Genetics

More than 100 genetic loci have been linked to asthma. Although the genetic linkages to asthma have sometimes differed between cohorts, asthma has been consistently linked with loci containing proallergic, proinflammatory genes (the interleukin [IL]-4 gene cluster on chromosome 5). Genetic variation in receptors for different asthma medications is associated with variation in biologic response to these medications (polymorphisms in the β₂-adrenergic receptor). Other candidate genes include ADAM-33 (member of the metalloproteinase family), the gene for the prostanoid DP receptor, and genes located on chromosome 5q31 (possibly IL-12).

Environment

Recurrent wheezing episodes in early childhood are associated with common respiratory viruses, including respiratory syncytial virus, rhinovirus, influenza virus, adenovirus, parainfluenza virus, and human metapneumovirus. This association implies that host features affecting immunologic host defense, inflammation, and the extent of airways injury from ubiquitous viral pathogens underlie susceptibility to recurrent wheezing in early childhood. Furthermore, injurious viral infections of the airways that manifest as pneumonia or bronchiolitis requiring hospitalization are risk factors for persistent asthma in childhood. Other airways exposures can also exacerbate ongoing airways inflammation, increase disease severity, and drive asthma persistence. Indoor and home allergen exposures in sensitized individuals can initiate airways inflammation and hypersensitivity to other irritant exposures, and are strongly linked to disease severity and persistence. Consequently, eliminating the offending allergen(s) can lead to resolution of asthma symptoms and can sometimes “cure” asthma. Environmental tobacco smoke and air pollutants (ozone, sulfur dioxide) aggravate airways inflammation and increase asthma severity. Cold dry air and strong odors can trigger bronchoconstriction when airways are irritated but do not worsen airways inflammation or hyperresponsiveness.

Types of Childhood Asthma

Asthma is considered to be a common clinical presentation of intermittent, recurrent wheezing and/or coughing, resulting from different airways pathologic processes underlying different types of asthma. There are 2 main types of childhood asthma: (1) recurrent wheezing in early childhood, primarily triggered by common viral infections of the respiratory tract, and (2) chronic asthma associated with allergy that persists into later childhood and often adulthood. A 3rd type of childhood asthma typically emerges in females who experience obesity and early-onset puberty (by 11 yr of age). Some children may be hypersensitive to common air pollutants (environmental tobacco smoke, ozone, endotoxin) such that exposures to these pollutants might not only make existing asthma worse but may also have a causal role in the susceptible. The most common persistent form of childhood asthma is associated with allergy and susceptibility to common respiratory virus–induced exacerbations (Table 138-2).

Pulmonary Function Testing

Forced expiratory airflow measures are helpful in diagnosing and monitoring asthma and in assessing efficacy of therapy. Lung function testing is particularly helpful in children with asthma who are poor perceivers of airflow obstruction or when physical signs of asthma do not occur until airflow obstruction is severe.

Many asthma guidelines promote spirometric measures of airflow and lung volumes during forced expiratory maneuvers as standard for asthma assessment. Spirometry is helpful as an objective measure of airflow limitation (Fig. 138-2). Knowledgeable personnel are needed to perform and interpret findings of spirometry tests. Valid spirometric measures depend on a patient’s ability to properly perform a full, forceful, and prolonged expiratory maneuver, usually feasible in children > 6 yr of age (with some younger exceptions). Reproducible spirometric efforts are an indicator of test validity; if the FEV₁ (forced expiratory volume in 1 sec) is within 5% on 3 attempts, then the highest FEV₁ effort of the 3 is used. This standard utilization of the highest of 3 reproducible efforts is indicative of the effort dependence of reliable spirometric testing.

Figure 138-2 Spirometry. A, Spirometric flow-volume loops. A is an expiratory flow-volume loop of a nonasthmatic person without airflow limitation. B through E are expiratory flow-volume loops in asthmatic patients with increasing degrees of airflow limitation (B is mild; E is severe). Note the “scooped” or concave appearance of the asthmatic expiratory flow-volume loops; with increasing obstruction, there is greater “scooping.” B, Spirometric volume-time curves. Subject 1 is a nonasthmatic person; subject 2 is an asthmatic patient. Note how the FEV₁ and FVC lung volumes are obtained. The FEV₁ is the volume of air exhaled in the 1st sec of a forced expiratory effort. The FVC is the total volume of air exhaled during a forced expiratory effort. Note that subject 2’s FEV₁ and FEV₁/FVC ratio are smaller than subject 1’s, demonstrating airflow limitation. Also, subject 2’s FVC is very close to what is expected. FEV₁, forced expiratory volume in 1 sec; FVC, forced vital capacity.

In asthma, airways blockage results in reduced airflow with forced exhalation and smaller partial-expiratory lung volumes (see Fig. 138-2). Because asthmatic patients typically have hyperinflated lungs, FEV₁ can be simply adjusted for full expiratory lung volume—the forced vital capacity (FVC)—with an FEV₁/FVC ratio. Generally, an FEV₁/FVC ratio <0.80 indicates significant airflow obstruction (Table 138-6). Normative values for FEV₁ have been determined for children on the basis of height, gender, and ethnicity. Abnormally low FEV₁ as a percentage of predicted norms is 1 of 6 criteria used to determine asthma severity in the National Institutes of Health (NIH)–sponsored asthma guidelines.

