Current and future challenges in pediatric severe asthma

Although the majority of children with asthma have their disease controlled with standard therapies, an estimated 5–10% of asthmatic children have severe disease remaining either poorly controlled or requiring high doses of inhaled corticosteroids (ICS), plus a second controller and/or systemic corticosteroids to be controlled¹. Children with severe asthma are at high risk for life-threatening exacerbations and medication-related side effects that significantly impair their quality of life, including absence from school and time off work for caregivers, and account for nearly 50% of all healthcare economic resources for asthma².

Children with persistent uncontrolled asthma, despite maximal therapy, are defined as having problematic severe asthma, an umbrella term including patients with asthma that is difficult to treat because of comorbid conditions, poor adherence and/or improper inhaler technique, other environmental factors (i.e. persistent allergen exposure), and patients with true severe therapy-resistant asthma, that both need to be first differentiated from several pediatric asthma-mimicking diseases³. Thus, severe asthma in children represents a clinical and therapeutic challenge requiring a multidisciplinary systematic assessment.

A step forward in the characterization of severe asthma has occurred thanks to the results of international research studies, such as the National Heart, Lung and Blood Institute’s Severe Asthma Research Program (SARP) and the European Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (UBIOPRED) cohorts, from which pediatric severe asthma arises as a heterogeneous disorder with clinical, molecular and cellular inflammatory features differing from those of adults^4,5. In particular, children with severe asthma are predominantly males, are severely atopic with high levels of total serum IgE, blood eosinophils with multiple aeroallergen sensitization; bronchial hyperresponsiveness and lower lung function are the main comorbidities found only in a small subgroup⁶. Moreover, pediatric phenotypes are also known to rapidly change over time, since pediatric asthma should be seen as ongoing disease in the context of a maturing immune system and during lung growth and development⁷.

Although these studies have advanced knowledge of the unique features of severe asthma in children, several and significant gaps remain to be still clarified, as reviewed by Larenas-Linnemann et al., starting from a shared definition of severe asthma that is not based solely on the levels of prescribed therapy, up to a better characterization of pediatric phenotypes and endotypes, such as pattern of inflammation, biomarkers, bronchial hyperresponsiveness and lung function⁸.

Our current understanding of the underlying pathophysiological features of pediatric severe asthma is still limited from the rarity of the disease, from the difficulty of reproducing age-related experimental models and from the invasiveness of airway diagnostics (i.e. bronchial samples) in children. For this reason, ongoing research on pediatric severe asthma is leaning towards identifying non-invasive reliable biomarkers that can help diagnosis and endotyping, in order to determine the most effective drug for the right patient phenotype⁹. Exhaled NO, blood eosinophils, serum IgE and periostin are well studied and established biomarkers for atopic/eosinophilic severe asthma endotype, while biomarkers of neutrophilic asthma are currently lacking, at least in clinical practice¹⁰.

Another significant limitation for the clinical management of pediatric severe asthma is that omalizumab, the anti-IgE humanized monoclonal antibody, is the only biological add-on therapy licensed for use in children, and this will probably be the case for a few years yet¹¹. Given the central role of IgE in allergic asthma, omalizumab interrupts the allergic inflammatory cascade by preventing binding of IgE with FcεRI receptors on mast cells, basophils, antigen-presenting cells and other inflammatory cells¹². Specific studies conducted on children (aged >6 years) with moderate-to-severe asthma established that omalizumab is effective in reducing severe exacerbations and hospitalizations with a consistent steroid-sparing effect, improving lung function tests and asthma control, together with a good safety profile¹³. The detection of FcεRI receptors expressed on the surface of airway smooth muscle cells recently highlighted a role of the IgE pathway in the development of airway remodeling¹⁴. Thus, an interfering action of omalizumab on airway remodeling has been attributed to its immunomodulatory effects and has been also demonstrated on bronchial biopsies of adults with severe asthma¹⁵. This promising effect has been strengthened by results from pediatric severe asthma cohort studies showing that the pathophysiological abnormalities of asthma, inflammation, airway hyperresponsiveness and remodeling develop in parallel¹⁶. This concept gives omalizumab great potential in the prevention of the progression of asthmatic disease. However, the use of omalizumab is actually limited in those children with serum IgE levels outside the recommended range (between 30 and 1500 IU/ml) and in those patients who do not respond to treatment.

Childhood severe asthma needs special attention in therapeutic management, since most pharmacological strategies are extrapolated from adult studies. Given the prevalent atopic and eosinophilic key features of pediatric severe disease, the results of therapeutic trials with mepolizumab and dupilumab, anti IL-5 and IL-4/IL-13 agents respectively, are highly awaited in order to extend the current targeted therapeutic strategies. A phase 2 clinical trial of Mepolizumab Adjunctive Therapy for the Prevention of Asthma Exacerbations in Urban Children (MUPPITS-2, NCT03292588) is active but not yet recruiting patients, while a phase 3 study to evaluate the efficacy of dupilumab in children 6 to <12 years of age with uncontrolled persistent asthma (VOYAGE, NCT02948959) is currently recruiting participants¹⁷.

In conclusion, a better insight into the mechanisms mediating pediatric severe asthma and a change in attitude regarding asthma management are needed in order to clarify the complex nature of the disease, improve diagnosis, identify risk factors and comorbidities, and provide novel targeted therapeutic strategies in childhood populations.

Transparency

Declaration of funding

The contents of this commentary and the opinions expressed within are those of the authors, and it was the decision of the authors to submit the commentary for publication.

Declaration of financial/other relationships

A.L. and G.L.M. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article.

CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

None.