Refractory Chronic Rhinosinusitis Research Articles

A comparison of doxycycline and conventional treatments of refractory chronic rhinosinusitis with nasal polyps: a systematic review and meta-analysis.

To compare the effects of doxycycline (DOX) and conventional management in patients with refractory chronic rhinosinusitis and nasal polyps (CRSwNP). Six databases were searched to September 2023. We retrieved studies that compared improvements in refractory chronic sinusitis-related symptoms between DOX-treated and control groups. DOX significantly reduced the Lund-Kennedy (LK) score [-0.3670 (range -0.6173; -0.1166); I2 = 92.8%], the nasal polyposis score [-0.9484 (-1.2287; -0.6680); I2 = 92.5%], the patient-reported Sinonasal Outcome Test (SNOT) score [-0.3141 (-0.4622; -0.1660); I2 = 91.2%], and the nasal obstruction score [-0.1813 (-0.3382; -0.0243); I2 = 86.2%]. On subgroup analyses by the measurement timepoints, the extent of nasal polyposis was significantly lower in the DOX group during treatment, at the end of treatment, and 4 and 8weeks later. The LK scores also indicated improvements during treatment and at the end of treatment. The SNOT score tended to decrease with time in the treatment group. Nasal obstruction symptoms improved during treatment and 4weeks later. DOX enhances the postoperative endoscopic outcomes of refractory CRSwNP patients by reducing recurrent polyposis and inflammation.

Comparison of Long-Term Postoperative Outcomes of the Subtypes of Chronic Rhinosinusitis with Nasal Polyps.

(1) Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic inflammatory condition that significantly impacts the health-related quality of life (HRQOL) of patients. This study aims to investigate the disparities in preoperative examination findings, postoperative HRQOL, and disease control status based on CRSwNP subtypes. (2) Methods: A retrospective analysis was conducted on 202 patients who underwent endoscopic sinus surgery for CRSwNP. The study assessed clinical characteristics, blood eosinophil and immunoglobulin E (IgE) levels, modified Lund-Kennedy and Lund-Mackay scores, and Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC) scores. HRQOL was evaluated using the Sino-nasal Outcome Test (SNOT-22) scores, and disease control status was assessed based on the European Position Paper on Rhinosinusitis and Nasal Polyps 2020 guidelines. (3) Results: Of the 202 patients, Eosinophilic CRSwNP patients exhibited significantly higher preoperative peripheral blood eosinophil ratios and IgE levels, and JESREC scores (p < 0.05). Two years postoperatively, patients in the non-eosinophilic group showed significantly improved SNOT-22 scores compared to preoperative scores (p = 0.007). Notably, the proportion of patients with uncontrolled disease was significantly higher in the eosinophilic group (p = 0.035). Logistic regression analyses identified preoperative SNOT-22 scores and eosinophilic CRSwNP subtype as influential factors on disease control status (p < 0.05). (4) Conclusions: Patients with more severe preoperative symptoms and eosinophilic CRSwNP demonstrated poorer long-term treatment outcomes.

The impact of middle meatal steroid-eluting implants on the postoperative outcomes of chronic rhinosinusitis: A systematic review and meta-analysis