Such measures of airflow alone are not diagnostic of asthma, because numerous other conditions can cause airflow reduction. Bronchodilator response to an inhaled β-agonist (e.g., albuterol) is greater in asthmatic patients than nonasthmatic persons; an improvement in FEV₁ ≥12% or >200 mL is consistent with asthma. Bronchoprovocation challenges can be helpful in diagnosing asthma and optimizing asthma management. Asthmatic airways are hyperresponsive and therefore more sensitive to inhaled methacholine, histamine, and cold or dry air. The degree of AHR to these exposures correlates to some extent with asthma severity and airways inflammation. Although bronchoprovocation challenges are carefully dosed and monitored in an investigational setting, their use is rarely practical in a general practice setting. Exercise challenges (aerobic exertion or “running” for 6-8 min) can help to identify children with exercise-induced bronchospasm. Although the airflow response of non-asthmatic persons to exercise is to increase functional lung volumes and improve FEV₁ slightly (5-10%), exercise often provokes airflow obstruction in persons with inadequately treated asthma. Accordingly, in asthmatic patients, FEV₁ typically decreases during or after exercise by >15% (see Table 138-6). The onset of exercise-induced bronchospasm is usually within 15 min after a vigorous exercise challenge and can spontaneously resolve within 30-60 min. Studies of exercise challenges in school-aged children typically identify an additional 5-10% with exercise-induced bronchospasm and previously unrecognized asthma. There are two caveats regarding exercise challenges: first, treadmill challenges in the clinic are not completely reliable and can miss exertional asthma that can be demonstrated on the playing field; and second, treadmill challenges can induce severe exacerbations in at-risk patients. Careful patient selection for exercise challenges and preparedness for severe asthma exacerbations are required.

Measuring exhaled nitric oxide (FE_NO), a marker of airway inflammation in allergy-associated asthma, has been thought to help with anti-inflammatory management and in confirming the diagnosis of asthma.

Peak expiratory flow (PEF) monitoring devices provide simple and inexpensive home-use tools to measure airflow and can be helpful in a number of circumstances (Fig. 138-3). “Poor perceivers” of airflow obstruction due to asthma can benefit by monitoring PEFs daily to assess objectively airflow as an indicator of asthma control or problems that would be more sensitive than their symptom perception. PEF devices vary in the ability to detect airflow obstruction: they are generally less sensitive than spirometry to airflow obstruction such that, in some patients, PEF values decline only when airflow obstruction is severe. Therefore, PEF monitoring should be started by measuring morning and evening PEFs (best of 3 attempts) for several weeks for patients to practice the technique, to determine a “personal best,” and to correlate PEF values with symptoms (and ideally spirometry). PEF variation >20% is consistent with asthma (see Fig. 138-3 and Table 138-6).

Figure 138-3 An example of the role of peak flow monitoring in childhood asthma. A, Peak expiratory flows (PEFs) performed and recorded twice daily, in the morning (AM) and evening (PM), over 1 mo in an asthmatic child. This child’s “personal best” PEF value is 220 L/min; therefore, the green zone (>80-100% of best) is 175-220 L/min; the yellow zone (50-80%) is 110-175 L/min; and the red zone (<50%) is <110 L/min. Note that this child’s PM PEF values are almost always in the green zone, whereas his AM PEFs are often in the yellow or red zone. This pattern illustrates the typical diurnal AM-to-PM variation of inadequately controlled asthma. B, PEFs performed twice daily, in the morning (AM) and evening (PM), over 1 mo in an asthmatic child in whom an asthma exacerbation developed from a viral respiratory tract infection. Note that the child’s PEF values were initially in the green zone. A viral respiratory tract infection led to asthma worsening, with a decline in PEF to the yellow zone that continued to worsen until PEF values were in the red zone. At that point, a 4-day prednisone course was administered, followed by improvement in PEF back to the green zone.

Radiology

The findings of chest radiographs (posteroanterior and lateral views) in children with asthma often appear to be normal, aside from subtle and nonspecific findings of hyperinflation (flattening of the diaphragms) and peribronchial thickening (Fig. 138-4). Chest radiographs can be helpful in identifying abnormalities that are hallmarks of asthma masqueraders (aspiration pneumonitis, hyperlucent lung fields in bronchiolitis obliterans), and complications during asthma exacerbations (atelectasis, pneumomediastinum, pneumothorax). Some lung abnormalities can be better appreciated with high-resolution, thin-section chest CT scans. Bronchiectasis, which is sometimes difficult to appreciate on chest radiograph but is clearly seen on CT scan, implicates an asthma masquerader, such as cystic fibrosis, allergic bronchopulmonary mycoses (aspergillosis), ciliary dyskinesias, or immune deficiencies.

