Although showing excellent outcomes and treatment responses in patients with CRSwNP [15], a subset of patients does not respond to treatment with dupilumab, as assessed with objective as well as patient-reported outcomes [12]. This emphasizes the need for predictive biomarkers of therapy response of dupilumab in CRSwNP. In the current study, we were able to observe an almost fourfold increased probability of reaching the post-treatment NPS value of 0 in patients with a high pretreatment PLR (> 131.2). The prognostic relevance of pretreatment NLR was not statistically significant. Importantly, confounders possibly indicating a non-type 2 respiratory disease were included in the analysis and showed no significant impact on the outcome.

The association of high pretreatment NLR and PLR values with poor outcome has already been presented for different malignant diseases, mainly explained as the reflection of the enhanced tumor-related systemic inflammation [16,17,18]. Even in sinonasal cancer, high NLR and PLR were reported in patients with worse survival outcomes in the study of Turri-Zanoni et al. [19]. However, besides two authors assessing the values of NLR and PLR in rhinosinusitis patients, no studies could be identified with regard to the prognostic value of these markers in CRSwNP patients treated with dupilumab. In contrast to results in cancer patients, high value of PLR seems to correlate with better therapy response to dupilumab in CRSwNP. Interestingly, high NLR was associated with a higher recurrence rate after ESS in CRSwNP, and the PLR was higher in patients with recurrence [10].

As noted, these ratios potentially reflect the degree of systemic inflammation. Several authors aimed to explain the underlining mechanism between inflammation and the values of these parameters [10, 20, 21]. Generally, systemic inflammation is mostly marked by a high number of neutrophils [10]. Furthermore, different inflammation mediators lead to an increased absolute platelet count [20]. Regarding the second component of both ratios, lymphocytes are involved in the regulation of different inflammatory processes. As furthermore noted, a low number of lymphocytes is usually observed simultaneously with systemic neutrophilia [21]. Therefore, high NLR and PLR should be associated with a higher degree of systemic inflammatory processes. However, the exact correlation with the type 2 inflammation in CRSwNP with these markers remains unclear and warrants further elucidation.

Therefore, the observed correlation of high PLR with total therapy response to dupilumab marks a novel finding. As noted, higher PLR was observed in patients with CRSwNP recurrence after ESS [15]. On the contrary, high PLR prior to dupilumab therapy was associated with a higher rate of the total response to dupilumab in our study (defined as post-treatment NPS of 0). Based on these findings, it could be hypothesized that a higher rate of systemic inflammation caused by the CRSwNP, as reflected by high PLR, warrants a systemic treatment rather than surgical therapy. Indeed, the underlying mechanistic effects should be further elucidated. It remains unsettled, why high PLR predicts better response to dupilumab, particularly due to the fact that high PLR mostly associated with worse outcome. Moreover, our findings certainly need to be validated in order to make a definitive statement. Importantly, we measured therapy response only by the polyp size reduction. Furthermore, the prognostic value of inflammatory markers including PLR should certainly be investigated in other conditions treated with dupilumab, such as asthma or atopic dermatitis.

The proper assessment of the therapy response to biologics, including dupilumab, has been a subject of discussion. The European Forum for Research and Education in Allergy and Airway Diseases has published a consensus paper that includes a proposed assessment of response to therapy with biologics [22]. In particular, they noted that the following factors reflected the treatment response: reduction of polyp size, reduced need for corticosteroids, improvement in olfactory perception, improvement quality of life, and reduction of the impact of comorbidities. Interestingly, they proposed the first evaluation after 16 weeks, followed by a definitive evaluation after one year. Similarly, one group assessed the therapy outcome post dupilumab treatment after 16 weeks [23]. On the other hand, Hopkins et al. [24] assessed subjective and objective outcomes 24 weeks after the dupilumab start in CRSwNP. However, the biggest NPS improvement was noticed during the first 8 weeks of dupilumab treatment in the SINUS-24 study [11]. As the primary endpoint of our study was the improvement of the NPS, we therefore included the 8-week time-point as post-therapeutic. Furthermore, the follow-up data afterwards was limited in our cohort.

The conclusions of the current study can be challenged by different limitations. First, the timepoint defined as post-treatment was not the same in all patients. Thus, the impact of different time points and duration of treatment on the response warrants further investigation, particularly the outcome 16 weeks after treatment start. Due to the retrospective nature of the study, a potential selection bias could not be excluded. Notably, we excluded the effects of several confounders in the multivariable analysis; however, other confounders could have an effect as well. Importantly, the mechanistic underlying effects behind our observation remain unclear and warrant further elucidation. Moreover, according to the clinical markers and PROMs, the majority of our patients had a milder CRSwNP, and would have possibly not be prescribed a biologic in other areas of the world. Last, the size of the patient cohort is limited, potentially contributing to the missing of some significant effects and to wide CI values. In particular, significant association between PLR and subjective outcomes could have been missed, especially due to missing values in several patients. However, as this is a novel treatment, the majority of studies on this subject included small cohorts. Indeed, large-scale, multicentric investigations are certainly needed in order to make a definitive statement.