Maintained effect of endoscopic sinus surgery in asthma responders to drugs targeting the IL5 pathway with persistent nasal polyposis

Although severe asthma and chronic rhinosinusitis with nasal polyps (CRSwNP) have been considered as the same entity leading to the concept of “united airways,” some patients treated with drugs targeting the IL5 pathway show a significant response on asthma but not on nasal polyposis.1 To our knowledge, the therapeutic options of those patients with a dissociated response have never been studied before. This study investigates the effects of endoscopic sinus surgery (ESS) in patients with significant response to anti-IL5 on asthma but with unchanged or worsening response on nasal polyposis. We conducted a retrospective study in consecutive patients with severe asthma treated with mepolizumab (anti-IL5) or benralizumab (anti-IL5Rα) at Toulouse University Hospital Centre. Inclusion criteria were: (1) initiation of mepolizumab or benralizumab for severe asthma and therapy still ongoing, (2) response to these drugs on asthma based on a reduction of at least 50% of annualized asthma exacerbations, and (3) no change or worsening of nasal polyposis based on ESS rescue. The patients were retrospectively assessed at different time points during their follow-up. Data were chronologically collected as follows. First, we collected the median time to polyp relapse after sinus surgery before biologic initiation for severe asthma. Second, asthma control test (ACT) score, annualized asthma exacerbation rate, and nasal polyp score (NPS) were collected at the time of biologic initiation. Third, SNOT-22 and NPS were collected at the time of ESS. Tissue eosinophil count was also completed in nasal polyps after surgery. Polyps with tissue eosinophil counts >10 per high-power field (HPF) were considered to have high tissue eosinophil count.2 Lastly, ACT score, annualized asthma exacerbation rate, and NPS were collected at the most recent follow-up visit. The Kaplan–Meier curve method was used to determine the probability of having a polyp relapse after ESS in patients treated with the anti-IL5/IL5Rα antibody. The control group encompassed the same patients having polyp relapse after ESS before they were treated with the anti-IL5/IL5Rα antibody. Statistical significance was defined as a p-value of <.05. Ten patients, six males and four females, with a median age of 54.5 [42.3–59.0] were included (Table 1). Before the initiation of mepolizumab (n = 3) or benralizumab (n = 7), median annualized asthma exacerbation rate was 6.0 [4.0–7.5]. Eight patients had sinus surgery before the initiation of mepolizumab or benralizumab with a median time to polyp relapse of 15.0 [6.3–22.5] months. At 6 months after biologic initiation, all the patients were super-responders with no asthma exacerbations. Given patients had no change or worsening of nasal polyposis despite a significant response to mepolizumab or benralizumab on asthma, ESS was performed 18.4 [11.2–27.2] months after biologic initiation. Histological analysis revealed that six patients presented a high tissue eosinophil count despite biologic use. After a median follow-up of 24.4 [11.8–34.3] months after surgery, only one patient experienced a sub-clinical relapse with an NPS of 2. All other patients had an NPS of 0. Compared to baseline, a significant improvement of asthma was still observed after a median follow-up of 24.4 [11.8–34.3] months (Figure 1). According to a log-rank test, time to polyp relapse was significantly longer after sinus surgery in patients treated with mepolizumab/benralizumab compared to the same patients before the use of mepolizumab/benralizumab (p = .0025). A dissociated response to mepolizumab/benralizumab in patients with combined severe asthma and CRSwNP is challenging in clinical practice. Indeed, in the context of a good response on asthma but no response on nasal polyposis, switching biological therapies is an option. However, asthma deterioration has been described after switching from anti-IL5/IL5Rα drugs to dupilumab.3 For this reason, switching from one biologic to another exposes the patient to asthma relapse with life-threatening symptoms.3 As described in our study, ESS is an alternative option in patients with a dissociated response despite mepolizumab or benralizumab because it is highly effective with a very low relapse rate for nasal polyps even if patients had poor functional results after previous ESS (without biologic). The discussion regarding the best treatment option in the case