When a pediatrician sees a wheezing infant, there are usually a number of questions that are posed by the parents. These include questions about diagnosis, prognosis, treatment, and side effects of treatment. Such questions are often the same questions pediatricians grapple with. "What makes my baby wheeze? Is it really asthma? What made my baby have asthma? Will the baby grow out of this? What can we do to help my baby to get better? Are these medications dangerous for my infant?" While the medical literature has advanced in some areas, it remains less than satisfactory in other aspects. In this article, some of these questions are addressed. To discuss these issues, it is imperative mat the pediatrician exclude omer confounding conditions that can predispose to recurrent wheezing. While these other confounding conditions are not addressed, they will be mentioned briefly. The epidemiology/natural history of the wheezing infant who does not have another underlying disease process will be addressed and prognostic factors will be examined. Risk factors and issues related to early treatment and to remodeling will be discussed.
Prior to diagnosing a child as having recurrent viral-associated wheezing, it remains important to rule out other causes. M. Silverman in the textbook Asthma, edited by Barnes et al., lists the differential diagnoses of the wheezing infant.1 Except for prematurity and reflux-associated aspiration, most of the conditions are relatively rare. Many of these can be suspected on history and physical examination if there are clues present. The items listed by Silverman include symptoms present from birth; neonatal conjunctivitis; family history of early respiratory diseases, cystic fibrosis, or sickle cell anemia; persistent cough without wheeze; persistent and recurrent emesis; symptoms during feeding; abnormal cry; failure to thrive; focal signs or fine crepitations on chest examination; and focal or persistent radiological signs.1
It is especially important to note that when symptoms are present from birth, developmental abnormalities, perinatal infections, cystic fibrosis, and chronic lung disease of prematurity all should be considered. Persistent cough without wheeze is also a marker for conditions such as recurrent aspiration, perinatal infection, and cystic fibrosis. Feeding difficulty or respiratory symptoms that are associated with feeds may imply anterograde direct aspiration or if more delayed, reflux-associated aspiration. An abnormal cry or stridor is suggestive of an upper airway defect, whether it is neurologic or structural. The presence of crepitations can imply pneumonia, cystic fibrosis, fibrosis, chronic lung disease of prematurity, or pulmonary edema. This is not meant to be an extensive review of differential diagnosis; for this the reader is referred to the previously mentioned chapter.1 Rather, this is a reminder that, although rare, these conditions should be screened for clinically, and all persistently wheezy infants should have at least a chest radiograph properly documented prior to establishing the diagnosis of viral-associated wheezing.
EPIDEMIOLOGIC RISK FACTORS
Questions that parents pose about why their child has a wheezing illness or asthma are are important to them. An appreciation of risk factors may help the pediatrician in these cases. It is important to note that there are a number of risk factors for early and/or transient wheezing that do not relate to allergy. However, for those infants who progress to develop persistent asthma, allergy is an intimately linked issue and a major risk factor. Allergy is associated with more eosinophilic inflammation on bronchoalveolar lavage even in children younger than 5 years of age when compared to viral-associated wheezing.2 This may also have significant relevance to treatment with inhaled corticosteroids even in the infant age group.3 Hence, a brief discussion of atopy and risk factors can set the stage for issues related to the diagnosis of asthma in infancy.
Atopy/allergy is one of the most important predictors for asthma. Other major factors in genetically predisposed infants potentially include viral infections, smoke exposure, and pollutants. Many studies have shown that high levels of exposure are correlated with sensitization to allergens such as house dust mite, cat, and cockroach. High levels of exposure in sensitized individuals increase rates of hospitalization for both indoor allergens (such as dust mite, cockroach, and cat) and outdoor allergens (such as alternaría and grass pollen). However, a recent epidemiologic study in Germany (the Multi-Center Allergy Study) did not show a direct relationship between exposure and asthma despite increases in sensitization.4 These authors hypothesized that the same factors that predispose to atopy also predispose to asthma. This would imply that while exposure to allergen alone is insufficient for the development of asthma, the forces that drive allergy remain the major forces that determine pediatric asthma.
