Introduction

Wheezing is a musical, high-pitched, largely expiratory sound, typically made through the partially obstructed larger airways, most commonly caused by asthma in school-age children. Nevertheless, wheezing can also be generated by narrowing in the distal trachea and by glottic closure. A number of other conditions can cause both acute and chronic wheezing in children, but many causes are associated with other symptoms that generally distinguish them from asthma ( Box 45.1 ). The major focus of this chapter will be on the diagnosis and treatment of asthma in children beyond the preschool years.

As defined in the National Heart, Lung, and Blood Institute (NHLBI) guidelines, asthma is characterized by variable, reversible obstruction of air flow (but not completely so in some patients), which may improve spontaneously or may subside only after specific therapy. Airway hyperreactivity, defined as the inherent tendency of the trachea and bronchi to narrow in response to a variety of stimuli (e.g., allergens, nonspecific irritants, or infection), is also a prominent feature. Both the airway obstruction and hyperreactivity may be associated with chronic, dysregulated airway inflammation that involves many cell types (e.g., eosinophils, lymphocytes, neutrophils, epithelial cells, airway smooth muscle, fibroblasts) and mediators (e.g., cytokines, chemokines, enzymes, growth factors, IgE). Symptoms of wheeze, cough, and shortness of breath are episodic in most patients but may occur daily in some. Asthma is now viewed as an “umbrella term” for a complex, heterogeneous disorder with numerous phenotypes and endotypes that differ in children and adults. Although all asthma phenotypes demonstrate airway obstruction, the pathophysiological processes, genetics, natural history, and response to treatment differ widely.

Although there has been an increased awareness of the prevalence of childhood asthma, substantial physical, psychological, and socioeconomic morbidity continue to occur. Among the 7 million children younger than 18 years of age in the United States with asthma, it is estimated that each year more than 10 million school days are lost, 3 million sick visits are made to health care providers, and more than 450,000 hospitalizations occur. The annual direct and indirect health care costs for treatment of asthma were recently estimated at over $50 billion per year in the United States. Poor, disadvantaged minority children who reside in central urban areas have both the highest prevalence and greatest morbidity. Nevertheless, both acute health care utilization and mortality rates from asthma appear to have stabilized and for some groups, declined slightly in recent years, following a steady rise in the period from 1980 to the mid-1990s. Mortality remains rare and is declining, and less than 150 children and adolescents younger than 15 years of age in the United States die annually from asthma.

Pathology

Examination of postmortem lung specimens of patients who died from asthma shows marked hyperinflation with smooth muscle hyperplasia in the bronchial and bronchiolar walls, thick tenacious mucous plugs often completely occluding the airways, markedly thickened basement membrane, and variable degrees of mucosal edema and denudation of bronchial and bronchiolar epithelium ( Fig. 45.1 ). Eosinophilia of the submucosa and secretions is often prominent whether or not allergic (IgE-mediated) mechanisms are present. Airway smooth muscle mass is also increased in the airways by school age and may begin in the preschool years. Mucous plugs contain layers of shed epithelial cells and eosinophils, as well as neutrophils and lymphocytes. Although the exact role of airway eosinophils in causing and perpetuating the asthma phenotype remains controversial, eosinophil products (e.g., major basic protein and other proteases) may play an important role in the destructive changes observed. The mucosal edema with separated columnar cells and stratified nonciliated epithelium, which replaces ciliated epithelium, results in abnormal mucociliary clearance. Mast cells are increased in airway smooth muscle of asthmatics. In addition, there is increased mast cell degranulation, which is often worse in those with more severe asthma. Submucosal gland hypertrophy and increased goblet cell size are not constant features of asthma, but mucous metaplasia caused by increased synthesis and stores frequently occurs across all ranges of asthma severity. The thickened basement membrane caused by submucosal deposition of type IV collagen and various other materials is a striking feature of asthma and has been reported even in mild asthmatics. Basement membrane thickening is thought to occur early in the disease, but its pathologic significance remains to be determined. All of these findings have been observed in symptom-free asthmatic individuals who died accidental deaths, as well as in endobronchial biopsy specimens from research subjects ( Fig. 45.2 ). Significant basement membrane thickening in airway mucosal biopsies taken from pediatric patients with severe asthma has been observed in the absence of active eosinophilic or neutrophilic infiltrates. Moreover, normal lung function as measured by forced expiratory volume in 1 second (FEV ₁ ) can be achieved by patients with severe airway remodeling. These observations call into question the role of inflammation and remodeling in asthma that is difficult to control. Although an occasional patient may show localized bronchiectasis and small focal areas of alveolar destruction, these are not characteristic of asthma, and there is little evidence that asthma leads to destructive emphysema. However, the incomplete reversibility of air flow limitation seen in some asthmatics suggests that a phenotype exists that may be considered a form of chronic obstructive pulmonary disease (COPD), the so-called overlap syndrome.

Sections of asthmatic lung. Top left, Cross-section of bronchus (original magnification ×66) showing cartilage (A), thickened basement membrane (B), epithelium containing many goblet cells (C), area of many ciliated epithelial cells (D), connective tissue (E), mucous gland (F), and mucous plug (G). Top right, Bronchial epithelium (original magnification ×136) showing mucous glands (A), hyaline basement membrane (B), goblet cells (C), and ciliated cells (D). Bottom left, Bronchial epithelium (original magnification ×700) showing goblet cell (A), basement membrane (B), connective tissue (C), and ciliated respiratory epithelial cells (D).

Autopsy specimen from an asthmatic child who died from toxic ingestion. Note the infiltration of cells around the bronchus with sloughing of epithelial cells into the bronchial lumen. The alveoli all appear normal.

