Wheezing and Asthma
Kenny Y.C. Kwong, MD, and Nasser Redjal, MD
A 7-year-old boy is referred to the office after being seen in the emergency department for wheezing. He has been treated in the emergency department for wheezing 4 times in the past month and was once hospitalized for 3 days. The boy’s father and paternal grandmother both have asthma.
The child’s physical examination is remarkable for end-expiratory wheezing on forced expiration.
1. What are the most common causes of wheezing in infants and children?
2. What are the causes of reversible bronchospasm?
3. What is the pathophysiology of reversible bronchospasm?
4. How should the child with asthma be treated?
Recurrent wheezing is a frequent symptom of obstructive airway disease in children that may be caused by intrinsic or extrinsic compression of the airway, bronchospasm, inflammation, or defective clearance of secretions. Ten percent to 15% of infants wheeze during the first year after birth, and as many as 25% of children younger than 5 years present to their physician with wheezing during a respiratory illness. Most infants and young children with recurrent wheezing have asthma; however, a wide variety of congenital and acquired conditions can cause narrowing of the extrathoracic or intrathoracic airways and may present with wheezing. Reactive airway disease is the most common cause of wheezing in childhood. Childhood asthma typically falls into 1 of 3 categories: transient wheezing, late transient wheezing, and atopic wheezing.
Transient wheezing occurs in infants who are born with smaller caliber airways and who wheeze with viral lower respiratory tract infections and bronchiolitis. These infants do not have atopy and usually have no more wheezing by 3 years of age. Most patients with no atopic predisposition who wheeze in the early years after birth fall into this category. Late transient wheezing occurs in children who usually have a history of serious lung insult, such as severe respiratory syncytial virus (RSV) infections, and persistent wheezing beyond 3 years of age. These children also have no atopy, and symptoms usually slowly resolve over time. Atopic wheezing occurs in children with a strong atopic predisposition. Such children are most likely to develop asthma that persists throughout the school-age years.
Wheezes can originate from airways of any size, from the large extrathoracic upper airway to the intrathoracic small airways. In addition to narrowing or compression of the airway, wheezing requires sufficient airflow to generate airway oscillation and produce sound. Thus, the absence of wheezing in a patient who presents with acute asthma may be an ominous finding suggestive of impending respiratory failure. The audible musical or squeaking sounds noted with obstruction are caused by turbulence of the air as it is forced through a narrowed airway. Infants and young children are more prone to wheezing when they have airway obstruction because air forced through smaller airways is more turbulent than air forced through the larger airways of older children and adults. Infectioninduced wheezing in children younger than 2 years is associated with RSV, especially in infants with passive exposure to smoke, and with rhinovirus in children older than 2 years. The most common causes of wheezing in infants and children are asthma, bronchiolitis, and pneumonia. Less common causes include congenital structural anomalies, gastroesophageal reflux and aspiration, cardiac failure, cystic fibrosis, foreign bodies, and vocal cord dysfunction (Box 96.1).
The modified Asthma Predictive Index (mAPI) is a clinical instrument used to predict persistence of asthma. Predictive factors include wheezing before 3 years of age and the presence of either 1 major risk factor (ie, parental history of asthma, personal history of atopic dermatitis, or patient sensitized to aeroallergen) or 2 of 3 minor risk factors (ie, patient sensitized to food, wheezing apart from colds, or eosinophilia). The mAPI has a positive predictive value of 76% and a negative predictive value of 95%. More than 80% of infants with a history of wheezing in the first postnatal years do not wheeze after 3 years of age.
Asthma is a common chronic disorder of the airways characterized by variable and recurring symptoms, airflow obstruction, bronchial hyperreactivity, and underlying inflammation. Bronchospasm is reversible spontaneously or with treatment. In some patients, permanent alterations in the airway structure, referred to as airway remodeling, occur and are not prevented by or fully responsive to currently available treatment. Clinically, asthma is characterized by recurrent episodes of cough, chest tightness, dyspnea, prolonged expiration, wheezing, hyperinflation of the chest (ie, air trappings), use of accessory chest muscles (ie, retractions), and, in severe cases, cyanosis.
Box 96.1. Causes of Wheezing
Reactive Airway Disease
•Nighttime cough asthma
•Toxic exposure (eg, smoke, organophosphate poisoning)
Laryngeal Dysfunction Congenital Structural Anomalies
Defective Secretion Clearance
•Immotile cilia syndrome
Asthma is the most common chronic childhood illness. In 2017, the National Health Interview Survey noted that 9.5 million children had asthma. Asthma is the leading cause of emergency department (ED) visits, hospital admissions, and school absenteeism. Over the past several decades, the prevalence of asthma has increased worldwide, an increase that varies from 40% in some areas of the United Kingdom and Australia to 3% in Indonesia, China, and India. Asthma prevalence, mortality, and hospitalization rates are higher in blacks than in whites. One-third of patients initially experience symptoms in the first year after birth, and 80% are diagnosed by the time they reach school age. In the United States, asthma is a leading diagnosis for children admitted to children’s hospitals. Hospitalization rates have remained relatively stable, with lower rates in some age groups but higher rates in children 0 to 4 years of age. Additionally, asthma is a major cause of school absence; 23% of school days missed can be attributed to asthma. The male-to-female ratio is 2:1 until age 10 years and is equal from ages 10 to 14 years; after puberty, asthma incidence is greater in girls and women.