Endoscopic sinus surgery (ESS) has become an established surgical option in refractory chronic rhinosinusitis (CRS). The goal of this review is to assess the impact of steroid-eluting middle meatal implants after ESS. Cochrane Central Register of Controlled Trials (CENTRAL), SCOPUS, PUBMED, and GOOGLE SCHOLAR were searched from inception to November 2022. All randomised controlled trials (RCTs) involving adult patients receiving ESS for CRS utilising a steroid-eluting middle meatal implants were eligible. The primary outcome was adhesion or synechiae. The secondary outcomes were mucosal inflammation, polyp reformation, the need for oral steroids and additional surgery, postoperative bleeding, sinus pain and discomfort, postoperative sinus-related infection, and change in intraocular pressure. Fourteen full articles were examined out of 496 potential abstracts. Seven RCTs satisfied the criteria. At 30days, steroid-eluting implants reduced adhesion (OR: 0.28, 95% CI: 0.14 to 0.56; P<0.001), mucosal inflammation (MD: −13.09, 95% CI: −18.22 to −7.97; P<0.001), polyp reformation (OR: 0.31; 95% CI: 0.22 to 0.44; P<0.001), and requirement of additional oral steroid (OR: 0.44; 95% CI: 0.25 to 0.78; P=0.005) or surgery (OR: 0.25; 95% CI: 0.12 to 0.50; P<0.001). While their use for adhesion (OR: 0.24; 95% CI: 0.11 to 0.54; P<0.001) and polyp reformation (OR: 0.24; 95% CI: 0.12 to 0.51; P<0.001) were favourable, there was no difference in mucosal inflammation (MD: −5.68, 95% CI: −12.39 to 1.03; P=0.100) or the need for surgery (OR: 0.96; 95% CI: 0.07 to 12.37; P=0.980) when evaluated after 30days. Overall, the findings suggest that steroid-eluting middle meatal implants improve ESS outcomes by lowering rates of adhesion formation, postoperative medical and surgical interventions, recurrent polyposis, and inflammation, while having no significant negative impact in the immediate postoperative period. More research is needed into the long-term impacts.

Association between peripheral eosinophilia, JESREC score, and olfactory dysfunction in patients with chronic rhinosinusitis.

The purpose was to evaluate the relationship between peripheral eosinophilia, Japan Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC) score, and olfactory dysfunction in chronic rhinosinusitis (CRS) patients and to explore the accuracy and specific cut points of the JESREC score in predicting olfactory dysfunction. In this cross-sectional, retrospective study, olfactory function was assessed by the Sniffin' Sticks 12-item test and multivariate logistic regression analyses were carried out. Receiver operating characteristic curves were plotted to derive accuracy and cutoff values for the JESREC scores of the olfactory dysfunction criterion. A total of 354 patients [mean (SD) age, 50.0 (14.9) years; 41.8% women] were included in the final analysis. The prevalence of olfactory dysfunction was 46.3%. Individuals who had olfactory dysfunction were more likely to be male (64.6% vs. 52.6%), have eosinophilic chronic rhinosinusitis (ECRS) (39.0% vs. 7.9%), have a longer course of CRS (2.3 years vs. 1.5 years), have higher JESREC scores (8.5 vs. 4.5), and have higher proportions of nasal polyps (78.7% vs. 18.9%) and peripheral eosinophilia (3.3% vs. 1.4%). In logistic analysis, the percentage of eosinophils (1.25, 1.13-1.37), JESREC score (1.31, 1.22-1.40), bilateral lesion (2.06, 1.25-3.41), nasal polyps (15.83, 9.23-27.16), CT shadow (2.73, 1.69-4.43), and ECRS (6.86, 3.68-12.80) were associated with olfactory dysfunction in CRS patients after controlling for covariates, while peripheral neutrophils were not significant. In addition, the area under the curve was 0.778 and the cutoff value for JESREC score for olfactory dysfunction was defined as 5.5. Peripheral eosinophilia and high JESREC scores were significantly associated with the risk of olfactory dysfunction in CRS patients, and special attention should be paid to patients with a JESREC score ≥6.

Oncostatin M's Involvement in the Pathogenesis of Chronic Rhinosinusitis: Focus on Type 1 and 2 Inflammation.

The cytokine oncostatin M (OSM) elicits pathogenic effects involving disruption of the epithelial barrier function as a part of immunological response networks. It is unclear how these integrated cytokine signals influence inflammation and other physiological processes in the pathology of chronic rhinosinusitis (CRS). We investigated the expression and distribution of OSM and OSM receptor (OSMR) in CRS patients' sinonasal specimens, and we compared the results with a panel of inflammatory cytokine levels and clinical features. We classified CRS patients as eosinophilic (ECRS, n = 36) or non-eosinophilic (non-ECRS, n = 35) based on the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis phenotypic criteria and compared their cases with those of 20 control subjects. We also examined OSM's stimulatory effects on cytokine receptor expression levels using the human bronchial epithelium cell line BEAS-2B. RT-PCR showed that the OSM mRNA levels were significantly increased in the CRS patients' ethmoid sinus mucosa. The OSM mRNA levels were positively correlated with those of TNF-α, IL-1β, IL-13, and OSMR-β. In BEAS-2B cells, OSM treatment induced significant increases in the OSMRβ, IL-1R1, and IL-13Ra mRNA levels. OSM is involved in the pathogenesis of CRS in both type 1 and type 2 inflammation, suggesting the OSM signaling pathway as a potential therapeutic target for modulating epithelial stromal interactions.

