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Asthma is a chronic condition associated with significant health and economic burden to patients, families, and society. 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, and its global pharmacotherapeutic costs exceed $5 billion per year. Although patients suffering from asthma share similar clinical symptoms, the disease itself is heterogeneous in terms of phenotypes and natural history. This heterogeneity is compounded by combinations of environmental exposures that occur in utero, in early life, and across the life span, which contribute to the difficulty in both studying and treating asthma. This challenge is especially evident in children, for whom asthma remains the leading cause of emergency care and hospitalization rates continue to rise.
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Currently, there are no national measures of the incidence of asthma and the rate at which it develops over time. However, the prevalence of asthma has been tracked by the National Health Interview Survey (NHIS), which is used to produce annual health estimates based on self-report of a nationally representative sample. Prevalence identifies the population in need of effective measures to control asthma symptoms. Between 1980 and 1995, the prevalence of asthma 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 then, prevalence remains high, 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). Although some countries have seen a decline in asthma-related hospitalizations and deaths, the global burden for patients from exacerbations and day-to-day symptoms has increased by almost 30% in the past 20 years. Nearly two-thirds of these children who currently have asthma reported at least 1 attack in the previous 12 months. Ambulatory care use for asthma has continued to grow since 2000, while the overall rate of ambulatory care use for children has not increased. Despite increased overall healthcare utilization and the fact that there are means to prevent attacks or exacerbations among children with asthma, 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. It is estimated that at least 70% of all children who have asthma have persistent asthma.
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In a recent systematic review, all existing childhood asthma prediction models were assessed for their potential to identify preschool children who will develop asthma at school age. Twelve prediction models were identified, and no single model was able to predict asthma development.
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Racial disparities in childhood asthma are extensive. Children of American Indian or Alaska Native descent have current asthma prevalence rates 25% higher and black children 60% higher than those of white children. African Americans are 4 times more likely to be hospitalized and 5 times more likely to die of asthma than are non-African Americans. When race and ethnicity are considered, Puerto Rican children have the highest prevalence of all groups, 140% higher than that of 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 rates between black and white children has increased in recent years. The relative importance of urban residence, low socioeconomic status, or minority (particularly black and Hispanic) status as independent risk factors for increased asthma morbidity and mortality remains controversial.
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Asthma Heterogeneity: Role of Phenotypes and Endotypes
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The concepts underlying asthma pathogenesis have changed dramatically over the last 5 years, and our understanding of this complex disease continues to evolve. It is now clear that asthma is not a single disease but rather a syndrome that can be caused by numerous distinct biologic mechanisms. Epidemiologic, clinical, genetic, genomic, immunologic, and molecular approaches have been used to classify clinically relevant variants of asthma, with the goal of maximizing the efficacy of treatment. This effort has led to the concept of “phenotype” versus “endotype.” A disease phenotype describes observable characteristics and consists of common patterns of clinical observations; phenotypic variants of asthma can be identified by natural history (age of onset, age of remission), sex, lung function, bronchial reactivity, exacerbation frequency, and severity of clinical symptoms (eg, symptom, physiology, behavior, biochemical marker, natural history). Cluster analyses of well-characterized asthma cohorts have identified several distinct clinical phenotypes in adults and children. However, these phenotypes have limited ability to improve management or guide treatment choices because the phenotypes often overlap and do not relate to specific underlying pathophysiologic mechanisms. This gap in understanding led to concerted efforts to define asthma endotypes. An asthma “endotype” is a disease subtype that is defined by a distinct functional or pathobiologic mechanism. Molecular biomarkers are used to define asthma endotypes. The biomarkers can include patterns of allergic sensitization, serum factors or proteins, metabolites, genetic/genomic and epigenetic markers, immunologic patterns, and sputum or blood cellularity. The linkage to pathogenic mechanisms renders recognition of endotypes especially valuable, as knowledge of pathogenic mechanisms of specific variants of asthma may serve as a more precise guide to treatment. Molecular differences likely exist even within endotypes, as well as overlap in inflammatory features among endotypes.
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Inflammation has a central and consistent role in the pathophysiology of asthma, regardless of the severity or subtype of 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 (Fig. 505-1). Airway narrowing and subsequent airflow limitation lead 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. In some persons who have asthma, airflow limitation may be only partially reversible due to permanent changes in the airway that increase airflow obstruction and airway responsiveness, known as airway remodeling (which may have occurred antenatally).
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The inflammatory response in the airways of patients with asthma is caused by genetic and environmental interactions that prompt an orchestrated series of events initiated by an interplay between the airway epithelium and the innate and adaptive immune system, driving a chronic inflammatory response (Fig. 505-2). Environmental factors are critical determinants of the development, persistence, and progression of asthma. Specific exposures in susceptible children during critical stages in development (especially during early life while the respiratory and immune systems are maturing) give rise to changes in developmental trajectories, which are in part mediated by changes in epigenetic markers and multigene regulation. The resulting asthma-related endotypes and intermediate phenotypes precede and may predict the development of the different clinical expressions of asthma.
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The immunohistopathologic features of asthma include epithelial injury and infiltration of inflammatory cells, consisting of eosinophils, lymphocytes, mast cells, neutrophils, and phagocytes. Inflammatory mediators released by these cells include cytokines, chemokines, lipid mediators, and proteases, which are the effectors of chronic inflammation. Differing asthma phenotypes, including eosinophilic asthma, neutrophilic asthma, and mixed eosinophilic and neutrophilic asthma, have been described based on the nature or pattern of inflammation. The recruitment of eosinophils and neutrophils is dependent on cytokines and chemokines, and recent data suggest that the specific T-cell types may be important in characterizing clinically relevant endotypes.
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The most predominant and clearly described endotype is eosinophilic asthma, which accounts for approximately 50% to 60% of the total asthma population. Most of these patients can be controlled on moderate to high doses of inhaled corticosteroids (ICS), but 5% to 10% have severe disease that requires oral corticosteroids to control the eosinophilic airway inflammation. In these patients, eosinophils are often increased in the blood (≥ 400/mL) when asthma is severe or uncontrolled. Type 2 innate lymphoid cells (ILC-2s) have been implicated in the pathogenesis of this form of asthma. ILC-2s become activated in response to the epithelial cell–derived cytokines interleukin (IL)-33, IL-25, or thymic stromal lymphopoietin (TSLP) and release mediators associated with a TH2 response. ILC-2s have been reported to secrete 40-fold more IL-5 and 10-fold more IL-13 than T cells. IL-5 and IL-13 that are locally produced by steroid-insensitive ILC-2s may contribute to persistent sputum eosinophilia in patients who may have normal blood eosinophils. The release of these cytokines is induced by proteases, which are present in various allergens, viruses, and bacteria.
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Other biomarkers have been suggested to identify eosinophilic asthma. Forced exhaled nitric oxide (FeNO) is possibly the most widely used method in clinical practice for the evaluation of airway inflammation because of the availability of a Food and Drug Administration–approved device (NIOX, Aerocrine, Sweden). However, the degree of correlation between FeNO and sputum eosinophils is low. A systematic review found that tailoring treatment based on FeNO failed to reduce the number of exacerbations, both in adults and children, and could potentially be harmful, as it was associated with use of higher ICS doses in children.
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Neutrophilic Asthma and Mixed Eosinophilic/Neutrophilic Asthma
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The presence of neutrophils in asthma is often characterized by more severe asthma, poor asthma control, a greater need for more potent and multipronged treatment approaches, and treatment resistance, especially to corticosteroids. The presence of eosinophils varies in “neutrophilic” asthma, but recent studies suggest that most patients have airway neutrophilia in combination with persistent airway eosinophilia, regardless of atopic status. The mixed cellular inflammatory state is accompanied by the presence of mixed cytokines. The presence of IL-17A is consistent with the neutrophilic infiltrate because IL-17A induces the expression of neutrophilic chemokines, resulting in neutrophil influx. Recently, exposure to numerous environmental factors including traffic-related air pollution (TRAP) and fungi has been shown to result in TH17 responses and severe asthma characterized by neutrophils and eosinophils.
