Applying a new set of core outcome measures for severe pediatric asthma in real-life: A single-center experience.

Severe asthma is a chronic airway disease and a relevant global health issue that affects approximately 5% of children and 7% of adolescents with asthma.1 Severe/uncontrolled asthma is generally defined by the inadequate control of asthma despite high doses of inhaled corticosteroids (ICS) and additional controllers, including oral corticosteroid (OCS), or by loss of asthma control in an attempt to reduce the high-intensity treatment.2 Patients with severe/uncontrolled asthma report a reduced quality of life (QoL) due to recurrent life-threatening asthma exacerbations, chronic therapies, missed school days, and side effects of systemic corticosteroids.2 Biologic therapies have revolutionized the management of severe asthma, mainly by reducing acute exacerbations and improving lung function and QoL.2 Randomized clinical trials demonstrated the efficacy and safety of biologics in treating pediatric moderate-to-severe asthma using heterogeneous outcome measures, making direct comparisons difficult.2 Differences in outcomes have also emerged in assessing the effectiveness and safety of these therapies in real-life studies. Recently a pan-European consensus standardized a set of core outcome measures to facilitate the synthesis of findings from different studies and allow meaningful comparisons of the effectiveness of different biological therapies for pediatric and adult severe asthma.3 This new core outcome measures for severe asthma (COMSA), developed collaboratively with patients, includes assessing lung function tests, asthma exacerbations, OCS treatment, asthma control tests, and QoL.3 This study aims to assess the applicability of COMSA for describing the efficacy and safety of biologics in a cohort of children and adolescents with severe uncontrolled or partially controlled asthma in a real-life setting. We retrospectively enrolled children and adolescents ( ≤ $\le $ 18 years) with severe uncontrolled or partially controlled asthma treated with omalizumab, mepolizumab, or dupilumab as add-on treatment and followed at the Pediatric Clinic in Pavia, Italy. Severe uncontrolled or partially controlled asthma was diagnosed according to GINA guidelines.4 In Italy, three biologics for pediatric asthma have been approved (Supporting Information: Table E1). Data were extracted from electronic clinical records. At baseline, demographic data (sex, race) and asthma-related clinical history (age at symptom onset and diagnosis of asthma, comorbidities, ICS dosage, asthma medications, lung function tests, blood peripheral eosinophils, and total serum IgE) were collected. We collected data on patients requiring systemic corticosteroids or OCS, emergency department (ED) visits, and hospitalizations for asthma exacerbations in the year before the biological therapy was started. Finally, we collected the results of the pediatric asthma quality of life questionnaire (PAQLQ), asthma control test (ACT), and childhood ACT (C-ACT) in patients younger than 12 years. ICS doses were standardized to fluticasone equivalent dose per day (mcg). The forced expiratory volume in 1 second (FEV1) and forced mid-expiratory flow (FEF25–75) were expressed as % predictive and absolute values. Patients were followed up at 6 and 12 months of therapy. Data on lung functions, ICS dosage, OCS need, hospitalizations, ED visits for asthma exacerbations, PAQLQ, and asthma control tests were collected 6 and 12 months after beginning the biological treatment. Safety data were collected at each visit. Significant and severe adverse events (AEs) were defined according to European Medicines Agency criteria. Every patient identifier was replaced with a specific numeric code. The Ethics Committee approved this study (protocol number 0003233/22). All patients provided written informed consent. Qualitative variables were presented as numbers (%), and quantitative variables as the median and interquartile range (IQR). Comparisons between lung function tests, PAQLQ, and asthma control tests at baseline and 6 months and between baseline and 12 months were assessed using the Wilcoxon signed-rank test for paired data. Comparisons between the number of patients requiring hospitalizations, ED visits, OCS cycles, and patients with uncontrolled or partially controlled asthma at baseline and 6 months and between baseline and 12 months were assessed using Fisher's exact test. Changes in ICS administered dose during the first year were evaluated using a one-way ANOVA test with repeated measures. Statistical significance was set at p < 0.05. The statistical analyses were performed through Prism 9, GraphPad Statistics software, Version 9.5.1. We retrospectively enrolled 31 patients (13 [42%] adolescents and 17 [55%] males) with severe uncontrolled (13 [42%]) and partially controlled asthma (18 [58%]) (Table 1). Patients underwent biological therapy at the median age of 10 years (IQR 7.0–17.0). Allergic rhinitis was the most common allergic comorbidity (24 [77%]), whereases obesity affected 11 (35%) patients. In the year before the biological therapy was implemented, 15 (48%) patients were hospitalized, 25 (81%) required an ED visit, and 28 (90%) needed a cycle of OCS for asthma exacerbations. The median ICS dosage was 500 mcg (IQR 250–500), and all patients were treated with a combination of ICS+LABA. No patients were on maintenance OCS. The median C-ACT value was 17 (IQR 15–21), whereases ACT was 18 (IQR 14–20) in the adolescents. The overall PAQLQ was 5.2 (IQR 4.2–6.1). Nineteen (62%) patients were treated with omalizumab, 6 (19%) with mepolizumab, and 6 (19%) with dupilumab. During the follow-up, we did not observe a reduction in the ICS dosage that remained stable over time. At 6 and 12 months of