Residual nasal polyp tissue following dupilumab therapy is associated with periostin-associated fibrosis.

Dupilumab, an anti-interleukin-4 receptor alpha monoclonal antibody, is a new treatment for severe uncontrolled chronic rhinosinusitis with nasal polyps. However, data on the effect of dupilumab on histological changes in nasal polyp tissue are lacking. We aimed to investigate the effect of dupilumab on real-life clinical conditions and nasal polyp tissues from patients with eosinophilic chronic rhinosinusitis (ECRS), which is a refractory subtype. We conducted an open-label, prospective, observational, single-centre study on 63 patients with refractory ECRS on the basis of the criteria of the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis Study. These patients had a history of surgery and received dupilumab for 24weeks. Patient-reported sinonasal symptoms, T&T olfactometry and nasal polyp scores were prospectively evaluated. In 23 patients with residual nasal polyps following dupilumab treatment, changes in systemic and local periostin expression, and total collagen deposition in nasal polyp tissues were investigated before and after dupilumab administration. Dupilumab rapidly improved sinonasal symptoms and reduced the nasal polyp score 24weeks after initiation. 40 (63.5%) patients had resolution of nasal polyps, but the reduction was limited in the remaining 23 (36.5%) patients. Periostin expression in serum and nasal lavage fluid was decreased, whereas periostin and the total collagen deposition area in subepithelial tissues in residual nasal polyps were enhanced after dupilumab administration. Dupilumab improves sinonasal symptoms and reduces the nasal polyp score in refractory ECRS. Periostin-associated tissue fibrosis may be involved in the differential effect of dupilumab on nasal polyp reduction.

Clinical characteristics in Japanese patients with chronic rhinosinusitis who underwent endoscopic sinus surgery

ObjectiveThere is heterogeneity in the pathophysiology of chronic rhinosinusitis (CRS). Obtaining a detailed understanding of patient profiles in specific regions can provide valuable information not only for clinical practice but also future research plans. The aim of this study was to investigate the characteristics of patients who underwent endoscopic sinus surgery (ESS) for CRS. MethodsThis retrospective, single-center study examined the features of 453 patients with CRS who underwent ESS in the Tokyo area of Japan. The study evaluated various factors in patients with CRS including sex and age, the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC) score, the recurrence rate of CRS, comorbidities of asthma and/or allergic diseases, and IgE sensitization to 12 inhaled allergens. ResultsAge-related declines in the sensitization rate to inhaled allergens were observed, and the most notable age-related decrease in specific IgE antibodies was observed for house dust mites (HDM) (p = 8.3 × 10−7). Sensitization to HDM, cat dander, and various types of fungi, including Aspergillus, was frequently observed in the CRS with asthma group, with rates of 54%, 17%, and 17%, respectively. We found that 23% of the patients had recurrence. In the recurrence group, the positive rates of specific IgE antibodies for birch and cat dander were significantly higher than in the no recurrence group. Bronchial asthma was identified as an important factor for recurrence. Among male patients, the recurrence group was younger than the no-recurrence group (p = 0.0032). Severe eosinophilic CRS (ECRS) showed early recurrence after surgery, with over the half of the patients experiencing at least one recurrence within 2 years post-surgery. Among patients with ECRS, the recurrence rate for females was 1.92 times higher than for males. ConclusionOur study revealed the influences of age and sex on various clinical phenotypes of CRS patients undergoing ESS. There was a high sensitization rate to cat dander in both the recurrence and asthma groups. Further research on diverse disease etiologies is necessary to improve therapeutic strategies for patients with CRS.

Can EPOS2020 criteria of type 2 inflammation be applied to Asian patients with chronic rhinosinusitis?