Pathophysiology

Air flow limitation in asthma results from a combination of obstructive processes, principally mucosal edema, bronchospasm, loss of alveolar tethering points, and mucous plugging. The relative roles of these processes in producing obstruction may differ, however, according to the age of the child, the size and anatomy of various portions of the airway, the type of agent precipitating obstruction, and the duration and severity of asthma. An example of acute bronchoconstriction following bronchial lavage with normal saline in a child with asthma can be viewed in the video clip. Note the furrowing of the bronchial mucosa prior to lavage, which is associated with smooth muscle hypertrophy in the airway (Video 45.1 ).

Airway obstruction results in increased resistance to air flow through the trachea and bronchi and in decreased flow rates due to narrowing and premature closure of the smaller airways. These changes lead to a decreased ability to expel air and result in hyperinflation. Although pulmonary overdistention benefits respiration by helping to maintain airway patency, the work of breathing increases because of the altered pulmonary mechanics. To a certain extent, increasing lung volumes can compensate for pulmonary obstruction, but compensation is limited as tidal volume approaches the volume of pulmonary dead space, with resultant alveolar hypoventilation.

Changes in resistance to air flow are not uniform throughout the tracheobronchial tree, and because of regional differences in this resistance, the distribution of inspired air is uneven, with more air flowing to the less resistant portions. In most patients with asthma, both larger and smaller airways are obstructed, but some patients may have small airway obstruction primarily, or even exclusively. The pulmonary circulation also is affected by hyperinflation, which induces increased intrapleural and intraalveolar pressures and uneven perfusion of the alveoli. The increased intraalveolar pressure, decreased ventilation, and decreased perfusion (the last through hypoxic vasoconstriction) lead to variable and uneven ventilation-perfusion relationships within different lung units. The ultimate result is early reduction in blood oxygenation, even though carbon dioxide is eliminated effectively because of its ready diffusibility across alveolar capillary membranes. Thus, early in acute asthma, hypoxemia occurs in the absence of CO ₂ retention. The hyperventilation resulting from the hypoxemic drive causes a fall in partial pressure of carbon dioxide in alveolar gas (Pa co ₂ ). However, as the obstruction becomes more severe and the number of alveoli being adequately ventilated and perfused decreases, a point is reached at which CO ₂ retention occurs.

Alterations in pH homeostasis result from respiratory and metabolic factors. Early in the course of acute asthma, respiratory alkalosis may occur because of hyperventilation. Metabolic acidosis can occur because of the increased work of breathing, increased oxygen consumption, and as a result of excessive β-adrenergic agonist treatment. The metabolic acidosis usually results from lactic acid accumulation, which most commonly occurs as a result of high and frequent doses of β-adrenergic agonist use. In such cases, the acidosis resolves as the β-agonist use is tapered. The mechanism of β-adrenergic agonist induced lactic acid production is somewhat controversial, but most likely results as a consequence of the increased plasma glucose concentration (caused by both beta-agonist and systemic glucocorticoid administration) and its conversion via glycolysis to pyruvate, which is then converted to lactate. When respiratory failure is superimposed, respiratory acidosis may result in a precipitous decrease in pH.

In short attacks of acute asthma, bronchospasm, mucosal edema, or both can occur. In a minority of asthmatics, acute severe episodes are characterized by neutrophilic, not eosinophilic infiltration, and bronchospasm occurs with little mucus secretion. These episodes may have an abrupt onset and cause severe or life-threatening symptoms. Mucous secretions become far more important as a cause of obstruction as the inflammation becomes more intense and prolonged, and when damage to and sloughing of epithelial cells impairs mucociliary function and increases reflex bronchoconstriction.

Inflammatory Cell Biology and Asthma Etiology and Pathophysiology

Although tremendous strides have been made in the cellular and molecular biology of asthma in the past two decades, a complete understanding of the causative factors and those responsible for perpetuating the asthmatic state remain inadequately explained. Current data support the hypothesis that inflammation underlies the pathophysiology of asthma, and the airway epithelium, inflammatory leukocytes, multiple immune cells, and other airway structural cells all play a role. The mechanisms producing airway inflammation are legion, cross-talk among various pathways occurs, and the predominant mechanisms responsible for cellular dysfunction vary among asthma phenotypes. The cell–cell communications that initiate and perpetuate asthma likely result from inhaled stimuli such as inhaled allergens, respiratory viruses, and air pollutants (particulate and gaseous) that cause airway epithelial cells to secrete cytokines, interleukins, and other mediators. In turn, these proinflammatory agents act on resident cells in the subepithelial layer, (e.g., dendritic cells, mast cells, and lymphoid cells, including lineage negative innate lymphoid cells) to recruit other leukocytes and the release of Th2 cytokines such as IL-4, IL-5, and IL-13. Biologically active neuropeptides and acetylcholine can also be released from afferent nerves in the epithelium by similar environmental triggers/irritants. The ongoing recruitment of T lymphocytes and release of other mediators, such as IL-17 and IL-33, further enhances the inflammation and dysfunction of the epithelium and airway smooth muscle.

