Oral corticosteroids are commonly used in the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP).1Fokkens W.J. Lund V.J. Mullol J. Bachert C. Alobid I. Baroody F. et al.EPOS 2012: European position paper on rhinosinusitis and nasal polyps 2012: a summary for otorhinolaryngologists.Rhinology. 2012; 50: 1-12Crossref PubMed Google Scholar However, the efficacy of oral-corticosteroid therapy varies between different patients with CRSwNP. IL-25–mediated TH2-biased response is reported to be associated with corticosteroid sensitivity in airway inflammatory response,2Cheng D. Xue Z. Yi L. Shi H. Zhang K. Huo X. et al.Epithelial interleukin-25 is a key mediator in Th2-high, corticosteroid-responsive asthma.Am J Respir Crit Care Med. 2014; 190: 639-648Crossref PubMed Scopus (141) Google Scholar while their value for predicting oral-corticosteroid response to CRSwNP has not been completely evaluated. IL-25, an important epithelial-derived proinflammatory cytokine, plays various roles in different inflammatory murine models, such as asthma, atopic dermatitis, and pulmonary fibrosis,3Angkasekwinai P. Park H. Wang Y.H. Wang Y.H. Chang S.H. Corry D.B. et al.Interleukin 25 promotes the initiation of proallergic type 2 responses.J Exp Med. 2007; 204: 1509-1517Crossref PubMed Scopus (456) Google Scholar and orchestrates type 2 responses at the mucosa site. The correlation of IL-25–mediated TH2-biased response and corticosteroid sensitivity is expected to be involved in airway inflammatory response. Recently, our group has identified that local IL-25 plays a crucial role in promoting TH2-biased inflammation in CRSwNP, and may serve as a promising therapeutic target in CRSwNP.E1 Moreover, we have demonstrated that nasal tissue IL-25 level is a novel biomarker for patients with CRSwNP with airway hypersensitiveness.E2 Cheng et al2Cheng D. Xue Z. Yi L. Shi H. Zhang K. Huo X. et al.Epithelial interleukin-25 is a key mediator in Th2-high, corticosteroid-responsive asthma.Am J Respir Crit Care Med. 2014; 190: 639-648Crossref PubMed Scopus (141) Google Scholar reported that the IL-25high patients with asthma have better improvements in FEV1 following inhaled corticosteroid treatment than do the IL-25low subgroup,2Cheng D. Xue Z. Yi L. Shi H. Zhang K. Huo X. et al.Epithelial interleukin-25 is a key mediator in Th2-high, corticosteroid-responsive asthma.Am J Respir Crit Care Med. 2014; 190: 639-648Crossref PubMed Scopus (141) Google Scholar and suggested serum IL-25 level as a predictor for corticosteroid sensitivity in asthma therapy. This study thus aimed to characterize the inflammatory profiles of patients with CRSwNP, and to evaluate the predictive biomarkers for oral-corticosteroid responses in a prospective clinical study. The study was approved by the Ethical Committees of the First and Fifth Affiliated Hospitals of Sun Yat-sen University (clinical-trial registration nos. ChiCTR-BON-16010179 and NCT02110654). An informed consent was obtained from each subject. We enrolled 52 patients with CRSwNP in this study, who underwent a 2-week oral prednisone treatment, and divided them into 2 subgroups (Fig 1, A; see Table E1 in this article's Online Repository at www.jacionline.org, corticosteroid-sensitive and nonsensitive subgroups).E3 Our results showed that there were 29 corticosteroid-sensitive patients with CRSwNP and 23 nonsensitive patients with CRSwNP. Clinical characteristics are listed in Table E2 in this article's Online Repository at www.jacionline.org. Nasal polyp (NP) specimens and blood samples were obtained before oral-corticosteroid treatment. The inflammatory profiles were evaluated by means of hematoxylin-eosin and immunohistochemistry staining, ELISA, and luminex-based multiplex assay. Data were expressed as medians and interquartile ranges. The predictive ability of the parameters was evaluated by receiver operating characteristic (ROC) curve. A P value of less than .05 was considered as statistically significant (see details in this article's Online