus cells. Increased mucus production can reduce the effective airway luminal area. Mucus plugs can obstruct medium-size airways and can extend into the small airways. Neuronal Proliferation Neurotrophins, which can lead to neuronal proliferation, are elaborated by smooth-muscle cells, epithelial cells, and inflammatory cells. Neuronal inputs can regulate smooth-muscle tone and mucus production, which may mediate acute bronchospasm and potentially chronically increased airway tone. ■■AIRWAY INFLAMMATION (TYPE 2 AND NON–TYPE 2 INFLAMMATION) Most asthma is accompanied by airway inflammation. In the past, asthma had been divided into atopic and nonatopic (or intrinsic) asthma. The former was identified as relating to allergen sensitivity and exposure, with production of IgE, and occurring more commonly in children. The latter was identified as occurring in individuals with later onset asthma, with or without allergies, but frequently with eosinophilia. This paradigm is being superseded by a nosology that favors consideration of whether asthma is associated with type 2 or non–type 2 inflammation. This approach to immunologic classification is driven by a developing understanding of the underlying immune processes and by the development of therapeutic approaches that target type 2 inflammation (see later sections on asthma therapy). Type 2 Inflammation Type 2 inflammation is an immune response involving the innate and adaptive arms of the immune system to promote barrier immunity on mucosal surfaces. It is called type 2 because it is associated with the type 2 subset of CD4+ T-helper cells, which produce the cytokines interleukin (IL) 4, IL-5, and IL-13. As shown in Fig. 287-3, these cytokines can have pleiotropic effects. IL-4 induces B-cell isotype switching to production of IgE. IgE, through its binding to basophils and mast cells, results in environmental sensitivity to allergens as a result of cross-linking of IgE on the surface of these mast cells and basophils. The products released from these cells include type 2 cytokines as well as direct activators of smooth-muscle constriction and edema. IL-5 has a critical role in regulating eosinophils. It controls formation, recruitment, and survival of these cells. IL-13 induces airway hyperresponsiveness, mucus hypersecretion, and goblet cell metaplasia. While allergen exposure in allergic individuals can elicit a cascade of activation of type 2 inflammation, it is now understood (see Fig. 287-3) that nonallergic stimuli can elicit production of type 2 cytokines, particularly due to stimulation of type 2 innate lymphoid cells (ILC2). These cells can produce IL-5 and IL-13. ILC2s can be activated by epithelial cytokines known as alarmins, which are produced in response to “nonallergic” epithelial exposures such as irritants, pollutants, oxidative agents, fungi, or viruses. Thus, these “nonallergic” stimuli can be associated with eosinophilia. The development of anti–IL-5 drugs that dramatically reduce eosinophils has allowed us to determine that, in many asthmatics, eosinophils play a major role in asthma pathobiology. They may induce hyperresponsiveness through release of oxidative radicals and major basic protein, which can disrupt the epithelium. In addition, recent CT imaging has suggested that mucus plugs, which may contain significant amounts of eosinophil aggregates, may accumulate in the airways and contribute to asthma severity. Non–Type 2 Processes As shown in Fig. 287-2, multiple processes can contribute to airway narrowing and apparent airway hyperresponsiveness. While type 2 inflammatory processes are most common, non–type 2 processes can exist either in combination with type 2 inflammation or without type 2 inflammation. Neutrophilic inflammation, as shown in Fig. 287-3, can also occur. This type of inflammation is more commonly seen in severe asthma that has not responded to the common anti-inflammatory therapies, such as corticosteroids, that usually suppress type 2 inflammation. In some cases, it may also be associated with chronic infection, occasionally with atypical pathogens such as Mycoplasma, perhaps accounting for the response of some of these patients to macrolide antibiotics. It is also commonly seen in reactive airway dysfunction syndrome (see “Etiologic Mechanisms and Risk Factors”). In a small subset of asthmatics, the pathologic changes seen in Fig. 287-2 may occur without any evidence of tissue infiltration by inflammatory cells. The etiology of such pauci-granulocytic asthma is unclear. ■■MEDIATORS Many chemical substances or signaling factors can contribute to the pathobiologic picture of asthma. Some of them have been successfully targeted in developing asthma therapies. Cytokines As illustrated in Fig. 287-3, and as discussed above, IL-4, IL-5, and IL-13 are the major cytokines associated with type 2 inflammation. They have all been targeted successfully in asthma therapies. Thymic stromal lymphopoietin (TSLP), IL-25, and IL-33 also play a role in the signaling cascade and are being actively studied as targets for treatment of asthma. IL-9 has been implicated as well. IL-6, IL-17, tumor necrosis factor α (TNF-α), IL-1β, and IL-8 have been implicated in non–type 2 inflammation. Fatty Acid Mediators Proinflammatory mediators derived from arachidonic acid include leukotrienes and prostaglandins. The cysteinyl leukotrienes (leukotrienes C4, D4, and E4) are produced by eosinophils and mast cells. They are potent smooth-muscle constrictors. They also stimulate mucus secretion, recruit allergic inflammatory cells, cause microvascular leakage, modulate cytokine production, and influence neural transmission. Cysteinyl leukotriene modifiers have shown clinical benefit in asthma. The non-cysteinyl leukotriene, LTB4, is produced primarily from neutrophils but can also be synthesized by macrophages and epithelial cells. It is a potent neutrophil chemoattractant. Prostaglandins are for the most part proinflammatory. Prostaglandin D2 (PGD2) is produced by mast cells. Receptors for PGD2 (CRTH2 receptors) are present on TH2 cells, ILC2 cells, mast cells, eosinophils, macrophages, and epithelial cells, and the activation of these receptors upregulates type 2 inflammation. Initial studies with drugs blocking CRTH2 have shown mild to moderate effectiveness in asthma. There are several classes of fatty acid–derived mediators