The propensity to develop IgE-mediated sensitization to environmental allergens, particularly in association with rhinovirus infection, coupled with subsequent exposure, is one of the strongest predictors for the development of childhood asthma. The persistence and chronic activation of mast cells, dendritic cells, eosinophils, and lymphocytes in the airways as a result of Th2 cytokine-mediated events (e.g., recruitment of circulating inflammatory cells, interruption of apoptosis) may be important in producing chronic asthma. In addition, innate immune responses modulated by Toll-like receptor recognition and Th17 cells also may be operative in some asthma phenotypes, such as those with more severe disease and neutrophilic predominance in the airways. Impaired production of natural airway defense mediators such as lipoxins, resolvins, and protectins (all important in the active resolution of airway inflammation) may also promote a proinflammatory state in the asthmatic airway. Prolonged or recurrent episodes of inflammation are associated with progressive structural and functional changes in the airway epithelium, musculature, and connective tissue. The continued dysregulation of the cytokine networks perpetuates inflammation in what now may be the structurally altered airways of chronic asthma. Several specific effector mechanisms (e.g., IgE, arachidonic acid metabolites, mast cell proteases, numerous cytokines, thymic stromal lymphopoietin [TSLP], nitric oxide [NO], the β-adrenergic receptor [BAR], growth factors, the airway microbiome, and intrinsic muscular abnormalities) appear to play key roles in airway inflammation and are discussed further in Chapter 7 .

Natural History and Prognosis

Knowledge of the natural history of asthma remains incomplete, but several longitudinal studies have added substantial insight. The widespread notion that most children “outgrow” their asthma in adolescence is only partially true. Between 30% and 70% of children with episodic asthma have less severe or absent symptoms by late adolescence, and some features of childhood presentation and course seem to predict clinical outcome. The presence of allergic sensitization, female sex, and severe or persistent asthma in early childhood are predictors of asthma in adulthood. Data from the Melbourne Asthma Study suggested that mild asthma or infrequent wheezing associated with viral infections in childhood was not likely to progress to severe disease in adulthood. In this longitudinal cohort of approximately 500 subjects, data have been collected on the symptoms, growth, and lung function for more than 50 years. Subjects were entered in the study at 7 years of age and were classified as never wheezed (controls), mild wheezy bronchitis, wheezy bronchitis, and asthma; a cohort with more severe asthma was added 3 years later. The loss of lung function seen in the groups with asthma and severe asthma by 10–14 years of age did not worsen over time. The rate of loss of lung function as measured by FEV ₁ had the same rate of decline up to age 50 in all the groups, even after adjusting for smoking history. Moreover, asthma remission, defined as no symptoms and no medical treatment for 3 years, occurred in 64% of those with intermittent childhood asthma, 47% of those with persistent childhood asthma, and 15% of those with severe childhood asthma. Data from the Childhood Asthma Management Program (CAMP) also indicate that outcomes in children initially diagnosed with moderate asthma vary and are predicted by certain features. During a 7- to 10-year follow-up period of 909 children initially enrolled in a 4-year-long clinical trial of placebo versus budesonide (BUD) versus nedocromil, 6% remitted, 39% had periodic asthma, and 55% had persistent disease. Prestudy factors associated with disease remission included lack of allergen sensitivity and exposure to indoor allergens, milder asthma, older age, less airway responsiveness (methacholine PC ₂₀ ), and higher prebronchodilator FEV ₁ . Moreover, there was no effect on disease outcome by treatment. These results also highlight the lack of current antiinflammatory treatments’ ability to alter disease natural history.

Studies of children with asthma based both on history and on assessment of pulmonary function indicate that many children who lose overt symptoms have persistent airway obstruction. Nonspecific airway hyperreactivity associated with asthma is present in formerly asthmatic patients who are free from clinical asthma. Individuals who had asthma as children have a significantly lower FEV ₁ , more airway reactivity, and more frequent persistence of symptoms than those with infection-induced wheezing or the controls. In addition, 88% of the adults with childhood asthma who had persistent symptoms had positive methacholine challenge test results, as did 42% of the asymptomatic former asthmatics. The recurrence of overt asthma after years of freedom from symptoms is not unusual. Thus asthma is often a lifelong disease with periodic exacerbations and remissions, although laboratory evidence of decreased pulmonary function, airway inflammation, and airway hyperresponsiveness may persist, even when symptoms are quiescent.

In children and adolescents, asthma is frequently a completely reversible obstructive airways disease, and indeed no abnormalities in pulmonary functions can be detected in many asthmatic patients when they become symptom-free. However, recent studies that examine not only symptoms and pulmonary function but also indices of airway inflammation and bronchial hyperresponsiveness suggest that airway inflammation may persist in the absence of symptoms. In a study of 54 young adults (18–25 years of age) with atopic asthma or asthma in clinical remission (absence of symptoms for at least 12 months, median duration 5 years), subjects in remission were found to have evidence of airway inflammation and remodeling. When compared with normal healthy controls, the subjects in remission had increased epithelial and subepithelial major basic protein and reticular basement membrane thickness; values were close to those of subjects with active asthma. Peripheral eosinophil counts were also elevated in the remission patients, and there was a significant correlation between basement membrane thickness, exhaled NO, and hyperresponsiveness to adenosine monophosphate. These findings indicate that the airways of some asymptomatic asthmatics, seemingly in clinical remission, may still show significant abnormalities and evidence of active inflammation. It is unclear that continued treatment in the face of absent symptoms will alter the natural history of the disease in these patients.

Asthma does appear to progress to chronic obstructive disease in some individuals, and features of asthma can be found in some adult patients with COPD (the so-called overlap syndrome). The functional and structural causes of this irreversible airway obstruction variant of asthma are not understood. A process referred to as airway remodeling is often suggested as the cause of chronic obstruction and severe asthma, but data to conclusively support this hypothesis are lacking. It is believed that chronic mucous plugging, tracheobronchial ciliary dysfunction, smooth muscle and goblet cell hyperplasia, and collagen deposition in the lamina reticularis of the basement membrane occur as a consequence of persistent inflammation. Genetically determined dysregulation of inflammatory mediator production with or without repeated exposure to certain environmental stimuli may also play a role. Data from animal models demonstrate that even when inflammation is suppressed and changes consistent with remodeling are reduced markedly, airway hyperresponsiveness persists. These data suggest that airway remodeling alone is probably not responsible for severe, irreversible airway obstruction or bronchial hyperresponsiveness.