Background There is a large diversity of mucosal immunologic chronic rhinosinusitis with nasal polyps (CRSwNP) endotypes across Western and Asian patient populations. Objectives The objective of the study was whether the European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS) 2020 criteria for type 2 inflammation are appropriate for biological use in CRSwNP patients. Methods A total of 207 participants are enrolled for the study. Retrospective evaluations of the tissues taken during surgery and the patients’ clinical features were performed. We investigated whether the criteria described in the EPOS2020 guideline were appropriate based on the criteria for type 2 inflammation identified based on prior studies using receiver-operating characteristic (ROC) analyses. Results The EPOS 2020 criteria are also shown to be an insufficient evaluation approach with low specificity (area under curve [AUC] = 0.645, specificity 8.4%). The authors created a novel scoring method using the total serum IgE level, blood eosinophil percentage, and tissue eosinophil percentage. This novel scoring system (AUC = 0.862, p < .001) fared better in ROC analyses than the EPOS 2020 criteria (AUC = 0.645) and Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis scoring system (AUC = 0.647). Conclusions and Significance A novel standard for type 2 inflammation in Asian CRSwNP patients must be established, as the EPOS 2020 criteria do not appear to be sufficient.

Chronic Rhinosinusitis After Maxillary Advancement Orthognathic Surgery.

Maxillomandibular advancement (MMA) remains an effective procedure for the management of obstructive sleep apnea (OSA). Maxillary advancement may lead to anatomical changes that impair paranasal sinus drainage, leading to chronic sinus inflammation. The aim of this study was to describe the clinical features and outcomes of patients suffering from chronic rhinosinusitis (CRS) following MMA. This is a retrospective case series study. Our study included subjects diagnosed with CRS following MMA from January 1992 to October 2018 at Stanford Hospital. We screened 730 patients undergoing MMA and identified a total of 57 with CRS after MMA. A descriptive analysis was performed using clinical data including patient demographics, comorbidities, prior surgical history, physical exam manifestations, CT findings, and quality of life outcomes (SNOT-22). Out of 730 patients undergoing MMA, 57(7.8%) were found to have CRS after orthognathic surgery. Presenting symptoms included facial pain (92.5%), nasal drainage (75%), nasal obstruction (67.5%), and hyposmia (20%). Endoscopic examination revealed recirculation (30.5%), purulent discharge (27.7%), polypoid changes (22.2%), and scarring (13.8%). Preoperative CT prior to undergoing endoscopic sinus surgery (ESS) demonstrated mucosal thickening in maxillary (64.2%), anterior ethmoid (39.2%), frontal (14.2%), posterior ethmoid (10.7%), sphenoid sinus (14.2%), and ostiomeatal complex (55.3%). Average Lund-Mackay score was 5.5(±3.8). Additional CT findings included secondary ostium in the inferior meatus (42.8%). Forty patients (70.1%) underwent ESS at a mean of 4.6 years after MMA. Patients undergoing ESS experienced significant improvement in SNOT-22 scores at 12-months post-surgery (P = .018). Patients undergoing maxillary advancement surgery are at risk of developing CRS postoperatively and should be advised of the risk of CRS associated with this procedure. Surgical treatment can be an option for medically refractory CRS related to MMA surgery.

Long-Term Efficacy of Dupilumab for Eosinophilic Chronic Rhinosinusitis.

Eosinophilic chronic rhinosinusitis (eCRS) is a type 2 inflammatory disease that frequently recurs after surgery. In recent years, dupilumab has been available for the treatment of refractory chronic rhinosinusitis since 2020 in Japan. Although there are some reports of its usefulness, there are not enough reports of its clinical efficacy for longer than 1 year, especially for olfactory recovery. Twenty patients with eCRS who had recurrence after surgery and had been receiving dupilumab were enrolled retrospectively. The nasal polyp score (NPS), computed tomography (CT) score, T&T olfactometer, and olfactory cleft opacification on CT were evaluated at baseline, at an average of 5.1 months later (short term), and at an average of 18.3 months later (long term). At the short-term evaluation, there were significant improvements in the NPS and CT scores (P < .001, P = .008, respectively). The CT score was further improved at the long-term evaluation compared to the short-term evaluation (P = .018) and baseline (P = .008). T&T detection/recognition thresholds and olfactory cleft opacification showed significant improvements only at the long-term evaluation compared to baseline (P = .002, P = .006, and, P = .006, respectively). The NPS remained improved, and the CT score showed further improvement with long-term treatment, whereas olfactory function and olfactory cleft opacification showed significant improvement only after long-term treatment. There was a dissociation between the time to improve in the NPS and CT scores and the time to improve in olfactory function and olfactory cleft opacification. Based on these results, dupilumab should be administered for longer than 1 year, especially for olfactory function.