that are responsible for the resolution of inflammation. These include the resolvins and lipoxins. Several studies suggest that deficiencies in these moieties may be responsible for the ongoing inflammation in asthma, especially in severe asthma. Nitric Oxide Nitric oxide is a potent vasodilator, and in vitro studies suggest that it can increase mucus production and smooth-muscle proliferation. It is produced by epithelial cells, especially in response to IL-13, and by stimulated inflammatory cells including eosinophils, mast cells, and neutrophils. Its precise role in the asthmatic diathesis is unclear. However, its production is increased in the airways in the presence of asthmatic eosinophilic inflammation, and it can be detected in exhaled breath. Reactive Oxygen Species When allergens, pollutants, bacteria, and viruses activate inflammatory cells in the airway, they induce respiratory bursts that release reactive oxygen species that result in oxidative stress in the surrounding tissue. Increases in oxidative stress have been shown to affect smooth-muscle contraction, increase mucus secretion, produce airway hyperresponsiveness, and result in epithelial shedding. Chemokines A variety of chemokines are secreted by the epithelium (as well as other inflammatory cells) and attract inflammatory cells into the airways. Those of particular interest include eotaxin (an eosinophil chemoattractant), TARC and MDC (which attract TH2 cells), and RANTES (which has pluripotent pro-phlogistic effects). ETIOLOGIC MECHANISMS, RISK FACTORS, TRIGGERS, AND COMPLICATING COMORBIDITIES As illustrated in Fig. 287-1, the development of asthma involves an interplay between risk factors and exposures (see Table 287-1) and genetic predisposition. ■■HERITABLE PREDISPOSITION Asthma has a strong genetic predisposition. Family and twin studies suggest a 25–80% degree of heritability. Genetic studies suggest complex polygenic inheritance complicated by interaction with environmental exposures. Further, epigenetic modifications related to environmental exposures may also produce heritable patterns of asthma. Many of the genes related to asthma have been associated with risk for atopy. However, there appear to be genetic modifications that predispose to asthma and its severity. Association studies have identified multiple candidate genes. In many cases, these genes vary from population to population. The most consistently identified include ORMDL3/ GSDMB (in the 17q21 chromosomal region), ADAM33, DPP-10, TSLP, IL-12, IL-33, ST2, HLA-DQB1, HLA-DQB2, TLR1, and IL6R. In many cases, association studies have identified polymorphisms in noncoding regions of the genome, suggesting that the majority of the currently identified traits act as “enhancers” of biologic processes. Genetic polymorphisms have also been associated with differential responses to asthma therapies. Variants in the β-receptor (Arg16Gly in ADRB2), the glucocorticoid-induced transcript 1 gene, and genes in the leukotriene synthesis and receptor pathways have been associated with altered response to the pharmacologic agents acting at those receptors or through those pathways. While genetic variation plays a key role in asthma susceptibility, it is important to understand that unraveling the complexities of the genetic contribution to asthma remains elusive. To wit, only 2.5% of asthma risk can be explained by the 31 single nucleotide polymorphisms that have been associated with asthma. A significant proportion of the heritability of asthma relates to the heritability of atopy. Atopy is the genetic tendency toward specific IgE production in response to allergen exposure. Serum levels of IgE correlate closely with the development of asthma. The National Health and Nutrition Examination Survey (NHANES) III found that half of asthma in patients aged 6–59 could be attributed to atopy with evidence of allergic sensitization. The allergens most associated with risk include house dust mites, indoor fungi, cockroaches, and indoor animals. FIGURE 287-3 Inflammatory cells and mediators involved in type 2 and non–type 2 inflammation. Allergens and nonallergic stimuli can trigger activation of multiple inflammatory cells and release of mediators that are responsible for recruiting and activating these cells. The mediators can affect airway smooth-muscle proliferation and hyperresponsiveness and fibroblast proliferation and matrix deposition. BLT2, leukotriene B4 receptor 2; CRTH2, chemoattractant receptor-homologous molecule (PGD2 receptor); CXCL8, CXC motif chemokine ligand 8; CXCR2, CXC chemokine receptor 2; GATA3, GATA Binding Protein 3; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN-γ, interferon gamma; ILC2, innate lymphoid type 2 cells; KIT, mast/stem cell growth factor receptor; LTB4, leukotriene B4; MPO, myeloperoxidase; NO, nitric oxide; IL, interleukin; PGD2, prostaglandin D2; ROS, reactive oxygen species; SCF, stem cell factor; Th, T helper; TNF-α, tumor necrosis factor α; TGF-β, transforming growth factor β; Th, T helper; TSLP, thymic stromal lymphopoietin. EXPOSURES AND RISK FACTORS Allergic Sensitization and Allergen Exposure Like asthma, the development of allergic sensitization involves an interplay between heritable susceptibility and allergen exposure. Allergen exposure during vulnerable developmental periods is believed to increase the risk of development of allergic sensitization in those with a tendency toward atopy. Allergic sensitization is increased in industrialized nations. Recent research has suggested that varied microbiome exposure (exposure to bacteria and bacterial products) may influence the development of atopy with decreased risk for atopy in those in rural environments. Studies of the role of early allergen avoidance in reducing the risk of developing asthma have produced contradictory results, possibly related to the inability to eliminate all allergen exposure. Tobacco Maternal smoking and secondhand smoke exposure are associated with increased childhood asthma. Childhood secondhand smoke exposure increased asthma risk twofold. Active smoking is estimated to increase the incidence of asthma by up to fourfold in adolescents and young adults. Air Pollution Early life exposure to pollution increases the risk of development of asthma. Proximity to major roadways increases the risk of early childhood asthma, thought to be