Recurrent wheezing is a common problem among infants, toddlers, and young children. The 2007 National Heart, Lung, and Blood Institute (NHLBI) Guidelines for the treatment of asthma attempt to address the significant problems of asthma in the very young. Despite recent scientific advances, the pathogenesis of recurrent wheezing, its relationship to the development of asthma, and ultimately its treatment options continue to be poorly defined. The purpose of this chapter is to review the factors important in the development of asthma in infants and very young children. The current difficulties of evaluation and management of wheezing in very young children also are discussed. In this chapter, infantile asthma refers to asthma in children less than 3 years of age with four or more episodes of wheezing. These episodes improve with bronchodilators or anti-inflammatory medications and may or may not be associated with viral infections. In many of these young asthmatics, environmental allergy is already playing an underappreciated role.

The prevalence rate for asthma in infants and young children is increasing, particularly in westernized countries (1). An increase in atopy may be a contributing factor (2). Hospital admission rates are climbing for infants with asthma (3). Asthmatic children under 24 months of age are four times more likely to be admitted to the hospital than teenagers with asthma (4). In Norway, 75% of all children hospitalized for asthma are under 4 years of age (5). Although the number of days in the hospital is declining in older children, hospital length of stay for asthmatic infants is not changing (6). In addition, infants are more likely to require emergency department assistance for asthma exacerbations (7). Ten percent of all childhood mortality from asthma occurs in children under 4 years of age (8). Overall, it appears that hospitalization rates may be improving for older children, but no substantial progress has been made in improving the quality of life of asthmatic infants.

Wheezing in infants and young children can be divided into three specific phenotypes: early transient wheezers; late-onset nonatopic wheezers; persistent atopic wheeze/asthma (9). The early transient wheezers have symptoms primarily with viral infections, do not wheeze in between infectious episodes, and are no longer wheezing by the time they are 6 years of age. They often respond poorly to bronchodilators and asthma-controller medications. The late-onset, nonatopic wheezers will wheeze with viral infections and also under other conditions such as exercise. Their prevalence peaks between 3 and 6 years of age and then gradually declines and frequently becomes asymptomatic early in the second decade of life. The third phenotype combines wheezing with evidence of IgE-mediated disease. This atopic phenotype is the group most likely to have persistent wheezing. This phenotype gradually increases until it becomes the most common cause of wheezing by 6 years of age.

Based on these observations, an Asthma Predictive Index (API) (10) was developed to predict which infants were more likely to go on to develop asthma when they were older. It was subsequently modified to include allergic sensitization to at least one aeroallergen as a major criteria and allergic sensitization to milk, egg, or peanut as minor criteria (11) (Table 20.1). In the API, recurrent wheezing episodes in the first 3 years of life was combined with at least one major risk factor consisting of a parental history of asthma or child atopic dermatitis. Two of three minor criteria are required; they include wheezing unrelated to colds, blood eosinophil counts of ≥4%, and physician diagnosed allergic rhinitis. The API was modified and used as the mAPI in the Prevention of Early Asthma in Kids (PEAK) study (12) to characterize the atopic profile of toddler-aged children with recurrent wheezing at high risk of developing persistent asthma.
They found that more than 60% of young children were already sensitized to either food or aeroallergens. Male toddlers were significantly more likely to be sensitized to aeroallergens, to have a blood eosinophil level of more than 4% and elevated serum IgE levels. Eosinophilia and total serum IgE concentration were strongly correlated with aeroallergen sensitization. The presence of allergen sensitization is considered significant criteria for the diagnosis of allergic rhinitis and indicative of increased risk of developing asthma. On the other hand a negative mAPI in the first 3 years of life has been shown to accurately predict 95% of those without persistent asthma between the ages of 6 and 13 years.

The PEAK trial was initiated to determine if young children at high risk of developing asthma could be treated with inhaled corticosteroids to modify the natural history of the disease. Guilbert et al. (12) randomly assigned 2-year-old to 3-year-old children with a positive mAPI to treatment with fluticasone propionate (88 μg twice daily) or placebo for 2 years. Patients then were followed for a subsequent 1-year period without study medication. During the treatment period, fluticasone use was associated with more episode-free days, less asthma exacerbations, and decreased supplementary use of rescue medication. However, after the treatment period ended, there was no difference between the treatment group and placebo for episode-free days, the number of exacerbations, or pulmonary function (12). Guilbert et al. concluded that in preschool children at high risk for asthma, 2 years of inhaled-corticosteroid therapy did not provide a subsequent long-term disease-modifying effect after treatment discontinuation.

Care for the asthmatic infant is predicated on the correct identification of asthma versus other conditions that cause wheezing. It is critical to identify triggers such as allergies or gastroesophageal reflux that cause asthma exacerbations. Once any triggers are identified, correct therapy, and ultimately long-term disease-modifying treatments can be delivered.

Parental smoking is a profound trigger for infantile asthma. Passive smoking increases airway responsiveness in normal 4 1/2-week-old infants (19). Overall, as much as 13% of asthma in children under 4 years of age is estimated to be secondary to maternal smoking (20). In lower socioeconomic households, children of mothers who smoke 10 cigarettes or more per day are at increased risk of asthma (21). Lower socioeconomic children of smoking parents have more emergency department visits
for asthma than nonsmoking parents (22). The likelihood of infantile asthma increases with increasing exposure to smoke by-products (23). Parents of asthmatics often underestimate how much smoke their children are actually exposed to when urinary nicotine metabolites are compared with parental history (24). It is believed that children with glutathione-S-transferase deficiency may be at increased risk for asthma symptoms (25).

Fetal smoke exposure during pregnancy is linked to childhood asthma (26) and may play a larger role in the development of childhood asthma than postnatal exposure (26,27). Prenatal exposure to smoke is associated with decreased peak expiratory flow, mid-expiratory flow, and forced expiratory flow rates by the time children become school-aged (28). In fact, this decrease in pulmonary function is noted shortly after birth in apparently normal infants. This increase in risk of asthma due to pre-natal and post-natal asthma is linked to increased risk of adult asthma (29). The most discouraging aspect to this public health problem is that maternal smoking during pregnancy is an entirely preventable cause of asthma.