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Exacerbations of asthma, including those that require emergency department care or hospitalization, occur variably in patients across all levels of severity. Although patients with severe asthma are more likely to have frequent exacerbations compared with patients suffering from mild and moderate disease, a proportion of asthmatics with milder phenotypes are exacerbation prone. These observations suggest that patients with frequent exacerbations may represent a separate phenotype of disease with potentially unique pathogenetic mechanisms. In line with this suggestion is that although improving baseline asthma control with inhaled glucocorticosteroids can reduce the risk of exacerbations in patients with atopic asthma, a decrease in asthma symptoms does not always reduce the number or severity of exacerbations. Recent evidence supports that it is a distinct endotype. In a genome-wide association study, CDHR3 was identified as a susceptibility locus for this phenotype. CDHR3 has been reported to serve as a receptor for human rhinovirus (HRV) type C strains.
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ENVIRONMENTAL RISK FACTORS FOR CHILDHOOD ASTHMA
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The impact of the environment, including lifestyle factors (eg, obesity, diet/nutrition), on the incidence and morbidity rates of asthma is increasingly being recognized. The increasing prevalence and marked variations in the proportion of children with asthma in different countries and in migrating populations over this relatively short period of time cannot be explained by genetic differences alone and strongly implicate environmental causations.
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The association of asthma and allergy has been long recognized, first in cross-sectional studies and more recently in prospective studies. Immunoglobulin (Ig) E–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 the exacerbation of existing asthma. Exposure to allergens is linked to sensitization, which is a risk factor for development of asthma. However, the role of allergens in the development of asthma is complex and is yet to be fully defined. Numerous epidemiologic studies have shown that children who grow up on traditional farms are protected from allergic sensitization and asthma. Studies support that the protection may be due to activation and modulation of innate immune responses by microbial exposures. Similarly, observations from longitudinal birth cohort studies have revealed that exposure to dogs in early life also protects against the development of asthma. Environmental influences may have different effects on disease during specific “windows of opportunity” or times when the child is most vulnerable. Allergy testing is recommended for patients who have persistent asthma.
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Despite the overall decrease in tobacco use in the United States over the last decade, the prevalence of cigarette smoking remains high in urban populations. An estimated 50% to 75% of children have detectable levels of serum cotinine, a nicotine metabolite. Families with lower incomes and education levels have disparately higher levels of parental reported secondhand smoke (SHS) exposures. 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 households having 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 SHS is associated with increased symptoms, decreased lung function, and greater use of health services. As SHS has many associated adverse health effects in children, it is important for clinicians to collect unbiased, precise, and accurate exposure histories. Questions posed to collect these histories in the clinical setting must be both comprehensive and concise to enable targeted interventions. In addition to inquiring about maternal smoking, recent studies reveal that it is important to ask questions about the number of smokers living in the home, the number of hours per day the child is exposed to smoke, and whether anyone ever smokes in the car with the child. Furthermore, the possibility that an older asthmatic child may be an active smoker should not be discounted.
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Exposure to TRAP and, in particular, diesel exhaust particles (DEPs), a major component of TRAP, has been associated with childhood asthma symptoms and exacerbations. A comprehensive and systematic review of worldwide traffic emissions and health science by a Special Panel convened by the Health Effects Institute (HEI) found sufficient evidence that exposure to TRAP causes exacerbation of asthma in children (HEI Special Report 17, Boston, MA: Health Effects Institute, 2010). Exposure to TRAP has been shown to enhance allergen-specific memory, thereby potentiating secondary allergen recall responses and promoting exacerbations. Ultra-fine DEPs reach small airways including the alveolar/gas exchange regions of the lung, exacerbating respiratory disease symptoms. This exposure is highly significant because in large cities in North America, up to 45% of the population resides in zones that are most impacted by TRAP, and more than 30% of schools are located in high TRAP-exposure areas. Further, although truck engines are being designed to decrease particle exposures, air quality and engine exhaust control policies implemented in 2005 to 2010 have not produced significant changes in TRAP levels. DEPs 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. DEPs can interact directly with allergens and have been shown to augment allergen-induced responses. In addition, DEPs absorb other metals and toxic gases produced by diesel engines, such as polycyclic aromatic hydrocarbons, which have direct detrimental effects on the lungs. Other components of TRAP, including ozone, nitrogen dioxide, and polycyclic hydrocarbons, have also been implicated as contributors to asthma symptoms.
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Respiratory Infections
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Numerous respiratory viruses in infancy have been associated with the subsequent development of asthma. HRV infection has been associated with the majority of exacerbations of asthma in pediatric patients. HRV is a positive-sense, single-stranded picornavirus that is subcategorized into A, B, and C strains, with HRV-A and HRV-C implicated in most exacerbations. The mechanism for the propensity of HRV infection to trigger exacerbation of asthma remains ill-defined for all viral strains. Most exacerbations of asthma caused by HRV occur in those who are atopic, and the risk for wheezing with HRV is strongly associated with high levels of total and allergen-specific IgE and with the presence of TH2-related airway inflammation prior to an infection. Some studies suggest that decreased production of interferon in response to viral infection in the setting of TH2 inflammation may contribute to exacerbations of asthma. The impact of viral infection on outcomes is not restricted to HRV. Further understanding of the viral mechanisms that contribute to persistent recurrent wheezing is needed.
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Fungi are ubiquitous in indoor and outdoor environments and have been associated with childhood asthma. Overwhelming and mounting evidence links mold exposure and asthma, and the mechanistic basis for the association has often been attributed to fungal sensitization. However, in addition to their ability to act as allergens, fungi have direct immunomodulatory activities. β-Glucans account for as much as 60% of the weight of the cell wall and can bind and signal directly through dectin-1, promoting fungal immunity by inducing dendritic cells to polarize T cells toward TH17 cells. Exposure to a fungus has been shown to promote the development of severe allergic asthma and render it more resistant to steroids. This reaction may be mediated via the induction of TH17 responses by β-glucans independent of sensitization.
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GENETIC CONTRIBUTION TO ASTHMA PATHOGENESIS
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Although environmental influences are important in the development of asthma, a strong genetic predisposition exists. The single most important factor in predicting asthma among infants and young children with wheezing is a family history of allergy. A recent meta-analysis of 71 twin studies estimated the heritability of asthma to be 0.54 (standard error, 0.048). It is now evident that the pathogenesis of asthma is dependent on the occurrence of multilayered gene–environment interactions over time. A particular asthma gene may be relevant only in the context of a specific environmental exposure during a key developmental period or age in a given population. In other words, environmental exposures that occur at the right time in a given individual may increase the penetrance of a given asthma susceptibility genotype, resulting in the development or progression of asthma. The same genetic susceptibility will not be evident in an individual who was not exposed to the relevant environmental factor or was exposed at a time when he/she was not fully susceptible to the negative health effects of the exposures. Accordingly, studies that focus on smaller, specific asthma phenotypes and endotypes have begun to yield identification of genetic risk alleles with larger effect sizes. The genetic underpinnings of different asthma phenotypes and endotypes are likely to be completely distinct and need to be studied independently.