Figure 138-4 A 4-year-old boy with asthma. Frontal (A) and lateral (B) radiographs show pulmonary hyperinflation and minimal peribronchial thickening. No asthmatic complication is apparent.

Other tests, such as allergy testing to assess sensitization to inhalant allergens, help with the management and prognosis of asthma. In a comprehensive U.S. study of 5-12 yr old asthmatic children (Childhood Asthma Management Program [CAMP]), 88% of the subjects had inhalant allergen sensitization according to results of allergy prick skin testing.

Component 1: Regular Assessment and Monitoring

Regular assessment and monitoring are based on the concepts of asthma severity, asthma control, and responsiveness to therapy. Asthma severity is the intrinsic intensity of disease, and assessment is generally most accurate in patients not receiving controller therapy. Hence, assessing asthma severity directs the initial level of therapy. The 2 general categories are intermittent asthma and persistent asthma, the latter further subdivided into mild, moderate, and severe. Asthma severity is to be assessed only once, during a patient’s initial evaluation, and only in patients who are not yet using a daily controller agent. In contrast, asthma control refers to the degree to which symptoms, ongoing functional impairments, and risk of adverse events are minimized and goals of therapy are met. In children receiving controller therapy, asthma control is to be assessed. Assessment of asthma control is important in adjusting therapy and is categorized in 3 levels: well-controlled, not well-controlled, and very poorly controlled. Responsiveness to therapy is the ease with which asthma control is attained by treatment. It can also encompass monitoring for adverse effects related to medication use.

Classification of asthma severity and control is based on the domains of Impairment and Risk. These domains may not correlate with each other and may respond differently to treatment. The NIH guidelines have criteria for 3 age groups—0-4 yr, 5-11 yr, and ≥12 yr—for the evaluation of both severity (Table 138-7) and control (Table 138-8). The level of asthma severity or control is based on the most severe impairment or risk category. In assessing asthma severity, impairment consists of an assessment of the patient’s recent symptom frequency (daytime and nighttime with subtle differences in numeric cutoffs between the 3 age groups), need for short-acting β₂-agonists for quick relief, ability to engage in normal or desired activities, and airflow compromise, which is evaluated with spirometry in children 5 yr and older. Risk refers to an evaluation of the likelihood of developing asthma exacerbations for the individual patient. Of note, in the absence of frequent symptoms, persistent asthma should be considered, and therefore long-term controller therapy should be initiated for infants or children who have risk factors for asthma (see earlier) and 4 or more episodes of wheezing over the past year that lasted longer than 1 day and affected sleep, or 2 or more exacerbations in 6 months requiring systemic corticosteroids.

Asthma management can be optimized through regular clinic visits every 2-6 wk until good asthma control is achieved. For children already on controller medication therapy, management is tailored to the child’s level of control. The NIH guidelines provide tables for evaluating asthma control for the 3 age groups (see Table 138-8). In evaluation of asthma control, as in severity assessment, impairment includes an assessment of the patient’s symptom frequency (daytime and nighttime), need for short-acting β₂-agonists for quick relief, ability to engage in normal or desired activities, and, for older children, airflow measurements. In addition, determination of quality of life measures for older children is included. Furthermore, with respect to risk assessment, besides considering severity and frequency of exacerbations requiring systemic corticosteroids, tracking of lung growth in older children and monitoring of untoward effects of medications are also warranted. As already mentioned, the degree of impairment and risk are used to determine the patient’s level of asthma control as well-controlled, not well-controlled, or very poorly controlled. Children with well-controlled asthma have: daytime symptoms ≤2 days/week and need a rescue bronchodilator ≤2 days/week; an FEV₁ of >80% of predicted (and FEV₁/FVC ratio >80% for children 5-11 yr of age); no interference with normal activity; and <2 exacerbations in the past year. The impairment criteria vary slightly depending on age group: there are different thresholds in the frequency of nighttime awakenings; addition of FEV₁/FVC ratio criteria for children 5-11 yr old, and addition of validated questionnaires in evaluating quality of life for older children. Children whose status does not meet all of the criteria defining well-controlled asthma are determined to have either not well-controlled or very poorly controlled asthma, which is determined by the single criterion with the lowest rating.

Two to four asthma checkups per year are recommended for reassessing and maintaining good asthma control. During these visits, asthma control can be assessed by determining the: (1) frequency of asthma symptoms during the day, at night, and with physical exercise; (2) frequency of “rescue” SABA medication use and refills; (3) quality of life for youths with an assessment tool; (4) lung function measurements for older children and youths; (5) number and severity of asthma exacerbations; and (6) presence of medication adverse effects since the last visit (see Fig. 138-5). Lung function testing (spirometry) is recommended at least annually and more often if asthma is inadequately controlled or lung function is abnormally low. PEF monitoring at home can be helpful in the assessment of asthmatic children with poor symptom perception, other causes of chronic coughing in addition to asthma, moderate to severe asthma, or a history of severe asthma exacerbations. PEF monitoring is feasible in children as young as 4 yr who are able to master this skill. Use of a stoplight zone system tailored to each child’s “personal best” PEF values can optimize effectiveness and interest (see Fig 138-3