Hypothesized Contributors to Asthma Development
The Table summarizes potential promotional factors for asthma and protective factors for allergy and hence asthma. The uniting theory currently favored to explain these protective factors is the so-called "hygiene hypothesis." This hypothesis proposes that the change in western lifestyle is associated with atopy due to the loss of normal factors that stimulate immune development. This is important because childhood asthma is associated with atopy.
This is corroborated by data from Holt and Prescott which show that infants at birth have peripheral blood mononuclear cells that have a humoral (T helper 2 cell) immune dominance, which also is associated with allergic diseases.5 It is hypothesized that the T helper 2 cell immune response is protective for the pregnancy, based on animal models. Those infants who went on to have atopic disease had this possibly "immature" Th2 response persist compared to those who did not develop atopy and progressed to a more "mature" cell-mediated response (T helper 1 cell).
On an epidemiologic basis, there are a number of studies comparing modern western lifestyle and other environments. These found lower prevalence of atopy in rural areas in France, Scandinavia, and Estonia. Increased atopy was observed in eastern Germany after reunification and westernization. Cohort studies in France, Germany, and Canada found prospectively that the rural lifestyle, including livestock exposure, was protective against atopy. Similarly, some studies of rural lifestyle found that exposure to unpasteurized milk was protective against atopy, and a Scandinavian group reported that exposure to lactobacillus in the perinatal and infancy period is associated with decreased atopy. Exposures to other organisms and infections also may be protective immune stimulants as noted by the protective influence of daycare centers and older siblings in both the Tucson Children's Respiratory Health Study6 and European cohorts.7 Other recent studies suggested that early life exposure to domestic animals was protective against atopy and asthma. A potentially key point that links these studies is that many of these rural, animal-associated, and infectious exposures may promote immune stimulation through endotoxin exposure. Furthermore, the Multicenter Allergy Study group has evidence that exposure to endotoxin may be associated with lower incidence of atopy and asthma.8
There are other factors listed in the Table that bear special comment in terms of risk factors for asthma in infancy. These include the role of respiratory syncytial virus (RSV) infection, smoke exposure, and abnormal lung function early in life (or remodeling).
The issue of whether RSV or other respiratory viral infection serves as a trigger for asthma development remains a topic of debate. Sigurs et al. compared a group of 47 hospitalized infants with RSV to 93 matched controls.9 Of the RSV group, 30% had asthma at 7.5 years compared to 3% of the controls (JP < 0.001 ). This contrasts with the Tucson data that by 13 years of age, previous RSV infection was no longer a significant risk factor for persistent wheezing. This may be due to differences in severity between the cohorts and also due to the longer follow-up. However, independent of whether RSV infection predisposes to asthma development, it is known that individuals who become allergic have a different immune response to RSV.
Does the viral infection cause a different immune response in predisposed individuals, or is me different immune response merely a marker of an "allergic" immune system mat was already committed to an allergic profile? We know that those with persistent wheezing showed an absence of me normal peri-infectious eosinopenia and a transient elevation of IgE compared to those with transient wheezing with RSV in the Tucson cohort. A different immune response had also been noted by Welliver in those with persistent wheezing. The question of whether such abnormal immune responses are present prior to infection may be resolved by ongoing prospective studies.
The role of exposure to perinatal smoke is being investigated further. Smoking has been found to be a risk factor for asthma development in multiple retrospective studies. In two prospective studies, smoke exposure was found to be a risk factor for persistent wheezing and asthma. In the Tucson Children's Respiratory Health study, children of mothers who smoked more man one-half pack per day had a greater likelihood of having asthma. The German Multi-Center Allergy Study also showed an increased risk of asthma if the mother smoked in pregnancy (OR = 2.46; 95% Cl, 1.284.73).4 In the Tucson study, maternal but not paternal smoking was the strongest factor.6 Both studies suggest that early smoke exposure may have the greatest impact on prognosis and lung function. This may be die difference between maternal and paternal smoking.