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CLINICAL MANIFESTATIONS
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Asthma is characterized by respiratory symptoms such as wheeze, shortness of breath, chest tightness, and cough that vary over time and in intensity. The symptoms may occur during the daytime and/or nighttime and may be triggered by exposure to exercise, allergens, irritants (TRAP, SHS, perfumes, paint fumes), cold weather, or other factors. The clinical manifestations of asthma often are shaped by the presence of comorbid conditions. Compared to children without asthma, children with asthma had higher prevalences of allergic rhinitis, eczema, and food allergy. The term multimorbidity may be more appropriate than is comorbidity because the primary allergic disease often is not clearly identifiable. Although the concept of multimorbidity of allergic diseases has been known for years, recent studies have shed important insights on allergic multimorbidity.
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Allergic Multimorbidity
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The atopic or allergic march describes the sequential progression of different allergic conditions frequently observed in children with IgE-antibody responses against common environmental allergens (atopy). Eczema or atopic dermatitis (AD) may predate the development of other allergic disorders later in life. An estimated one-third to half of patients with AD will develop asthma; however, the mechanisms that promote disease progression remain unclear. Atopic sensitization has been reported to be a major determinant of AD progression to respiratory allergy; however, the mechanisms of disease progression are far more complex. The discovery of the filaggrin loss-of-function mutations has provided genetic evidence linking skin barrier deficiency to eczema and asthma. The skin matrix protein filaggrin promotes keratin aggregation; abnormal function of this protein has been associated with eczema, asthma, and allergic rhinitis. Furthermore, a genome-wide association study of eczema followed by childhood asthma implicated several new susceptibility loci.
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The importance of monosensitization versus polysensitization in allergic disease multimorbidity also has been demonstrated. Data reveal that mono- and polysensitization represent 2 different phenotypes of IgE-associated diseases. Polysensitization, as compared to nonsensitization and monosensitization, is associated with a higher frequency of family history of allergic disease (asthma and rhinitis), a higher prevalence of symptoms of asthma and rhinitis, a higher prevalence of multimorbidity, a broader sensitization to different allergens, and the persistence of allergic diseases with a lower probability of remission. Thus, it has been suggested that sensitization should be considered as a qualitative and quantitative trait (monosensitization and polysensitization), as important clinical differences exist between monosensitized and polysensitized subjects. Epidemiologic studies confirm that sensitization among genetically susceptible populations to allergens, including house dust mites, pet dander, Alternaria mold, and cockroaches, confers risk for childhood asthma. Sensitization to outdoor pollens has been associated with seasonal asthma. Further, recent data suggest that polysensitization defined in part by food sensitization may have additional clinical impact.
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The upper and lower airways exist as a continuum and show similar histopathologic changes, including epithelial damage, thickening of the basement membrane, and a predominantly eosinophilic cellular infiltrate, when inflamed. Segmental bronchial allergen challenge causes inflammatory changes in both nasal and bronchial mucosa. Exposure of sensitized subjects to allergens leads to increased inflammation and airway hyperresponsiveness. Anti-inflammatory treatment aimed at the upper airway results in decreased markers of lower airway inflammation. Furthermore, treatment of allergic rhinitis with antihistamines and intranasal steroids has been reported to decrease emergency department visits for asthma.
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Similar to rhinitis, sinusitis can contribute to asthma symptoms. An association was observed between the extent of sinusitis, markers of lower airway inflammation, exhaled nitric oxide, and decreases in pulmonary function. Further, in children with asthma, treatment of the concurrent sinusitis with intranasal corticosteroids and antibiotics resulted in an improvement in respiratory symptoms and decreased airway inflammation.
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Allergic Bronchopulmonary Aspergillosis
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Allergic bronchopulmonary aspergillosis (ABPA) should be suspected in patients who have asthma and have the presence or a history of pulmonary infiltrates; it is rarely seen in children with asthma. 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). These patients should be referred to a specialist.
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Gastroesophageal Reflux Disease
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Symptoms of gastroesophageal reflux disease (GERD) may be seen in children who have asthma. According to the National Guidelines, medical management of GERD should be instituted for patients who have asthma (especially nocturnal symptoms) and complain of frequent heartburn or pyrosis; however, some recent studies have not noted any benefit of GERD therapy.
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The parallel rise in the prevalence of asthma and obesity suggests that they are related. Obesity has been associated with persistence and severity of asthma in both children and adults. Compared with nonasthmatics, body mass index (BMI) in asthmatics was 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 the risk for developing asthma is increased with increasing BMI. Indeed, a recent meta-analysis confirmed that obesity is a strong risk factor for incident asthma. Notably, as obese asthmatics lose weight, their asthma symptoms and lung function improve. Weight loss following gastric bypass surgery improved self-reported severity of asthma. Epidemiologic studies that have controlled for potential effects of diet and physical activity when examining the relationship of obesity to onset of asthma observed that the effects of obesity on asthma appear to be independent of diet and physical activity, although these 3 factors are clearly interrelated.
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Obstructive Sleep Apnea
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Nocturnal asthma and obstructive sleep apnea (OSA) may have similar clinical symptoms. Nocturnal symptoms in asthma frequently are underdiagnosed, and OSA may be prevalent in nocturnal asthma. A high prevalence of OSA has been reported in patients who have unstable asthma. Evaluation for OSA 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 expressions of both OSA and asthma. Patients who have unstable asthma and sleep apnea demonstrated improvement when treated with nasal continuous positive airway pressure (CPAP). In contrast, nocturnal nasal CPAP in individuals who have asthma and who do not have apnea is associated with disrupted sleep. Thus, confirmation of diagnosis is important.
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The classic aspirin triad (also known as Samter’s triad) of asthma, aspirin intolerance, and nasal polyposis most commonly develops in adulthood. However, as many as 5% of children with asthma may have aspirin-induced symptoms. Avoidance of nonsteroidal anti-inflammatory drugs should be considered in children with severe persistent asthma.
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Anxiety and Affective Disorders
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Estimates of the prevalence of internalizing disorders, such as anxiety and affective disorders, are significantly above the prevalence in the general pediatric population. These disorders are common illnesses in childhood but are often unnoticed because of their subtle features. Recognizing the presence of these disorders is important, as they may contribute to asthma symptoms and poor quality of life. Significantly higher rates of internalizing difficulties have been reported among children with severe asthma compared with those who have mild or intermittent asthma. Further, depression was an identified risk factor among severely asthmatic children who died of asthma. It is important to assess for the presence of maternal anxiety and depression as well because these conditions in the mother may contribute to severe asthma.
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Asthma is defined by the history of respiratory symptoms such as wheeze, shortness of breath, chest tightness, and cough that vary over time and in intensity, together with variable expiratory airflow limitation. The diagnosis of asthma should be based on a history of characteristic symptom patterns and evidence of variable airflow limitation, from bronchodilator reversibility testing or other tests. A diagnosis of asthma should be considered if any of the following clinical indicators are present: wheezing (however, 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 the diagnosis. Pulmonary function testing is recommended if any of the indicators are present.
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The history of symptoms varies with age. An infant or young child often has a history of recurrent wheeze or persistent cough with colds, whereas older children often complain of chest tightness or persistent cough/wheeze. Triggers for childhood asthma often include viral infections (especially RSV and HRV), allergen exposure, irritants (environmental tobacco smoke, pollution), weather changes, stress or emotional factors, gastroesophageal reflux, aspirin sensitivity, hormonal factors such as menses, and exercise.
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Per the Global Initiative for Asthma (GINA) guidelines, there is an increased probability that symptoms are due to asthma if more than 1 type of symptom (wheeze, shortness of breath, cough, chest tightness) is present, symptoms are worse at night or in the early morning, symptoms vary over time and in intensity, and/or symptoms are triggered by exposure to viral infections, exercise, allergens, changes in weather, or irritants. There is a decreased probability that symptoms are due to asthma in isolated cough with no other respiratory symptoms. If the cough is associated with chronic production of sputum or with dizziness, light-headedness or peripheral tingling, or chest pain, then additional workup for other causes is warranted.