Repository at www.jacionline.org). Our results showed that the protein levels of IL-25 in NP tissues and in serum, as well as the NP endoscopic scores, were significantly elevated in the corticosteroid-sensitive subgroup compared with the nonsensitive subgroup (Fig 1, B and C; see Table E2 in this article's Online Repository at www.jacionline.org). The immunoreactivity of IL-25 was significantly increased in the corticosteroid-sensitive subgroup (Fig 1, D and E). Hematoxylin-eosin and immunohistochemistry staining showed that eosinophil, but not neutrophil, counts were significantly increased in the corticosteroid-sensitive subgroup (see Fig E1 A-D, in this article's Online Repository at www.jacionline.org). Similarly, a significantly increased eosinophil, but not neutrophil, count was found in peripheral blood of the corticosteroid-sensitive subgroup (Fig E1, E and F). Using tissue luminex-based multiplex assay and serum ELISA, we also found that serum IL-5 level was significantly increased in the corticosteroid-sensitive subgroup compared with the nonsensitive subgroup (see Fig E2 in this article's Online Repository at www.jacionline.org). Next, we further performed logistic regression analysis to determine the factors associated with corticosteroid efficacy by between-group comparison analysis followed by ROC curve analysis. The following variables were introduced into the multivariate model: the endoscopy scores, tissue IL-25 levels and eosinophil counts, serum IL-5 and IL-25 levels, and peripheral blood eosinophil counts. The multivariate analysis showed that corticosteroid sensitivity was significantly associated with tissue and serum IL-25 levels (both P < .05), and marginally associated with tissue eosinophil counts (P = .05; see Table E3 in this article's Online Repository at www.jacionline.org) in this cohort. Sensitivity analysis by including individuals with robust NPs (NP endoscopy scores ≥3) also showed similar results (see Tables E4-E6 in this article's Online Repository at www.jacionline.org). Following these observations, we further examined the sensitivity and specificity of NP tissue and serum IL-25 levels in predicting oral-corticosteroid sensitivity in this CRSwNP cohort using an ROC curve analysis. As shown in Fig 2, A, the ROC curve analysis indicated that the NP tissue IL-25 levels (area under the curve = 0.963) had a higher predictive value for oral-corticosteroid sensitivity than did the serum IL-25 levels. The best cutoff point for NP tissue IL-25 level was determined using the Youden index (based on the optimal sensitivity and specificity), to discriminate oral-corticosteroid sensitivity and nonsensitivity in patients with CRSwNP. Our data demonstrated that a cutoff point of 22.50 pg/mL NP tissue IL-25 level provided a Youden index of 81.5%, with a sensitivity of 85.7% and a specificity of 95.8%, and positive and negative predictive values of 96% and 85.2% for oral-corticosteroid sensitivity (Fig 2, B). Although oral corticosteroids are one of the frequently used treatments in the management of CRSwNP,1Fokkens W.J. Lund V.J. Mullol J. Bachert C. Alobid I. Baroody F. et al.EPOS 2012: European position paper on rhinosinusitis and nasal polyps 2012: a summary for otorhinolaryngologists.Rhinology. 2012; 50: 1-12Crossref PubMed Google Scholar there is lack of effective means of predicting corticosteroid sensitivity in patients with CRSwNP. It was reported that the overall sensitivity rates of topical corticosteroid therapy to NP were only between 53.8% and 80%.1Fokkens W.J. Lund V.J. Mullol J. Bachert C. Alobid I. Baroody F. et al.EPOS 2012: European position paper on rhinosinusitis and nasal polyps 2012: a summary for otorhinolaryngologists.Rhinology. 2012; 50: 1-12Crossref PubMed Google Scholar, 4Deng J. Xu R. Zuo K.J. Chen D. Xu G. Shi J.B. Clinical observation of topical steroid for the treatment of chronic rhinosinusitis in Chinese adults.Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2012; 47 ([in Chinese]): 1027-1029PubMed Google Scholar, 5Tuncer U. Soylu L. Aydogan B. Karakus F. Akcali C. The effectiveness of steroid treatment in nasal polyposis.Auris Nasus Larynx. 2003; 30: 263-268Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar Hissaria et al6Hissaria P. Smith W. Wormald P.J. Taylor J. Vadas M. Gillis D. et al.Short course of systemic corticosteroids in sinonasal polyposis: a double-blind, randomized, placebo-controlled trial with evaluation of outcome measures.J Allergy Clin Immunol. 2006; 118: 128-133Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar reported that 36% of patients with CRSwNP were nonsensitive to corticosteroid therapy based on the 31-item rhinosinusitis outcome measure scores. Milara et al7Milara J. Morell A. Ballester B. Armengot M. Morcillo E. Cortijo J. MUC4 impairs the anti-inflammatory effects of corticosteroids in patients with chronic rhinosinusitis with nasal polyps.J Allergy Clin Immunol. 2017; 139: 855-862Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar found that about 27% of patients with CRSwNP with a high expression of Mucin 4 were resistant to 15-day oral-corticosteroid therapy, inferring that the high expression of Mucin 4 participated in corticosteroid resistance. Our results also showed that 44.2% (23 of 52) of patients with CRSwNP were nonsensitive to 14-day oral-corticosteroid therapy based on the nasal endoscopic scores.E3 A recent retrospective cohort study including more than 200,000 patients with asthma8Sullivan P.W. Ghushchyan V.H. Globe G. Schatz M. Oral corticosteroid exposure and adverse effects in asthmatic patients.J Allergy Clin Immunol. 2018; 141: 110-116.e7Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar revealed that exposure to 4 or more prescriptions of oral-corticosteroid therapy within a year was associated with significantly greater odds of adverse effects for osteoporosis, fractures, gastrointestinal ulcers/bleeds, cataracts, obesity, type 2 diabetes, and hypertension (odds, 1.21-1.44 depending on the adverse effects). Each prescription might result in a cumulative burden on current and future health regardless of dose and duration, which signify the need for careful and accurate prescription of corticosteroids in CRSwNP management. It is thus important to develop useful methods for identifying distinct endotypes of CRSwNP and predicting responses to oral-corticosteroid therapy. To this aim, we previously reported that the NP neutrophilia impaired oral-corticosteroid sensitivity of patients with CRSwNP,9Wen W. Liu W. Zhang L. Bai J. Fan Y. Xia W. et al.Increased neutrophilia in nasal polyps reduces the response to oral corticosteroid therapy.J Allergy Clin Immunol. 2012; 129: 1522-1528Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar but the key factor determining oral-corticosteroid sensitivity remains elusive. In this study, we further identified the correlation of oral-corticosteroid sensitivity and predictive biomarkers in CRSwNP oral-corticosteroid therapy. All data indicated that the NP tissue IL-25 level, and to a certain extent, serum IL-25 level, can be used for predicting the clinical efficacy of oral-corticosteroid sensitivity in patients with CRSwNP, which might expand our understanding on CRSwNP endotypes and contribute to the basis of personalized treatment for CRSwNP. In addition, the use of NP tissue IL-25 level as a biomarker may also enhance the quality of life of nonsensitive patients whereby it shortens the time frame to receive the appropriate treatment by at least 14 days while preventing unnecessary steroid usage and side effects mentioned. We thank Dr Annad Andiappan (Singapore Immunology Network, A*star Institute) and Dr Kai Sen Tan (Department of Otolaryngology, National University of Singapore) for their critical discussions and helpful comments. We thank Prof Lin Xu (School of Public Health, Sun Yat-sen University, Guangzhou, China) for her critical discussions and kind help on data statistics. 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