Summary
Airway hyperresponsiveness improved after mepolizumab, particularly for indirect bronchial challenge.
Analyses were exploratory and not pre‐specified in the randomised trial protocol.
To the Editor,
Chronic rhinosinusitis with nasal polyps (CRSwNP) is a type 2 inflammatory disease frequently associated with lower airway involvement, even in the absence of diagnosed asthma [1, 2]. While biologic therapies targeting interleukin‐5 improve clinical outcomes in CRSwNP [3], their effects on airway physiology remain incompletely characterised. We therefore examined airway hyperresponsiveness (AHR) and lung function outcomes in a randomised controlled trial of mepolizumab with or without adjunctive functional endoscopic sinus surgery (FESS).
This study was conducted as part of a randomised controlled trial in patients with severe CRSwNP, comparing mepolizumab alone with mepolizumab plus FESS [4]. The primary clinical outcome (SNOT‐22 at 6 months) has been reported separately [5]. The present analyses focus on airway physiology outcomes over 12 months. These airway physiology analyses were not pre‐specified in the original study protocol and should therefore be considered exploratory. Detailed methods and primary outcomes are reported in the parent randomised trial [5].
Fifty‐eight patients were randomised to mepolizumab alone (n = 29) or mepolizumab plus FESS (n = 29). Spirometry and bronchial provocation testing using mannitol and methacholine were performed at baseline, 6 months and 12 months. Airway sensitivity was assessed by PD15 (mannitol) and PD20 (methacholine), and airway reactivity by response–dose ratio.
Airway hyperresponsiveness improved in both treatment groups over 12 months. The proportion of participants with a positive mannitol challenge (PD15) decreased from 52.6% (30/57) at baseline to 28.3% (15/53) at 12 months. Similarly, methacholine responsiveness (PD20) decreased from 69.6% (39/56) to 50.9% (27/53). In paired analyses, 28.6% (16/56) of participants converted from PD15 positive to negative, while 1.8% (1/56) converted from negative to positive. For methacholine, 25.0% (14/56) converted from PD20 positive to negative, and 5.4% (3/56) converted from negative to positive.
These findings were supported by a rightward shift in airway sensitivity curves at 12 months (Figure 1), indicating that a substantial proportion of participants no longer reached the diagnostic threshold response. Improvements were more pronounced for mannitol than methacholine, suggesting a greater effect on indirect, inflammation‐mediated bronchoconstriction.
FIGURE 1.
Airway sensitivity during bronchial provocation testing at baseline and 12 months. (A) Mannitol (PD15). (B) Methacholine (PD20). Curves represent the proportion of participants not reaching the threshold response across increasing cumulative doses. A rightward shift indicates reduced airway sensitivity.
Spirometric improvements were modest, with increases in FEV1 of approximately 100–150 mL and FVC of 2%–4% predicted. No consistent changes were observed in impulse oscillometry parameters. No significant between‐group differences were observed for physiological outcomes.
The greater improvement in indirect compared with direct airway responsiveness is consistent with suppression of type 2 airway inflammation rather than reversal of structural airway changes [6, 7]. While adjunctive FESS improved symptom outcomes at 6 months in the parent trial, it did not significantly modify airway physiology compared with biologic therapy alone.
These findings should be interpreted in light of the exploratory nature of the analyses. As airway physiology outcomes were not pre‐specified in the study protocol, the results are hypothesis‐generating and require confirmation in studies with predefined endpoints.
In conclusion, mepolizumab treatment in patients with CRSwNP was associated with improvements in airway hyperresponsiveness, particularly for indirect bronchial challenge. These findings suggest that airway physiology measures may provide complementary insight into treatment response in CRSwNP and support further investigation in future studies.
Author Contributions
All authors contributed to the study conception and design. The study initiative was Vibeke Backer’s and Jens Tidemandsen’s. The analyses were performed by Jens Tidemandsen. The first draft of the manuscript was written by Jens Tidemandsen and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
This work was supported by GlaxoSmithKline.
Conflicts of Interest
Jens Tidemandsen: received personal fees from GSK, Morten Hostrup: No conflicts of interest, Anne Sophie Homøe: received personal fees from GSK, Marie Høxbro: received personal fees from GSK, Kasper Aanæs: received personal fees from GSK, Sanofi and AstraZenica, Howraman Meteran: receiving honoraria for lectures and advisory board meetings from GSK, Teva, AstraZeneca, Novartis, Sanofi‐Aventis, ALK‐Abelló and Chiesi not related to this study within the past 5 years, Vibeke Backer: received personal fees from AstraZeneca, GSK, TEVA, Sanofi Genzyme, MSD, Chiesi, Boehringer‐Ingelheim, Novartis, ALK‐Abello, Mundipharma, BIRK NPC and Pharmaxis., and Peter G. Gibson: reports speakers fees from astrazeneca, glaxosmithkline, orion and sanofi and research grants to the institution from glaxosmithkline.
Data Availability Statement
The datasets generated and analysed during the current study are not publicly available due to institutional and ethical restrictions but are available from the corresponding author on reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets generated and analysed during the current study are not publicly available due to institutional and ethical restrictions but are available from the corresponding author on reasonable request.