attributed to levels of nitrogen dioxide exposure. Decreasing nitrogen dioxide exposure has been found to decrease asthma incidence in children. Studies of exposure to mixed pollutants suggest that most risk lies with carbon monoxide and nitric dioxide, with marginal effects of sulfur dioxide. Indoor air pollution from open fires and use of gas stoves has been associated with increased risk of children developing asthma symptoms. Mechanistically, pollutants are thought to cause oxidative injury to the airways, producing airway inflammation and leading to remodeling and increased risk of airway sensitization. Infections Respiratory infections clearly can precipitate asthma deteriorations. However, the degree to which respiratory infections indicate susceptibility to asthma, represent a causal factor, or in some cases provide protection from asthma is unclear. Incidence and frequency of human rhinovirus and respiratory syncytial virus infections in children are associated with development of asthma, but whether they play a causal role is unclear. Evidence of prior Mycoplasma pneumoniae infection has been associated with the development of asthma in Taiwanese adults. Occupational Exposures Occupational asthma is estimated to account for 10–25% of adult-onset asthma. The occupations associated with the most cases in European Community Health Surveys were nursing and cleaning. Two types of exposures are recognized: (1) an immunologic stimulus (further subdivided into high-molecularweight [e.g., proteins, flour] and low-molecular-weight [e.g., formaldehyde, diisocyanate] stimuli based on whether they act as haptens or can directly stimulate a response), and (2) an irritative stimulus. The immunologic form is associated with a latency period between time of exposure and development of symptoms. The irritative form, known as reactive airway dysfunction syndrome (RADS), will be discussed below. A combination of genetic predisposition (including atopy), timing, intensity of exposure, and co-exposure (e.g., smoking) influences whether an individual will develop occupational asthma. Diet There are suggestions that prenatal diet or vitamin deficiency may alter the risk of developing asthma. The evidence is not yet definitive, but vitamin D insufficiency may increase asthma risk in the progeny and supplementation may decrease such risk. Similarly, preliminary studies suggest that maternal supplementation with vitamins C and E and zinc may decrease asthma in children. One study suggested that maternal polyunsaturated fatty acid supplementation may decrease childhood asthma risk. Observational studies have suggested that increased maternal sugar intake may increase childhood asthma risk. Obesity Multiple studies suggest that obesity may be a risk factor for development of childhood and adult asthma. Adipokines and IL-6 have been thought to play a pathobiologic role. Some have argued that the risk is overestimated, and a study from NHANES II found an association with dyspnea but not with airway obstruction. Medications There are conflicting data regarding prenatal and early childhood risk for asthma posed by certain classes of medications. Use of H2 blockers and proton pump inhibitors in pregnancy has been associated with an increased risk of asthma in children (relative risk, 1.36–1.45); however, another study found a small risk for H2 blockers only. Conflicting data have been presented on the risk of perinatal acetaminophen and early childhood acetaminophen use. In a prospective study, the use of acetaminophen was not associated with an increased risk of exacerbations in young children with asthma, when compared to ibuprofen. Prenatal and Perinatal Risk Factors Preeclampsia and prematurity have been associated with increased risk of asthma in the progeny. Babies born by cesarean section are at higher risk for asthma. Those with neonatal jaundice are also at increased risk. Breast-feeding reduced early wheezing but has a less clear effect on later incidence of asthma. Endogenous Developmental Risk Factors Asthma is more prevalent among boys than girls, with the difference receding by age 20 and reversing (more prevalent among women) by age 40. Atopy is more prevalent among boys in childhood, and they have reduced airway size compared with girls. Both factors are thought to contribute to the sex discrepancy. A subset of women develop asthma around menopause. Such asthma tends to involve non–type 2 mechanisms. Pregnancy may precipitate or aggravate asthma as well. High-Concentration Irritant Exposure and RADS A solitary exposure to a high concentration of irritant agents that rapidly (usually within hours) produces bronchospasm and bronchial hyperactivity is known as RADS. Causative agents include oxidizing and reducing agents in an aerosol or high levels of particulates. The acute pathology usually involves epithelial injury with neutrophilia. There is little evidence of type 2 inflammation. This syndrome differs from occupational asthma in that these patients have not become sensitized to the provocative agent and can return to work in that environment once they have recovered. However, the course of the disease may be variable, with some series showing documented abnormalities and persistent symptoms 10 years after exposure. Fungi and Allergic Airway Mycoses One to 2% of patients with asthma may have an IgE-mediated sensitization to colonization of the airway by fungi, with the most common fungus causing such a reaction being Aspergillus fumigatus. So-called allergic bronchopulmonary aspergillosis (ABPA) is characterized by a type 2 airway inflammatory response to aspergillus with IgE >1000 IU/mL, eosinophils >500/μL, positive skin test to Aspergillus, and specific IgE and IgG antibodies to Aspergillus. Patients may have intermittent mucus plugging and central bronchiectasis. Up to two-thirds of patients will grow Aspergillus from the sputum. Treatment involves systemic antifungal treatment with itraconazole or voriconazole and oral corticosteroids. Exercise-Induced Symptoms in Elite Athletes Exerciseinduced airway narrowing in elite athletes undertaking extreme exercise in strenuous condition. These athletes may have little, or no, airway hyperreactivity or asthma risk factors. The condition may involve additional mechanisms including direct epithelial injury. Such a syndrome has also been