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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 the presence of AD/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. Wheezing may be absent during severe exacerbations of asthma due to severely reduced airflow. It is important to note that the presence of wheezing is nonspecific and may also be heard with upper airway dysfunction, respiratory infections, tracheomalacia, or inhaled foreign body. Crackles and inspiratory wheezing are not features of asthma. Examination of the nose may reveal signs of allergic rhinitis or nasal polyposis.
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Pulmonary Function Tests
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In a patient with typical respiratory symptoms, obtaining evidence of excessive variability in expiratory lung function is an essential component of the diagnosis of asthma. Pulmonary function tests (PFTs) should be attempted in children ≥ 5 years old with symptoms suggestive 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’s 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 expressed as a ratio of forced vital capacity (FEV1/FVC) relative to appropriate reference or predicted values. If obstruction is detected on the baseline PFT, a bronchodilator (albuterol) should be administered and the PFT repeated in 20 minutes. An improvement of 12% or greater and an absolute change of at least 200 mL 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 PFT results, the patient’s history and symptoms, along with the exclusion of other possible diagnoses, are needed to establish a diagnosis of asthma.
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Methacholine challenge testing (MCT) usually is 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. Bronchoprovocation testing should be carried out by a trained individual in an appropriate facility. Although a positive test is consistent with asthma, MCT 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 MCT is complicated and depends on the pretest probability. Methacholine concentrations between 8 and 16 mg/mL are consistent with bronchial hyperresponsiveness. 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 frequency of symptoms. Conversely, in another study, children who were classified as having mild-to-moderate asthma by symptoms had normal FEV1.
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Exercise-Induced Asthma
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Exercise-induced bronchoconstriction is a transient narrowing of the airways that affects 40% to 90% of asthmatic children and adolescents. Prevention is essential as it causes limitations in daily life activities in as many as 30% of children. The mechanisms underlying exercise-induced asthma (EIA) are not known. The optimal method for diagnosis of EIA is to perform a standardized exercise challenge test. A diagnosis of EIA cannot be made with an MCT, 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. The presence of exercise-induced bronchoconstriction is defined by plotting forced expiratory volume (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 are critical parts of managing asthma, especially considering that quality of life in children with asthma has been found to correlate with shortness of breath during exercise.
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EIA is best treated with ICSs to control inflammation as well as pretreatment before exercise with short-acting or long-acting bronchodilators. The use of β2-agonists before exercise will prevent EIA in more than 80% of patients. Short-acting agents confer protection for 2 to 3 hours, whereas long-acting agents may be protective for as long as 12 hours. However, frequent or chronic use of long-acting β2-agonists for EIA is not recommended as the protective effect wanes with frequent use and they may disguise poorly controlled persistent asthma. Other agents including leukotriene receptor antagonists and cromolyn are alternative therapies for EIA but are not as effective as is a steroid combined with β2-agonists. A mask or scarf over the mouth may attenuate cold-induced EIA. Objective testing for EIA is important. A European study showed that 50% of those treated for EIA did not have asthma or EIA.
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DIFFERENTIAL DIAGNOSIS OF ASTHMA IN CHILDHOOD
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A diagnosis of asthma requires an exclusion of other possible diagnoses. In hospitalized children, a chest x-ray should be strongly considered. Radiographic findings in asthma range from normal to hyperinflation with peribronchial interstitial infiltrates and atelectasis. In a 3-year study of hospitalized children with asthma, 76% had evidence of hyperinflation, whereas 20% had infiltrates, pneumonia, and/or atelectasis.
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The differential diagnosis of asthma in children is summarized in Table 505-1. It is important to note that any of these alternative diagnoses may be found together with asthma. A sweat test should be considered in children with recurrent wheezing and associated symptoms of failure to thrive, diarrhea, steatorrhea, nasal polyps, chronic or pan-sinusitis, and/or digital clubbing. An x-ray should also be done in these circumstances.
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Several conditions can coexist with asthma or mimic asthma symptoms and include rhinitis/sinusitis, GERD, OSA, 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.
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Cough-variant asthma is considered as 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. MCT or exercise-tolerance testing should be used to establish the presence of bronchial hyperresponsiveness to avoid overtreatment.
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Vocal Cord Dysfunction
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Vocal cord dysfunction (VCD) often mimics asthma. VCD 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 frequently is confused with asthma, leading to inappropriate medication of affected individuals with antiasthma medications. Asthma medications are not effective in treating VCD; thus, 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 management of the asthma. 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.
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ASSESSMENT OF ASTHMA CONTROL
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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. It involves (1) identifying triggers for the patient’s asthma; (2) identifying comorbidities that may be contributing to the patient’s asthma symptoms; (3) assessing treatment issues, particularly inhaler technique and adherence; and (4) assessing asthma control and severity, including assessment of symptoms and future risk (summarized in Table 505-2). Per the GINA guidelines, the level of asthma control is the extent to which the manifestations of asthma can be observed in the patient or have been reduced or removed by treatment. It is determined by interactions of the genetic background, environmental and psychosocial factors, and treatments.
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Identification of Asthma Triggers
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The evaluation of a patient with asthma should include identification of the patient’s asthma triggers, such as exposure to allergens (eg, pets, seasonal pollens), irritants (eg, environmental tobacco smoke, air pollution), fungi, 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.
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Assessment of Asthma Control and Severity
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The concept of asthma control should be discussed as patients often understand the concept of “asthma control” differently from health professionals. The frequency or severity of symptoms that patients regard as unacceptable or bothersome will vary from patient to patient and may not align with the current guidelines regarding the goals of asthma treatment. Further, a patient may state that his/her symptoms do not interfere with daily activities but neglect to mention that they have excluded exercise from their daily activities due to symptoms.
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Asthma severity is the intrinsic intensity of disease. Assessment of patients who have confirmed asthma includes classification of severity because the selection of drug class and dose of therapy should correspond to the level of asthma severity. This initial assessment of asthma severity is made immediately after diagnosis and before treatment based on the symptom burden, lung function, and exacerbations (Fig. 505-3). Asthma severity is a dynamic variable and can change over time. After initiation of treatment, it can be determined retrospectively from the level of treatment required to control symptoms and exacerbations. Classification of severity is based on the spirometry and frequency of symptoms over the previous month per the patient history. According to the Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma, classification of severity 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 (occurrence of either exacerbations of asthma or the loss of pulmonary function over time) since these domains may respond differentially to treatment. The term asthma control is used in the GINA guidelines and also encompasses both current impairment and risk.
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Assessment of the impairment domain can be elicited by careful, directed history and measurement of lung function. 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 developing exacerbations. However, even children with really severe asthma may have normal spirometry. Recent data have suggested that, in contrast to FEV1 measures, FEV1/FVC may be a more sensitive marker of asthma severity in children. Peak expiratory flow (PEF) monitoring has not been found to be a reliable variable for classifying severity but may be helpful in some children. Short-term PEF monitoring may be used to establish a baseline for action plans. After starting ICS, personal best PEF (from twice-daily readings) is reached on average within 2 weeks. Average PEF continues to increase, and diurnal PEF variability to decrease, for about 3 months. Excessive variation in PEF suggests suboptimal asthma control and increases the risk of having exacerbations. Long-term PEF monitoring is now generally recommended only for patients with severe asthma who have impaired perception of airflow limitation.