Treatment with biological products for chronic rhinosinusitis with nasal polyp

Background: Chronic rhinosinusitis (CRS) is further classified as CRS with nasal polyp and CRS without nasal polyp. It is also divided into type 2 and none-type 2 by immunological endotype. Nowadays, novel biological products targeting type 2 inflammation are developed and used for the treatment of CRS with nasal polyp.Current Concepts: Dupilumab, which inhibits interleukin-4 and interleukin-13, and omalizumab, which targets immunoglobulin E, were recently approved and are currently being used as the treatment regimen for patients with recurrent CRS with nasal polyp in Korea. Many studies demonstrated enough effects of both biological products on nasal symptoms, including smell, quality of life, and polyp size. The indication of biological products is refractory CRS with nasal polyp with severe symptoms even after endoscopic sinus surgery. However, the main drawback of these biological products is a high cost since they are non-reimbursement regimens as defined by Korean national health insurance.Discussion and Conclusion: Further research on the use of dupilumab and omalizumab in Korean patients will be needed because the Korean CRS endotype, which is characterized by less-type-2 CRS, is different from Western CRS endotypes. Additionally, investigations on the comparison of efficacy among various biological products are essential to prescribe the most appropriate biological products depending on the patients’ endotypes.

Optimizing the timing of biologic and surgical therapy for patients with refractory chronic rhinosinusitis with nasal polyposis (CRSwNP).

Chronic rhinosinusitis with nasal polyposis (CRSwNP) is often treated with endoscopic sinus surgery (ESS); however, patients may require revision surgery due to recurrence. To date, no studies have compared outcomes for combined surgery and biologic therapy for CRSwNP compared with biologic therapy alone. Retrospective case-control study of CRSwNP patients who underwent ESS while on dupilumab or mepolizumab (ESS-biologic cohort) compared with CRSwNP patients on biologic therapy (biologic-only controls). Cohorts were matched according to indication, aspirin-exacerbated respiratory disease (AERD), sinonasal outcome test-22 (SNOT-22), and total polyp scores. Sixteen patients underwent ESS while on biologic therapy (13 dupilumab and 3 mepolizumab). Sixteen patients were biologic-only controls. There were no significant differences between indication, baseline SNOT-22 scores, polyp scores, and AERD status between cohorts. Patients underwent surgery a median of 33 days after starting biologic therapy. After 12 months of follow-up, the total polyp score for the ESS-biologic cohort decreased from 4.73 to 0.09 compared with a decrease from 5.22 to 3.38 for the biologic-only controls (95% confidence interval [CI] of difference: -5.37 to -1.38, Cohen's d: 2.40, p=0.005). In the ESS-dupilumab subanalysis, the ESS-dupilumab cohort had a significant reduction in polyp burden from 4.85 to 0.00 compared with 4.88 to 3.50 for the controls (95% CI of difference: -5.68 to -1.32, Cohen's d: -1.69, p=0.009). In CRSwNP patients, combined ESS and biologic therapy results in a significant and sustained decrease in polyp burden compared with biologic therapy alone. Larger studies are warranted to further examine the impact of combined therapy.

Sinonasal Outcome Test (Snot-22) Scores as a Predictor of Outcome in Patients Undergoing Functional Endoscopic Sinus Surgery (FESS) for Chronic Rhinosinusitis (CRS) at a Tertiary Care Centre in Eastern Nepal

