Remission in Children Receiving Biologic Therapy for Severe Asthma

Biologic therapy has transformed the management of severe asthma, with benefits including reduced asthma exacerbations and hospital admissions, along with improved asthma control, quality of life, and lung function [1]. Often, patients are also able to reduce background asthma therapy. The response to biologic therapy can be so profound that some patients are said to be in remission. While the definition of remission in asthma has been debated, consensus criteria have been published by the American College of Allergy, Asthma, and Immunology, American Academy of Allergy, Asthma, and Immunology, and American Thoracic Society (herein referred to as consensus criteria) [2]. A recent analysis of the International Severe Asthma Registry (ISAR), which included data from 23 countries and 3717 participants, reported that 20.3% of people treated with biologics achieved remission [3]. Of note, the definition of remission used in the ISAR study differed from the consensus criteria, with the ISAR definition being easier to achieve. Further, the ISAR study only included participants aged 18 years and older. Biologic therapy is approved down to 6 years of age; however, data regarding the rates of remission in children and adolescents are lacking. To help address this knowledge gap, we conducted a retrospective review of patients aged 18 years or less who received biologic therapy for severe asthma, treated at the Royal Children's Hospital (Melbourne, Australia). The electronic medical record was used to identify potential participants, based on the prescription of a relevant medication between August 2017 and August 2023. The medical record was then reviewed to confirm inclusion based on the following criteria: biologic therapy used for treatment of asthma (and not another condition), sufficient data present in the medical record, and medication received for 12 months or greater. Data related to baseline characteristics and treatment response were extracted from the medical record. Treatment response was based on the most recent clinical assessment. Inhaled corticosteroid (ICS) use was converted to budesonide equivalent and classified as low/medium/high based on the age-appropriate GINA classification [4]. Clinicians altered/weaned asthma therapy at their own discretion, as opposed to using a protocol. Further, in some cases, patients self-ceased ICS. Race-neutral Global Lung Initiative reference equations were used for spirometry [5]. The regulatory process to access biologic medications in Australia requires that the asthma control questionnaire (ACQ) must be documented at baseline and then every 6 months thereafter, and as such was used to assess asthma control. Descriptive statistics were used, and the Wilcoxon matched pairs test was used to compare continuous variables. GraphPad Prism (v10) was used for analysis. As the study was a retrospective chart review, with no risk of harm, the Royal Children's Hospital Human Research Ethics Committee deemed that patient consent was not needed and provided approval for the study (QA/104508). A total of 38 participants met the inclusion criteria with demographics summarized in Table 1. The cohort used four biologics: dupilumab (n = 22, 57.9%), omalizumab (n = 14, 36.9%), mepolizumab (n = 1, 2.6%), and benralizumab (n = 1, 2.6%). Atopic dermatitis, n (%) Allergic rhinitis, n (%) Eosinophilic esophagitis, n (%) Obstructive sleep apnea, n (%) Family history of asthma, n (%) ICS/LABA, n (%) ICS/LABA, LTRA, n (%) ICS/LABA, LAMA, n (%) ICS/LABA, LTRA, LAMA, n (%) ICS/LABA, OCS, n (%) ICS/LABA, LTRA, OCS, n (%) Biologic therapy was associated with significant improvements in all domains (Table 2). With regard to oral corticosteroid (OCS) use, 32 participants (84.2%) did not use any OCS in the 12 months before their most recent assessment. Of the six participants who were OCS dependent before biologic therapy, five had ceased daily OCS. Change in ICS usage is summarized in Figure S1. Using the consensus criteria, 14 participants (36.8%) achieved remission on biologic therapy (Table S1). All participants who did not have lung function data available (n = 6), failed to achieve consensus criteria remissions due to another criteria; hence, these criteria could be applied to all participants. Application of the ISAR criteria demonstrated that 18 participants (47.4%) achieved remission, and remission status was unknown for four participants (10.5%) who did not have lung function data available (but did fulfill the other three criteria, Table S1). These data demonstrate that in this real-world cohort, biologic therapy in children is associated with significant improvements in asthma control and lung function, with associated reduction in both ICS and OCS exposure. Further, using the strict consensus criteria 36.8% achieve remission, and using the less stringent ISAR criteria 47.4% achieve remission. This is higher than the 20.3% of adults who achieve remission using the ISAR criteria [3]. One potential explanation is that the ISAR study reported the odds of achieving remission reduced the longer a patient had asthma, and hence, earlier initiation in childhood may increase the likelihood of remission. To the authors knowledge, there are limited studies which have assessed remission in the pediatric population. A post hoc analysis of the VOYAGE trial, which was a randomized controlled trial of dupilumab in children aged 6−11 years with moderate to severe asthma, assessed remission defined as no severe exacerbations, normal FEV1 and FEV1/FVC, and an ACQ of < 0.75 or 1.5 [6]. They found that 41.9% of participants treated with dupilumab achieved remission when the ACQ cutoff of 0.75 was used, which is similar to the 36.8% in our study using the consensus criteria (which also requires an ACQ < 0.75). When an ACQ threshold of 1.5 was used in the VOYAGE cohort, 45.8% achieved remission, again similar to the 47.4% in our study using the ISAR criteria (which uses this ACQ threshold). Our study has several limitations including the single-center nature, small sample size, and reliance on documentation in the medical record. Further, at the time of this study, to access biologic therapy for those 12 years and older, it was a regulatory requirement that they had been exposed to > 500 mg of prednisolone in the prior 12 months, which may pre-select a group with extremely high baseline OCS use, thus biasing the assessment. As a retrospective observational study, only associations can be described, and causality can not be determined. It is possible that the improvements observed may be due to the ongoing effect of nonbiological treatments or spontaneous remission that has been observed in longitudinal asthma cohorts [7]. Despite these limitations, our study would suggest that 36.8%−47.4% of children and adolescents treated with biologic therapy achieve remission, which is higher than in adult patients. This information will be useful for families and clinicians when deciding whether to commence biologic therapy, and regulatory bodies when considering how to allocate resources to support biologic therapy. If validated in larger studies, these data would support the early initiation of biologic therapy to minimize iatrogenic toxicity and maximize the chance of remission. Eilidh Bruce: writing–review and editing, data curation, investigation. Yi Cheau Chua: investigation, writing–original draft, supervision. Shivanthan Shanthikumar: conceptualization, investigation, methodology, supervision, writing–review and editing, formal analysis. The authors received no specific funding for this work. Open access publishing facilitated by The University of Melbourne, as part of the Wiley - The University of Melbourne agreement via the Council of Australian University Librarians. Dr Shivanthan Shanthikumar has received honoraria from Sanofi for speaking at educational events. The other authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Supplemental Figure 1. Change in inhaled corticosteroid use from baseline to post treatment. OCS: Oral Corticosteroid. *The participants who used medium ICS at baseline were those using a budesonide formoterol maintenance and reliever regime, with a maintenance dose of 800mcg per day (maxum dose, medium ICS as per GINA), and additional ICS containing doses for relief, and given their poor asthma control likely had a daily ICS intake in the high range. Supplemental Table 1. Remission Assessment by Participant. Green: meets criteria. Red: does not meet criteria. Orange: unknown. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.