Two questions posed at me beginning of this article, "Does my baby have asthma and will he/she grow out of this?," are intimately linked. To address the first question, it is imperative that the clinician ascertain that other causes of wheezing are excluded. After doing so, we are left with a large population of postviral and in some cases intermittently wheezing infants. A seminal series of articles by Martinez and coworkers,6,10 confirmed prospectively that noted by retrospective and crosssectional studies. Martinez found that 60% of infants who wheezed before 3 years of age did so transiently and no longer wheezed by school age. This cohort included 1246 infants of whom follow-up was available for 826 subjects at 6 years of age. These children were followed prospectively out to 6, 11, and 13 years of age. At 6 years of age, serum IgE levels, skin tests, and pulmonary function tests were performed. Of the 826 children with available data, 425 (5 1 .5%) had no wheezing by 6 years of age, 164 (19.9%) had wheezing in the first year of life with no wheeze in the 12 months prior to follow-up at 6 years, 113 (13.7%) had persistent wheezing, and 124 (15%) had late onset wheezing, which started outside of tiie infant age range.6
This is in keeping with the European data from a cross-sectional populationbased study, which has the weaknesses of being retrospective and questionnaire based. However, the numbers are quite similar with approximately 64% of infants who wheezed early in life having no further wheeze noted by school age.7 The implication is that infants who wheeze are a heterogeneous group who have different natural histories. Some evolve to have asthma but a larger group do not.
We are still left with the parent's question, "Will my child grow out of this?." The risk factors for persistent wheezing identified in the Tucson cohort included maternal asthma, maternal smoking (more than one pack of cigarettes per day), male sex, severity (frequent and early onset of wheeze), and markers for atopy in the infants. These markers of atopy included eczema at younger than 1 year, rhinitis other than colds, and elevated serum IgE levels at 9 months.6 This is in agreement with the European study that also cited maternal smoking during pregnancy and maternal asthma as associated with persistence of wheezing in infants.7
The Tucson group analyzed their data retrospectively to examine predictive indices to quantify this risk.10 They developed a set of criteria that were characterized as stringent or loose based on whemer tlie infants included only those with frequent (stringent) or less frequent wheezing (loose). Infants wim one of the two major criteria (parental asthma or MD-defined eczema) or two of the three minor criteria (wheezing inbetween viral illness, MD-defined nonviral rhinitis, or eosinophilia), had a greater chance of having persistent asthma. Of note, the sensitivities of such indices were low (15.7% in some analyses), but the positive predictive value rose to 76.6%. Hence, while such criteria cannot be used to rule out asthma, the presence of these risk factors are strong indicators of asthma.
Although there are some predictive measures for the resolution of wheezing, these measures are not very sensitive. The clinician is faced with the dilemma of appropriate treatment for this heterogeneous group of patients, which involves assessing treatment efficacy and also side effects. Treatment options for children younger than 5 years with asthma have included inhaled steroids as the first line of treatment in asthma guidelines. However, while these guidelines include younger children in their scope, they are not specifically designed for wheezing infants. Other common medications that have been assessed in the setting of the infant with wheezing and viral infection include montelukast and also disodium chromoglycate (DSCG). The evidence for these medications is reviewed, and concern sregarding inhaled steroid use in this age range are consisered.
Two factors will emerge during this overview of treatment. The first is the role of severity in treatment decisions such as the use of inhaled steroids. The second is that the criteria that establish risk of wheezing persistence are linked to atopy, and these children may be more likely to have eosinophilic inflammation. In this case, inhaled steroids may be more helpful.
Regarding DSCG, a group of preschool children without atopy who were symptom free between illnesses was evaluated.11 This group compared regular DSCG and beclomethasone diproprionate (BDP) used regularly regarding prevention of episodes and bronchial responsiveness in a doubleblind crossover study. Neither agent changed bronchial hyper-responsiveness. However, BDP resulted in fewer exacerbations in this small group of children (7 versus 16, P < 0.005). The youngest patient was 43 months, and the mean age was 56 months. Of note, this study and others looking at nedocromil sodium in "viral wheezing" have included older children. These agents presumably are more likely to be effective in atopic individuals in whom mast cell stabilization and any antihistamine effect would be helpful. Therefore, older children are more likely to benefit.
Leukotriene antagonists have also been evaluated in wheezing infants in an as of yet unpublished study by Bisgaard et al. (Merck company data). However, this study was in infants after RSV bronchiolitis, not specifically in recurrently wheezing infants.