reported in swimmers possibly related to pool chlorination. ■■TRIGGERS OF AIRWAY NARROWING The risk factors and exposures reviewed above lead to increased airway reactivity and a propensity to react to factors that trigger airway narrowing (see Fig. 287-1). Almost all asthmatics can identify triggers that will make their asthma worse. These triggers are listed in Table 287-2. Many of them overlap with the risk factors and etiologic factors reviewed above. In some cases, elimination of these triggers may dramatically reduce the impairment caused by asthma. In a minority, abatement can lead to “remission” so that these patients no longer require asthma medications and do not experience bronchospasm with their daily activities and routines. While acute exposures to these triggers generally cause short-lived bronchospasm, the bronchospasm may be severe enough that treatment for an exacerbation is required. Chronic exposure may lead to permanent deterioration in asthma control, although this does not appear to be true for exercise or stress. It should be noted that evidence suggests that severe asthma exacerbations (those requiring systemic corticosteroids) may, in and of themselves, accelerate lung function decline. Allergens In patients with sensitization to particular allergens through production of allergen-specific IgE, exposure to those allergens by inhalation can result in activation of mast cells and basophils with acute production of bronchoactive mediators (see Fig. 287-3). Such exposure can produce immediate bronchospasm (early response) and a late response (2–24 h after exposure) with bronchial narrowing and inflammation. These mechanisms can account for reactions to inhalation of pollens, mold, or dust; insects (especially cockroaches); animals; occupational materials; seasonal worsening of asthma; and so-called “thunderstorm asthma.” Chronic exposure may lead to persistent symptoms. While food allergies can produce bronchospasm through anaphylaxis, food allergies are generally not etiologically linked to asthma. Irritants Many asthmatics report increased symptoms on exposure to strong odors, smoke, combustion products, cleaning fluids, or perfumes. In general, the effects are short-lived, although chronic exposure (see “Occupational Exposures” above) and large-quantity exposures (see discussion of RADS above) can lead to long-lasting or permanent symptoms. Viral Infections Most asthmatics report that asthma exacerbations can be triggered by upper respiratory infections. The inflammation that occurs may be neutrophilic as well as eosinophilic. There is some evidence that IgE generation may reduce production of interferon, possibly predisposing to the effects of upper respiratory viruses. Increased airway reactivity after viral infections generally persists for 4–6 weeks but, in some cases, may be associated with permanent changes and impairment. Exercise and Cold/Dry Air Exercise may be a trigger to asthmatic bronchoconstriction in patients with asthma. Hyperventilation that occurs with exercise dries the airway lining, changing the tonicity of lining cells and causing release of bronchoconstrictive mediators. This effect is more prominent the lower the moisture content of the air, and since cold air has a lower absolute moisture content, the lower the temperature of the inspired air, the less exercise is required to induce bronchoconstriction. In addition, cold air may produce airway edema during airway wall rewarming. At routine levels of exercise, these effects are short-lived. Air Pollution Increased rates of exacerbations have been associated with increased ambient ozone, sulfur dioxide, and nitrogen dioxide, among other air pollutants. Drugs Beta blockers may trigger bronchospasm even when used solely in ophthalmic preparations. While the more selective beta blockers are safe for most asthmatics, beta blocker use may be a cause of difficult-to-control asthma. Aspirin may precipitate bronchospasm in those with aspirin-exacerbated respiratory disease (see “Special Considerations”). Angiotensin-converting enzyme (ACE) inhibitors (and to a lesser extent angiotensin receptor blockers) may cause cough. Occupational Exposures In addition to RADS (see above), episodic and/or recurrent exposures to workplace irritants and/or substances to which one has become sensitized can produce symptoms. These symptoms are usually reduced when patients are away from such exposures on weekends or vacation. Stress Asthmatics may report increased symptoms with stress. The mechanisms are poorly understood. Hormonal Factors A small proportion of women report a regular increase in perimenstrual symptoms, and symptoms may worsen during perimenopause. This may be related to rapid fluctuations in estrogen levels. Pregnancy can precipitate worsening of asthma in approximately one-third of pregnant patients. ■■COMORBIDITIES Comorbidities may make asthma difficult to manage, and the common comorbidities are listed in Table 287-3. Obesity Obese adults with asthma have more severe asthma symptoms than lean adults and are two to four times more likely to be hospitalized with an asthma exacerbation. Nonrandomized studies have shown an improvement and significant reduction in exacerbations after bariatric surgery. TABLE 287-3 Differential Diagnosis and Comorbidities That May Make Asthma Difficult to Control Differential Diagnosis of Diseases with Overlapping Symptoms That Can Present with Obstructive Pulmonary Function Tests 1. Heart failure 2. Chronic obstructive pulmonary disease (COPD) 3. α1 antitrypsin deficiency 4. Airway obstruction from mass or foreign body 5. Inducible laryngeal dysfunction (vocal cord dysfunction) 6. Bronchiolitis obliterans 7. Bronchiectasis 8. Tracheobronchomalacia Comorbidities That Can Make Asthma Difficult to Control 1. Chronic rhinosinusitis +/– nasal polyposis 2. Obesity 3. Gastroesophageal reflux disease 4. Inducible laryngeal dysfunction (vocal cord dysfunction) 5. COPD 6. Anxiety/depression 7. Obstructive sleep apnea Gastroesophageal Reflux Disease The presence of gastroesophageal reflux disease (GERD) predicts poor quality of life and is an independent predictor of asthma exacerbations. Treatment of symptomatic reflux disease has been shown to produce modest improvements in airway function, symptoms, and exacerbation frequency. Treatment of asymptomatic patients has not