Chapter 512. Asthma

Asthma is a chronic inflammatory disorder of the airways characterized by increased airways hyperresponsiveness and mucus production. Its symptoms of cough, wheeze, shortness of breath, and chest tightness are associated with variable airflow limitation that is at least partly reversible. Asthma is estimated by the World Health Organization to affect 150 million people worldwide,1 and its global pharmacotherapeutic costs exceed $5 billion per year. In children, where asthma remains the leading cause of emergency care and hospitalization, rates continue to rise. The National Asthma Education and Prevention Program recently issued its third Expert Panel Report outlining guidelines for the diagnosis and management of asthma. The importance of inflammation in the pathogenesis of asthma remains recognized and highlighted. The heterogeneity of asthma is also a key feature of the report. The Panel emphasizes the importance of individualizing treatment for patients because of the heterogeneous nature of the disease.

Asthma is one of the leading chronic childhood diseases in the United States and a major cause of childhood disability.1 From 1980 to 1996, asthma prevalence among children 0 to 17 years of age more than doubled, from 3.6% in 1980 to 7.5% at the peak of the trend in 1995. Although the prevalence rate has leveled off since 1995, prevalence remains at high levels, and in 2005, 12.7% of children had been diagnosed with asthma at some point in their lifetime (9 million children), of whom 70% were reported to currently have asthma (6.5 million). Nearly two thirds of these children who currently have asthma reported at least 1 attack in the previous 12 months, highlighting the problem of poorly controlled asthma in the childhood age group. Despite increased overall health care utilization and that there are means to prevent attacks or exacerbations, the majority of children with asthma still suffer from attacks. Furthermore, the burden of avoidable emergency department visits and hospitalizations for asthma is high and has remained resistant to intervention efforts.

Racial Disparities

Racial disparities in childhood asthma are extensive.2 Children of American Indian or Alaska Native descent have current asthma prevalence rates 25% higher, and black children 60% higher, than those in white children. African Americans are 4 times more likely to be hospitalized and 5 times more likely to die of asthma than non–African Americans. When race and ethnicity are considered, Puerto Rican children have the highest prevalence of all groups, 140% higher than non-Hispanic white children. In light of these differing prevalence rates, the lower rate for ambulatory care visits among black children compared with white children suggests that black children may be underutilizing ambulatory care. Rates in adverse outcomes such as emergency department visits, hospitalizations, and death are substantially higher for black children. The disparity in asthma mortality between black and white children has increased in recent years. The relative importance of urban residence, low socioeconomic status, and minority (particularly black and Hispanic) status as independent risk factors for increased asthma morbidity and mortality remains controversial.

Natural History of Asthma in Early Life

The Tucson cohort study,3 which followed children from birth or early childhood, described 2 asthmatic phenotypes in children: Transient wheezing is associated with symptoms in the first 3 to 5 years of life and with decreased lung function, maternal smoking during pregnancy, and exposure to other siblings or children at day care centers. Family history of asthma or allergic sensitization was not part of this phenotype. Episodic asthma symptoms were associated with apparent viral infections. Nonatopic wheezing independent of either sensitization or atopy but associated with wheezing and respiratory syncytial virus in the first years of life carried an increased likelihood of wheezing up to 13 years of age. Immunoglobulin E (IgE)-mediated wheezing is associated with evidence of allergic sensitization and portrays the classic asthma phenotype. Early allergic sensitization is a significant risk factor for persistent asthma. Among school-age children, allergies/atopic sensitization starts to become an even more prominent cause of wheezing and displaces respiratory infections as a main trigger of attacks. Follow-up from the Tucson cohort at age 16 revealed that 60% of children with asthma in the prepubertal period continue to have intermittent wheezing after puberty. Asthma was found to remit in adolescence in 21% of cohort participants, but 11% had newly diagnosed asthma, so the global burden of the disease was largely unchanged. Allergic sensitization and obesity were associated with persistent asthma.

The important insights that have been gained in the natural history of asthma yield questions about the potential for early intervention and prevention or attenuation of childhood asthma by early identification of the high-risk population of children who have symptoms before 3 years of age and will develop persistent asthma. It is important to distinguish this group from the majority of children who wheeze before 3 years of age and do not experience any more symptoms after 6 years of age. Recently, the asthma predictive index was developed4 and subsequently validated2 to predict which children among those who had asthmalike symptoms early in life would go on to have persistent asthma. The asthma predictive index identifies the following risk factors for developing persistent asthma among children younger than 3 years of age who had 4 or more episodes of wheezing during the previous year: either one of the following major criteria: parental history of asthma, a physician diagnosis of atopic dermatitis, or evidence of sensitization to aeroallergens; or two of the following minor criteria: evidence of sensitization to foods, 4% or higher peripheral blood eosinophilia, or wheezing apart from colds. Ninety-five percent of wheezy young children with a negative index never developed asthma between their 6th and 13th years. Using this index to identify the young children at highest risk for persistent asthma, Guilbert and colleagues examined whether inhaled corticosteroids could modify the subsequent development of asthma in preschool children at high risk for asthma.2 However, no significant differences were seen between the treatment and placebo groups in the proportion of episode-free days, the number of exacerbations, or lung function after corticosteroids were discontinued. Thus, in preschool children at high risk for asthma, 2 years of inhaled-corticosteroid therapy did not change the development of asthma symptoms or lung function during a third, treatment-free year. Thus, the natural history course of asthma was not altered by anti-inflammatory treatment with inhaled corticosteroids under the conditions examined in this study. The concept of prevention is very important, and the age, duration, and nature of the intervention obviously may affect the findings.

Evidence of the impact of the environment on asthma incidence and morbidity—especially allergens and irritants such as cigarette smoke and outdoor pollutants—has been mounting. The hygiene hypothesis was proposed in 1986 in an attempt to provide a framework to understand the epidemiological observations in the late 19th and early 20th centuries that allergic disorders were increasing in prevalence and were more prevalent in westernized than in developing countries. It proposed that reduced exposure to infections in early childhood, due to increased use of antibiotics, decreased rural exposures, diminishing family size, improved living standards, and improved personal hygiene, resulted in increased risk of developing allergic disease.5 The underlying mechanism for the hygiene hypothesis has focused traditionally on a skewing of the Th1/Th2 balance toward Th2 responses. Th1 and Th2 cells are functional subsets of CD4+ T cells defined phenotypically by the production of polarized sets of cytokines: Th1 cells produce interleukin (IL)-2, interferon-γ, and tumor necrosis factor-β, which are important in macrophage activation, phagocytic responses, and the development of cell-mediated immunity. Th2 cells produce IL-4, IL-5, IL-10, and IL-13 and are important in the inhibition of macrophage activation and the development of IgE responses and eosinophilia. The immunologic milieu during T-cell priming is important in driving CD4+ T-cell polarization. IL-12 is indispensable for the development of most Th1 responses, and IL-4 has a similar role for Th2 responses. A reduction in developed regions of environmental factors and microbial exposures that promote Th1 responses leads to skewing of the immune response toward a Th2 immunologic milieu that favors the development of Th2-mediated allergic disorders. However, this hypothesis has now evolved to incorporate the worldwide epidemiologic trends witnessing the simultaneous increase in the prevalence of both Th1- and Th2-mediated disorders. In order to accommodate these observations, the hygiene hypothesis has evolved along with novel insights into the development of innate immunity. It is now proposed that early-life microbial and environmental exposures modify the development of the host immune system and affect future adaptive immune responses by invoking counterregulatory mechanisms. Alterations in these critical early life exposures has resulted in biologically significant changes in these counterregulatory mechanisms, and this has translated to the observed trends in prevalence rates for allergic disorders, including asthma. There are many recognized environmental exposures that impact the development of asthma, and undoubtedly, there are many more that are not yet recognized.