Both of these studies evaluated wheezing infants who were excluded if they wheezed outside of the current episodes or had previously received asthma medications. This is not the same population as the recurrently wheezing infant who may go on to have asthma. Other large studies included patients up to 5 years of age who were defined as having persistent asthma.12 Again, this is an older population. However, despite those limitations, there were significant improvements in symptom control compared to placebo, and there were even fewer exacerbations requiring oral steroid over the 12 weeks of the study. It is notable that there were almost 20% of patients receiving montelukast whose disease exacerbated over this time. This was not directly compared to inhaled steroid, which should be borne in mind when comparisons are made to similar reductions in symptomatic days for budesonide or fluticasone. A direct comparison still needs to be performed.
There are data that starting oral steroids at the first sign of an upper respiratory infection significantly decreased the number of emergency department visits and hospitalizations for wheezing in preschool children. However, the children were at least 3 years old;13 there are no studies of this specifically in infants outside of those done for RSV. Even if one does extrapolate this to the younger infants, there are major concerns about recurrent courses of oral steroid with all upper respiratory infections in this age range.
Inhaled Steroids: Intermittent Versus Continuous Treatment
A number of studies have examined the issue of intermittent use of inhaled steroid medications for the treatment of viral-associated wheezing attacks in infants. These studies report a preference by the parents of patients receiving budesonide compared to those receiving placebo. In some studies, symptom scores for day and night wheeze improved in tiiose who received budesonide. Patients who received oral steroid courses confounded most of these studies. Also, there was no statistically significant difference in courses of oral steroids received in patients who received intermittent budesonide.
Other studies have evaluated tiie continuous use of inhaled steroids. Volovitz et al.14 carried out a double-blind placebo-controlled trial of high dose budesonide in 42 children who were 6 months to 3 years of age and had not previously needed oral steroids. In these children with ongoing symptoms without a viral infection, there was a decrease in wheezing by 60% and in cough by 40% in parental diaries compared to the placebo group.
Other studies have also found a decrease in the amount of oral steroid needed in the more severe range of this population. Bisgaard et al.15 treated 77 children aged 11 to 36 months (mean age 24 months) who had moderately severe recurrent wheezing with budesonide 400 µg twice a day or placebo for 12 weeks with a 12- week follow-up. Symptom scores for both nocturnal wheeze and cough in this age range were decreased below 50% in the budesonide group without change in the placebo group (P < 0.05). The number of days taking prednisolone also decreased, from 5.1% to 0% at 8 weeks, compared to an increase in the placebo group. Dangovan et al.16 also carried out a randomized, double-blind, placebocontrolled trial of 36 children with a mean age of 27.6 months who had severe steroid-dependent asthma. There was a reduction of 80% in the budesonide group compared to 40% in the placebo group (P < 0.05). De BHc et al.17 also found mat me proportion of severely asthmatic infants who experienced exacerbations was reduced by half in the budesonide group as well as a decrease in the number of days requiring oral steroids (P < 0.05).
These findings conflict with two other studies. It has been argued that one negative study was because of a lower dose than that used by de BHc and included only 23 infants. The other study looked at infants with much less severe symptoms who were asymptomatic between episodes. It is quite possible that these participants represent a different population (transient wheezers).
Who Should Receive Inhaled Steroids?
Hence, while the data for milder infants and intermittent use of inhaled steroids are less clear, the data for moderate to severe wheezing infants suggest greater efficacy of inhaled steroids to decrease symptoms and possibly to reduce the number of courses of oral steroids.
Another clue, other than persistence or severity of wheezing, that suggests that inhaled steroids may be effective in a patient is atopy. As stated above, there is an increase in eosinophils in bronchoalveolar lavage even in children younger than 5 with atopic astìima compared to viral nonatopic wheezers.2 However, while it is clear that more bronchoalveolar lavage studies need to be conducted in me infant age group, a recent randomized, double-blind, placebo-controlled crossover trial reinforced that atopic children are more likely to benefit from inhaled steroids. These atopic preschool children (median age 3.5 years) had a much greater decrease in airway resistance (16% compared to 3.5% in nonatopics) after 6 weeks of 100 µg of fluticasone propionate taken twice daily.3
In summary, regular use of inhaled steroids appears to be more appropriate for the severe recurrently wheezing infant, the steroid-dependent wheezing infant, the atopic infant, or the infant with recurrent wheezing and risk factors for persistent asthma. These would include a first degree family history of asthma, or a personal history of atopic diseases such as food allergy or atopic dermatitis.