of nasal polyposis persistence despite biological therapies for asthma should also take into account the potential complications of ESS. It has been reported that minor and transitory complications are estimated at around 5%; nonetheless major complications are uncommon (<0.5%).4, 5 This surgery performed by trained specialists is a safe option. Before making a choice between switching the biologic and ESS in the context of a dissociated response to biologic therapy for asthma, it is useful to phenotype/endotype CRSwNP. It is well established that low-type 2 inflammation is sometimes observed in nasal polyposis.6, 7 In such a case, switching from one biologic to another anti-type 2 biologic may be ineffective. Moreover, shared decision making is crucial in the context of persistent polyposis despite biologic therapy for severe asthma. It is essential to make the patient a participant in the decision. For this reason, in the EUFOREA expert publication on CRSwNP, it is clearly mentioned that a patient must be informed about the aims, reasonable expectations, and possible side effects and complications of all authorized treatments available for the disease.8 It has been described that eosinophilia and elevated IL5 are associated with greater rates of CRSwNP recurrence after ESS.9 IL5 is crucial for eosinophil recruitment in tissue.10 The neutralization of the IL5 pathway with mepolizumab or benralizumab could be associated with a reduction of eosinophil recruitment in nasal tissue leading to a low relapse rate for nasal polyps after ESS. Due to the interaction of eosinophils with other immune cells, a reduction or depletion of eosinophils with biologics could also have an impact on the recruitment of other cells in nasal polyps.9 Moreover, given the crucial role of type 2 cytokines in severe asthma, inhibition of those cytokines could have an impact on the relapse of polyps. For this reason, it is likely that the low relapse rate of CRSwNP observed with anti-IL5/IL5Rα is not limited to these treatments. Indeed, other biologics such as dupilumab, an anti-IL4R antibody, or tezepelumab, an anti-TSLP antibody, should also have a beneficial impact on the prevention of nasal polyposis recurrence after surgery. One of the limitations of this study is the lack of data on drug compliance. However, all the patients are super-responders for asthma. For this reason, we assume that these patients were all compliant. To conclude, in patients with dissociated response to mepolizumab/benralizumab (good for asthma and no response for CRSwNP), ESS is associated with a very low relapse rate of nasal polyps. Laurent Guilleminault: Conceptualization; formal analysis; investigation; methodology; project administration; supervision; validation; visualization; writing—original draft; writing—review & editing; data curation resources. Guillaume de Bonnecaze: Conceptualization; investigation; methodology; project administration; supervision; validation; visualization; writing—original draft; writing—review & editing; data curation resources. Thomas Villeneuve, Alain Didier, Laurent L. Reber, Aurore Sigfried, Elie Serrano: Investigation; methodology; project administration; validation; visualization; writing—review & editing. We are grateful to INSERM for supporting this work via an “interfacing contract” for Laurent Guilleminault between Inserm and Toulouse University Hospital Center. We would also like to thank the “Fondation du souffle” for supporting this work. LG has been an investigator in clinical trials for AstraZeneca, MSD, and Novartis and reports grants or consultation fees from AstraZeneca, GlaxoSmithKline, Novartis, and Sanofi-Regeneron, and consultation fees from Bayer, Chiesi, MSD, not related to the work submitted. AD reports consultation fees from AstraZeneca, GlaxoSmithKline, Novartis, Sanofi-Regeneron, Chiesi, ALK, and Stallergenes, not related to the work submitted. LLR reports consultations fees from Argenx, Neovacs, Ceva, and Novartis, not related to the work submitted. ES reports consultation fees from Viatris, Zambon, GlaxoSmithKline, Sanofi-Regeneron, Menarini, ALK, and Stallergenes, not related to the work submitted. GDB reports consultation fees from Viatris, Zambon, GlaxoSmithKline, Sanofi-Regeneron, ALK, and Medtronic, not related to the work submitted. TV reports consultations fees from Boehringer Ingelheimnot related to the work submitted. AS reports no disclosure of interests. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. 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