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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 or school days missed, the child’s ability to engage in normal activities including sports activities, and quality-of-life assessments. Standardized questionnaires such as the Asthma Control Test, the Childhood Asthma Control Test, the Asthma Control Questionnaire, and others have been developed to facilitate and standardize the assessment of the impairment domain of asthma control.
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More recently, tools that integrate impairment and risk (symptoms and exacerbations) and, as such, more comprehensively represent asthma control and severity have been developed. These measures include the Composite Asthma Severity Index (CASI) and the GINA symptom control tool. In well-treated asthma populations, symptom scores lose their discriminatory ability. With the addition of controller treatment, lung function measures, and exacerbations to symptom scores, CASI allows for the measurement of asthma activity even in well-treated populations. This measure of asthma severity provides a means to discriminate among individuals who may have well-controlled symptoms but continue to have frequent exacerbations or persistently low airflow limitation. Some of the available tools that can be used for initial and ongoing monitoring of childhood asthma are presented in Table 505-3.
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A history of previous exacerbations requiring emergency department (ED) visits, hospitalization, or intensive care unit (ICU) admission can help identify a patient’s risk for having future exacerbations. Symptoms, exacerbations, spirometry (especially FEV1 percent predicted value or 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, even intermittent asthma, can have severe exacerbations.
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Many biomarkers have been proposed. Serum IgE has been implicated in severity of asthma including exacerbation severity. Mounting evidence supports that allergic sensitization, especially polysensitization, is a risk factor for persistence of the asthma. However, no biomarkers are recommended in the current guidelines.
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Assessment and monitoring of asthma control and severity should be performed regularly because the course of asthma is variable. Asthma may persist or remit with time. Although childhood asthma is a significant risk factor for persistent asthma in adults, 40% to 60% of children with asthma remit by the time they reach adulthood. Remission is more likely to occur in children with milder disease (less frequent and less severe symptoms), who have less atopic sensitization, normal lung function, mild airway hyperresponsiveness, and no comorbid allergic disease. In contrast, persistence is strongly associated with polysensitization, more severe disease (more frequent and severe symptoms), abnormal lung function, and a greater degree of airway hyperresponsiveness.
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The primary goal of therapy is to reduce impairment and 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/no side effects.
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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 ICSs, inhaled long-acting bronchodilators, leukotriene modifiers, theophylline, and immunomodulators. These medications act predominantly by decreasing airway inflammation. A summary of a childhood asthma treatment plan algorithm is shown in Figure 505-4.
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Asthma severity is the intrinsic intensity of the disease process and dictates which step to initiate treatment. Treatment is selected based on each patient’s level of severity based on the frequency and severity of symptoms, frequency and severity of exacerbations, and lung function (see Fig. 505-3). Severity can also be defined retrospectively by identifying the level of treatment required to control symptoms. At each treatment step in asthma management, different medication options are available. For each treatment step, a preferred controller medication is recommended that provides the best benefit-to-risk ratio (including cost) for both symptom control and risk reduction. Choice of the preferred controller is based on group mean data from efficacy studies in well-characterized populations. In addition, to population-level recommendations, patient-level medication choices termed personalized or precision medicine choices have increased in the literature. They take into account patient’s characteristics (phenotypes) or endotypes that predict a clinically important difference in treatment response compared with other patients, along with the patient’s preferences and practical issues (cost, family issues, health literacy, and adherence). At present, most research activity about individualized treatment is focused on severe asthma.
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OVERALL STRATEGY FOR ASTHMA TREATMENT
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Detailed strategies for prescribing asthma medications are proposed in all guidelines. Age is an important feature and should be taken into account. In adolescents, compliance is an important consideration, and treatments should be selected carefully based on the patient’s lifestyle and wishes. Medication for acute relief of symptoms (typically, a short-acting inhaled β2-agonist) should be available to all asthma patients, irrespective of age, severity, or control. The type and extent of controller therapy is selected based on step classification, which is dependent on asthma severity (see Fig. 505-3).
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Step 1: For intermittent asthma, no controller medication is proposed.
Step 2: Mild persistent asthma entails the use of 1 controller medication.
Steps 3/4: ICSs can be increased to a medium/high dose, and/or a second controller medication can be added. For children age 5 to 12 years, the guidelines recommend either doubling the ICS dose or adding a long-acting β-agonist (LABA). Omalizumab may also considered at this step by the National Asthma Education and Prevention Program.
Steps 5/6: In cases for which control cannot be achieved with the maximum dose of ICSs and additional medication, the final resort is the use of oral corticosteroids. Biologic therapies should be considered.
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CONTROLLER MEDICATIONS
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Inhaled Corticosteroids
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ICSs 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. ICSs have a variety of anti-inflammatory effects on many different cell types, which may contribute to their success in the treatment of asthma. They 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 mucus secretion by goblet cells.
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ICSs are very effective as preventive therapy, leading to reduced severity of symptoms, 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 ICSs 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 having corticosteroid insensitivity.
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High, medium, and low doses of ICS for children are summarized in Table 505-4. 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 old who require more than low-dose ICS alone to control asthma (ie, step 3 care or higher), combination therapy with a LABA along with ICS is preferred. In a study of children who have uncontrolled asthma despite the use of low-dose ICS, a randomized trial comparing step-up therapies revealed that LABA step-up was superior to increasing the ICS dose or adding a leukotriene receptor antagonist (LTRA). However, some children had a best response to ICS or LTRA step-up therapy, highlighting the need to regularly monitor and appropriately adjust each child’s asthma therapy. Several studies show that for patients who have mild or moderate persistent asthma, use of higher doses of ICS negligibly improves asthma control compared with lower doses. However, in other studies, higher doses have demonstrated added benefit. Once asthma is well controlled for at least 3 months, stepping down 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 a loss of control. However, there is significant variability in response, and the ICS should be decreased cautiously. The patient/family should be given a plan if symptoms worsen while the ICSs are being decreased. Each patient/family should be given a written asthma action plan based on signs and symptoms and/or PEF. It is particularly important to provide an action plan for those with moderate or severe asthma or those at higher risk for exacerbations. Written action plans are particularly recommended for patients who have moderate or severe persistent asthma, a history of severe exacerbations, or poorly controlled asthma.
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ICSs are well tolerated and safe at the recommended dosages. Oral candidiasis (thrush) is rare in patients on low-dose ICS but is a common adverse effect of high-dose ICS (Expert Panel Report 3). 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 (MDI) will reduce the risk of developing 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 will minimize risk. Reflex cough and bronchospasm have been reported after use of ICS. These effects can be reduced by optimizing the inhaler technique and using 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; however, these studies 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/medium ICS doses may decrease growth velocity, the effects are small and nonprogressive. Combination therapy should be initiated when high-dose ICSs 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 ICSs appear to have no serious adverse effects on bone mineral density in children. Disseminated varicella has been reported in children who have severe persistent asthma and are taking immunosuppressive doses of systemic corticosteroids. 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 1000 μg/d (budesonide) did not affect fasting glucose or glycosolated hemoglobin. However, ICS at high doses can be associated with systemic side effects including cushingoid features and growth suppression, as well as effects related to hypothalamic–pituitary axis suppression, which can result in adrenocortical atrophy and glucocorticoid insufficiency. Presentation may be with severe hypoglycemia. Clinicians should be aware of the possibility of clinical adrenal suppression in children with asthma on high doses of ICS and should consider adrenal function monitoring in these children.
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Oral corticosteroids should be used for only the most severe asthma patients who are not controlled on the other therapies due to the considerable side effects of systemic steroids. These patients should be referred to a specialist for management.
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Long-Acting β2-Agonists
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In a study of children who have uncontrolled asthma despite the use of low-dose ICS, a randomized trial comparing step-up therapies revealed that LABA step-up was superior to increasing the ICS dose or adding an LTRA. Salmeterol and formoterol are β2-agonists that 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 approximately 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 ≥ 5 years of age). These drugs should not be used for the treatment of an acute exacerbation.