Background: Sino nasal outcome test (SNOT) is a subjective tool in which both nasal and health-related symptomatic improvements are assessed in cases of Chronic Rhinosinusitis (CRS). We aim to report the demography of CRS patients and magnitude of symptoms, along with its improvement over time after the surgery, using SNOT questionnaire. Methods: A hospital based prospective, descriptive study was done in 35 patients with medically refractory CRS cases who underwent Functional endoscopic sinus surgey (FESS), over one year. All patients were routinely examined the 1st week, the 4th week, and 3 months after surgery. The cases were assessed preoperatively and then after surgery, using the Sino-nasal Outcome Test-22 (SNOT-22) questionnaire, for a maximum of 3 months period. The results were expressed in number and percentage. Mean and standard deviation were used to describe the findings and compare the initial and follow up values. Association between preoperative and postoperative symptoms was analyzed using paired sample t-test and p value less than 0.05 were considered significant. Results: The age range was 14-64 years, with a mean age of 33.11 ± years. 12(34.28%) were male and 23(65.71%) were female. Polyps were present in 12 (34.28%). 23 (65.71%) cases were without polyp. The mean SNOT score overall preoperatively was 33.94±SD, while postoperative SNOT score was 19.05±SD. There was a significant improvement in nasal, ear and facial symptoms, quality of life symptoms and psychological symptoms. Conclusion: There was an overall improvement in all the symptoms postoperatively, though the Cough and dizziness improvement was not statistically significant.

Real Life Observational Study of Treatment Success of Monoclonal Antibodies for Refractory Chronic Rhinosinusitis with Nasal Polyps.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a mainly type-2-driven inflammatory disease that is often refractory to medical and surgical treatment and characterized by a high rate of recurrence. Monoclonal antibodies have been approved for severe refractory CRSwNP. Randomized controlled trials (RCT) have shown significant improvement in objective and subjective parameters. The results of these RCTs cannot necessarily be transferred to daily routine. The purpose of this retrospective study is to evaluate the treatment effects of biologics in patients with CRSwNP in a real-life setting. Patients treated with one of the approved biologics since July 2020 with at least 6 months follow-up were included in the study. Changes in SNOT-22 and nasal polyp score (NPS), as well as subjective change in sense of smell, number of sinus surgeries prior to and during treatment, comorbidities, discontinuation or change of monoclonal antibody and adverse events were evaluated. Thirty-three patients were included in this study. The mean SNOT-22 score and NPS improved significantly. The subjective assessment of sense of smell showed an improvement in 81.8% of patients. The monoclonal antibody had to be changed in seven patients. No severe adverse events occurred during the initiation of the treatment and follow-up. Biologics can be a treatment option in patients with severe refractory CRSwNP, showing significant improvements in quality of life, symptoms and polyp scores in randomized controlled trials and clinical routine with rare complications. Further research is needed to evaluate possible biomarkers, interdose interval prolongation and long-term safety.

Evaluation of Improvement in Chronic Rhinosinusitis After Endoscopic Sinus Surgery Using Sino-Nasal Outcome Test-22 (SNOT22) Symptom Score.

Sino-Nasal Outcome Test (SNOT-22) symptom score is the most widely used questionnaire due to its easy interpretation with respect to quality of life (QOL) in patients with chronic rhinosinusitis (CRS). It helps in deciding further treatment plan in patients with refractory CRS despite maximal medical therapy (MMT). Endoscopic sinus surgery (ESS) is suggested in patients not responding to medical treatment. The preoperative and post-operative QOL for patients with CRS is assessed using SNOT-22. To assess SNOT-22 score change in CRS resistant to MMT. This is a longitudinal study conducted from April 2021-September 2022 included patients diagnosed to have CRS, satisfying the inclusion criteria. SNOT-22 for symptom severity assessed at the first visit, 1week and 12weeks and after MMT. Patients who failed MMT, posted for ESS. Post-operatively SNOT-22 symptom score re-assessed at 15days, 1month, 2months and 3months. 56 patients (male-51% and female-49%) who failed to respond to MMT included in the study. The five major troublesome symptoms nasal blockage (92.86%), need to blow nose (75%), facial pressure/pain (53.57%), post nasal discharge (51.79%), and sneezing (42.86%). The mean SNOT-22 symptom score when compared with pre-operatively (69.54 ± 8.973) and after FESS (2.09 ± 1.881) had improved significantly (p < 0.001). CRS is more frequently seen in males aged between 21 and 30years. The patient-based outcome measures, like SNOT-22 helps to foresee the extent of post- operative improvement. The effective management of CRS is by surgical intervention.