shown a benefit. Rhinosinusitis And/Or Nasal Polyposis Rhinosinusitis may be a manifestation of the eosinophilic inflammation in the lower airway in asthma. In addition, poorly controlled rhinosinusitis is believed to aggravate asthma by several potential mechanisms including inflammatory and irritant effects of the secretions on the lower airway, neural reflexes, and production of inflammatory mediators and cells that produce systemic inflammation. Treatment with intranasal corticosteroids has been shown to decrease airway reactivity and emergency department visits and hospitalizations. Evidence for the benefit of surgical therapy is inconclusive. There is increasing evidence that biologics targeted at type 2 inflammation may also be particularly useful for asthma associated with rhinosinusitis and polyposis in particular. Nasal polyposis is rare in children, and its presence in adults with asthma should raise suspicions of aspirin-exacerbated respiratory disease (see “Special Considerations”). Vocal Cord Dysfunction Now known as inducible laryngeal obstruction, vocal cord dysfunction involves inappropriate narrowing of the larynx, producing resistance to airflow. It can complicate asthma and mimic it. It is more commonly seen in women and patients with anxiety and depression. Definitive diagnosis involves laryngoscopy during symptomatic episodes or during induced obstruction. Chronic Obstructive Pulmonary Disease (COPD) See “Asthma-COPD Overlap” under “Special Considerations.” Anxiety/Depression Increased rates of asthma exacerbations occur in asthmatics with anxiety, depression, or chronic stress. Some patients may be unable to distinguish anxiety attacks from asthma. DIAGNOSIS AND EVALUATION ■■APPROACH A presumptive diagnosis of asthma can usually be made based on a compatible history of recurrent wheezing, shortness of breath, chest tightness, or cough related to common bronchoconstrictor precipitants when appropriate components of the differential diagnosis have been considered and/or eliminated. In some cases, a therapeutic trial of low-dose inhaled corticosteroid (ICS) may be considered. In all but the mildest cases, the diagnosis should be confirmed with pulmonary function testing or demonstration of airway hyperresponsiveness. Unfortunately, the diagnosis may be difficult to confirm after initiation of therapy since airway obstruction and hyperresponsiveness may be mitigated with therapy. A trial of tapering medications may be necessary. Studies have shown that more than one-third of patients with a physician diagnosis of asthma do not meet the criteria for the diagnosis. Adjunctive evaluation, as outlined below, should be undertaken to identify precipitating factors and underlying mechanisms that may be amenable to specific therapies (e.g., allergen avoidance). Cases that require more than a daily moderate-dose ICS combined with a long-acting β2-agonist (LABA) (together known as ICS/LABA) should undergo more formal evaluation to assess comorbidities that may make asthma difficult to control and a reassessment of any possible confounding diagnoses that may mimic asthma symptoms (see Table 287-3). ■■PRIMARY ASSESSMENT TOOLS FOR ESTABLISHING A DIAGNOSIS History Patients with asthma most commonly complain of episodes of wheezing, shortness of breath, chest tightness, mucus production, or cough upon exposure to triggers listed in Table 287-2. Symptoms may be worse on arising in the morning. Some may have nocturnal symptoms alone. However, such patients should be evaluated for postnasal drip or GERD if that is their sole presenting symptom. Patients frequently complain of symptoms with rapid changes of temperature or humidity. Exercise-induced symptoms are common with increased sensitivity to cold air. As compared to cardiac sources of dyspnea, exercise symptoms tend to develop more slowly after initiation of exercise and tend to resolve more slowly unless a β2-agonist is administered after the onset of symptoms. A careful exposure history should be obtained for home (e.g., pets, molds, dust, direct or secondhand smoke), work (work environment and exposure to occupational sensitizers), and recreational (e.g., hobbies, recreational inhalants) exposures. Allergen-sensitized patients may complain of symptoms on exposure to known allergens such as animals and may complain of increased symptoms during specific pollen seasons. Up to two-thirds of patients with asthma will be atopic (as opposed to half of the U.S. population), and almost half will have a history of rhinitis, with many complaining of intermittent sinusitis. In patients with adult-onset asthma, a careful occupational history should be obtained and a history of reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) or use of new medications, such as beta blockers (including ophthalmic preparations) and ACE inhibitors (due to potential cough), should be elicited. Physical Examination In between acute attacks, physical findings may be normal. Many patients will have evidence of allergic rhinitis with pale nasal mucus membranes. Five percent or more of patients may have nasal polyps, with increased frequency in those with more severe asthma and aspirin-exacerbated respiratory disease. Some patients will have wheezing on expiration (less so on inspiration). During an acute asthma attack, patients present with tachypnea and tachycardia, and use of accessory muscles can be observed. Wheezing, with a prolonged expiratory phase, is common during attacks, but as the severity of airway obstruction progresses, the chest may become “silent” with loss of breath sounds. Pulmonary Function Tests Effective reduction of the airway lumen in asthma produces increased resistance to airflow, which can be detected as a reduction in expiratory airflow during forced expiratory maneuvers. The peak expiratory flow rate (PEFR), forced expiratory volume in 1 s (FEV1), and the FEV1/forced vital capacity (FVC) ratio are reduced below the lower limit of normal. The flow-volume loop may show a characteristic scalloping (see Chap. 286). These findings may not be present during acute attacks or on therapy (especially after recent use of bronchodilators). Reversibility is defined as a ≥12% increase in the FEV1 and an absolute increase of ≥200 mL at least 15 min after administration of a β2-agonist or after several weeks of corticosteroid therapy. Diurnal