A related question is whether the use of mese agents alters the natural history of this disease. The Childhood Asthma Management Program (CAMP) study did not show any difference in lung function in milder asthmatics.18 Most of these had used inhaled steroids after the age of 2 years. The Melbourne asthma cohort found that asthma tended to track in severity from 6 years of age into adult life.19 Persistent wheezers in the Tucson Children's Respiratory Health Study did not have significantly different lung function in infancy, but at 6 years of age had diminished lung function. This and the findings of Rasmussen et al. suggest mat remodeling occurs early.20 Indeed, there was a difference in (postbronchodilator) lung function at 6 and at 18 years of age that favored patients who had ever received an inhaled steroid. Ongoing studies using criteria from me Tucson group may shed more light on this unresolved issue.10
The enthusiasm for this modality of treatment remains tempered by questions about side effects and safety in this young age range. The CAMP study was reassuring, but these children were aged 4 years or older. The respective studies of de BHc and Bisgaard did not show side effects but involved relatively small numbers of subjects over a short period of time. Volovitz included even smaller numbers but found no change in morning Cortisol over the time of the study. Shapiro's dose-ranging study included only children older than the age of 4 years. A subsequent analysis of three open-label, 52-week extensions of three combined trials of budesonide did not find hypothalamicpituitary-adrenal axis effects. The number of infants in this study is not clear. A comparision of DSCG with 100 mg of fluticasone propionate taken twice daily in 503 patients with a mean age of 31 months for 1 year21 showed a 2mm difference in growth, which was not statistically significant. Morning Cortisol levels were slightly decreased in the fluticasone group, and this was described as clinically insignificant. One small posterior capsular opacity was noted in a patient in the fluticasone group. This was an open-label study without a placebo group.
While there are risk factors for predicting persistent wheezing disease in infants such as atopic family history, personal history of atopy, and severity, these remain more specific than sensitive and they cannot be used as screening tools. They may be helpful to the clinician in establishing a high index of suspicion when other causes of wheezing are ruled out. Treatment, as advocated in the 2002 National Asthma Education and Prevention Program guidelines (www.nhlbi.nih.gov/guidelines/asthma/), should be based on severity. The cumulative literature leaves physicians more comfortable in the regular use of inhaled steroids in severe infant wheezers who have frequent oral steroidrequiring exacerbations or hospitalizations. Those risk factors for persistence that are readily available to the clinician (parental asthma or personal history of food allergy, atopic dermatitis, or true allergic rhinitis) may give some guidance. Also the data showing better response to inhaled steroids in atopic infants may be helpful. Infants who are at risk of persistence or who are atopic on testing may also be more likely to benefit from the use of inhaled steroids. More data need to be accumulated in infants related to treatment effect, remodeling, and safety. Inhaled steroids also need to be compared directly with other treatments in this age range, including leukotriene receptor antagonists. This is especially true of the milder patients who are asymptomatic between viral episodes. Until then, physicians will need to weigh the risks and benefits carefully. It is hoped that future studies will contribute to such decision making.
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17. de BHc, Delacourt C, LeBourgeois M, et al. Efficacy of nebulized budesonide in treatment of severe infantile asthma: A double blind study. J Allergy Clin Immunol. 1996;98:14-20.
18. Szefler SJ, Weiss S, Tonascia J, et al. Long term effects of budesonide or nedocromil in children with asthma. New Engl } Med. 2000;343:1054-1063.
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20. Rasmussen F, Taylor DR, Hannery Em, et al. Risk Factors for airway remodeling in asthma manifested by a low postbronchodilator FEVl/ vital capacity ratio: a longitudinal study from childhood to adulthood. Am J Respir Crit Care Med. 2002;165:1480-1488.
21. Bisgaard H, Allen DB, Milanowski J, Kalev I, Davies P, Willits L. A long term study comparing the safety (including growth) and efficacy of fluticasone propionate 100 meg bid with sodium cromoglycate 5mg qds in asthmatic children aged 12 to 47 months. J Allergy Clin Immunol. 2002;109:S155.
Hypothesized Contributors to Asthma Development