Allergens

The association of asthma and allergy has been long recognized, first in cross-sectional studies and more recently in prospective studies. IgE-mediated hypersensitivity to environmental allergens is present in the majority of children and young adults with asthma, and exposure to allergens appears to be involved in the initial development of asthma as well as in the exacerbation of existing asthma. Sensitization and exposure to house dust mites and Alternaria mold are important factors in the development of asthma in children. Data from the Childhood Asthma Management Program (CAMP) revealed that house dust mite and cockroach exposure are strong risk factors for sensitization. Thus, allergen exposure is linked to sensitization, which is a risk factor for asthma. However, the role of allergens in the development of asthma is complex and is yet to be fully defined. Recent observations from longitudinal birth cohort studies have revealed that dog exposure in early life may actually protect against the development of asthma. Thus, environmental influences may have different effects on disease during specific windows of opportunity or times when the child is most vulnerable. There is a strong association between asthma, allergic rhinitis, and atopic dermatitis in childhood, and the sequence of these events has been termed the atopic march, where atopic dermatitis is the earliest manifestation, followed by allergic rhinitis and then the onset of asthma. Due to the high prevalence of allergy in children with asthma, allergy testing is recommended for patients who have persistent asthma. Based on data on children in the United States, it is estimated that at least 70% of all patients who have asthma have persistent asthma.

Environmental Tobacco Smoke (ETS)

Despite an overall decrease in tobacco use in the United States over the last decade, the prevalence of cigarette smoking remains high in urban populations. Fifty-nine percent of urban asthmatic children enrolled in the National Cooperative Inner-City Asthma Study and 48% of urban asthmatic children enrolled in the Inner-City Asthma Study live in a house with at least 1 cigarette smoker. In the National Cooperative Inner-City Asthma Study, a household member was smoking during 10% of the home visits, and 48% of urine samples collected from asthmatic children had cotinine/creatine ratios that were consistent with significant tobacco smoke exposure in the last 24 hours. Among children who have asthma, exposure to environmental tobacco smoke is associated with increased symptoms, decreased lung function, and greater use of health services.

Air Pollution

Epidemiologic and laboratory studies have provided evidence that inhalation of respirable particulate matter adversely affects lung function in patients with asthma. Diesel exhaust particles are respirable with over 90% in the fine or ultrafine size range. They are composed of elemental carbon cores with large surface areas capable of binding organic polycyclic aromatic hydrocarbons, transition metals, and airborne allergens, all of which have the potential to induce reactive oxygen species and inflammation. Diesel exhaust particles can interact directly with allergens and have been shown to augment allergen-induced responses.

Respiratory Infections

A number of respiratory viruses in infancy have been associated with the subsequent development of asthma. Prospective longitudinal studies of children admitted to hospital with documented respiratory syncytial virus have observed that approximately 40% of these infants will continue to wheeze or have asthma in later childhood. Symptomatic rhinovirus infections in early life also are emerging as risk factors for recurrent wheezing. As discussed previously, the majority of children who wheeze with viral infections do not go on to develop asthma; further understanding of the viral mechanisms that contribute to persistent recurrent wheezing is needed.

Allergic Rhinitis and Sinusitis

The upper and lower airways exist as a continuum and show similar histopathologic changes when inflamed, including epithelial damage, thickening of the basement membrane, and a predominantly eosinophilic cellular infiltrate. Epidemiologic studies support a strong association between allergic rhinitis and asthma. Segmental bronchial allergen challenge causes inflammatory changes in both nasal and bronchial mucosa. Epidemiologic studies confirm that sensitization among genetically susceptible populations to allergens, including house dust mite, pet dander, Alternaria mold, and cockroach, confers risk for childhood asthma.6 Anti-inflammatory treatment aimed at the upper airway results in decreased markers of lower airway inflammation.7 Furthermore, treatment of allergic rhinitis with antihistamines and intranasal steroids have been reported to decrease emergency department visits for asthma.3 Similar to rhinitis, sinusitis can contribute to asthma symptoms.

Allergic Bronchopulmonary Aspergillosis

Allergic bronchopulmonary aspergillosis (ABPA) should be suspected in patients who have asthma and have the presence or a history of pulmonary infiltrates. The primary cause is Aspergillus fumigatus, which grows in moist environments and is deposited in the peripheral airways. The fungus grows saprophytically in bronchial mucus in the bronchi. Although there is no tissue invasion, a predominantly eosinophilic inflammation occurs, leading to damage of the bronchial wall and development of the typical proximal bronchiectasis. The classic clinical presentation of ABPA includes transient migratory lung shadows on chest x-ray or computed tomography (CT), peripheral blood eosinophilia, fever, and sputum containing brown plugs or flecks (Aspergillus recovered in 50% of cases). The criteria for the diagnosis of ABPA complicating asthma include (1) positive immediate skin test to Aspergillus, (2) total serum IgE greater than 417 IU (1,000 ng/mL), (3) elevated Aspergillus-specific serum IgE and/or IgG, and (4) central bronchiectasis.8 An earlier form of the disease, before it has progressed to produce central bronchiectasis, can be diagnosed on the basis of the first 3 criteria in patients who have asthma. Additional supporting findings for a diagnosis of ABPA include a sputum culture positive for Aspergillus, serum-precipitating antibodies to Aspergillus, and an arthus late-phase response after intradermal injection of Aspergillus. The standard treatment for ABPA is oral steroids. Serum total IgE levels and follow-up chest radiographs are used to monitor response to therapy.8 Early, aggressive therapy may prevent progression to advanced-stage disease. Azole antifungal agents have also been tried as adjunctive treatment in patients who are stable and who have ABPA. Itraconazole administered orally for 16 weeks reduced sputum eosinophilia, serum IgE and IgG levels, and the number of exacerbations requiring oral corticosteroids.

Gastroesophageal Reflux Disease (GERD)

Symptoms of GERD are common in both children and adults who have asthma. According to the National Guidelines Expert Panel Report 3, medical management of GERD should be instituted for patients who have asthma (especially nocturnal symptoms) and complain of frequent heartburn or pyrosis.6 In patients who have poorly controlled GERD, treatment with a proton pump inhibitor has been reported to reduce nocturnal symptoms, reduce asthma exacerbations, and improve quality of life related to asthma.

