Asthma exacerbations persisting in patients with severe asthma on biologic therapy reflect distinct inflammatory phenotypes, and identifying the phenotype should come before treatment escalation, according to a presentation at the European Respiratory Society (ERS) Congress 2026 in Barcelona, Spain.¹
“In routine clinical practice, we still see a significant proportion of patients who continue to experience exacerbations despite receiving biologics,” said Florence Schleich, MD, PhD, a respiratory physician at the University of Liège in Belgium, in an interview with HCPLive. "For these patients, it's really important to try to understand the underlying mechanisms for these residual exacerbations, to avoid inappropriate treatment escalation and to prevent future exacerbations.”
Exacerbation Phenotypes on Mepolizumab, Benralizumab, and Tezepelumab
According to Schleich, residual exacerbations on mepolizumab, an anti-interleukin (IL)-5 antibody, split roughly evenly between eosinophilic events and infection-driven, more neutrophilic events. In the prospective observational MEX study of 145 patients with severe eosinophilic asthma receiving mepolizumab, a fractional exhaled nitric oxide (FeNO) level of ≤20 ppb or ≥50 ppb was the most useful discriminator of exacerbation phenotype.²
Non-eosinophilic events in MEX were associated with low FeNO and elevated C-reactive protein, consistent with infection.² MEX investigators also cautioned against switching biologics for treatment failure without first profiling the inflammatory phenotype of ongoing exacerbations.²
Exacerbations on benralizumab (Fasenra), an anti-IL-5 receptor α antibody, follow a different pattern. In the multicenter, prospective BenRex cohort study across 15 UK severe asthma centers, airway neutrophilia was present in 55% of exacerbations with available sputum, and new acquisition of Haemophilus influenzae occurred in 18.2% of sampled cases.³ BenRex investigators concluded eosinophilic inflammation is not involved in exacerbations on benralizumab, pointing instead to viral pathogens, airway neutrophilia, and sputum microbiome alteration.³
The newest data, from the TezEx study of exacerbations on tezepelumab (Tezspire), an anti-thymic stromal lymphopoietin (TSLP) antibody, surprised her most. TezEx is a retrospective and prospective observational study collecting blood, nasal, and sputum samples at exacerbation and at 1-year stable state in patients with severe asthma receiving tezepelumab.⁴ According to Schleich, 60% of residual exacerbations on tezepelumab were eosinophilic, and airway eosinophilic inflammation did not correlate with FeNO in these patients.¹,⁴
Choosing Biomarkers and Addressing Comorbidities in Residual Exacerbations
Schleich described FeNO and blood eosinophil count as strong predictors of future exacerbation risk and of response before biologic initiation. Once a patient is on treatment, their utility depends on the agent. Blood eosinophils offer little information during anti-IL-5 or anti-IL-5 receptor therapy because these agents reduce or deplete them, leaving FeNO as the more practical marker, with values between 20 ppb and 50 ppb remaining indeterminate and potentially warranting sputum analysis.¹
"With tezepelumab, FeNO is not helpful anymore, and you should look at the blood eos count, which is still correlated with the presence of eosinophilic inflammation in the sputum," Schleich said. "The biomarkers you will use to predict the exacerbation will change according to the treatment the patient receives."
Beyond phenotyping, Schleich urged clinicians to evaluate uncontrolled comorbidities in patients who continue to exacerbate, including chronic rhinosinusitis with nasal polyps, bronchiectasis, and obesity. She cited ORACLE2 data presented at ERS 2026, drawn from more than 7000 patients with moderate to severe asthma, in which a body mass index (BMI) above 25 kg/m² was already associated with increased exacerbation risk.¹ For infection-driven exacerbations, particularly in patients with chronic bronchitis, purulent sputum, or concomitant bronchiectasis, she said macrolides could provide additional benefit on top of biologic therapy.¹
References
Schleich F. Asthma: why do asthma exacerbations persist, even in well-treated patients on biologics? Presented at: European Respiratory Society Congress 2026; September 2026; Barcelona, Spain.
McDowell PJ, Diver S, Yang F, et al. The inflammatory profile of exacerbations in patients with severe refractory eosinophilic asthma receiving mepolizumab (the MEX study): a prospective observational study. Lancet Respir Med. 2021;9(10):1174-1184. doi:10.1016/S2213-2600(21)00004-7
Logan J, Martin K, Gillespie L, et al. Asthma exacerbation profile of benralizumab for severe eosinophilic asthma (the BenRex study): a multicentre, prospective cohort study. Lancet Respir Med. Published online 2026. doi:10.1016/S2213-2600(26)00096-2
The inflammatory profile of exacerbations in patients with severe asthma receiving tezepelumab: the TezEx study. ClinicalTrials.gov identifier: NCT06666504. Accessed October 6, 2026. https://clinicaltrials.gov/study/NCT06666504
