Can Biologics Induce Asthma Remissions in Children?

The prevalence of asthma in Indian children is estimated to be around 7.9%, based on a 2022 meta-analysis, though specific study results can range from 2% to over 18% due to geographical and methodological variations.[1] Although Indian data are not available, a study in the Netherlands estimated that around 3.7% of asthma patients have severe asthma, which is therapy-resistant.[2] Severe asthma is associated with more frequent asthma exacerbations, impaired lung function, reduced health-related quality of life, and increased risk of death.[3] Asthma is increasingly understood as a heterogeneous disease with different phenotypes and endotypes. In most children, the pathogenesis of asthma is driven by a type 2 inflammatory response, involving the release of proinflammatory cytokines (including thymic stromal lymphopoietin, interleukin [IL]-4, IL5, and IL13), production of immunoglobulin E (IgE), and recruitment of innate immune cells (eosinophils, mast cells, and basophils) to the lung.[4] Traditional medications for asthma broadly aim to reduce airway inflammation (corticosteroids and leukotriene receptor antagonists) and reverse bronchoconstriction (beta-agonists and muscarinic antagonists). Biologics are a new class of drugs and offer a targeted and personalized treatment approach to asthma. They represent a major advance in the treatment of difficult-to-treat severe asthma, providing a therapeutic option that is highly effective in reducing severe exacerbation risk in selected patients with specific phenotypes. They also provide an opportunity to reduce patient dependence on high-dose oral corticosteroid (OCS) and inhaled corticosteroid therapy and the associated risks of systemic adverse effects.[5] There are currently five biologics that are approved by the United States Food and Drug Administration for use in pediatric asthma: omalizumab (anti-IgE), mepolizumab (anti-IL5), benralizumab (anti-IL5Ra), dupilumab (anti-IL4Ra), and tezepelumab (anti-thymic stromal lymphopoietin), each targeting a specific component of the type 2 inflammatory pathway. Omalizumab is indicated for allergic asthma, benralizumab and mepolizumab for eosinophilic asthma, and dupilumab for eosinophilic asthma and OCS-dependent asthma, whereas tezepelumab can be prescribed for all phenotypes of asthma, including nonallergic noneosinophilic asthma.[6] Research studies have shown that in selected patients with uncontrolled, moderate-to-severe persistent asthma, biologics reduce the annualized rate of asthma exacerbations by approximately 50% compared with placebo. They also improve asthma control, lung function, and health-related quality of life, although these beneficial effects seem to be more modest.[7] Overall, asthma biologics have very favorable short-term safety profiles.[8] Current treatment algorithms for asthma biologics use certain biomarkers to guide the choice of biologic agent for patients. Key biomarkers are blood eosinophil count, fractional exhaled nitric oxide, and IgE. Cutoff levels of these biomarkers for pediatric patients have been extrapolated from adult studies.[9] Beyond biomarkers, the selection of asthma biologics is guided by patients’ age and comorbid atopic conditions targeted by biologics, such as chronic idiopathic urticaria (omalizumab), hypereosinophilic syndrome (mepolizumab), or atopic dermatitis and eosinophilic esophagitis (dupilumab).[8] No randomized controlled trials (RCTs) to date have directly compared asthma biologics with each other for efficacy and safety. There are no validated biomarkers to monitor for response during and after treatment. Measures of response are currently clinical, such as asthma symptom control, exacerbation frequency and severity, OCS use, and side effects of biologics. The improvement in asthma control with biologics has suggested that improved outcomes may relate to a more precise and effective regulation of underlying inflammation, which is not fully accomplished with corticosteroids. Moreover, those observations have led investigators, clinicians, and industry to consider the new outcome concept of asthma control—remissions. The approval of some asthma biologics for use in young children has led to great interest in whether early targeted inhibition of the type 2 inflammatory pathway could prevent the development of pediatric asthma altogether. The Preventing Asthma in High Risk Kids study—a National Institutes of Health-funded RCT of omalizumab in toddlers at high risk of developing asthma—is currently investigating this concept.[10] Two key risk factors for the development of persistent asthma are as follows: (1) aeroallergen sensitization via allergen-specific IgE antibody production, and (2) viral lower respiratory tract infections, especially with rhinovirus, likely worsened by IgE-mediated reduction in the innate antiviral immune response.[10] By blocking the circulating IgE and IgE-mediated responses, the hypothesis is that early treatment with omalizumab can prevent asthma development and, in children who do develop asthma, reduce asthma severity.[10] Predicting which children may benefit most from starting biologics for asthma early requires careful phenotyping of wheeze trajectories in young children and characterizing the underlying etiology and pathophysiology of these phenotypes. Compared with modifying early-life health or environmental risk factors, biologics are attractive as a potential targeted prevention strategy because they inhibit components of asthma pathogenesis likely shared across wheeze phenotypes. Early studies and analyses, largely retrospective, support the concept that biologics promote the criteria for a remission in a subpopulation of patients. This association is exciting and may represent a “next step” to improved treatment outcomes in asthma. The resulting message to patients and their families is especially encouraging. However, questions remain to be addressed, including a uniformity of acceptable and evidence-based criteria for remission.[11] There are important knowledge gaps that ongoing research seeks to address the following: (1) the long-term efficacy and safety of using biologics in children, (2) the comparative efficacy of different biologics, (3) multi-omics-based classification of asthma endotypes and phenotypes in children to find potential new therapeutic targets and enable identification and validation of biomarkers that may help predict and monitor response to treatment, and (4) whether starting biologics in early childhood can modify the natural history of asthma and perhaps even prevent asthma development at the forefront. This concept definitely marks the dawning of a new therapeutic paradigm in asthma care. The concept of remission has been a step forward in treatment outcomes and holds promise for the patient. Acknowledgement None. Author contribution SSR conceived the idea, designed the study, drafted the manuscript, and submitted it for publication. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.