Risk Factors for COVID-19 mRNA Vaccine-Associated Exacerbations in Patients With Obstructive Airway Diseases: REsearch for Asthma and COPD ExacerbaTION Caused by COVID-19 mRNA Vaccination (REACTION Study)

Purpose Coronavirus disease 2019 (COVID-19) mRNA vaccines have reduced the severity and mortality of severe acute respiratory syndrome coronavirus 2 infection. However, several reports of asthma exacerbations following COVID-19 mRNA vaccination have raised safety concerns for patients with obstructive airway diseases. This study aimed to evaluate the risk of mRNA vaccine-associated exacerbations and identify associated clinical factors among patients with asthma and chronic obstructive pulmonary disease (COPD). Methods This multicenter historical cohort study enrolled 455 patients (387 with asthma, including 30 with COPD overlap and 68 with COPD) from 13 Japanese institutions between September 2022 and September 2024. Demographic data, pulmonary function, biomarkers, and questionnaire responses were collected. Exacerbation was defined as worsening of respiratory symptoms occurring within 1 week after vaccination. Independent risk factors were identified by multivariate logistic regression. Results Patients with asthma had a higher COVID-19 mRNA vaccine-associated exacerbation rate than those with COPD (14.5% vs. 0%, P < 0.001). Among patients with asthma, exacerbations were more frequent after COVID-19 mRNA vaccination than after influenza vaccination (14.5% vs. 1.8%, P < 0.001). Younger age, atopic predisposition, lower fractional exhaled nitric oxide levels (< 25 ppb), and poor asthma control (asthma control test < 20 and/or frequent exacerbations ≥ 2/year) were identified as independent risk factors (all P < 0.05). Most exacerbations were mild, with no severe outcomes. Conclusions Poorly controlled atopic asthma in younger individuals was associated with increased risk of COVID-19 mRNA vaccine-associated exacerbation. Despite this, the overall benefits of COVID-19 mRNA vaccination support its continued use, with an emphasis on optimizing asthma control beforehand in high-risk patients.