Assessing chronic rhinosinusitis with nasal polyps severity by “Japanese epidemiological survey of refractory eosinophilic chronic rhinosinusitis” algorithm

Aim: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a complex disease with different subtypes that affect patients’ quality of life. This study aim to evaluate the severity of CRSwNP and the risk of treatment resistance using the “Japanese epidemiological survey of refractory eosinophilic chronic rhinosinusitis” (JESREC) algorithm in outpatients at a university hospital. Methods: A retrospective study was conducted reviewing the medical records of CRSwNP outpatients. Clinical data including age, sex, blood eosinophilia, computered tomography (CT) scans, presence of asthma, and nonsteroidal anti-inflammatory drug (NSAID) use were assessed. Results: Medical records of 83 patients diagnosed with CRSwNP were analyzed, with 44 (53%) females and 39 (47%) males. The mean age was 61.8 years ± 14.1 years (range: 19–90 years). According to the JESREC algorithm, 9 (10.8%) patients were categorized as non-eosinophilic chronic rhinosinusitis (neCRS), and 74 (89%) were classified as eosinophilic chronic rhinosinusitis (eCRS). Among the eCRS patients, 13 (17.6%) were mild, 32 (43.2%) were moderate, and 29 (39.2%) were severe. Asthma was identified as a comorbidity in 57 patients (68.6%). Conclusions: A predominance of eCRS with moderate to severe risk of treatment resistance was confirmed. Considering the heterogeneity of chronic rhinosinusitis (CRS), the JESREC algorithm comes up as an instrument that uses objective criteria to assess higher risks of recurrency and refractoriness among patients before surgical treatment, helping to predict type2-driven biologics need.

Biological therapy in the inflammatory disorders of the upper airway: the endotype-driven treatment of chronic rhinosinusitis

Patients with difficult-to-treat chronic bilateral rhinosinusitis with nasal polyps - a type 2 inflammatory endotype - who are resistant to conventional medical and surgical therapy exhibit prolonged and not controlled symptoms. Quality of life, daily activities and sleeping are severely affected. Symptomatic, etiopathologic, surgical and general antiinflammatory (systemic steroid) therapeutic options of the past decades have not been sufficient enough in the treatment of refractory chronic rhinosinusitis. The new therapy with humanized monoclonal antibodies directed against the most relevant mediators and effector cells resulted in outstanding impovements in this field. Other type 2 manifestations may also be effectively treated at the same time, which improves the quality of life and is considered cost-effective as well. The author summarizes the actual etiopathogenic and clinical implications, the approved and available biologics, the related evidences and the preliminary clinical experiences. Orv Hetil. 2023; 164(18): 694-701.

Eosinophilic granulomatosis with polyangiitis developed after dupilumab administration in patients with eosinophilic chronic rhinosinusitis and asthma: a case report

BackgroundEosinophilic granulomatosis with polyangiitis (EGPA) is a form of anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis characterized by eosinophil-rich granulomatous inflammation and small-to-medium vessel vasculitis associated with asthma, rhinosinusitis, and eosinophilia. EGPA is often difficult to distinguish from severe asthma and eosinophilic chronic rhinosinusitis (ECRS) in cases when there are no findings that suggest vasculitis. Dupilumab, an anti-IL-4Rα monoclonal antibody, is expected to be effective in eosinophilic airway inflammatory diseases, such as refractory asthma and chronic rhinosinusitis (CRS). Although transient eosinophilia and eosinophilic pneumoniae have been reported in patients with refractory asthma and CRS associated with dupilumab, few studies have examined the development of EGPA.Case presentationWe report a case of a 61-year-old woman treated with dupilumab for refractory ECRS and eosinophilic otitis media (EOM) complicated by severe asthma. Although she had a previous history of eosinophilic pneumoniae and myeloperoxidase (MPO) ANCA positivity, there were no apparent findings of vasculitis before the initiation of dupilumab. After the second administration of dupilumab, several adverse events developed, including worsening of ECRS, EOM and asthma, and neuropathy. A blood test showed an eosoinophilia and re-elevation of MPO-ANCA levels after the administration of dupilumab. Therefore, dupilumab was discontinued owing to the development of EGPA, and prednisolone and azathioprine administration was initiated for a remission induction therapy.ConclusionTo the best of our knowledge, this is the first case report that suggests that dupilumab may directly trigger the manifestation of vasculitis in patients who were previously MPO-ANCA-positive. Although the precise mechanism of how dupilumab could trigger the development of EGPA requires further elucidation, measuring MPO-ANCA in patients with multiple eosinophilic disorders before the initiation of dupilumab might be helpful when considering the possibility of a latent EGPA. When administering dupilumab to patients with a previous history of MPO-ANCA positivity, clinicians must carefully monitor and collaborate with other specialists in the pertinent fields of study for appropriate usage.

