Asthma is another important cause of wheezing in infants and children (see Chapter 38). This clinical entity is characterized by recurrent episodes of airway obstruction that are at least partially reversible with bronchodilators. Another pathogenic feature of the disease is chronic inflammation of the airways. Whereas extensive bronchiolar epithelial cell necrosis and T-helper cell type 1 (Th1) cytokines like interferon-γ are present in viral bronchiolitis, inflammation in asthma is often driven by allergic (Th2) cytokines such as interleukin-13 (IL-13), IL-4, and IL-5. Other abnormalities of the asthmatic airway include constriction and hypertrophy of the airway smooth muscle, mucosal edema, hypertrophic mucous glands, and sometimes eosinophilic infiltration.

Viral infections are the most common causes of exacerbations in infantile asthma. As opposed to bronchiolitis, lower respiratory symptoms in asthma tend to recur during exposure to other triggers, such as exercise, allergens, or cold air. Depending on the clinical course of their wheezing, infants may be early transient wheezers with at least one episode before the age of 3 years but complete resolution by school age; persistent wheezers with episodes before 3 years that are still present at 6 years of age; or late-onset wheezers with no history of wheezing by 3 years but with wheezing by 6 years. Approximately 60% of infants who wheeze will outgrow wheezing by 6 years of age. Risk factors for persistent wheezing include a maternal history of asthma, maternal smoking, elevated immunoglobulin E (IgE) level, and eczema at younger than 1 year of age. In addition, early respiratory viral infections, particularly RSV and rhinovirus, are associated with the presence of subsequent recurrent wheezing and asthma.

Whether bronchiolitis modifies the immune response or airway biology to evoke asthma later in life is still unclear. Experimental studies primarily based on animal models have reported that early RSV infection can upregulate neurokinin-mediated neurogenic inflammation, potentially leading to airway hyperreactivity. Other proasthmatic mechanisms postulated include a viral-induced bias of the host toward allergic Th2 immune responses during early infancy and the production of virus-specific IgE antibodies. Notwithstanding these hypotheses, infants with bronchiolitis may be a select group of patients with an inherent predisposition to asthma that is simply unmasked by an episode of viral respiratory infection. The relationship between early respiratory viral infections and subsequent wheezing and asthma remains a topic of intense investigation and controversy.

Other Causes of Wheezing

Gastroesophageal reflux (GER) is another important cause of acute or chronic wheezing in infants and children. Wheezing in GER is caused by pulmonary aspiration of gastric contents or by a vagal reflex that induces bronchospasm without aspiration. Other conditions associated with widespread involvement of the intrathoracic small airways such as cystic fibrosis (CF), primary ciliary dyskinesia (PCD), or immunodeficiency can present with heterophonous wheezing as well (see Figure 37-1).

The presence of homophonous wheezing is suggestive of narrowing or obstruction in the large central airways. Homophonous wheezing is commonly heard in children with tracheomalacia, bronchomalacia or anatomic abnormalities (i.e., vascular ring). In addition, an isolated homophonous wheeze localized in just one area may signal bronchial obstruction by an extrinsic compression or intraluminal foreign body (see Figure 37-1).

Clinical Presentation

When evaluating an infant with an acute respiratory illness a critical question to answer is whether or not there is involvement of the lower airways. In RSV infection, non-specific upper respiratory tract symptoms consisting of nasal discharge and mild cough begin about 3 to 5 days after exposure. The progression of the disease to the lower respiratory tract is characterized by the presence of tachypnea, hypoxemia, nasal flaring and intercostal or subcostal retractions. The typical course for a previously healthy infant older than 6 months is one of improvement over the subsequent 2 to 5 days. Significant hypoxemia, grunting and marked use of accessory muscles are signs of severe disease and impending respiratory failure (Figure 37-3). Central apnea can also be an early manifestation of RSV infection, at times also resulting in respiratory failure.

Figure 37-3 Clinical evaluation of wheezing and bronchiolitis.

