Asthma in Childhood: Expression, Exacerbation, and Progression

For many patients with asthma, the disease had its roots in early life, with the initial clinical presentation being wheezing primarily caused by respiratory viral and/or bacterial infections. These wheezing illnesses in preschool children have been classified phenotypically based on their temporal pattern (episodic, multi-trigger)⁽¹⁾ or duration (transient, persistent, and late onset).⁽²⁾ Eventually, when these wheezing illnesses persist, clinicians confirm that asthma inception has occurred. Once the disease is expressed, it can be characterized in children by variable symptoms and significant exacerbations that may increase both morbidity and mortality. Unfortunately, in some children, the clinical manifestations of the disease progress, resulting in the development of severe asthma that requires more aggressive treatment to achieve and maintain control over time. In this issue of the Journal of Allergy and Clinical Immunology: In Practice, three articles describe the nuances of the clinical presentations and treatment approaches for these various stages of childhood asthma including preschool wheezing illnesses, exacerbations in older children and adolescents, and severe asthma.

In the first article, Drs. Beigelman and Bacharier review⁽³⁾ published clinical trials dealing with treatment approaches to children with various preschool wheezing phenotypes performed by two NHLBI-funded asthma networks [Childhood Asthma Research and Education (CARE) network and AsthmaNet]. They report on findings in three separate trials using daily or intermittent inhaled corticosteroids (ICS). The first trial, Prevention of Early Asthma in Kids (PEAK)⁽⁴⁾, enrolled children 2 and 3 years of age with a positive modified asthma predictive index (mAPI) and demonstrated that daily low dose inhaled corticosteroid (ICS) treatment for two years significantly increased the number of episode free days and reduced glucocorticoid-requiring exacerbations and step-up therapy to maintain adequate symptom control. Within three months of going off study treatment, all of these clinical significant improvements were no different in frequency or magnitude compared to those children who were randomized to placebo during these same two years.⁽⁴⁾ The second trial, Acute Intervention Management Study (AIMS)⁽⁵⁾, used intermittent therapy with either an ICS or montelukast (compared to albuterol alone) at the first sign of an impending illness based on symptom characteristics that the parents historically identified as heralding the progression to more significant lower airway involvement. Although the primary outcome, episode free days, was negative, a subgroup of children with either a mAPI or a history of previous oral glucocorticoid administration for more significant episodes, demonstrated a significant attenuation of symptom severity as the illness progressed over the next 7-10 days.⁽⁵⁾ These results prompted the CARE investigators to perform the Maintenance and Intermittent Inhaled Corticosteroids in Wheezing Toddlers (MIST) trial⁽⁶⁾, a direct head to head comparison of daily versus intermittent ICS in children who were both mAPI positive and had a history in the previous year of experiencing an exacerbation requiring oral glucocorticoid administration. Interestingly, after a year of therapy, there were no differences found between the groups in either the primary outcome (frequency of exacerbations) or any of the secondary ones, except a lower cumulative dose of ICS use in the intermittent group.⁽⁶⁾

The results of these studies beg the question as to what treatment approach should be chosen in preschool wheezing children who are mAPI positive? From the results of the PEAK trial,⁽⁴⁾ if symptoms tend to be present between significant episodes of lower airway involvement, daily therapy has the benefit of increasing episode free days along with reducing prednisone-requiring events and/or initiating step-up supplemental controller therapy.⁽⁴⁾ For the primary outcome of episode free days, these benefits demonstrated significantly greater improvement among boys, white subjects, participants with an emergency department (ED) visit or hospitalization within the past year, and those who experienced more symptomatic days at baseline. Children with aeroallergen sensitization experienced greater benefits in terms of oral corticosteroid use, urgent care and ED visits, and use of supplemental controller medications.⁽⁷⁾ For children with minimal to no symptoms between more severe episodes, either a daily or intermittent approach may be tried with close follow up to determine efficacy and safety. The authors also rightly point out that the results of these three trials, while informative in mAPI positive children, do not provide guidance regarding preferred management options for mAPI negative children who are at lower risk of subsequently developing childhood asthma.

Once asthma is established in later childhood and adolescence, a major clinical challenge is to address the risk domain of asthma control by reducing the frequency and severity of severe exacerbations. The article by Dr. Gergen addresses this topic in his review of data obtained from studies performed by the Inner City Asthma Consortium in children living in the inner cities of the USA.⁽⁸⁾ Early work indicated that the development of allergic sensitization was an important contributing risk factor for not only asthma control in relationship to impairment, but to the risk domain as well. Allergic sensitization was found to be more of a risk following allergen-specific exposures both in the homes (cockroach) as well as in the schools (mouse). Reductions in exposures through environmental control interventions were most effective in reducing asthma symptoms with a lesser effect on exacerbations. However, while at least partially effective, this intervention strategy would be difficult to propose on a more global basis due to the high quantity of allergens present and the expense involved in achieving a significant and continuous reduction in these allergen levels within the indoor environments.

Perhaps the most striking observations related to the combined influence of allergic sensitization and seasonal viral infections on asthma exacerbations were the results generated with the use of the monoclonal anti-IgE antibody, omalizumab, in children living in inner city environments.⁽⁹⁾ Children treated with omalizumab for an entire year had significant and dramatic reductions in asthma exacerbations at the two highest risk times of the year: fall and spring. Indeed, exacerbation rates were reduced by 38% in those children receiving the active treatment.⁽⁹⁾ Mechanisms to explain these findings may relate to the bridging of the high affinity IgE receptor on antigen presenting cells in the presence of allergen and virus and the resultant decrease in the production of interferons, an important aspect of the host's innate immune response to viral infections.^(10;11)

The third article in this series by Dr. Fitzpatrick discusses the unfortunate progression of childhood asthma into a more severe form that requires high doses of ICS and/or daily oral glucocorticoids to maintain control.⁽¹²⁾ Fortunately, in the United States, this more serve form is only present in probably less than 5% of all children and adolescents with asthma, but its social and economic consequences are formidable. In addition, in severe asthma the side effects from the required medication burden and the frequency and severity of exacerbations can be devastating. In contrast to severe asthma in adults where atopic characteristics are not as prevalent, the pattern of aeroallergen sensitization is different in children with severe asthma in that they in general are sensitized with greater frequency to outdoor pollens, molds, and indoor allergens. While air trapping and airflow limitation are present in children with severe asthma, the abnormalities are not as severe as seen in adults. Male sex, race, and obesity are all risk factors for severe asthma in children.

One of the advances made in the study of asthmatic children across the severity spectrum has been the recognition of the marked heterogeneity seen in this population and the fact that a number of disease and demographic characteristics can be used to derive clusters of patients who share similar features. In children, four clusters have been defined and, interestingly, a percentage of children with severe asthma can be found in all of them. Endotypic patterns have also been described. Children with severe versus non-severe asthma have been shown to have unique cytokine and chemokine patterns that more commonly demonstrates Th2-mediated inflammation, but Th-1 defined characteristics have been noted as well.

Taken together, these three articles describe the variable clinical patterns, both on an acute and chronic basis, that childhood asthma can demonstrate from birth through adolescence. What is desperately needed is the elucidation of biologic and/or genetic markers that can be used to identify children at an early stage of their disease process who are destined to develop more severe exacerbations acutely, and/or who will be one of the unfortunate individuals whose disease progresses in severity over time.