In recent years, the incidence of more serious disease in younger children and adolescents has increased. Low socioeconomic status is associated with an increase in asthma prevalence, morbidity, and mortality. Inner-city blacks are most at risk, but studies suggest that socioeconomic class and health care disparities only partially account for these differences.
The child with asthma may present with acute symptoms of cough, shortness of breath, prolonged expiration, use of accessory muscles of respiration, wheezing, reports of chest tightness or congestion, hyperinflation of the chest, cyanosis, exercise intolerance, tachycardia, and abdominal pain.
Wheezing may be audible and detected by the parent or guardian or may not be appreciated until the child is examined by a physician. The child with severe bronchoconstriction may have no wheezing because the flow of air is impeded; however, wheezing may occur after bronchodilator treatment resulting from partial opening of the airway.
Some children have cough, which may be nocturnal or recurrent as a predominant symptom. Some pediatric patients have symptoms, such as cough or wheezing, that are precipitated or exacerbated by exercise (Box 96.2).
Abdominal pain and vomiting also are common in younger children and may be followed by temporary relief of respiratory symptoms. During an acute asthma attack, a low-grade fever, profuse sweating, and fatigue from the hard work of breathing may be apparent.
Asthma is a chronic inflammatory disorder of the airways. The immunohistopathologic features of asthma include alteration and denudation of the airway epithelium, thickening of the basement membrane, fibrotic changes in the subbasement membrane, bronchial smooth muscle hypertrophy, edema and angiogenesis, mast cell activation, and inflammatory cell infiltration (ie, neutrophils, lymphocytes, eosinophils), which release mediators such as histamine, prostaglandin, leukotriene, and major basic proteins. These changes result in airway hyperreactivity, airflow limitation, respiratory symptoms, and disease chronicity. The limitation to the flow of air results from acute bronchoconstriction, airway edema, mucus plug formation, and airway wall remodeling. The unique anatomy and physiology of the lung in infants compared with adults predisposes infants to obstructive airway disease. These anatomic differences include reduced number and size of the alveolar pores and canals of Lambert, causing deficient collateral ventilation and a predisposition to atelectasis distal to the obstructed airway. Mucous gland hyperplasia favors increased intraluminal mucus production. Decreased smooth muscle in the peripheral airway results in less support and narrower airways. Decreased number of fatigue-resistant skeletal muscle fibers in the diaphragm, its horizontal insertion to the rib cage (versus oblique in adult), and a highly compliant rib cage increase the work of breathing in children. Decreased static elastic recoil predisposes to early airway closure during tidal breathing, resulting in ventilation-perfusion mismatch and hypoxemia.
Box 96.2. Diagnosis of Asthma in the Pediatric Patient
•Shortness of breath
•History of allergies
•History of atopic dermatitis
•History of nighttime cough
Atopy, the genetic predisposition to the development of immunoglobulin (Ig) E–mediated response to common aeroallergens, is a predisposing factor for developing asthma. At least 50 genes influence susceptibility to asthma and its clinical expression. Sites located on chromosomes 6p, 12q, 5q, 11q, and 16p are known to be associated with allergic diseases and encoding for major histocompatibility complex, IgE, interferon, and cytokine.
Environmental changes, such as wind, temperature fluctuations, and increased exposure to allergens or air pollutants (eg, tobacco smoke, ozone, sulfur dioxide, nitrogen dioxide), and particulate matter (eg, diesel exhaust, biologic residues [eg, endotoxin]), may precipitate clinical attacks. Inhalant allergens, particularly indoors, play an important role. The most important allergens are house dust mite feces (Der p1 and Der p2), cat allergen (Fel d1), and cockroach saliva (Bla g2, Bla g4, and Bla g5). Other inhalant allergens, such as dog dander, outdoor fungus (ie, Alternaria), and some pollens, also play a role. Infections, particularly respiratory ones, are implicated, influencing not only the exacerbation of asthma but also its inception and persistence. Viral infections, such as RSV, parainfluenza, and rhinovirus, are the most frequent precipitants of asthma exacerbations in infancy. The frequency of lower tract respiratory infection during early childhood with these viruses is a strong independent factor in development of asthma. Mycoplasma and Chlamydia infections can cause wheezing and persistence of asthma. Emotional stress may also play a role in the exacerbation of asthma.