Viral bronchiolitis is one of several syndromes associated with obstruction of the intrathoracic small airways; thus, the presence of expiratory heterophonous wheezing is a common but non-specific sign of the disease. Wheezing in infants can be better appreciated on pulmonary auscultation when elicited by gentle chest compression (so-called “squeeze the wheeze”) to induce forced expiratory flow. A marked reduction in amplitude of breathing sounds suggests very severe disease with nearly complete bronchiolar obstruction. Auscultation in bronchiolitis may also reveal inspiratory crackles as small airways re-open, and prolongation of the expiratory phase. The other cardinal feature of small airways obstruction is pulmonary hyperinflation. This clinical feature helps to localize the disease in the small airways as it is a manifestation of alveolar air trapping. The key signs of hyperinflation are an increase in antero-posterior diameter of the chest wall, the presence of subcostal retractions and the palpation of a normal sized liver below the costal margin (see Figure 37-3).

Given that early respiratory viral infections are associated with the presence of recurrent wheezing and asthma, the initial differentiation between these entities is often difficult. Many infants originally diagnosed with viral bronchiolitis are later categorized as asthmatics. In the asthmatic child, the presence of intermittent symptoms such as coughing or wheezing at night or in response to exercise, crying, laughing, mist, or cold air can facilitate the diagnosis. Adequate responses to bronchodilator therapy and typically also to corticosteroids are characteristic features of asthma as well. An atopic phenotype (i.e., eczema or elevated IgE levels) and a positive family history of asthma also point toward the diagnosis of this disease.

The clinical evaluation of wheezing should also include a detailed feeding history. Respiratory symptoms such as cough, cyanosis, or respiratory distress during feeds suggest laryngeal penetration or pulmonary aspiration. Given that aspiration can also be “silent,” especially at night, early morning symptoms may be the only clue for the diagnosis. Aspiration of gastric contents or direct penetration of oral liquids during feeding is particularly common in children with neurodevelopmental abnormalities or anatomic defects of the respiratory system such as tracheoesophageal fistula (TEF) or laryngeal cleft.

When wheezing is persistent and nonresponsive to therapy, the consideration of uncommon but serious medical conditions such as CF, PCD, and immunodeficiency is in order. As opposed to asthma, these diseases are often associated with failure to thrive. This is particularly true in patients with CF because of the presence of malabsorption caused by pancreatic insufficiency. Digital clubbing may be present in patients with CF, PCD, and other causes of bronchiectasis but should never be present in uncomplicated asthma. Recurrent sinusitis and bacterial bronchitis are common features of CF, PCD, and some immunodeficiencies. PCD invariably causes significant abnormalities of the middle ear and is often associated with situs inversus or abdominal heterotaxy. Tachypnea during the neonatal period and persistent purulent rhinorrhea during infancy are also typical features of this disease.

The presence of homophonous wheezing is suggestive of abnormalities in the large rather than the small intrathoracic airways. Tracheal collapse secondary to highly compliant airways can produce homophonous wheezing in infants. This condition, termed tracheomalacia, seldom affects respiratory function at rest (infants are often referred to as “happy wheezers”), and isolated congenital tracheomalacia usually resolves after 1 year of age. Nevertheless, infants with significant collapse of the central airways during the expulsive phase of cough, particularly those with congenital or acquired tracheal abnormalities (e.g., TEF), can have inadequate clearance of airway secretions. A harsh “barking” cough is a key clinical sign present in this situation. These patients often have a protracted clinical course accompanied by recurrent lower tract infections and frequent hospital visits.

Congenital malformations cause homophonous wheezing in early infancy when they externally compress the airway or cause intrinsic obstruction of the airway lumen. Vascular rings secondary to abnormal development of the aortic arch can produce considerable constriction of the subjacent trachea (see Figure 37-1). Virtually any type of congenital intrathoracic lesion, depending on its size and location, can potentially cause external compression of the airways. Other causes of external compression include mediastinal lymphadenopathy secondary to infections (e.g., tuberculosis) or malignancies (e.g., lymphoma) (see Figure 37-1). Intrinsic obstruction of the airway lumen may be caused by foreign body aspiration, hemangiomas, and rarely carcinoid tumors (see Figure 37-1). Airway hemangiomas should be suspected particularly when they are present in other areas of the body (e.g., skin).