Obesity

The parallel rise in the prevalence of asthma and obesity suggests that they are related. Obesity has been associated with asthma persistence and severity in both children and adults.9 Compared with nonasthmatics, body mass index in asthmatics was 44% to 48% higher in 3 cross-sectional US health surveys. Further support for an association between asthma and obesity is provided by prospective studies, which show that risk for asthma is increased with increasing body mass index. A recent meta-analysis confirmed that obesity is a strong risk factor for incident asthma.10 Notably, as obese asthmatics lose weight, their asthma symptoms and lung function improve.

Obstructive Sleep Apnea

Nocturnal asthma and obstructive sleep apnea may have similar clinical symptoms.6 Nocturnal symptoms in asthma are frequently underdiagnosed, and obstructive sleep apnea may be prevalent in nocturnal asthma. A high prevalence of obstructive sleep apnea has been reported in patients who have unstable asthma. According to the National Guidelines Expert Panel Report 3, evaluation for obstructive sleep apnea is recommended in patients with unstable, poorly controlled asthma, particularly those who are overweight or obese. Congestion of the nasopharynx due in part to allergic rhinitis, with resultant mouth breathing, may heighten the expression of both obstructive sleep apnea and asthma. Patients who have unstable asthma and sleep apnea demonstrated improvement when treated with nasal continuous positive airway pressure.6 In contrast, nocturnal nasal continuous positive airway pressure in individuals who have asthma and who do not have apnea is associated with disrupted sleep.9 Thus, confirmation of diagnosis is important.

Aspirin Sensitivity

The classic aspirin triad (also known as the Samter triad) of asthma, aspirin intolerance, and nasal polyposis most commonly develops in adulthood; however, up to 5% of children with asthma may have aspirin-induced symptoms. Avoidance of aspirin and nonsteroidal anti-inflammatory drugs should be considered in children with severe, persistent asthma or nasal polyps. Studies have shown relative overproduction of cysteinyl leukotrienes linked to an imbalance between proinflammatory and anti-inflammatory mediators derived from arachidonic acid.

According to the Expert Panel Report 3, asthma is defined as

a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role: in particular, mast cells, eosinophils, T lymphocytes, macrophages, neutrophils, and epithelial cells. In susceptible individuals, this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. The inflammation also causes an associated increase in the existing bronchial hyperresponsiveness to a variety of stimuli. Reversibility of airflow limitation may be incomplete in some patients with asthma.

Airway inflammation in asthma is found in patients with mild, moderate, and severe disease. The pathologic features of the asthmatic airways include denudation of the airway epithelium, mucus overproduction, goblet cell hyperplasia, basement membrane thickening with variable subepithelial fibrosis, bronchial smooth muscle hyperplasia, and cellular infiltration with eosinophils, lymphocytes, and neutrophils (especially in acute or fatal disease; Fig. 512-1). Airway narrowing and subsequent airflow limitation leads to clinical symptoms in acute exacerbations of asthma whereby bronchoconstriction occurs quickly to narrow the airways in response to exposure to a variety of triggers, including allergens, irritants, and viral infection. As the disease becomes more persistent and inflammation plays a bigger role, other factors further limit airflow. These include edema, inflammation, mucus overproduction, and airway smooth muscle hypertrophy and hyperplasia. In some persons who have asthma, airflow limitation may be only partially reversible due to permanent changes in the airway known as airway remodeling.

Inflammation has a central and consistent role in the pathophysiology of asthma regardless of the severity or subtype of asthma. It is due to many mediators and processes, including cytokines, chemokines, leukotrienes, oxidative stress, and neuropeptides. The airway inflammation involves an interaction of many cell types, including lymphocytes (specifically Th2 cells), mast cells, eosinophils, macrophages, dendritic cells, and neutrophils, and leads to airflow limitation that is reversible (Fig. 512-2).

Although environmental influences are important in the development of asthma, there is a strong genetic predisposition. The single-most important factor in predicting asthma among infants and young children with wheezing is a family history of allergy. Children who have 1 parent with asthma have about a 25% chance of developing asthma, and those whose mother and father both have asthma may have as high as a 50% risk of the disease. Identification of the genes relevant to asthma has been an area of considerable investigation. A recent review11 of nearly 500 papers on asthma genetic studies identified 10 genes (IL4, IL13, CD14, ADRB2, HLA-DRB1, HLA-DQB1, TNF, FCER1B, IL4RA, ADAM33) that have been associated with an asthma or atopy phenotype in more than ten populations. An additional 15 genes have been associated in 6 to 10 populations. It is now evident that the pathogenesis of asthma is dependent on multilayered gene-environment interactions over time. A particular asthma gene may be relevant only in the context of a specific environmental exposure in a given population. Likewise, the relevant environmental exposures are dependent on the genetic context. Several examples of this now exist in the literature. The study of the genetics of asthma is further complicated by the fact that asthma is a heterogeneous disorder, and although the end point is airway inflammation resulting in airway hyperresponsiveness, there may be several distinct pathways to reach this end point of asthma.

According to the National Expert Panel Report 3,6 a diagnosis of asthma should be considered if any of the following clinical indicators are present: wheezing (high-pitched whistling sounds, especially in children), but asthma can occur in the absence of wheezing; recurrent cough; recurrent chest tightness or difficulty breathing; worsening symptoms with exercise or at night; or worsening symptoms during viral infection, exposure to furry pets, changes in weather, exposure to pollen, or environmental tobacco smoke (all known triggers for asthma). Improvement of symptoms after treatment with a bronchodilator is suggestive of asthma, but a lack of improvement does not rule out asthma. Pulmonary function testing is recommended if any of the indicators is present.

Symptom history varies with age. An infant or young child often has a history of recurrent wheeze or persistent cough with colds, while older children often complain of chest tightness or persistent cough/wheeze. Triggers for childhood asthma often include viral infections (especially respiratory syncytial virus and rhinovirus), allergen exposure, irritants (environmental tobacco smoke, pollution), weather changes, stress or emotional factors, gastroesophageal reflux, aspirin sensitivity, hormonal factors such as menses, and exercise.

The upper respiratory tract, chest, and skin are the focus of the physical examination for childhood asthma. Physical findings that increase the probability of asthma include hyperexpansion of the thorax, use of accessory muscles of breathing, wheezing during normal breathing or elicited by forced exhalation (typical of airflow obstruction), rhinitis, swollen pale nasal turbinates and/or nasal polyps, and the presence of atopic dermatitis/eczema. The absence of these findings does not rule out asthma, because the disease is by definition variable, and signs of airflow obstruction are often absent between attacks.