peak flow variability of >20% has also been proposed as an indicator of reversible airways disease, but it is less reliable due to difficulties with quality control and variability of home assessments. Lung volumes and diffusing capacity should be normal in uncomplicated asthma. Assessment of Airway Responsiveness In cases where pulmonary function tests are nonconfirmatory and the diagnosis remains in doubt, testing to demonstrate increased reactivity to provocative stimuli in the laboratory can be undertaken. Methacholine, a cholinergic agonist, inhaled in increasing concentrations is most commonly used. A provocative dose producing a 20% drop in FEV1 (PD20) is calculated, with a value ≤400 μg indicative of airway reactivity. Mannitol is used as well, and occasionally, hypertonic saline may be used. Challenge with exercise and/or cold, dry air can be performed, with a positive response recorded if there is a ≥10% drop in FEV1 from baseline. In the case of suspected environmental/occupational exposures, specific allergen challenges may be undertaken in highly specialized labs. ■■ADJUNCTIVE ASSESSMENT TOOLS Eosinophil Counts A large proportion of asthma patients not treated with oral or high-dose ICSs will have eosinophil counts ≥300 cells/μL. Eosinophil counts correlate with severity of disease in population studies. Their presence in patients with severe asthma indicates a likelihood that the patient would respond to medications targeted at type 2 inflammation. Extremely elevated levels should prompt consideration of eosinophilic granulomatosis with polyangiitis or primary eosinophilic disorders. IgE, Skin Tests, and Radioallergosorbent Tests Total serum IgE levels are useful in considering whether patients with severe asthma would be eligible for anti-IgE therapy. Levels >1000 IU/mL should prompt consideration of ABPA. Skin tests, or their in vitro counterparts that detect IgE directed at specific antigens (radioallergosorbent test [RAST]), can be useful in confirming atopy and suggesting allergic rhinitis, which can complicate asthma management. Allergy investigations may be useful, when correlated with a history of reactions, in identifying environmental exposures that may be aggravating asthma. Exhaled Nitric Oxide Fraction of exhaled nitric oxide (FeNO) in exhaled breath is an approximate indicator of eosinophilic inflammation in the airways. It is easily suppressed by ICSs and, thus, can be used to assess adherence in patients in whom it was initially elevated. Elevated levels (>35–40 ppb) in untreated patients are indicative of eosinophilic inflammation. Levels >20–25 ppb in patients with severe asthma on moderate- to high-dose ICS indicate either poor adherence or persistent type 2 inflammation despite therapy. ■■ADDITIONAL EVALUATION IN SEVERE/POORLY RESPONSIVE ASTHMA In patients with poorly responsive asthma, additional evaluations for comorbidities (see Table 287-3) may be necessary, including sinus radiographic studies (even in those who have no symptoms of sinus disease) and esophageal studies in those who have symptoms of reflux. In patients with nonreversible disease, many obtain a serum α1 antitrypsin level. Additionally, the following evaluations may be of utility in poorly responsive asthma. Chest Radiography Chest CT can be useful to assess for the presence of bronchiectasis and other structural abnormalities that could produce airway obstruction. New image analysis tools are being used in the research setting to assess airway properties such as airway wall thickness, airway diameter, and evidence of air trapping. Sputum Induced sputum may be used in more specialized centers to help characterize type 2 and non–type 2 inflammation by detection of eosinophils and neutrophils, respectively. In severe asthma, there is some evidence that some patients may have localized persistent eosinophilic airway inflammation despite lack of peripheral eosinophils on blood analysis. TREATMENT Asthma GOALS OF ASTHMA THERAPY AND ASSESSMENT OF CONTROL Goals of asthma therapy in terms of achieving control of symptoms and reducing risk (as reflected in frequency of asthma exacerbations) are listed in Table 287-4. The therapeutic agents used in treatment are discussed below, and an integrated approach to care is discussed subsequently. A comprehensive treatment approach involves avoiding and reducing asthma triggers and, if necessary, the adjunctive use of medications. Asthma medications are primarily divided into those that relax smooth muscle and produce a fairly rapid relief of acute symptoms and those that target inflammation or mediator production. The former medications are commonly referred to as reliever medications, and the latter are known as controller medications. REDUCING TRIGGERS Mitigation As shown in Tables 287-1 and 287-2, triggers and exposures can cause asthma and make it difficult to control. In the case of those with occupational exposures, removal from the offending environment may sometimes result in complete resolution of symptoms or significant improvement. Secondhand smoke exposure and frequent exposure to combustion products of cannabis are remediable environmental exposures as well. The removal of pets that are clearly associated with symptoms can reduce symptoms. Pest control at home and in the school in those with evidence of IgE-mediated sensitivity (skin test or IgE RAST) may also be beneficial. The effect of dust or mold control in reducing asthma symptoms has been more variable. There is moderate evidence that dust control (impermeable mattress and pillowcase covers) in those patients with symptoms and sensitization may be effective in reducing symptoms only when conducted as part of a comprehensive allergen mitigation strategy. Allergen Immunotherapy Allergen immunotherapy reduces IgEmediated reactions to the allergens administered. It clearly reduces the symptoms of allergic rhinitis and thus may be helpful in reducing this comorbidity. The evidence for its effectiveness in isolated asthma in those who are sensitized and have clinical symptoms is variable. Due to the risk of anaphylaxis, guidelines generally recommend immunotherapy only in patients whose asthma is under control and who have mild to moderate asthma. The evidence base for the effectiveness of sublingual allergen immunotherapy in the treatment of asthma is not substantial. Vaccination