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Although LABAs have previously been associated with an increased risk of asthma-related deaths and an increased numbers of severe asthma exacerbations, a recent trial prospectively evaluated the safety of salmeterol in a fixed-dose combination in children and found that salmeterol did not confer increased risk over fluticasone alone. In children ≥ 5 years of age who have moderate persistent asthma that is not well-controlled on ICS, the option to escalate therapy should be taken after consideration of other factors, including inhaler technique, optimizing education, and monitoring adherence, which is a contributor to lack of response to treatment in a majority of cases. In the cases for which escalation of therapy is warranted, there is no evidence for the use of a combination ICS plus LABA inhaler as first-line therapy, but this treatment should be considered in children requiring more than low doses to achieve control. LABA inhalers should never be used as monotherapy and carry a US Food and Drug Administration (FDA) warning stating this in the United States.
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Leukotriene Receptor Antagonists
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Leukotrienes are products of arachidonic acid metabolism released from mast cells, eosinophils, and basophils. LTRAs are effective in improving symptoms and lung function and preventing exacerbations at all ages. They are less efficacious than is ICS in clinical trials and, as such, are recommended as second choice after low-dose ICS for the initial step of chronic treatment. They may also be effective add-on medications, but less so than are LABAs. Some guidelines suggest that LTRA may be particularly useful when a patient has rhinitis or exercise-induced symptoms. Some evidence suggests the effectiveness of LTRA for children with exercise-induced asthma. Although ICSs are the preferred controller therapy for persistent asthma, LTRAs are an alternative treatment for mild persistent asthma in children younger than 12 years old. They can also be used as adjunct therapy with ICS for children younger than 12 years old. In children ≥ 12 years of age, the preferred adjunct therapy is an LABA. The use of LTRAs as adjunctive therapy in moderate or severe asthma has not been studied adequately in children. Hepatic dysfunction, including some cases of fulminate hepatic failure, has been reported as a side effect of zafirlukast. Patients should stop taking zafirlukast if any signs or symptoms of hepatitis occur.
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Tiotropium is a long-acting once-daily anticholinergic initially approved for the treatment of persistent asthma in children age 12 and older. Tiotropium has been studied as an add-on therapy to ICSs in adolescents and children. An improvement in lung function has been demonstrated in symptomatic pediatric and adolescent patients with asthma with the addition of tiotropium to ICS, improving peak and trough FEV1 and morning and evening PEF. In adults with severe asthma, the addition of tiotropium significantly increased the time to the first severe exacerbation and improved lung function.
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Methylxanthines also can be used as step-up treatment to ICS, although the addition of theophylline to ICS produces a small improvement in lung function similar to doubling the dose of ICS. Studies on the use of methylxanthines in combination with ICS (with or without LABA) in severe asthma are lacking. Theophylline is proposed as add-on therapy for children age 12 and older with severe asthma.
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Cromolyn sodium and nedocromil are mast cell stabilizers. They are not the preferred treatment for any category of asthma. They are still included in some guidelines as alternative treatment for mild persistent asthma but are less effective than is ICS in improving outcomes and are no longer available in many countries.
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Biologic Therapies in Asthma
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For the majority of asthmatic patients, disease control is achieved within the first 3 treatment steps, which include the use of ICSs either alone or in combination with LABAs or LTRA. This approach has provided a safe and effective mode of treatment. However, some patients do not respond fully to these treatment choices, and for those patients, additional therapy options are needed along with referral to a specialist. The next choices are limited and have begun to extend into the use of biologics.
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Omalizumab is a recombinant DNA-derived humanized monoclonal antibody directed against the Cε3 domain of IgE. It blocks the ability of IgE to bind to its high-affinity receptor (FcεRI) on mast cells, basophils, eosinophils, Langerhans cells, and dendritic cells. 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. Omalizumab is currently recommended as a potential adjunctive therapy in patients ≥ 12 years old who have allergies and severe persistent asthma (step 5) that is not controlled with the combination of high-dose ICS and LABAs.
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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 resulted in a small improvement in lung function in some studies. Omalizumab has also been demonstrated to have a modest steroid-sparing effect.
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Anaphylactic reactions are estimated in 0.2% of treated patients, which resulted in an FDA alert in 2007. These reactions occur for the most part within 2 hours of the first 3 injections of omalizumab; however, reactions can occur at any time. Thus, administration of omalizumab should be performed only in settings equipped for the identification and treatment of anaphylaxis. Adverse effects reported from omalizumab in the trials have also included injection-site pain and bruising in as many as 20% of patients.
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Eosinophils are a frequent finding in asthmatic inflammation, and a high blood eosinophil count often reflects inflammation and disease severity in asthma. A reduction of sputum eosinophils by ICS reduces the frequency of exacerbations and usually indicates an establishment of disease control. IL-5 is the key cytokine that promotes terminal differentiation, survival, migration, and activation of eosinophils; thus, anti–IL-5 is a reasonable target for asthma treatment. In November 2015, the FDA approved mepolizumab for use with other asthma medicines for the maintenance treatment of asthma in patients age 12 years and older.
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The safety and efficacy of mepolizumab were established in 3 double-blind, randomized, placebo-controlled trials in patients with severe asthma on currently available therapies. Mepolizumab or placebo was administered to patients every 4 weeks as an add-on asthma treatment. Compared with those on a placebo, patients receiving mepolizumab had fewer exacerbations requiring hospitalization and/or ED visits and a longer time to the first exacerbation. In addition, patients with severe asthma receiving mepolizumab experienced greater reductions in their daily maintenance oral corticosteroid dose while maintaining asthma control, compared with patients receiving placebo. Treatment with mepolizumab did not result in a significant improvement in lung function. The effects of IL-5 modulation are limited to patients who are already on corticosteroid treatment but have persistent eosinophilia despite taking corticosteroids and continue to experience exacerbations. The most impressive results have been seen in patients with significant peripheral blood eosinophilia at baseline.
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The most common side effects of mepolizumab include headache, injection-site reactions, back pain, and weakness (fatigue). Hypersensitivity reactions can occur within hours or days of being treated with mepolizumab. Herpes zoster infections (shingles) have also been reported in patients receiving mepolizumab.
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Other Biologics on the Horizon
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In a study of adult atopic asthmatic patients who were uncontrolled with ICS, treatment with anti–IL-13 improved lung function compared to placebo. Studies with humanized monoclonal antibodies directed at IL-4Rα have shown initial promise, with a reduction in exacerbation frequency, as well as improvements in asthma control. TSLP is an epithelial-derived cytokine that is produced in response to proinflammatory stimuli and mechanical stress and leads to the induction of TH2-related cytokines. A humanized anti-TSLP monoclonal antibody has shown some initial promise and is under investigation.
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QUICK-RELIEF MEDICATIONS
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Quick-relief medications are used to provide prompt relief of acute symptoms. These medications include short-acting β2-agonists (SABAs) and anticholinergics (ipratropium bromide). SABAs relax airway smooth muscle, thereby 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. SABAs are very effective in the treatment of acute symptoms and are the preferred and recommended treatment. However, regular use is not recommended because it has not been shown to have added benefit when compared to as-needed use with regard to asthma control. Use of SABAs > 2 times per week may signify that the asthma is not well controlled and controller therapy should be adjusted accordingly. Increasing use of SABAs has been associated with increased risk of having an acute exacerbation requiring hospitalization and increased risk for death.