Calprotectin in chronic rhinosinusitis eosinophil extracellular traps.

Calprotectin is an antimicrobial peptide primarily secreted by neutrophils. Furthermore, calprotectin secretion increases in patients with chronic rhinosinusitis (CRS) with polyps (CRSwNP) and positively correlates with neutrophil markers. However, CRSwNP is known to be associated with type 2 inflammation related to tissue eosinophilia. Therefore, the authors investigated calprotectin expression in eosinophils and eosinophil extracellular traps (EETs) and explored the associations between tissue calprotectin and the clinical findings of patients with CRS. A total of 63 patients participated, and patients diagnosed with CRS were classified based on the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC) score. The authors performed hematoxylin and eosin staining, immunohistochemistry, immunofluorescence with calprotectin, myeloperoxidase (MPO), major basic protein (MBP), and citrullinated histone H3 with the participant's tissues. Finally, correlations between calprotectin and the clinical data were examined. Calprotectin-positive cells are co-localized not only in MPO-positive cells but also in MBP-positive cells in human tissues. Calprotectin was also involved in EETs and neutrophil extracellular traps. The number of calprotectin-positive cells in the tissue was positively correlated with the number of tissue and blood eosinophils. In addition, calprotectin in the tissue is associated with the olfactory function, Lund-Mackay computed tomography score, and JESREC score. Calprotectin, known to be secreted by neutrophils, in CRS was also expressed in eosinophils. In addition, calprotectin, which functions as an antimicrobial peptide, may play an important role in the innate immune response based on its EET involvement. Therefore, calprotectin expression could reflect as a disease severity biomarker for CRS.

Response to intranasal Lactococcus lactis W136 probiotic supplementation in refractory CRS is associated with modulation of non-type 2 inflammation and epithelial regeneration.

We have previously documented that in individuals with chronic rhinosinusitis (CRS) refractory to surgery, intranasal application of live Lactococcus lactis W136, a probiotic bacterium, improves sinus-specific symptoms, SNOT-22, and mucosal aspect on endoscopy, accompanied by a reduction in sinus pathogens and an increase in protective bacteria. The present work explores the molecular mechanisms underpinning these observations using transcriptomics of the sinus mucosa. Epithelial brushings collected prospectively as a sub-study of the L. lactis W136 clinical trial were used to probe epithelial responses to microbiome supplementation using a hypothesis-free bioinformatic analysis of gene expression analysis. Samples from twenty-four patients with CRS refractory to medical and surgical management were prospectively collected during a clinical trial assessing the effect of 14 days of BID nasal irrigation with 1.2 billion CFU of live L. lactis W136 probiotic bacteria (CRSwNP = 17, CRSsNP = 7). Endoscopically guided sinus brushings were collected as part of the initial study, with brushings performed immediately before and after treatment. Following RNA extraction, samples were assessed using the Illumina HumanHT-12 V4 BeadChip. Differential gene expression was calculated, and pathway enrichment analysis was performed to identify potentially implicated processes. Differentially identified transcripts and pathways were assessed for the overall population and the clinical phenotypes of CRSwNP and CRSsNP. Patterns of response to treatment were similar across all groups, implicating pathways for the regulation of immunity and epithelial cell regulation. These resemble the patterns of improvement observed following successful treatment with endoscopic sinus surgery or azithromycin. Gene expression profiling following the application of live bacteria to the diseased sinus epithelium highlights the implication of multiple components of the inflammation-microbiome-epithelial barrier axis implicated in CRS. These effects appear to involve both epithelial restoration and modulation of innate and adaptive immunity, supporting the potential interest of targeting the sinus epithelium and the microbiome as potential CRS therapies.