Pulmonary Function Tests

Pulmonary function tests are objective and noninvasive. A pulmonary function test should be attempted in children 5 years old or older with symptoms suggestive of asthma. Objective assessments of pulmonary function are recommended for the diagnosis of asthma because medical history and physical examination are not reliable means of excluding other diagnoses or of characterizing the status of lung impairment. These measurements help to determine whether there is airflow obstruction, its severity, and whether it is reversible over the short term. Demonstration of reversibility of airflow obstruction following inhalation of a bronchodilator is central to the definition of asthma. Examination of the volume time curve and the shape of the flow-volume loop provides an estimate of the adequacy of the patient effort in performing the test. Airflow obstruction is indicated by a reduction in the values for both the forced expiratory volume in 1 second, FEV1, and the FEV1 relative to FVC, forced vital capacity, or FEV1/FVC when compared to reference or predicted values. Predicted values for FEV1/FVC are based on National Health and Nutrition Examination Survey (NHANES) data, National Center for Health Statistics, Centers for Disease Control and Prevention (CDC). Significant reversibility is indicated by American Thoracic Society standards as an increase in FEV1 of at least 12% from the baseline measure after inhalation of a short-acting bronchodilator (eg, albuterol, 2–4 puffs of 90 mcg/puff). If obstruction is detected on the baseline pulmonary function test, a bronchodilator (albuterol) should be administered and the test repeated in 20 minutes. An improvement of 12% or greater in the FEV1 is consistent with a diagnosis of asthma; however, neither this finding nor any other single test or measure is adequate to diagnose asthma. In addition to the pulmonary function test results, the patient’s history and symptoms along with the exclusion of other possible diagnoses are needed to establish a diagnosis of asthma.

Methacholine challenge testing is most often considered when asthma is a serious possibility and traditional methods, most notably spirometry performed before and after administration of a bronchodilator, have not established or eliminated the diagnosis. The optimal diagnostic value of methacholine challenge testing (the highest combination of positive and negative predictive power) occurs when the pretest probability of asthma is 30% to 70%. Symptoms that increase the pretest probability of asthma include wheezing, dyspnea, chest tightness, or cough in the following circumstances: (1) with exposure to cold air, (2) after exercise, (3) during respiratory infections, and (4) after exposure to allergens and other asthma triggers. Bronchoprovocation testing should be carried out by a trained individual in an appropriate facility. Although a positive test is consistent with asthma, methacholine challenge testing is more useful in excluding a diagnosis of asthma than in establishing one. The end point is the provocative concentration that results in a 20% fall in FEV1 (PC20). A PC20 of 8 mg/mL or lower is indicative of bronchial hyperresponsiveness; however, the interpretation of the methacholine challenge testing is complicated and depends on the pretest probability.9 Under circumstances of high pretest probability, methacholine concentrations between 8 and 16 mg/mL are consistent with bronchial hyperresponsiveness. The degree of abnormality of spirometric measurements is evaluated by comparison of the patient’s results with reference values based on age, height, sex, and race. Pulmonary function measures often do not correlate directly with symptoms. One study reports that one third of the children who had moderate to severe asthma were reclassified to a more severe asthma category when pulmonary function reports of FEV1 were considered in addition to symptom frequency. Conversely, in another study, children who were classified as mild to moderate asthma by symptoms had normal FEV1.

Exercise-Induced Asthma

Exercise-induced asthma (EIA) occurs in 80% of children with asthma and may cause limitations in daily life activities in up to 30% of children.12 The mechanisms underlying EIA are not known, but studies have shown that the temperature in the segmental bronchi is decreased with increasing ventilation and when breathing cold air. This cooling may stimulate airway receptors and lead to bronchial constriction. In addition, cold air induces pulmonary vasoconstriction, resulting in a reactive hyperemia, which leads to airway edema and narrowing. Furthermore, increased water loss from the respiratory tract due to increased ventilation results in changes in the osmolarity of the fluid lining the respiratory epithelium, and this increased osmolarity is thought to result in the release of inflammatory mediators from mast cells and other resident lung cells. The optimal method for diagnosis of EIA is to perform a standardized exercise challenge test. A diagnosis of EIA cannot be made with a methacholine challenge test, and EIA cannot be excluded by a negative response to methacholine. Vigorous exercise should be avoided for at least 4 hours before testing, as prior exercise has been found to exert a protective effect. The preferred modes of exercise are the motor-driven treadmill with adjustable speed and grade or the electromagnetically braked cycle ergometer. An appropriate postexercise testing schedule is 5, 10, 15, 20, and 30 minutes after cessation of exercise. The presence of exercise-induced bronchoconstriction is defined by plotting FEV as a percentage of the preexercise baseline FEV, at each postexercise interval. A 15% decrease is an accepted abnormal response. Effective recognition and treatment of EIA is a critical part of asthma management, especially since quality of life in children with asthma has been found to correlate with shortness of breath during exercise.13

EIA is best treated with inhaled corticosteroids to control inflammation as well as pretreatment before exercise with short-acting or long-acting bronchodilators. The use of β2-adrenergic agonists before exercise will prevent EIA in more than 80% of patients. Short-acting agents confer protection for 2 to 3 hours, while long-acting agents may be protective for up to 12 hours. However, frequent or chronic use of long-acting β2-agonists for EIA is not recommended because the protective effect wanes with frequent use, and they may disguise poorly controlled persistent asthma. Other agents including leukotriene receptor antagonists and cromolyn (discussed under “Treatment”) are alternative therapies for EIA but not as effective as steroid combined with β2-agonists. A mask or scarf over the mouth may attenuate cold-induced EIA6.

A diagnosis of asthma requires an exclusion of other possible diagnoses. As such, all children with asthma should have a chest radiograph at some time to rule out parenchymal disease, a congenital anomaly, or evidence of foreign body. Radiographic findings in asthma range from normal to hyperinflation with peribronchial interstitial infiltrates and atelectasis. In hospitalized children, a chest x-ray should be strongly considered. In a 3-year study of hospitalized children with asthma, 76% had evidence of hyperinflation, while 20% had infiltrates, pneumonia, and/or atelectasis.

The differential diagnosis of asthma in children is summarized in Table 512-1. A sweat test should be considered in children with chronic respiratory symptoms or in children with recurrent wheezing and associated symptoms of failure to thrive, diarrhea, steatorrhea, nasal polyps, chronic or pansinusitis, and digital clubbing. An x-ray should also be done in these circumstances.

Several conditions can coexist with asthma or mimic asthma symptoms, including rhinitis/sinusitis, gastroesophageal reflux disease, obstructive sleep apnea, obesity, and aspirin sensitivity (discussed earlier). Radiographic imaging of the sinuses should be considered for children with persistent nocturnal cough, nasal symptoms, and dental pain. Similarly, the presence of the other conditions should be evaluated if indicated and treated if present.

Cough-Variant Asthma

Cough-variant asthma is considered an asthma subset in which chronic cough is the only symptom. Triggers for cough-variant asthma often include exercise and cold air or changes in weather. As such, methacholine challenge testing or exercise tolerance testing to establish whether there is bronchial hyperresponsiveness may be helpful in diagnosis. The diagnosis of cough-variant asthma is confirmed by a positive response to asthma treatment.