The natural history of childhood asthma and the effects of aggressive long-term management on outcomes remain incompletely understood, but a great deal of data have come from the CAMP study. CAMP was a well-designed comprehensive longitudinal study in which the primary objective was to compare the effects of long-term treatment (4 years) with an inhaled steroid (BUD) and a nonsteroidal treatment (nedocromil) to placebo in school-age children ( n = 1041) with mild to moderate asthma. The hypothesis was that treatment with an inhaled steroid would result in better lung growth compared with no or lesser treatment. Primary outcome was postbronchodilator FEV ₁ , but a wealth of other data on atopy, airway reactivity, symptoms, exacerbations, and linear growth was obtained. After a brief improvement in FEV ₁ in the BUD group, there was no difference in FEV ₁ between the groups over the last 3 years of the study. However, patients in the BUD group had decreased hospitalizations and urgent care visits compared with the placebo group. Patients in the nedocromil group also had fewer emergency visits but not hospitalizations, and both groups had less oral prednisone use. There was a small, transient decrease in growth velocity in the BUD group compared with the placebo and nedocromil groups. These data suggest that long-term treatment with inhaled steroids in school-aged asthmatics does not alter pulmonary function over time, even though the symptom control and airway reactivity improved. Failure to alter the natural history of asthma, as measured by lung function, in the CAMP study was thought in part to be caused by beginning treatment too late after the onset of disease. However, subsequent studies of inhaled steroid treatment (Fluticasone 88 µg twice a day) in younger children (2–3 years of age) who had recurrent wheezing and were at very high risk for developing asthma showed improvement in clinical symptoms and exacerbations compared with those receiving placebo. However, the treatment did not prevent clinical symptoms or alteration in lung function (measured by impulse oscillometry) in the subsequent year when treatment was stopped. These data again indicate the inability of inhaled corticosteroids (ICSs) to modify the long-term disease state.

Asthma Mortality

Despite the relatively high prevalence of asthma, mortality rates for childhood asthma are extremely low and have stabilized and actually decreased over the past decade. This is evident when adjusting outcome metrics for the population at risk rather than the overall population. Overall, fewer than 4000 individuals (of whom fewer than 150 are children) die of asthma in the United States each year. However, death rates are significantly higher in African Americans of all ages. Analyses of causes of death in children with asthma suggest that the major causes are the failure of the physician, parent, or patient to appreciate the severity of asthma, which results in inadequate or delayed treatment, poor access to health care, and the use of inappropriate medications (e.g., overreliance on β-adrenergic agonists and avoidance of use of corticosteroids). In fact, recent data from Costa Rica demonstrated that a 129% increase in the prescription of ICSs over a 7-year period was associated with an approximately 80% reduction in deaths due to asthma. Labile asthma, regardless of severity, is also a risk factor, as are respiratory infections, nocturnal asthma, history of respiratory failure, and marked diurnal variation in air flow limitation. Some patients cannot perceive severe air flow obstruction, especially when it occurs gradually, and a small number may have sudden profound bronchospasm, which can be fatal. Other factors, such as exposure to allergens (mold), psychosocial disadvantage, poverty, previous episodes of respiratory failure, history of hypoxic seizure, previous admission to an intensive care unit, and psychological factors in both the patient and family have been implicated in deaths from asthma.

Diagnosis of Asthma

An asthma diagnosis requires demonstration of episodic symptoms of air flow obstruction, which must be at least partially reversible, and alternative diagnoses should be excluded. Although airway hyperresponsiveness is an almost universal feature of asthma, it is not unique and therefore cannot be used as a defining characteristic. The methods to establish the diagnosis include a detailed medical history, a physical examination with a focus on the respiratory system, and performance of spirometry in children who are 5 years of age or older. A number of ancillary tests (e.g., allergy skin tests, inhalation or exercise challenge tests, home peak flow monitoring) may also be useful and, in some cases, necessary.

Although patients with asthma may present in a variety of ways, most have certain common historical features, such as intermittent or recurrent wheezing, an expiratory, musical, high-pitched, whistling sound produced by air flow turbulence in the large airways below the thoracic inlet. Many parents and even older children cannot accurately describe wheezing and may actually report stridor (from upper airway obstruction), stertor, snoring, or rhonchorous breathing. Careful explanation or even demonstration of wheezing is often necessary to obtain an accurate history. Wheezing can also be generated by adduction of the vocal cords and forceful inspiration and expiration. Inspiratory wheezing per se is not characteristic of asthma and suggests obstruction in the laryngeal area, such as that induced by croup or vocal cord dysfunction (VCD). However, wheezing also occurs during inspiration when asthma worsens and may disappear altogether as obstruction becomes more severe and air flow is limited. Asthma can occur without wheezing if the obstruction involves predominantly the small airways. Coughing or shortness of breath may be the only complaint. However, so-called cough-variant asthma may be overdiagnosed. Probably no more than 5% of asthmatic children have cough as the only or primary symptom, and the cough should resolve with appropriate asthma medications and recur when the medications are stopped. Older children often complain of a “tight” chest with colds, recurrent “chest congestion,” or bronchitis. Usually, symptoms are more severe at night or in the early morning and improve throughout the day. A history of symptomatic improvement after treatment with a bronchodilator suggests the diagnosis of asthma, but a failure of response does not rule out asthma. When asymptomatic, many asthmatic children will have normal lung function (FEV ₁ ). Reduction of the FEV ₁ /FVC is considered to be a more reliable indicator of airway obstruction in children. An inhalation challenge test (e.g., methacholine or mannitol) should be performed when asthma is suspected but spirometry is normal or near-normal.

