Preschool wheeze prognosis: how do we predict outcome?

Preschool wheezing is extremely common. Despite its prevalence, prognosis is often hard to determine. Preschool wheezing is not without significant associated morbidity which may result in increased utilization of medical resources. The child with preschool wheezing may represent one of at least three distinct phenotypes, each having different clinical significance and therapeutic implications. The challenge to the clinician is to correctly identify the operative phenotype as a basis for family education, effective therapy and ultimately a reasonable assertion regarding prognosis. The current article reviews clinical presentation, potential etiologies and triggers as well as historical, hereditary and laboratory markers that may aid in the diagnosis and management of this challenging presentation among preschool children.

The exact prevalence of preschool wheezing is unclear, though a number of studies suggest that it is significant. The National Asthma Campaign study conducted in the UK concluded that preschool children demonstrated the highest prevalence of wheezing, the greatest increase in asthma incidence over the preceding two decades and the highest hospitalization rate among the cohort of wheezing children of all ages. Of note, the hospitalization rate was three times higher than that observed in older children and 6 times greater than the rate observed in adults.

There is considerable diagnostic confusion in this age group. Many children with preschool wheezing are given vague and non-specific diagnoses such as asthmatic bronchitis, viral induced wheezing, reactive airway disease and transient wheezing. Viral infection is clearly associated with wheezing in this age group and in older children as well. In a survey of children with wheezing exacerbations, respiratory viruses were detected in 85% of cases. Viruses identified included Rhinovirus, Coronavirus, Influenza, Parainfluenza and Respiratory Syncitial Virus (RSV). A seasonal correlation between viral upper respiratory tract infections (URIs) and hospital admissions for asthma is well described. In many cases of ultimately persistent asthma, symptomatic onset occurs in the first year of life. The import of this observation is that children with early (<3 years of age) wheezing lower respiratory infections with subsequent persistent episodic wheeze have reduced lung function at age 6 when compared with children with late onset wheezing. These observations suggest that early identification of such children may be the requisite platform for early effective intervention.

Martinez has described at least three distinct phenotypes among children with early wheezing. These include transient infant wheezers, non-atopic wheezers who may persist with albeit reduced prevalence beyond the preschool years and those atopic wheezers with elevated IgE and probable persistent asthma. The Tucson Children's Respiratory Study (TCRS) on which these observations are based suggests that true transient infant wheezers will peak in prevalence before age three and completely resolve this symptom complex in later childhood. All three phenotypes are still quite prevalent between the ages of three and six years. As compared to the transient infant wheezers, both the atopic and non-atopic wheezing phenotypes persist into later childhood and adolescence.

The need to better understand and possibly predict the outcome for the preschool aged child with wheezing would seem to be critical. As previously noted, these children are not without significant morbidity which results in increased utilization characterized by unscheduled office visits, ED visits and hospitalizations.1 Furthermore, early intervention may offer the opportunity to interdict long term sequelae.

In a study designed to identify early (≤4 years of age) risk factors associated with wheeze, asthma and bronchial hyperresponsiveness (BHR) at 10 years of age, several factors were identified to have significant independent relative risk based on logistic regression analysis. Asthmatic heredity, atopy at age 4, passive smoke exposure and recurrent chest infections were all found to be significant risk factors for current wheeze and currently diagnosed asthma at age 10. Interestingly, bronchial hyperresponsiveness had a narrower risk profile that included atopy at age 4 and higher social class standing. This may suggest that factors influencing wheezing symptom expression may differ from those predisposing the patient to bronchial hyperresponsiveness.

Yu et al. noted enhanced bronchial hyperresponsiveness as well as elevated serum eosinophilic cationic protein in children who had early wheezing and subsequently demonstrated persistent wheezing at age 4 to 6 years when compared to children who had preschool wheezing without persistence into later childhood.

A clinically simple yet useful tool in predicting the outcome for children with preschool wheezing is the Asthma Predictive Index designed by Castro-Rodriguez utilizing data from the TCRS. The index identifies both major and minor criteria in identifying children who will likely have persistent wheezing beyond their early years (i.e. asthma). The major criteria are physician diagnosed atopic dermatitis and physician diagnosed parental asthma. The minor criteria are peripheral blood eosinophilia (≥4%), wheezing apart from colds and physician diagnosed allergic rhinitis. The study identifies two indices for the prediction of persistent asthma, a loose and stringent positive index. A stringent positive index included frequent wheezing during the first three years of life and either one major or two minor criteria. A loose index required any wheezing in the first three years of life plus the same combination of minor criteria as noted above. A child with a loose positive index was 2.6–5.5 times more likely to have active asthma between the ages of 6 and 13 than a child with a negative loose index. If the child had a positive stringent index, they were 4.3 to 9.8 times more likely to have active asthma in later childhood. This index is quite helpful in that it has an extremely high specificity at 97%. Its limitation may be its relative low sensitivity at 15%.

In conclusion, wheezing in the preschool child is very prevalent. A significant percentage of these children will have persistent asthma in later childhood. These children are more likely to be atopic as evidenced by eosinophilia, elevated IgE or atopic dermatitis in addition to having a parental history of physician diagnosed asthma. Unfortunately, there are no absolutes and assessment of risk factors offers the best data to date for providing a reasonable assessment of prognosis. Identifying children with preschool wheezing that may evolve into persistent asthma may be the requisite step in providing early effective therapy that may alter long term outcomes.