Vocal Cord Dysfunction

Vocal cord dysfunction (VCD) often mimics asthma. It is characterized by episodic dyspnea and wheezing caused by intermittent paradoxical vocal cord adduction during inspiration. The cause of VCD is not well understood. Although VCD is clearly distinct from asthma, it is often confused with asthma, leading to inappropriate medication of affected individuals with antiasthma medications. Asthma medications are not effective in treating VCD, so VCD should be considered in patients who are resistant to treatment. It is important to note, however, that VCD and asthma often coexist and that VCD may complicate asthma management. Elite athletes, in particular, are prone to both exercise-induced bronchospasm and VCD, so careful workup is warranted for athletes who present with exercise-related breathlessness. VCD can be difficult to diagnose. Flattening of the inspiratory flow loop on spirometry in addition to the symptoms is strongly suggestive of the diagnosis, but abnormalities of the inspiratory loop may be absent between episodes. The diagnosis of VCD comes from direct observation of paradoxical vocal cord movement by flexible laryngoscopy during an acute episode. Most patients with VCD cannot voluntarily induce an episode. Therapy generally consists of speech therapy and relaxation techniques.6

Once the diagnosis of asthma has been made, it is important to characterize the patient’s asthma in order to design the most optimized therapeutic strategy for that patient. This involves (1) identifying triggers for the patient’s asthma, such as exposures at home, daycare, or school; (2) identifying comorbidities that may be contributing to the patient’s asthma symptoms (eg, sinusitis, rhinitis, GERD); and (3) classifying asthma severity.

The evaluation of a patient with asthma should include identification of the patient’s asthma triggers—such as exposure to allergens (eg, pets, molds, seasonal pollens), irritants (eg, environmental tobacco smoke, air pollution), or respiratory viruses. It is important to elicit the location and duration of the exposure as well as the relationship of the exposure to the symptoms. Allergy testing is recommended for all children with persistent asthma (approximately 70% of children with asthma), especially those with triggers suggestive of allergy. It is also important to identify whether the patient has chronic comorbid conditions (discussed earlier) that may exacerbate asthma and complicate treatment.

Asthma severity is the intrinsic intensity of disease. Initial assessment of patients who have confirmed asthma begins with a severity classification because the selection of type, amount, and scheduling of therapy should correspond to the level of asthma severity. This initial assessment of asthma severity is made immediately after diagnosis, ideally before the patient is taking some form of long-term control medication. Classification of severity is based on the spirometry and symptom frequency over the previous month per the patient history. According to the Expert Panel Report 3,6 severity classification should include parameters of both impairment (assessment of the frequency and intensity of symptoms and functional limitations that a patient is experiencing or has recently experienced) and risk (likelihood of either asthma exacerbations or of the loss of pulmonary function over time) because these domains may respond differentially to treatment. A summary of the severity classification in children is presented in Figure 512-3.

Assessment of the impairment domain can be elicited by careful, directed history and lung function measurement. Spirometry is the preferred method for measuring lung function to classify severity. Analysis of a large, longitudinal study of children confirmed a relationship between the severity of airflow obstruction, especially FEV1, and the risk of exacerbations. Recent data have suggested that, in contrast to FEV1 measures, FEV1/FVC may be a more sensitive marker of asthma severity in children because FEV1/FVC decreased with increasing asthma severity. Peak flow has not been found to be a reliable variable for classifying severity but may be helpful in some children. In the history, it is important to ascertain the frequency of nighttime symptoms and awakenings, the frequency of short-acting bronchodilator use for quick relief of symptoms, the number of work/school days missed, the child’s ability to engage in normal activities including sports activities, and quality-of-life assessments.

In contrast, no definitive tests or tools are available to predict risk. Summarized in Table 512-2 is a list of predictors associated with increased risk for asthma exacerbations and death from asthma. A history of previous exacerbations requiring emergency department visits, hospitalization, or intensive care unit admission can help identify patients at risk for future exacerbations. Symptoms, exacerbations, spirometry (especially the FEV1/FVC), and quality of life over time are currently the best available measures of asthma control. It is important to note that patients at any level of severity, evenintermittent asthma, can have severe exacerbations.

The primary goal of therapy is to achieve asthma control by reducing impairment and reducing risk. Reducing impairment is focused on prevention of symptoms, resulting in decreased need for relief use of a short-acting bronchodilator, maintenance of normal activity level, normal pulmonary function, and patient satisfaction with control. Reducing risk is focused on prevention of exacerbations and loss of lung function. Treatment should include identification and education regarding the individual patient’s asthma triggers, as well as pharmacologic treatment optimized for maximal effectiveness with minimal or no side effects.

There are 2 types of asthma medications: controller medications, which are taken daily to provide long-term control, and quick-relief medications. Patients who have persistent asthma require both classes of medication. Long-term control medications include inhaled corticosteroids, inhaled long-acting bronchodilators, leukotriene modifiers, cromolyn, theophylline, and immunomodulators. These medications act predominantly by decreasing airway inflammation. A summary of a childhood asthma treatment plan algorithm is shown in Figure 512-4.

Controller Medications

Inhaled Corticosteroids

Inhaled corticosteroids (ICS) are the most effective long-term therapy available for patients with persistent asthma. Corticosteroids exert their effects by binding to glucocorticoid receptors in the cytoplasm of target cells. ICS have a variety of anti-inflammatory effects on many different cell types, which may contribute to their success in the treatment of asthma. These include modulation of anti-inflammatory proteins including cytokines, adrenergic receptor expression, cytokine expression, inflammatory receptors, and adhesion molecules. In addition, steroids markedly reduce the number of circulating eosinophils by decreasing their survival. They inhibit the release of inflammatory mediators from alveolar macrophages, the production of inflammatory cytokines and chemokines by human airway epithelial cells, and inhibit mucous secretion by goblet cells.

ICS are very effective as preventive therapy, leading to reduced symptom severity, improvement in asthma control and quality of life, improvement in lung function measures, diminished airway hyperresponsiveness, and prevention of exacerbation frequency and severity. Sensitivity to ICS varies among patients. Corticosteroid responsiveness is decreased in smokers and persons who have asthma with predominantly neutrophilic inflammation. In addition, African American children with poorly controlled asthma are at increased risk for corticosteroid insensitivity.6

Studies comparing ICS therapy to other single-control medications reveal that in patients with mild or moderate persistent asthma, treatment with ICS demonstrates greater improvements in lung function, symptom scores, frequency and severity of exacerbations, and relief use of bronchodilators. According to the Expert Panel Report 3, in patients 12 years and older who require more than low-dose ICS alone to control asthma (ie, step 3 care or higher), combination therapy with a long-acting β-agonist along with ICS is preferred. Alternative, adjunctive therapies include leukotriene receptor antagonists, or theophylline. For children 0 to 11 years of age, long-acting β-adrenergic agonists or leukotriene receptor antagonists, and, in children 5 to 11 years of age, theophylline, may be considered as adjunctive therapies in combination with ICS. It is important to note that although studies have examined adjunctive therapy in adults, adjunctive therapy has not been studied adequately in children. Studies in adults support that the addition of a long-acting β-agonist to ICS leads to greater improvement in lung function and symptoms than increasing the dose of ICS or using leukotriene receptor antagonists as adjunctive therapy. Several studies show that for patients who have mild or moderate persistent asthma, use of higher dose ICS negligibly improves asthma control compared with lower doses.14 However, in other studies, higher doses have demonstrated added benefit. Once the asthma is well controlled for at least 3 months, stepdown of the therapy should be considered. Several studies have shown that for most patients whose asthma has been well controlled by high-dose ICS alone, a 50% reduction in dose can be tolerated without peak expiratory flow loss of control.14 However, there is significant variability in response, and the ICS should be decreased cautiously. The patient and family should be given a plan if symptoms worsen while the ICS are being decreased. Each patient and family should be given a written asthma action plan based on signs and symptoms and/or peak expiratory flow, especially those with moderate or severe asthma or those at higher risk for exacerbations.