Family history is often positive for asthma or allergy (allergic rhinitis, eczema) in a first-degree relative. A history of personal allergy is found in more than two-thirds of children with asthma.

Physical Examination

The physical examination should focus on overall growth and development; the condition of the entire respiratory tract including the upper airway, ears, and paranasal sinuses as well as the chest; and other associated signs of allergic disease. Although severe asthma can adversely affect linear growth, this is not a common feature, and its presence should suggest evaluating for alternative causes of growth failure.

Unless acutely ill, examination of the lungs is frequently normal in children who are ultimately diagnosed with asthma. In some cases, particularly during periods with acute symptoms, auscultation reveals coarse crackles or unequal breath sounds, which may clear at least partly with coughing. If they persist, particularly during clinical stability, the possibility of another diagnosis should be considered. Although wheezing can often be elicited with a forced expiratory maneuver, occasionally there is only prolongation of expiration without wheezing. The older child or adolescent may resist exhaling forcefully to induce latent wheezes, because such a maneuver may induce coughing, which can increase bronchospasm. Some patients with severe asthma do not wheeze because too little air is moving to generate the sound. Wheezing from the lower respiratory tract should be differentiated from similar sounds that can emanate from the laryngeal area in even nonasthmatic children with sufficient forced expiration.

A variety of extrapulmonary signs indicating the presence of complicating factors or alternative diagnoses (e.g., allergy or cystic fibrosis) should be sought in all children being evaluated for asthma. Nasal polyps occur rarely in the child with uncomplicated asthma, and their presence suggests cystic fibrosis. However, nasal polyps can occur in highly allergic adolescents or those with aspirin sensitive asthma. Digital clubbing is not a feature of asthma; although clubbing may be a nonpathologic familial trait, its presence suggests cystic fibrosis, congenital heart disease, inflammatory bowel disease, or another chronic lung disorder. The conjunctivae should be examined for edema, inflammation, and tearing, suggesting allergy. Flexor creases and other areas of the skin should be examined for active or healed atopic dermatitis.

Hyperventilation and VCD syndrome should be considered in the differential diagnosis of the child with asthma that is apparently refractory to all therapy, especially if there are no symptoms during sleep. Both conditions are more likely to occur in adolescence or later childhood and may be mistaken for asthma, or may coexist with it. Typically the patient with hyperventilation is anxious and complains of marked dyspnea and difficulty getting enough air to breathe in spite of excellent air exchange on auscultation and an absence of wheezing. Often there are associated complaints of headache and tingling of the fingers and toes. Pulmonary function tests (PFTs) are helpful in differentiating hyperventilation syndrome from asthma; a normal spirogram during or around the time of symptoms is inconsistent with asthma. Immediate therapy consists of giving reassurance and having the patient rebreathe into a paper bag to elevate Pa co ₂ . VCD is another condition that must be differentiated from true asthma. In these patients, wheezing is often a prominent feature, may occur on inspiration and expiration, and is typically loudest over the trachea or central, anterior chest. This condition is more common in older children, adolescents, and females, and it may also be seen in elite athletes. Most patients with VCD cannot voluntarily induce an episode, although in many patients, including highly trained athletes, exercise can precipitate an attack. Although VCD was originally described in adults with psychiatric disorders, in children it is not usually associated with serious psychological disturbances and should not be labeled as such. The etiology in children remains poorly understood. The mechanism involves holding the anterior third of the vocal cords in a position of relative adduction during inspiration, but also in expiration. There may also be inward deflection of the supraglottic structures as well; this condition is sometimes called exercise-induced laryngomalacia (EILO). A recent study suggested that EILO in adolescence may be related to a diagnosis of clinically significant congenital laryngomalacia in infancy. The result is loud, monophonic wheezing in a patient who has normal oxygen saturation and responds poorly to inhalation of a bronchodilating aerosol. Patients may appear comfortable or anxious in the face of loud wheeze. Pulmonary function testing may reveal a pronounced flattening of the inspiratory loop; however, since some patients with VCD also have true asthma, there may be evidence of large and/or small airway obstruction on the expiratory loop as well ( Fig. 45.3 ). An increase in the mid–vital capacity expiratory/inspiratory flow ratio from the normal value of about 0.9 to a value of greater than 2 indicates extrathoracic obstruction consistent with VCD. It should be noted that most patients with VCD will have normal pulmonary function testing when asymptomatic. The diagnosis is confirmed by direct observation of paradoxical vocal cord movement via flexible laryngoscopy during an acute episode. Upper and lower airway examination with a flexible bronchoscope should be considered in patients with atypical reports of wheeze, dyspnea on exertion, or stridor to identify anatomic lesions such as cysts, hemangiomas, or laryngotracheomalacia. Older children with both VCD and asthma often can distinguish the “site” of the wheezing when the source of the problem is explained to them. The absence of nocturnal symptoms may also be a diagnostic clue that VCD is the diagnosis rather than asthma. Effective treatment consists of appropriate asthma medication (when an asthma diagnosis has been confirmed), treatment of aggravating conditions (reflux, rhinitis), and referral to a speech therapist or psychologist specializing in behavior modification in order to learn relaxation techniques and alternative breathing strategies. The vast majority of patients will improve with this treatment.

Flow-volume curve from a patient with vocal cord dysfunction. The thin line represents the flow at normal baseline. The thick line represents the flow during an obstructive episode and depicts a slight decrease in expiratory flow and a marked decrease in and flattening of the inspiratory loop.