Respiratory infections are a major cause of asthma exacerbations. Patients with asthma are strongly advised to receive both types of currently available pneumococcal vaccines and yearly influenza vaccines. COVID-19 vaccination is advised, as well. MEDICATIONS Bronchodilators Bronchodilators relax airway smooth muscle. There are three major classes of bronchodilators, β2-agonists, anticholinergics, and theophylline. a2-Agonists Available in inhaled or oral form, these agents activate β2-receptors present on airway smooth muscle. Such receptors are also present on mast cells, but they contribute little to the efficacy of these agents in asthma. β2-receptors are G protein–coupled receptors that activate adenyl cyclase to produce cyclic AMP, which results in relaxation of smooth muscle. Use β2-Agonists are primarily used in inhaled forms to provide relief of bronchospasm or to reduce the degree of bronchospasm anticipated in response to exercise or other provocative stimuli. Regular use has been associated with tachyphylaxis of the bronchoprotective effect and possible increased airway reactivity. This may be more common in patients with a polymorphism at the 16th amino acid position of the β2-receptor. Frequent short-acting β-2 agonist use has been associated with increased asthma mortality resulting in decreased enthusiasm for use in isolation without inhaled corticosteroids. Short-Acting a2-Agonists Albuterol (also known as salbutamol) is the most commonly used agent. Bronchodilation begins within 3–5 min of inhalation, and effects generally last 4–6 h. It is most commonly administered by metered-dose inhaler. Solutions for nebulization are also used, especially for relief of bronchospasm in children. Oral forms are available but are not commonly used. TABLE 287-4 Goals of Asthma Therapy 1. Reduction in symptom frequency to ≤2 times/week 2. Reduction of nighttime awakenings to ≤2 times/month 3. Reduction of reliever use to ≤2 times a week (except before exercise) 4. No more than 1 exacerbation/year 5. Optimization of lung function 6. Maintenance of normal daily activities 7. Satisfaction with asthma care with minimal or no side effects of treatment Long-Acting a2-Agonists Salmeterol and formoterol are the two available LABAs. They have an ~12-h duration of action. Formoterol has a quick onset comparable to the short-acting β2-agonists. Salmeterol has a slower onset of action. These agents can be used for prophylaxis of exercise-induced bronchospasm. In contrast to their use in chronic obstructive pulmonary disease (COPD), these agents are not recommended for use as monotherapy in the treatment of asthma. Their use in asthma is generally restricted to use in combination with an ICS. Ultra-Long-Acting a2-Agonists These agents (indacaterol, olodaterol, and vilanterol) have a 24-h effect. They are only used in combination with ICSs in the treatment of asthma. Safety β2-Agonists are fairly specific for the β2-receptors, but in some patients and especially at higher doses, they can produce tremor, tachycardia, palpitations, and hypertension. They promote potassium reentry into cells, and at high doses, they can produce hypokalemia. Type B (nonhypoxic) lactic acidosis can also occur and is thought to be secondary to increased glycogenolysis and glycolysis and increased lipolysis, leading to a rise in fatty acid levels, which can inhibit conversion of pyruvate to acetyl-coenzyme A. Increased asthma mortality was associated with highpotency β2-agonists in Australia and New Zealand. Increased use of β2-agonists for relief of bronchospasm is a clear marker of poor asthma control and has been associated with increased mortality. Questions had been raised as to whether adding LABAs to ICS might be associated with severe adverse asthma outcomes, but several studies have not detected such outcomes in comparison to maintaining the ICS dose. Anticholinergics Cholinergic nerve–induced smooth-muscle constriction plays a role in asthmatic bronchospasm. Anticholinergic medications can produce smooth-muscle relaxation by antagonizing this mechanism of airway narrowing. Agents that have been developed for asthma have been pharmacologically designed to be less systemically absorbed so as to minimize their systemic anticholinergic effects. The long-acting agents in this class are known as long-acting muscarinic antagonists (LAMAs). Use The short-acting agents in this class can be used alone for acute bronchodilation. They appear to be somewhat less effective than β2-agonists and have a slower onset of action as well. Safety Dry mouth may occur. At higher doses and in the elderly, acute glaucoma and urinary retention have been reported. There was a numerical (but not significant) difference in mortality in African Americans treated with ICS/LAMA versus ICS/LABA for asthma. Theophylline Theophylline, an oral compound that increases cyclic AMP levels by inhibiting phosphodiesterase, is now rarely used for asthma due to its narrow therapeutic window, drug-drug interactions, and reduced bronchodilation as compared to other agents. Controller (Anti-Inflammatory/Antimediator) Therapies So-called “controller” therapies reduce asthma exacerbations and improve long-term control, decreasing the need for intermittent use of bronchodilator therapies. None of these therapies have yet been shown to prevent progression of airway remodeling or the more rapid decline in lung function that can occur in a subset of asthma patients. Corticosteroids Corticosteroids are particularly effective in reducing type 2 inflammation and airway hyperresponsiveness. Corticosteroids bind to a cytoplasmic glucocorticoid receptor to form a complex that translocates to the nucleus. The complex binds to positive and negative response elements that result in inhibition of T-cell activation; eosinophil function, migration, and proliferation; and proinflammatory cytokine elaboration and activation of nuclear factor-κB. It also attaches to other transcription factors, resulting in deactivation of other proinflammatory pathways. Use Corticosteroids reduce airway hyperresponsiveness, improve airway function, prevent asthma exacerbations, and improve asthma symptoms. Corticosteroid use by inhalation (ICSs) minimizes systemic toxicity and represents a cornerstone of asthma treatment. ICS and ICS/LABA ICSs are the cornerstone of asthma therapy. They