ICS are well tolerated and safe at the recommended dosages. Oral candidiasis (thrush) is uncommon in patients on low-dose ICS, but it is a common adverse effect of high-dose ICS.6 In order to minimize this risk, use the lowest dose of ICS that provides control and advise patients to rinse their mouths (rinse and spit) after inhalation of the ICS. In addition, use of a spacer or valved holding chamber with a non-breath-activated metered-dose inhaler will reduce the risk of thrush. Dysphonia is another side effect of ICS therapy, especially at higher doses, although it is less common in children. Use of a spacer or valved holding chamber minimizes risk. Reflex cough and bronchospasm have been reported after use of ICS. These effects can be reduced by optimizing inhaler technique and the use of a spacer or valved holding chamber. The side effect that is most worrisome in children is the potential effect on linear growth. Longitudinal studies have shown that a reduction in growth velocity may occur in children or adolescents as a result of ICS therapy, but they are difficult to interpret because poorly controlled asthma may delay growth in children. Per the Expert Panel Report 3, the available cumulative data regarding children suggest that although low to medium ICS doses may decrease growth velocity, the effects are small, nonprogressive, and may be reversible. Combination therapy should be initiated when high-dose ICS are necessary to control symptoms in order to reduce the dose of ICS and minimize possible dose-related long-term effects on growth. Low- and medium-dose ICS appear to have no serious adverse effects on bone mineral density in children. Cases have been reported of children who have severe, persistent asthma and are taking immunosuppressive doses of systemic corticosteroids developing disseminated varicella. Children on immunosuppressive doses of corticosteroids who have not been immunized against varicella and are exposed to varicella infection are candidates for oral antiviral therapy. In children, low- and medium-dose ICS therapy has not been found to have a significant effect on the incidence of subcapsular cataracts or glaucoma. In a study of children, ICS at dosages from 400 to 1,000 mcg/day (budesonide) did not affect fasting glucose or glycosylated hemoglobin.

Oral Systemic Corticosteroids

Because of the considerable side effects of systemic steroids, oral systemic corticosteroids should be used only for the most severe asthma patients who are not controlled by the other modes of therapy. Other modes of therapy should be maximized in order to minimize the systemic steroid dose. It is necessary, therefore, to monitor for the development and progression of adverse effects and to take appropriate steps to minimize the risk and impact of adverse corticosteroid effects.

Leukotriene Modifiers

Leukotrienes (LT) are products of arachidonic acid metabolism released from mast cells, eosinophils, and basophils. Via the cyclooxygenase pathway, arachidonic acid is converted to prostaglandins and thromboxanes. Through the action of 5-lipoxygenase, arachidonic acid is converted to LTA4 (leukotriene A4), which can then be converted to LTB4 (leukotriene B4) through the action of the LTA4 hydrolase or to LTC4 via LTC4 synthase. LTC4 can then be converted to LTD4 and LTE4. LTB4 is produced by a variety of cell types and is strongly chemoattractive for neutrophils. To a lesser extent, it is also chemoattractive for eosinophils. The effects of LTB4 are mediated by the LTB4 receptor.

In 1983, Samuelson identified the slow-reacting substance of anaphylaxis (SRS-A) as the cysteinyl leukotrienes LTC4, D4, and E4. The cysteinyl leukotrienes are potent bronchoconstrictors of human smooth muscle, stimulate mucous production, and increase vascular permeability, resulting in exudation of plasma into the airway walls and lumen. Patients with asthma are very sensitive to the bronchospastic effects of inhaled leukotrienes.

Three leukotriene modifiers—montelukast, zafirlukast, and zileuton—are available as oral tablets for the treatment of asthma. There are 2 classes of compounds: 5-lipoxygenase pathway inhibitors (eg, zileuton), and leukotriene receptor antagonists (eg, montelukast and zafirlukast, which block the effects of the CysLT1 receptor). Only montelukast (for children as young as 1 year) and zafirlukast (for children as young as 7 years) are approved for use in children. Three randomized, controlled, double-blind studies in children 5 to 15 years of age demonstrated greater effectiveness of ICS compared to montelukast.15 Although ICS are the preferred controller therapy for persistent asthma, leukotriene receptor antagonists are an alternative treatment for mild, persistent asthma in children under 12 years. They can also be used as adjunct therapy with ICS for children under 12 years. In children 12 years or older, the preferred adjunct therapy is long-acting β-agonists. The use of leukotriene receptor antagonists as adjunctive therapy in moderate or severe asthma has not been studied adequately in children. Hepatic dysfunction has been reported as a side effect of zafirlukast, including some cases of fulminate hepatic failure. Patients should stop taking zafirlukast if any signs or symptoms of hepatitis occur.

Long-Acting β2-Adrenergic Agonists

Salmeterol and formoterol are β2-agonists, which bind to β2-adrenergic receptors and result in relaxation of airway smooth muscle. Both produce clinically relevant cardiovascular effects (tachycardia, QTc interval prolongation, and hypokalemia) at doses approximately 4 to 5 times those recommended. Due to their increased lipophilicity prolonging retention in lung tissue, a single dose results in a bronchodilation effect for about 12 hours. Formoterol has a more rapid onset of bronchodilation (similar to albuterol).

They should not be used alone for treatment of persistent asthma but rather in combination with ICSs for long-term control and prevention of symptoms in moderate or severe persistent asthma (step 3 or higher in children Å  5 years of age). These drugs should not be used for the treatment of an acute exacerbation.

Long-acting β2-agonists have been associated with an increased risk of asthma-related deaths and an increased number of severe asthma exacerbations. Thus, all preparations containing a long-acting β2-agonist carry a black box warning. The beneficial effects of long-acting β2-agonists in combination therapy for patients who require more therapy than low-dose ICS alone to control asthma (ie, require step 3 care or higher) should be weighed against the increased risk of severe exacerbations, although uncommon, associated with the daily use of long-acting β2-agonists. In children 5 years or older who have moderate, persistent asthma that is not well controlled on ICS, the option to increase the ICS dose should be given equal weight to the option of adding a long-acting β2-agonist.6 Long-acting β2-agonists may be used to prevent exercise-induced symptoms; however, it is important to note that chronic, regular use of long-acting β2-agonists has been shown to result in a decrease in the duration of action to less than 5 hours.