Nonallergic Hypersensitivity to Drugs and Chemicals

Aspirin and nonsteroidal antiinflammatory drugs (NSAIDs), such as ibuprofen, can exacerbate asthma in selected individuals by increasing production of 5-lipoxygenase metabolites, including leukotrienes. The typical aspirin-sensitive asthmatic has nasal polyps, urticaria, and chronic rhinitis. Aspirin ingestion may diminish pulmonary function and produce wheeze, cough, rhinitis, conjunctivitis, urticaria, and angioedema in 10%–20% of adults with asthma. Although more common after the third decade of life, the prevalence in children (as determined by a decrease in FEV ₁ of at least 20% from baseline following aspirin or NSAID ingestion) has been reported to be as high as 5% when determined by direct challenge testing. Although aspirin in particular is rarely given to children and adolescents because of the risk of Reye syndrome, there is a very high cross-reactivity to common NSAIDs in aspirin-susceptible patients. High-dose acetaminophen may also cause wheezing in a small portion (<2%) of aspirin-sensitive asthmatics. Some (but not all) studies suggest that early-life use of acetaminophen may increase the risk of developing asthma, and one large trial found a reduced risk of an acute care visit for asthma following treatment with ibuprofen compared with treatment with acetaminophen. However, the data are more compelling for prenatal exposure to acetaminophen and development of asthma. Moreover, some studies are “confounded by indication,” and when adjusted for the incidence of respiratory tract infection, the risk of developing asthma is greatly attenuated. The absence of a history of increased symptoms following NSAID ingestion in asthmatic children is generally sufficient to warrant safe use of NSAIDs as needed. A recent trial comparing acetaminophen use with ibuprofen in children aged 1–5 years found no difference in the incidence of asthma exacerbations. However, aspirin/NSAID sensitivity should be considered in children and adolescents with severe or difficult-to-control asthma, who also have chronic rhinitis, urticaria, and nasal polyps.

Metabisulfite has been reported as a precipitant or aggravator of asthma, both by allergic and nonallergic mechanisms. Sensitive individuals should avoid foods containing or preserved using sulfites (e.g., shrimp, dried fruit, beer, and wine).

Laboratory Diagnosis

A number of laboratory studies may be useful in confirming the diagnosis of asthma, and objective measures of pulmonary function are among the most important.

Lung Function Tests

PFTs, particularly spirometry, are objective, noninvasive, and extremely helpful in the diagnosis and follow-up of patients with asthma. Examination of the forced vital capacity (FVC), FEV ₁ , and forced expiratory flow rate over 25%–75% of the FVC (FEF _25–75 ) is a reliable way to detect baseline airway obstruction. Examination of the volume-time curve and shape of the flow-volume loop provides an estimate of the adequacy of the patient effort in performing the test. A PFT should be attempted on all children older than 5 years of age when considering the diagnosis of asthma. However, there is some controversy regarding the value of repeated measures of lung function compared with symptom report in improving asthma outcomes. Nevertheless, attempting to achieve and maintain normal or near normal lung function is a goal for all asthmatic children.

In children, measurement of FEV ₁ alone may miss airway obstruction; the FEV ₁ /FVC has been proposed as a more sensitive measure of obstruction. FEF _25–75 has been proposed as a more sensitive indicator of airway obstruction, in the small airways in particular, and a better indicator of a response to bronchodilators and airway hyperresponsiveness than either FEV ₁ or FVC. However, recent data indicate that this information is not entirely accurate. The FEF _25–75 is a highly variable measure that is readily influenced by expiratory time and change in FVC. Examination of large data sets including children with asthma and cystic fibrosis indicates that less than 3% of the test results showed a reduced FEF _25–75 % with both FEV ₁ /FVC and FVC within the normal range. Documentation of reversibility of air flow obstruction following inhalation of a bronchodilator is central to the definition of asthma. If obstruction is demonstrated on a baseline PFT, a bronchodilating aerosol (albuterol) should be administered and the PFT repeated in 10–20 minutes. An improvement of at least 12% and 200 mL in the FEV ₁ is considered a positive response and is indicative of reversible air flow obstruction; however, in children, an improvement of 10% may be adequate to indicate significant improvement. A 10% improvement in the percent predicted FEV ₁ is also considered a positive response.

Use of a peak flow meter in the office setting may provide some useful information about obstruction in the large central airways, but the test should not be used to diagnose asthma. PEFR is extremely effort-dependent and is only reflective of obstruction in the large central airways.

Although standard spirometry has long been considered the gold standard for use in diagnosing and monitoring change in airway function in patients with asthma, other modalities may have particular application in both younger and older children. Forced oscillation capitalizes on the resonant oscillation properties of the airways to measure conductance and reactance and, indirectly, airway resistance. The technique requires only tidal breathing on a mouthpiece for 30 seconds in order to obtain a measurement; response to a bronchodilator can also be detected. In some studies, area of reactance (AX) as measured by forced oscillation was able to discriminate those with asthma, even when FEV ₁ was not different between the two groups. Widespread adoption of forced oscillation techniques has not occurred largely due to lack of reliable normative values.