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Ipratropium has been shown to be effective only in the ED setting. Studies of children with asthma requiring hospitalization have failed to show any benefit by the addition of ipratropium to their treatment regimens after the transition from the ED to the inpatient setting.
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TREATMENT OF ACUTE ASTHMA IN CHILDREN
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Severe exacerbations of asthma can be life threatening. Care must be prompt, and rapid recognition of a severe exacerbation is critical as it requires close observation for deterioration, frequent treatment, and transfer to an ED. 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 ED. Clinical signs characterizing a severe episode include the use of accessory muscles, limited ability to speak, preference to sit upright, a paradoxical pulse of > 25 mm Hg, a heart rate of > 130 bpm, a respiratory rate of > 25 breaths/min, a PEF of less than 50% of predicted, and an oxygen saturation < 92%. If any of these signs are present, the patient should be transferred to an ED immediately.
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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 ED visits and hospitalizations (including ICU and need for intubation) for asthma. The physical exam 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, such as a pneumothorax, pneumomediastinum, pneumonia, or lobar atelectasis, is suspected. The differences in the anatomy and physiology of the lungs of infants and young children place them at greater risk for respiratory failure; thus, it is important to monitor oxygen saturation (SaO2) by pulse oximetry.
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According to the National Guidelines outlined in the Expert Panel Report 3, initial treatment for an acute exacerbation should include oxygen to maintain an SaO2 > 92%, and 3 treatments of an SABA (each 2.5–5.0 mg albuterol) spaced every 20 to 30 minutes should be given. Systemic corticosteroids (1–2 mg/kg/d up to a maximum 60 mg/d for 3–10 days) are recommended for patients who have moderate or severe exacerbations and do not respond completely to initial therapy. Once-daily and multiple-daily dosing approaches are comparable in clinical outcomes. There appears to be no significant difference in the efficacy of oral corticosteroids or parenteral corticosteroids on the length of hospital stay in children with acute asthma exacerbations. Parenteral administration should be used in the child who is unable to tolerate oral medications due to vomiting. Given its longer biologic duration of action, dexamethasone may be preferred in the ED management of acute asthma. A meta-analysis concluded there was no difference in the relative risk of relapse between dexamethasone (intramuscular or oral, 1 or 2 doses) and prednisone/prednisolone (oral for 5 days) and that children treated with dexamethasone were less likely to experience emesis. A 5- to 10-day course following ED discharge is recommended to prevent early relapse. Improvement from an asthma exacerbation usually is gradual, and even when symptoms have resolved, evidence of inflammation in the airways has been shown to continue for to 2–3 weeks. When systemic corticosteroids are administered for asthma exacerbations, the child should continue to receive maintenance ICS to reinforce the importance of this medication, although studies have not addressed the clinical utility of this practice. Intramuscular depot injections of corticosteroids have been shown to be effective in preventing relapse after discharge from the ED. Thus, this option may be considered as an alternative to oral corticosteroids for patients who are at high risk of nonadherence. Systemic corticosteroids can speed resolution of airflow obstruction and reduce the rate of relapse. There are considerable side effects of systemic corticosteroids, but little information is available regarding the side effects of brief courses. 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 having a 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. 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 adrenocorticotropic hormone.
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Ipratropium bromide, an inhaled anticholinergic agent, is a useful additional treatment for acute asthma and should be considered for patients who have severe exacerbations. Ipratropium exerts its effects by blocking cholinergic receptors, leading to diminished bronchomotor tone, mucosal edema, and secretions. It is not effective when administered alone, but in combination with SABA, it can improve lung function and reduce hospitalization rates in children with moderate-to-severe exacerbations. National Asthma Education and Prevention Program guidelines recommend 2 or 3 doses of 250 to 500 μg via nebulization or 2 to 3 puffs of 17 μg/puff administered via MDI. Ipratropium treatment has not been shown to have any benefit outside of the ED setting and is not recommended in the inpatient setting or as an outpatient.
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For severe exacerbations unresponsive to the initial treatments, adjunct treatments 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 ED patients with severe asthma exacerbations. Magnesium sulfate has not been shown to be beneficial in mild or moderate exacerbations. Heliox (a mixture of helium and oxygen) may improve gas exchange in patients with severe obstruction, although studies have been conflicting regarding its efficacy. Some studies have observed no added benefit with heliox, whereas others have found a significant improvement in pulmonary index and a trend toward reduced incidence of hospitalizations in children with moderate-to-severe exacerbations who received heliox-driven albuterol nebulization.
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An important component of asthma management is education. Evidence is abundant that asthma self-management education is effective in improving outcomes of chronic asthma. The value of establishing the child-family-physician partnership for optimal asthma management has been shown in randomized controlled trials. Specific training in self-management skills is necessary to produce behavior that modifies the outcomes of chronic illnesses including asthma. Patients must actively participate in their own care by learning how to use strategies and to minimize exposure to triggers and adjust treatments to improve disease control. Patient’s self-management should be partnered with the care provided by the healthcare team with the goal of reducing the impact of asthma on related morbidity, functional ability, and quality of life. The benefits of equipping patients and families with the necessary tools for self-assessment, optimization of medications, and actions to prevent exacerbations include reduction in incidence of urgent care visits and hospitalizations, reduction of asthma-related healthcare costs, and improvement in health status. This training 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. Mismatches between parent reports and provider intentions regarding asthma treatment have been reported to occur for more than half of asthmatic children. Efforts should focus on ways to reduce mismatches. The Expert Panel recommends that clinicians provide patients with asthma self-management education that includes asthma information, training in asthma management skills, self-monitoring, a written asthma action plan, and regular ongoing assessment by a physician. Physicians should involve patients and families in the decisions about the types of self-monitoring. Written asthma action plans are particularly recommended for patients who have moderate or severe persistent asthma, a history of severe exacerbations, or poorly controlled asthma.
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Poor inhaler technique leads to poor asthma control, increased risk of exacerbations, and increased adverse effects. Most patients (up to 70–80%) are unable to use their inhaler correctly. Unfortunately, many healthcare providers are unable to demonstrate how to correctly use the inhalers they prescribe. Most people with incorrect technique are unaware that they have a problem. Both spacers and valved holding chambers are intended to retain large particles emitted from the MDI, reduce deposition in the oropharynx, and promote inhalation of a higher proportion of small, respirable particles.
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In vitro and in vivo studies comparing various spacers and valved holding chambers with the same MDI have demonstrated significant variation in the respirable dose emitted from the devices and 2- to 5-fold difference in systemic availability of the drug. Valved holding chambers are preferred in children because they have 1-way valves that do not allow the child to exhale into the device. Thus, the child does not need to coordinate actuation and inhalation. Checking and correcting inhaler technique using a standardized checklist takes only 2 to 3 minutes and leads to improved asthma control. A physical demonstration with a placebo inhaler is preferred to improve inhaler-use technique. After training, proper inhaler-use technique diminishes with time, so checking and retraining must be repeated regularly. Pharmacists and nurses are key partners in asthma education and can provide highly effective inhaler-skills training. Training is equally important with dry powder devices and breath-actuated devices.
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Asthma Education Partnerships
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Visits to the ED and hospitalizations for asthma exacerbation are important opportunities for providing asthma education for a population of children with exacerbations. The Expert Panel concluded that it is important to assess inhaler-use techniques for all prescribed medications and reinforce correct technique before patients are discharged home. Further, the Expert Panel recommends that patients should be referred for a follow-up asthma care appointment within 1 to 4 weeks of discharge. The follow-up appointment should include patient education and asthma self-management education. Some studies support that better outcomes may result for patients referred from the ED to asthma specialists.