Omalizumab

Omalizumab is a recombinant DNA–derived humanized monoclonal antibody to the Fc portion of IgE. It blocks the ability of IgE to bind to its high-affinity receptor (FcεRI) on mast cells and basophils. The use of this antibody results in reduction of the serum concentration of free IgE and attenuates the allergic response to inhaled allergens in sensitized individuals. It may be considered as adjunctive therapy in patients 12 years or older who have allergies and severe, persistent asthma (step 5) that is not controlled with the combination of high-dose ICS and long-acting β2-agonists.

In clinical trials of patients with moderate or severe persistent allergic asthma (IgE > 30 IU/mL) incompletely controlled with ICS, addition of omalizumab to ICS therapy produced a reduction in asthma exacerbations, improved quality of life, and showed a small improvement in lung function in some studies.6 Omalizumab appears to have a modest steroid-sparing effect and is the only adjunctive therapy to demonstrate added efficacy in patients who are already on high-dose ICS and long-acting β2-agonists.

Anaphylactic reactions are estimated to occur in 0.2% of treated patients, which resulted in a US Food and Drug Administration alert (FDA 2007; http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatients andProviders/ucm103291.htm). These reactions occur for the most part within 2 hours of the first 3 injections of omalizumab injection, but reactions can occur at any time. Thus, administration of omalizumab should be performed only in settings equipped for the identification and treatment of anaphylaxis (FDA 2007). Adverse effects reported from omalizumab in the trials have also included injection-site pain and bruising in up to 20% of patients.16

Cromolyn Sodium and Nedocromil

These agents are mast cell stabilizers. They are not the preferred treatment for any category of asthma but can be used as an alternative treatment for mild, persistent asthma. They may also be efficacious as preventive treatment prior to exercise, cold air, or unavoidable exposure to known allergens.6 However, these agents are less effective than ICS in improving outcomes measures.

Treatment of Acute Episodes

Asthma remains a leading cause of emergency department visits by children. Severe exacerbations of asthma are potentially life threatening. Care must be prompt, and rapid recognition of a severe exacerbation is critical, as this requires close observation for deterioration, frequent treatment, and transfer to an emergency department. The assessment of the severity of an acute asthma exacerbation is an important guide to treatment. All clinicians treating patients who have asthma should be prepared to treat an asthma exacerbation, be familiar with the symptoms and signs of severe and life-threatening exacerbations, and have procedures for facilitating immediate transfer to an emergency department. Clinical signs characterizing a severe episode include the use of accessory muscles, limited ability to speak, preference to sit upright, a paradoxical pulse greater than 25 mm Hg, a heart rate greater than 130/min, a respiratory rate of more than 25 breaths/min, a peak expiratory flow of less than 50% of predicted, and an oxygen saturation less than 92%. If any of these signs are present, the patient should be transferred to an emergency department immediately.

A brief history should include ascertainment of the onset of the exacerbation, identification of any potential triggers, current medications and timing of the most recent dose, comorbid conditions, and the number of previous emergency department visits and hospitalizations (including intensive care unit and need for intubation) for asthma. The physical examination should focus on assessment of the severity of the exacerbation and possible complications, including pneumonia, pneumothorax, or pneumomediastinum. Most patients who have an asthma exacerbation do not require any initial laboratory studies. Chest radiography is not recommended for routine assessment but should be obtained if a complicating process is suspected, such as a pneumothorax, pneumomediastinum, pneumonia, or lobar atelectasis. The differences in the anatomy and physiology of the lungs of infants and young children place them at greater risk for respiratory failure, so it is important to monitor arterial oxygen saturation (SaO2) by pulse oximetry.

According to the Expert Panel Report 3, initial treatment for an acute exacerbation should include oxygen to maintain an SaO2 greater than 92% and 3 treatments of a short-acting β2-adrenergic agonist (each 2.5–5.0 mg albuterol by nebulizer or 4–8 puffs of metered-dose inhaler) spaced every 20 to 30 minutes should be given.6 Ipratropium bromide (0.25–0.5 mg nebulizer solution or 4–8 puffs by metered-dose inhaler in children) should be added for patients who have severe exacerbations. Systemic corticosteroids (1–2 mg/kg/day up to a maximum 60 mg/day for 3–10 days) are recommended for patients who have moderate or severe exacerbations and do not respond completely to initial therapy. Oral administration of prednisone has been shown to be as effective as intravenous methylprednisolone. A 5- to 10-day course following emergency department discharge is recommended to prevent early relapse. Improvement from an asthma exacerbation is usually gradual, and even when symptoms have resolved, evidence of inflammation in the airways has been shown to continue for up to 2 to 3 weeks. Intramuscular depot injections of corticosteroids have been shown to be effective in preventing relapse after discharge from the emergency department. Thus, this option may be considered as an alternative to oral corticosteroids for patients who are at high risk of noncompliance. Systemic corticosteroids can speed resolution of airflow obstruction and reduce the rate of relapse but may be associated with considerable side effects. Little information is available regarding the side effects of brief courses of systemic corticosteroids. One epidemiologic study suggests that children 4 to 17 years of age who require more than 4 courses of oral corticosteroids (average duration 6.4 days) as treatment for underlying disease have an increased risk of fracture. Another study concluded that multiple short courses of oral corticosteroids (median 4 courses in the preceding year) in the treatment of asthma in children 2 to 17 years of age were not associated with any lasting effect on bone metabolism, bone mineralization, or adrenal function.18 In another study, children who received 4 or more bursts of oral corticosteroids for acute asthma exacerbations in the previous year demonstrated a subnormal response of the hypothalamic-pituitary-adrenal axis to hypoglycemic stress or adrenocorticotrophic hormone.

Quick-Relief Medications

Quick-relief medications are used to provide prompt relief of acute asthma symptoms, including cough, chest tightness, and wheezing. These medications include short-acting β2-adrenergic agonists and anticholinergics (ipratropium bromide). Short-acting β2-agonists (albuterol, levalbuterol, pirbuterol, etc.) relax airway smooth muscle, resulting in a rapid increase in airflow and symptomatic relief. These agents exist as racemic mixtures, and the (R)-enantiomers have been shown to possess the majority of the therapeutic activity. However, there has been no consistent added benefit of the (R)-enantiomer versus the racemic mixture. Short-acting β2-agonists are very effective in the treatment of acute symptoms, but regular use is not recommended because it has not been shown to have added benefit when compared to use when needed with regard to asthma control. Use of short-acting β2-agonists more than 2 times per week may signify that the asthma is not well controlled, and controller therapy should be adjusted accordingly. Increasing use of short-acting β2-agonists has been associated with increased risk of acute exacerbation requiring hospitalization and increased risk for death. Several common genetic polymorphisms have been identified in the β2-adrenergic receptor gene, some of which may be relevant to the function of the receptor. Two studies have shown that patients who are homozygous for arginine at position 16 (Arg/Arg 16) are more likely than patients who are homozygous for glycine (Gly/Gly 16) to experience decline in lung function when taking regularly scheduled daily albuterol treatment.17 Additional studies are needed to delineate the clinical utility of these observations.

