Increase in FeNO Levels Following IL5/IL5R-Targeting Therapies in Severe Asthma: A Case Series

Abstract

Purpose

Monoclonal antibodies targeting interleukin-5 (IL5) and its receptor (IL5R), used for severe asthma treatment, reduce eosinophils to almost complete depletion. Fractional exhaled nitric oxide (FeNO), a surrogate marker of eosinophilic airway inflammation, is expected to decrease after their initiation. Our center noticed increased FeNO levels in a few patients in whom anti-IL5/IL5R therapy was initiated. Limited data are available on the kinetics of T2 inflammation biomarkers after initiation of a biologic in that population. This study aims to identify if a subgroup of severe asthma patients experiences increased FeNO levels after initiation of anti-IL5/IL5R therapy and to describe their clinical characteristics.

Patients and Methods

This is a retrospective case series of 5 patients on Benralizumab (4M:1F) and 8 on Mepolizumab (5M:3F) who showed a significant increase in FeNO (>20% AND >25 ppb) following initiation of an anti-IL5/IL5R treatment. Clinical data, expiratory flows, and inflammation were extracted from the patients’ chart at initiation of treatment (T₀), 3 months (T₁) and 12 months (T₂) post-treatment. Descriptive statistics were used.

Results

In patients treated with Benralizumab, the increase in FeNO was observed between T₀ and T₁ (mean delta = 82 ± 72 ppb) with a subsequent decrease (N = 3). In most patients taking Mepolizumab (N = 6), the FeNO increase was observed between T₁ and T₂ (mean delta = 57 ± 35 ppb). Under treatment, no Benralizumab patient experienced asthma exacerbation while two on Mepolizumab did. All patients had a significant decrease in blood eosinophils.

Conclusion

Although initiation of anti-IL5/IL5R may cause a transient rise in FeNO levels in a subgroup of patients, it does not appear to affect clinical outcomes. A compensatory mechanism involving other inflammatory pathways such as IL13 or IL4, both involved in FeNO production, could theoretically explain these findings. Further investigation is needed to elucidate the actual underlying mechanisms.

Keywords:

• biologics
• biomarkers
• Benralizumab
• Mepolizumab

Abbreviations

BMI, Body-mass index; EGPA, Eosinophilic granulomatosis with polyangiitis; FeNO, Fractional exhaled nitric oxide; FEV₁, Forced expiratory volume in one second; GERD, Gastroesophageal reflux disease; ICS, Inhaled corticosteroids; IL-4, Interleukin-4; IL-5, Interleukin-5; IL-5R, Receptor of the IL-5; IL-13, Interleukin-13; iNOS, inducible nitric oxide synthase; IUCPQ, Quebec Heart and Lung Institute; mcg, microgram; mg, milligram; NO, Nitric oxide; OCS, Oral corticosteroids; ppb, parts per billion; T2 inflammation, Type 2 inflammation.

Acknowledgments

There are no other collaborators to declare.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

KG reports grants and personal fees from AstraZeneca, Covis, Novartis, and Sanofi, personal fees from GSK, Merck, TEVA, and Valeo, outside the submitted work. LPB considers having no conflict of interest related to this study, but wishes to declare what can be perceived as potential conflicts of interest: Research grants for participation to multicentre studies, AstraZeneca, Boston Scientific, GlaxoSmithKline, Hoffman La Roche, Novartis, Ono Pharma, Sanofi, Takeda: Support for research projects introduced by the investigator, AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck, Takeda: Fee for consulting and advisory boards, Astra Zeneca, Novartis, Methapharm: Nonprofit grants for production of educational materials, AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck, Novartis: Conference fees, AstraZeneca, GlaxoSmithKline, Merck, Novartis. AC considers having no conflict of interest related to this study, but wishes to declare what can be perceived as potential conflicts of interest: Research grants for participation to multicentre studies, AstraZeneca: Fee for consulting and advisory boards, AstraZeneca, Sanofi: The authors report no other conflicts of interest in this work.

Additional information

Funding

This study was supported by AC research funds: There are no other financial disclosures or sponsors to declare.