The physiological changes involved in asthma occur in 2 phases: early and late. An immediate response (early phase) to the offending agent causes edema and bronchial smooth muscle constriction that result in narrowing of the airway and plugging with secretions. Air is trapped behind the narrowed airways, resulting in altered gas exchange, increased respiratory rate, decreased tidal volume, and increased work of breathing. The late response, which occurs 4 to 12 hours after the initial symptoms, primarily involves infiltration of the airways with inflammatory cells. The end pathway in the disease process is obstruction to airflow. The pathophysiology of asthma is reviewed in Figure 96.1.
An extensive differential diagnosis of asthma is listed in Box 96.1. Most conditions are differentiated from asthma by the presence of associated symptoms or the child’s response to bronchodilators.
A thorough history, including how the child and family are coping with the asthma, should be obtained (Box 96.3). If acute respiratory distress is present, an abbreviated history focusing on potential precipitating factors and medication use should be obtained first, saving the more detailed history for a later time.
Vital signs, including pulse oximetry, should be obtained. Objective determination of pulmonary function involves measuring the peak expiratory effort. Paradoxical pulse, the difference between systolic arterial blood pressure during inspiration and expiration, is usually under 10 mm Hg. This difference may be increased during an acute asthma exacerbation, but the measurement is difficult in young children. Breath sounds, work of breathing, the inspiratory-expiratory ratio, use of accessory muscles, presence of retractions, quality of breath sounds (whether decreased), presence of prolonged expiration, and quality of wheezing should be carefully assessed (Table 96.1). Polyphonic wheezing (ie, many different pitches, starting and stopping at varying points in the respiratory cycle) and cough are strongly suggestive of asthma. Monophonic wheezing (ie, a single, distinct noise of 1 pitch and starting and stopping at 1 discrete time) and cough should always raise suspicion for large airway obstruction caused by foreign body aspiration, vascular ring, or tracheomalacia. The nose and associated nasal passages should be examined for secretions, edema, pallor, and polyps. The skin should be assessed for eczema and other rashes. The chest should be carefully checked for increased anteroposterior diameter of the chest wall, a sign of air trapping. Fingers should be examined for signs of digital clubbing, which is suggestive of a diagnosis other than asthma.
Figure 96.1. Proposed pathways in the pathogenesis of bronchial inflammation and airway hyperreactivity.
Reprinted from the National Asthma Education and Prevention Program. Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma. Bethesda, MD: National Heart, Lung, and Blood Institute; 1991. NIH Publication No. 91-3042.
Laboratory assessment of wheezing children is indicated if the diagnosis is unclear or to eliminate disorders that mimic asthma. Pulmonary function tests are noninvasive, objective, and cost-effective in the diagnosis and follow-up of patients with asthma. These tests can be performed in children older than 5 years with appropriate coaching. After the administration of an aerosolized bronchodilator, dynamic tests of airflow increase or return to normal. An improvement in forced expiratory volume in 1 second (FEV1) greater than 12% is nearly diagnostic, but lack of improvement in FEV1 does not preclude asthma. Exercise tolerance tests using a treadmill or free running followed by pulmonary function tests can be performed; a decrease greater than 12% in FEV1 or 30% in forced expiratory flow is diagnostic for exercise-induced asthma. Peak flow meters, which measure forced peak expiratory flow, are useful in the office and at home to monitor expiratory flow rate. A decrease in peak expiratory flow may predict the onset of an exacerbation and suggests the need for early intervention, using additional drug therapy. A complete blood cell count with a differential count may be suggestive of infection or allergies. Peripheral eosinophil counts may be elevated in asthma. Pulse oximetry assesses the degree of oxygen saturation. Although not used as a parameter in North American asthma guidelines for classification or assessment of asthma control, fractional exhaled nitric oxide (FeNO) has been shown to help differentiate diagnosis of asthma from other conditions that may mimic asthma, such as upper airway disease and reflux (ie, chronic cough). Additionally, some specialists use serial FeNO measurements to help wean patients off anti-inflammatory medications.
Box 96.3. What to Ask
•What symptoms (eg, wheezing, exercise intolerance) does the child experience?
•Does the child experience any nocturnal awaking or cough?
•What time of day and year do the symptoms occur?
•When did the symptoms begin? How old was the child?
•Are the symptoms associated with any particular activity? Does anything seem to trigger the symptoms?
•Are the child’s activities limited in any way?
•How often do asthma attacks occur?
•What is the child’s living situation? Are there pets in the home?
•Does anyone smoke in the home?
•Do asthma attacks cause the child to be absent from school?
•Does the child manage the condition at home with any particular treatments or medications?
•Has the child visited any urgent care facility or emergency department for treatment for asthma or related episodes in the past? Has the child had any hospitalizations?
•Does the child have a history of allergies?