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Several studies suggest that comprehensive school-based education programs about asthma can improve health and quality of life in children with persistent asthma. Further, asthma education incorporating technology that includes video gaming media has been shown to be useful in improving knowledge of asthma self-management and quality of life for high-risk children who have asthma.
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Studies of community-based asthma interventions and education have revealed that asthma-education programs delivered by trained community residents are feasible and can result in changes in behavior and improved quality of life. Similarly, home-based interventions show significant promise for the treatment of childhood asthma. The home may be a useful point of care to assess and identify potential challenges to optimal asthma control including adherence obstacles, environmental exposures, and psychosocial factors, which may not be evident in a clinical setting. This information could be used to tailor personalized interventions including strategies to increase adherence and reduce household allergens.
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Poor adherence is defined as the failure of treatment to be taken as agreed upon by the patient and the healthcare provider. There is considerable evidence regarding the importance of poor adherence in chronic diseases. As many as 50% of adults and children on long-term therapy for asthma fail to take medications as directed. In clinical practice, poor adherence may be identified by checking the date of the last prescription, checking the expiration date on the inhaler, and monitoring the electronic inhaler. In some health systems, pharmacists can assist in identifying poorly adherent patients by monitoring dispensing records. It is important to elicit patients’ beliefs and concerns about asthma and asthma medications in order to understand the reasons behind their medication-taking behavior. They include both intentional and unintentional factors and may be related to side effects of the medication as well as psychosocial factors including maternal depression, home environment, ethnicity, health literacy, and numeracy. A patient’s concerns about side effects may or may not be valid, but either way, the impact on their adherence is the same. Interventions that have been shown to improve adherence in asthma management include shared decision-making for medication choices and dosing regimens, medication reminders, less frequent dosing regimens, and home visits.
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The essential components of effective, guided asthma self-management are self-monitoring of symptoms, a written asthma action plan that outlines how to recognize and respond to worsening asthma, and ongoing assessment of asthma control and management by a healthcare provider. Self-management education that includes these 3 components dramatically reduces asthma morbidity in adults and children.
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OTHER TREATMENT CONSIDERATIONS
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Environmental Allergen Avoidance
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Avoidance of environmental allergens is one of the goals of asthma management. Allergic sensitization is common among asthmatics (60% in adults and as high as 90% of children). Sensitized asthmatic subjects 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.
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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. Studies examining the effectiveness of dust mite–proof encasings for bedding have shown 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°F in order to kill dust mites. Other recommendations for decreasing exposure to dust mites include removal of wall-to-wall carpeting, replacement with hardwood floors or tiled floor surfaces, and implementation of methods to decrease humidity.
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Control of pet allergens 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. Cats carry very large amounts of allergen, and only a tiny fraction becomes airborne. The transfer of allergen from houses to public places, schools, and daycare centers occurs by means of clothing. Optimal strategy for controlling cat allergens is relocation of the cat to another environment, which results in a drop in allergen levels by as much as 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.
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Sensitivity and exposure to cockroaches are common findings 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.
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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/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.
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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. 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 has confirmed the effectiveness of immunotherapy in asthma, with a significant reduction in asthma symptoms and medication and improvement in bronchial hyperreactivity. Furthermore, immunotherapy may prevent the development of asthma in children with allergic rhinitis. The course of allergen immunotherapy is typically 3 to 5 years in duration. Immunotherapy carries a risk of allergic reactions including severe anaphylaxis, and these risks are more frequent among patients with poorly controlled asthma. Thus, immunotherapy should be administered only in a physician’s office equipped to handle anaphylaxis.
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Assessment of Control
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Periodic assessments of asthma control measures (see Table 505-2) 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, at least every 6 months. Patients with poorly controlled and/or severe persistent asthma and those who need additional supervision to help them follow their treatment plan should be seen more often.
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Ongoing assessment of control 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. Per the Expert Panel Report 3, clinicians should use self-assessment tools to determine the patient’s/family’s assessment of the control of the asthma. Several multidimensional instruments have been developed to assess control (see Table 505-3).
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Spirometry is recommended at the time of initial assessment, after the patient’s asthma symptoms have stabilized, and then every 1 to 2 years. It is also recommended during periods of progressive or prolonged loss of asthma control. 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. PEF is dependent on effort and technique; thus, it is important to review the technique frequently with the patient.
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It is important 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.
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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, ICU, 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 505-5.
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With the development of effective asthma-control medications, most children with asthma can attain and maintain good asthma control. Unfortunately, a small group of severe asthmatic children will continue to have symptoms despite maximal medical therapy. Whereas most children with asthma achieve good symptom control when treated with low- to medium-dose ICS, children with severe asthma have sustained symptoms despite treatment with high doses of ICSs or oral corticosteroids. Although this group is comprised of only 5% to 10% of all children with asthma, it accounts for nearly 50% of all asthma-related expenditures.
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Most definitions of severe asthma have included frequent day and nighttime symptoms, need for rescue bronchodilator therapy several times a day, and an FEV1 less than 60% of predicted. The European Respiratory Society/American Thoracic Society Task Force Report on severe asthma simplified the definition of severe asthma by stating that severe asthma requires treatment with high-dose ICS plus a second controller and/or systemic corticosteroids to prevent it from becoming uncontrolled or that remains uncontrolled despite this therapy. Children with severe asthma may fall into 2 categories: difficult-to-treat asthma or severe therapy-resistant asthma. Difficult-to-treat asthma is defined as poor control due to an incorrect diagnosis and/or comorbidities and/or poor adherence due to adverse psychological or environmental factors. In contrast, treatment-resistant asthma (also called refractory asthma) is defined as difficult asthma despite management of these factors. It is important to recognize that a child may have difficult-to-treat and treatment-resistant asthma. Although difficult-to-treat asthma is relatively common, only a fraction of these patients will have true refractory asthma. The true prevalence of refractory childhood asthma is difficult to determine as studies often do not account for inhaler technique and adherence.
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Guideline-based drug therapy of severe childhood asthma is based primarily on extrapolated data from adult studies. The recommendation is that children with severe asthma be treated with higher-dose inhaled or oral corticosteroids combined with LABAs and other add-on therapies such as LTRAs and methylxanthines. It is important to identify and address the influences that render asthma difficult to control including reviewing the diagnosis and the removal of causal or aggravating factors. With the development of highly effective medications, children with severe asthma are less likely to be steroid-dependent, have better baseline lung function, require far less rescue albuterol, and are less growth-suppressed. Despite these gains, children with severe asthma continue to have frequent exacerbations, and osteopenia continues to be a common steroid-induced adverse effect.
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Extrapolating adult severity classifications to children is difficult for a number of reasons. Adults with asthma are more likely to exhibit a persistent pattern, whereas children may have a pattern of rapidly evolving, frequent, and often severe exacerbations. Children have severe exacerbations triggered by viral infections and/or exposure to allergens that can result in healthcare utilization but then often remain asymptomatic between these episodes. Lung-function measurements also show different patterns, are age-dependent, and may be within normal limits despite significant symptom burden and medication use. In children, the distal airways are more affected, and increased distal lung resistance explains the often unimpaired FEV1 values. Other measures of lung function such as FEV1/FVC, forced expiratory flow at 25% to 75% of predicted, or the degree of airway responsiveness to bronchodilators may relate better to asthma severity.
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Most children with severe asthma present in school age. Among school-aged and adolescent children, those with severe asthma were more likely to have higher serum IgE levels, increased allergic sensitization (especially to mold), increased load of aeroallergen sensitization earlier in life, a higher prevalence of AD, and greater bronchial hyperresponsiveness, and to report being of African American or more than one race than were children with milder disease. Adolescents are at an increased risk of having a higher prevalence of severe asthma and death from asthma due to reduced adherence to treatment and increased risk-taking behaviors.
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