biological therapy, the rate of hospitalizations and ED visits for asthma exacerbations significantly reduced (p = 0.0004 and p < 0.0001; p < 0.0001 and p < 0.0001) (Table 2). From baseline to 12-month of follow-up, the number of patients requiring hospitalizations and ED visits for asthma exacerbations dropped by 93% and 96%. The number of patients who needed OCS for asthma exacerbations significantly reduced (−82%) from baseline to 6 and 12 months of biological therapy (p < 0.0001 and p < 0.0001, respectively). The overall PAQLQ, ACT, and C-ACT scores significantly improved from baseline to 6 and 12-month of follow-up. Compared to baseline, no patients have uncontrolled asthma at 6 and 12-month of follow-up (p < 0.0001 and p < 0.0001, respectively). Prebronchodilator FEV1 and FEF25–75 absolute values significantly improved from baseline to 6 and 12 months of the study period (p = 0.02 and p = 0.002; p = 0.01 and p = 0.003). During the study period, no patients interrupted the biological therapy. Two (10%) patients treated with omalizumab respectively developed an episode of migraine a few hours after the injection and alopecia areata that recovered with analgesic and topical steroids. Two (6%) patients on dupilumab reported increased upper airway infections without asthma exacerbations. This study confirmed the efficacy and safety of biological therapies currently available in Italy for severe pediatric asthma, applying the new core outcome measure set for severe asthma for the first time. After 12 months, children and adolescents with severe uncontrolled and partially controlled asthma treated with omalizumab, mepolizumab, and dupilumab reported an improvement in all the pediatric COMSA parameters (Supporting Information: Figure E1), confirming their applicability also in real-life studies. In this study, lung function parameters included not only the FEV1 but also FEF25%–75%, which is considered more sensitive in reflecting airway hyperresponsiveness, inflammation, and disease severity in patients with asthma.5 The lung function significantly improved over the first 6 months of treatment with biological therapies, and this improvement was maintained at 12 months. At baseline, FEV1 was >80% in most enrolled patients whose lung function is generally not reduced because of the pediatric age. We also found a significant ACT and C-ACT score improvement, confirming the excellent effectiveness of these treatments on asthma symptoms reported in clinical trials.2 Notably, after 12 months of biological therapy, the rate of hospitalization and ED visit for asthma exacerbations dropped by 93% and 96%. Concurrently, the number of patients who needed OCS for acute exacerbations significantly reduced from baseline to 6 and 12 months of biological therapy. Moreover, at the end of the study period, none of the enrolled patients had uncontrolled asthma (GINA 3–4). Globally, these results are more meaningful than those already reported by randomized clinical trials.2 We finally observed a significant improvement in the QoL of patients enrolled, with results more encouraging than those reported in clinical trials so far.2 The ICS dose reduction was insignificant from baseline to 6 and 12 months. This result is probably due to the limited follow-up period considered in the study design. Although most patients maintained their ICS dosage, none needed maintenance OCS therapy at baseline and during the 12 months of the study. During the study period, no patients discontinued the biological treatment, and no severe AEs have been reported, highlighting the safe profile of these treatments. In conclusion, this study confirmed and reinforced the evidence that biological therapies are safe, reduce asthma exacerbations and OCS use and improve QoL and lung function in a cohort of children and adolescents with severe uncontrolled or partially controlled asthma, as widely reported in the literature. Moreover, this research applied the pediatric COMSA parameters in a real-life setting for the first time, suggesting their potential applicability for standardizing the results of observational studies. This study has some limitations related to the retrospective nature and the small sample size due to the monocentric design. Therefore, more extensive and multicentric studies are needed to confirm the role of COMSA in assessing asthma biological therapy efficacy in observational studies. Martina Votto: Conceptualization; writing—original draft; writing—review and editing; formal analysis; methodology; data curation. Maria De Filippo: Conceptualization; review and editing. Alessia Marseglia: Review and editing. Ilaria Brambilla: Review and editing. Gian Luigi Marseglia: Review and editing; supervision. Amelia Licari: Conceptualization; methodology; writing—review and editing; project administration; supervision. This study is a part of the research projects: (1) “Integrating deep learning CT-scan model, biological, and clinical variables to predict severity of asthma in children” (BREATHE, protocol number 0003233/22) supported by the 5 × 1000 funding, Ricerca Corrente, Fondazione IRCCS Policlinico San Matteo; and (2) “Data-driven forecasting of pediatric asthma endotypes” (DREAMS) promoted under the National Operative Program (NOP) on Research and Innovation 2014–2020 of Italian Ministry of University and Research. The authors would like to thank the BREATHE study group, including academic clinicians and researchers such as Stefania La Grutta, Velia Malizia, Giovanna Cilluffo, Salvatore Fasola, Andrea Albarelli, Giuseppe Roberto Marseglia, Mara De Amici, Giorgia Testa, Maria Sole Prevedoni Gorone, Lorenzo Preda, and Federica De Matteis for their significant contribution to the research project. The authors declare no conflict of interest. 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.