Bronchial Challenge Tests

Airway hyperreactivity to substances such as methacholine, histamine, hypertonic saline, adenosine monophosphate, or mannitol forms the basis of an adjunctive diagnostic test for asthma (Video 45.2 ). However, the sensitivity and specificity of the tests vary widely, and bronchoprovocation testing cannot serve as the sole determinant of an asthma diagnosis. Methacholine and histamine are considered direct bronchoprovocation agents because they act directly on smooth muscle. Direct bronchoprovocation challenge testing with methacholine is very sensitive and has a better negative than positive predictive value. As such, it is generally more helpful in excluding than diagnosing asthma because positive results may be seen in disorders such as cystic fibrosis, COPD, chronic bronchitis, allergic rhinitis, and even in some normal individuals. FEV ₁ is the primary measure used to assess response, and the concentration of methacholine at which a 20% decrease in FEV ₁ occurs is recorded (PC ₂₀ ); other methods use the cumulative dose (PD ₂₀ ). A PC ₂₀ of ≤ 4 mg/mL is considered a positive test result indicative of airway hyperreactivity. However, there is no universally accepted threshold PC ₂₀ value that is considered diagnostic of asthma ( Table 45.1 ). Accurate interpretation must account for degree of baseline obstruction (if any), the pretest probability of asthma, the presence of current symptoms, and the degree of recovery in postchallenge FEV ₁ . Mild transient adverse effects (i.e., cough, wheezing, chest tightness, and dizziness) are uncommon and occur in less than 20% of patients receiving either histamine or methacholine challenge. Delayed or prolonged reactions are extremely rare, and fatalities after methacholine have not been reported. However, methacholine (or any bronchoprovocation test) should not be performed if the baseline FEV ₁ is low (generally less than 60% predicted).

Indirect bronchoprovocation agents (i.e., hypertonic saline, adenosine monophosphate [AMP], mannitol) act by inducing release of inflammatory mediators in the airway, which then cause bronchoconstriction. In addition, indirect testing is well correlated with the degree of airway inflammation. Inhalation testing with dry-powder mannitol has good validity, and a commercial kit is approved for use in Europe, Australia, and the United States. Mannitol has the advantage of being safe and easy, and it requires no special equipment apart from a spirometer. A cut point of 15% decrease in FEV ₁ from baseline had a specificity of 98% but a sensitivity of only 58%. Other agents such as allergens and occupational sensitizers have been used for inhalation challenge tests, but such challenges may pose significant risk and should only be performed by experienced physicians and investigators in the context of specific clinical or research settings. Indeed, bronchial challenge tests with any inhaled agents should only be performed in certified pulmonary function laboratories under the direct supervision of a trained specialist.

Exercise Challenge Test

In individuals 6 years of age through adulthood, a treadmill or bicycle ergometer exercise test provides useful information about the presence of EIB or EIA. In children with histories suggestive of EIB, an exercise challenge test is a more useful diagnostic aid than a methacholine challenge test (Video 45.3 ). The inhaled air should be dry, and the child should exercise at maximal level for 4–6 minutes and for a total time of 6–8 minutes. Maximal exercise is usually determined by heart rate (80%–90% of age maximum) or maximum voluntary ventilation (FEV ₁ × 35); the target should be reached relatively quickly. Pulmonary function should be measured 5 minutes before exercise. Following exercise, serial pulmonary function measurements should be obtained for at least 20 minutes (at 5, 10, and 20 minutes postexercise) to determine the presence and severity of EIA. A decrease in FEV ₁ of more than 10% is diagnostic of exercise-induced bronchoconstriction; some sources suggest a threshold of 15% decrease.

Other Tests

Radiographs

Most children with suspected asthma should have a chest radiograph at some time to rule out parenchymal disease, congenital anomaly, and (direct or indirect) evidence of a foreign body, particularly if the asthma diagnosis is questionable. However, a normal chest radiograph does not rule out other diagnoses, particularly a retained airway or esophageal foreign body. A chest radiograph should be considered for the child admitted to a hospital with asthma, particularly if there are localized findings on physical examination (i.e., crackles, egophony, diminished breath sounds), fever, or persistent hypoxemia. Radiographic findings in asthma may range from normal to hyperinflation with peribronchial interstitial markings and atelectasis ( Fig. 45.4A ); infiltrates, atelectasis, pneumonia, or a combination of the three (see Fig. 45.4B ); and pneumomediastinum (see Fig. 45.4C ), often with infiltrates. Pneumothorax occurs rarely (see Fig. 45.4D ).

Radiographic findings in asthma. (A) Hyperinflation with increased bronchial markings. (B) Atelectasis involving a complete lobe. (C) Massive pneumomediastinum complicating asthma. (D) Pneumothorax secondary to paroxysmal coughing in asthma. Arrows mark air in (C), lung margin in (D).

Paranasal sinus radiographs or screening sinus computed tomography can also be considered for children with persistent nocturnal coughing, nasal symptoms, and headaches. Although acute and chronic rhinosinusitis have long been associated with an increase in symptoms in children with asthma, a recent study indicates that long-term treatment with nasal corticosteroids did not improve asthma control. In a 24-week placebo controlled trial of daily intranasal mometasone, children with asthma and symptoms of rhinosinusitis did not show improvement in asthma control or reduction in exacerbations compared to placebo. Nasal symptoms did improve, but the study results argue against treating nasal symptoms to improve asthma control.

Therapeutic Considerations

Both the most recent US guidelines for the diagnosis and management of asthma (Expert Panel Report 3) and the international Global Initiative for Asthma (GINA) guidelines stress the importance of asthma control as compared with severity. Asthma severity refers to the intrinsic intensity of the disease and is typically assigned prior to beginning treatment with controller medications, and is also reassessed at intervals after treatment to determine degree of responsiveness to treatment. As a result, severity becomes defined by the level of treatment necessary to achieve and maintain adequate control. Identifying children and adolescents with severe or therapy resistant asthma is important because the need for close monitoring and aggressive treatment will be significant. For most other patients, accurate assessment of control is more important than severity assignment in order to adequately manage asthma.