take advantage of the pleiotropic effects of corticosteroids to produce salutary impact at levels of systemic effect considerably lower than oral corticosteroids. Their use is associated with decreased asthma mortality. They are generally used regularly twice a day as first-line therapy for all forms of persistent asthma. Doses are increased, and they are combined with LABAs to control asthma of increasing severity. European guidelines now recommend their intermittent use even in intermittent asthma. Combining them with LABAs permits effective control at lower ICS dose. Longer-acting preparations permitting once-a-day use are available. Their effects can be noticeable in several days, but continued improvement may occur over months of therapy, with the majority of improvement evident within the first month of regular use. Adherence to regular therapy is generally poor, with as few as 25% of total annual prescriptions being refilled. Very high doses are sometimes used to reduce oral corticosteroid requirements. Not all patients respond to ICS. Increasing evidence suggests that the most responsive patients are those with significant type 2–mediated asthma. Oral Corticosteroids Chronic oral corticosteroids (OCSs) at the lowest doses possible (due to side effects) are used in patients who cannot achieve acceptable asthma control without them. Alternate- day dosing may be preferred, and pneumocystis pneumonia prophylaxis should be administered for those maintained on a daily prednisone dose of ≥20 mg. OCSs are also used to treat asthma exacerbations, frequently at a dose of 40–60 mg/d of prednisone or equivalent for 1–2 weeks. Since they are well absorbed, they may also be used for managing hospitalized patients. Intravenous Corticosteroids Intravenous preparations are frequently used in hospitalized patients. Patients are rapidly transitioned to OCS once their condition has stabilized. Intramuscular Corticosteroids In high-risk, poorly adherent patients, intramuscular triamcinolone acetonide has been used to achieve asthma control and reduce exacerbations. Safety Chronic administration of systemic corticosteroids is associated with a plethora of side effects including diabetes, osteoporosis, cataracts and glaucoma, bruising, weight gain, truncal obesity, hypertension, ulcers, depression, and accelerated cardiac risk, among others. Appropriate monitoring and infectious (pneumocystis pneumonia prophylaxis for those treated chronically with ≥20 mg prednisone/d) and bone health prophylaxis are necessary. Intermittent “bursts” of systemic corticosteroids to treat asthma exacerbations are associated with reduced side effects, but observational studies have suggested that the cumulative dose over time is associated with deleterious side effects. ICSs have dramatically reduced side effects as compared to OCSs. At higher doses, bruising occurs and osteoporosis can accelerate. There is a small increase in glaucoma and cataracts. Local effects include thrush, which can be reduced by use of a spacer and gargling. Hoarseness may be the result of a direct myopathic effect on the vocal cords. Rare patients exhibit side effects even at moderate doses of ICS. Children may experience growth suppression. Leukotriene Modifiers Agents that inhibit production of leukotrienes (zileuton, an inhibitor of 5-lipoxygenase) or the action of leukotrienes at the CysLT1 receptor (montelukast and zafirlukast) are moderately effective in asthma. They can improve airway function and reduce exacerbations but not to the same degree as bronchodilators or ICS, respectively. They are also effective in reducing symptoms of allergic rhinitis and, thus, can be used in patients with concomitant allergic rhinitis. Montelukast, in particular, is frequently used in children with mild asthma due to concerns of ICS-related growth suppression. Montelukast use may decrease due to safety warnings regarding depression with this compound. Leukotriene modifiers are effective in preventing exercise-induced bronchoconstriction without the tachyphylactic effects that occur with regular use of LABAs. Leukotriene modifiers are particularly effective in aspirin-exacerbated respiratory disease, which is characterized by significant leukotriene overproduction. They have also shown modest effect as add-on therapy in patients poorly controlled on high-dose ICS/LABA. CysLT1 Antagonists Montelukast and zafirlukast are administered orally once or twice daily, respectively. The onset of effect is rapid (hours), with the majority of chronic effectiveness seen within 1 month. 5-Lipoxygenase Inhibition Zileuton in its extended form is administered orally twice a day. Safety Montelukast is well tolerated, but an association with suicidal ideation has now resulted in a warning label from the U.S. Food and Drug Administration. Zileuton increases liver function tests (transaminases) in 3% of patients. Intermittent monitoring is suggested. It inhibits CYP1A2, and appropriate dose adjustments of concomitant medications may be necessary. Cromolyn Sodium Cromolyn sodium is an inhaled agent believed to stabilize mast cells. It is only available by nebulization and must be administered two to four times a day. It is mildly to modestly effective and appears to be helpful for exercise-induced bronchospasm. It is used primarily in pediatrics in those concerned about ICS side effects. Anti-IgE Omalizumab, a monoclonal antibody to the Fc portion of the IgE molecule, prevents the binding of IgE to mast cells and basophils. Reduction in free IgE that can bind to effector cells blocks antigen-related signaling, which is responsible for production or release of many of the mediators and cytokines critical to asthma pathobiology. In addition, through feedback mechanisms, reduction in IgE production occurs as well. Anti-IgE has been shown to increase interferon production in rhinovirus infections, decrease viralinduced asthma exacerbations, and reduce duration and peak viral shedding. This effect is believed to be due to IgE’s ability to reduce interferon γ production in response to viral infections. Use In asthma, anti-IgE has been tested in patients with a circulating IgE ≥30 IU/mL and a positive skin test or RAST to a perennial allergen. It is generally used in patients not responsive to moderate- to high-dose ICS

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