Other Treatment Considerations

Immunotherapy

According to the Expert Panel Report 3, allergen immunotherapy should be considered for patients who have persistent asthma, evidence of allergen sensitization, and a history supporting a relationship between asthma symptoms and allergen exposure.6 Clinical studies have demonstrated that immunotherapy is effective in reducing asthma symptoms caused by exposure to grass, cat, house-dust mite, ragweed, Cladosporium, and Alternaria. A meta-analysis of 75 randomized, placebo-controlled studies confirmed the effectiveness of immunotherapy in asthma, with a significant reduction in asthma symptoms and medication and with improvement in bronchial hyperreactivity.19 Furthermore, immunotherapy may prevent the development of asthma in children with allergic rhinitis.20 The duration of a course of allergen immunotherapy is typically of 3 to 5 years. Immunotherapy carries a risk of allergic reactions, including severe anaphylaxis, and these are more frequent among patients with poorly controlled asthma. Thus, immunotherapy should be administered only in a physician’s office equipped to handle anaphylaxis.

Environmental Allergen Avoidance

Environmental allergen avoidance is one of the goals of asthma management. Allergic sensitization is very common among asthmatics: 60% in adults and as high as 90% of children. Sensitized asthmatic patients, challenged with extracts of the aeroallergens to which they are sensitive, display symptoms of acute asthma. Asthmatic symptoms and objective measurements of lung function improve when patients avoid allergens to which they are sensitive.21

Specific strategies for allergen avoidance are dependent on the allergen. The allergen that has been best studied is the house dust mite. The key target for control of dust mite exposure is bedding because of the high level of mite allergen exposure in mattresses as well as the proximity of the patient to the source of dust mite and the prolonged period of time that is spent in this one site. In studies examining the effectiveness of dust mite–proof encasings for bedding, there were long-term reductions in the amount of allergen recovered as well as in the allergen concentrations. Another recommendation is weekly washing of all sheets and bedding in hot water at a temperature of greater than 130°Cin order to kill dust mites. Other recommendations for decreasing dust mite exposure include removal of wall-to-wall carpeting and replacement with hardwood floors or tiled floor surfaces and using methods to decrease humidity.

Pet allergen control represents a unique problem. Almost all residences contain detectable cat and dog allergen regardless of whether there is a cat or dog in the home. Although the mean level in houses without cats is significantly lower than that found in houses with pets, the lower level is still sufficient to cause symptoms in some individuals. Optimal strategy for cat allergen control is relocation of the cat to another environment. This results in a drop in allergen levels by up to 70%, although it takes years for the levels to decline to levels found in homes without a cat. Other measures, such as frequent washing of the cat, air filtration, and treatment with drugs or emollients have not been shown to be effective.

Cockroach sensitivity and exposure are common among patients who have asthma and live in inner cities. In a study of asthma in an inner-city area, asthma severity increased with increasing levels of cockroach antigen in the bedrooms of sensitized children. Cockroach control measures are recommended if the patient is sensitive to cockroaches and infestation is present in the home.6 The data for other environmental control measures, including control of molds, are still not definitive but support that decreasing exposure may be beneficial. As a routine part of their asthma care, patients and families should be counseled concerning the negative effects of smoking and environmental tobacco smoke. Notably, smoking out of doors does not adequately reduce exposure for children. There is insufficient evidence to recommend indoor air cleaning devices.

For severe exacerbations unresponsive to the initial treatments, adjunct treatments (magnesium sulfate or heliox) can be considered. Studies in children and adults have demonstrated that adjunct intravenous magnesium sulfate (25–75 mg/kg up to 2 g in children) reduces hospitalization rates in emergency department patients with severe asthma exacerbations. Magnesium sulfate has not been shown to be beneficial in mild or moderate exacerbations.

Use of Metered-Dose Inhalers

An important component of asthma management is education. This includes education regarding the goals of therapy, the different types of medication (controller versus quick relief), the importance of taking the medications as prescribed, the actions to be taken for worsening symptoms, and the correct inhaler technique.

Spacers and Valved Holding Chambers

Both spacers and valved holding chambers are intended to retain large particles emitted from the metered-dose inhaler, reduce deposition in the oropharynx, and promote inhalation of a higher proportion of small, respirable particles. In vitro and in vivo studies comparing various spacers and valved holding chambers with the same metered-dose inhaler have demonstrated a 2- to 6-fold variation in the respirable dose emitted from the devices and a 2- to 5-fold difference in systemic availability of the drug. Valved holding chambers are preferred in children because they have one-way valves that do not allow the child to exhale into the device. Thus, the child does not need to coordinate actuation and inhalation.

Periodic assessments of asthma control are recommended to determine if the goals of therapy are being met and if adjustments in therapy are needed. The frequency of visits to a clinician for review of asthma control is a matter of clinical judgment but should be, as a general rule, about every 6 months. Patients with poorly controlled and/or severe, persistent asthma (ie, requiring steps 5 or 6 treatment) and those who need additional supervision to help them follow their treatment plan should be seen more often.

Ongoing control assessment should include monitoring of signs and symptoms of asthma, pulmonary function, quality-of-life/functional status, history of asthma exacerbations, adherence to therapy, and potential side effects from medication, as summarized in Table 512-3.22-24 Per the Expert Panel Report 3,6 clinicians should use self-assessment tools to determine the patient and family assessment of the control of the asthma. Several multidimensional instruments have been developed to assess control (Table 512-3).

Spirometry is recommended at the time of initial assessment, after the patient’s asthma symptoms have stabilized, and then every 1 to 2 years. They are also recommended during periods of progressive or prolonged loss of asthma control.6 Although spirometry is the preferred method to assess pulmonary function, peak flow monitoring should be considered for patients who have moderate or severe persistent asthma, patients who have a history of severe exacerbations, and patients who have difficulty accurately perceiving their level of airflow obstruction and worsening asthma. Peak expiratory flow rate is dependent on effort and technique; thus, it is important to review the technique frequently with the patient.

The goals of asthma treatment include improving quality of life for people who have asthma in addition to controlling symptoms, reducing the risk of loss of lung function, exacerbation, and death. It is important, therefore, to examine how the disease expression and control are affecting the patient’s quality of life. Correlations between asthma symptoms and quality of life are often in the low to moderate range, while correlations with pulmonary function measures are even weaker. Thus, the impact of the disease on the patient must be assessed directly and cannot reliably be inferred from the pulmonary function or symptoms.

A history of previous exacerbations, especially in the past year, is the strongest predictor of future severe exacerbations. Thus, it is critical to ascertain a careful history of exacerbations, including the frequency, rate of onset, severity (length of hospital stay, use of corticosteroids, admission to intensive care unit, intubation), and causes of exacerbations. Referral to an asthma specialist should be considered in patients whose asthma is severe or difficult to control, as outlined in Table 512-4.