Asthma control is divided into two components: impairment or symptom control and risk. The impairment domain refers to daytime and nighttime symptoms (i.e., cough, wheeze, exercise limitation), the need for rescue medication (SABA) for the treatment of symptoms, deviation from normal levels of activity (i.e., playing, sleeping, attending work or school), preserving normal or near-normal lung function, and meeting patient and parent expectations. The risk domain refers to preventing severe exacerbations that require medical attention, such as prescription of systemic steroids, emergency medical treatment or hospitalization, loss of lung function or impairment of normal lung growth, and adverse effects caused by medication use. This strategy draws attention to the management of current symptoms and functional impairment, as well as the future effects of asthma and its treatment on lung function and severe exacerbations. It also highlights the very important observation that asthma treatment strategies that improve symptoms may not always result in the prevention of significant exacerbations.

Asthma is best managed in a continuous fashion by forming a partnership with a knowledgeable physician or other health care provider. The concept of expecting a near symptom-free lifestyle (for all but the most severely affected patients) should be instilled in patients and their families. Unnecessary restrictions of the child’s and family’s lifestyles should be avoided. Participation in recreational activities, sports, and school attendance should all be expected. Psychosocial factors such as the child’s behavior, social adjustments in the family and at school, and attitudes toward managing asthma should also be addressed. Parents should understand that asthma is a chronic disease with acute exacerbations that with currently available treatments can be controlled, but not cured. As better characterization of the inflammatory processes and pathways that affect the airway in specific patients and development of real-time noninvasive monitoring techniques occurs, more precise control of asthma symptoms or even primary or secondary disease prevention may become a realistic goal of asthma management.

Classification of Asthma

Over the past decade, increasing awareness has been focused on the broad heterogeneity of asthma, both with respect to its causes, manifestations, and response to treatment. Identification of specific asthma phenotypes is expanding, and the use of biomarkers, molecular phenotyping, and cluster analysis based on symptoms, lung function, and comorbidities can help identify specific subtypes. Age of onset of symptoms, lung function, inflammatory cell types and mediators in induced sputum, and atopic versus nonatopic are all markers used to characterize disease severity, symptom pattern, and response to treatment. Considerable research is still needed to accurately identify asthma phenotypes and to determine clinically useful methods for classification.

Although the clinical utility is somewhat questionable, asthma severity refers to the intrinsic intensity of the disease and may be classified into broad categories based on frequency of daytime and nighttime symptoms, play or activity limitation, need for rescue/reliever treatment, and objective measures of pulmonary function (PEFR or FEV ₁ ) that are typically present before the patient is treated. In addition, the number, frequency, and intensity of severe exacerbations—defined as an increase in symptoms sufficient to warrant treatment with oral corticosteroids or treatment in the emergency department or inpatient hospital unit—are considered. Some patients who have relatively well-controlled symptoms and good functional status may have frequent or intense exacerbations. Although the correlation between the number and intensity of exacerbations with severity levels is less clear, the greater the number and severity (e.g., need for hospitalization, intensive care treatment), the higher the severity. However, the degree of severity of asthma often changes in a given individual with time, response to treatment, airway injury or growth, the development of newly acquired allergic sensitivities, or change in exposure to recognized triggers. As a result, determination of control after treatment has been instituted is of greater significance than assigning a severity level. Using very similar criteria, asthma is determined to be well controlled, not well controlled, or very poorly controlled ( Table 45.3 ). Control is determined at every visit, and appropriate treatment adjustments are made. The frequency of physician office visits for assessment of asthma control is variable and depends on disease activity but typically is every 1–6 months. Those with poor control or recent exacerbation may require more frequent visits for treatment monitoring of response and adjustment and monitoring of lung function. Since asthma is a chronic disorder that may become clinically obvious only periodically—one in which the severity of airway obstruction, intensity of symptoms, and degree of impairment is frequently underestimated by physicians and patients alike, the use of a standard, validated questionnaire can help overcome this discrepancy.

Table 45.3

Assessing Asthma Control and Adjusting Therapy in Children 5–12 Years of Age

Components of Control	CLASSIFICATION OF ASTHMA CONTROL (5–11 YEARS OF AGE)
		Well Controlled	Not Well Controlled	Very Poorly Controlled
Impairment	Symptoms	≤2 days/week but not more than once on each day.	>2 days/week or multiple time on less than 2 days/week	Throughout the day
	Nighttime awakenings	≤1×/month	≥2×/month	≥2×/week
	Interference with normal activity	None	Some limitation	Extremely limited
	Short acting beta-agonist use for symptom control (not prevention of EIB)	≤2 days/week	>2 days/week	Several times per day
	Lung function
	FEV 1 or peak flow	>80% predicted/personal best	60%–80% predicted/personal best	<60% predicted/personal best
	FEV 1 /FVC	>80%	75%–80%	<75%
Risk	Exacerbations requiring oral systemic corticosteroids	0–1/year	≥2/year (see note)
		CONSIDER SEVERITY AND INTERVAL SINCE LAST EXACERBATION
	Reduction in lung growth	Evaluation requires long-term follow-up
	Treatment related adverse effects	Medication side effects can vary in intensity from none to very troublesome and worrisome. The level of intensity does not correlate to specific levels of control but should be considered in the overall assessment of risk.
	Recommended action for treatment (See Fig. 45.1B for treatment steps)	Maintain current step Regular follow-up every 1–6 months Consider step down if well controlled for at least 3 months	Step up at least 1 step and Reevaluate in 2–6 weeks For side effects consider alternative treatment options	Consider short course of oral systemic corticosteroids Step up at least 1 step and Reevaluate in 2–6 weeks For side effects consider alternative treatment options

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