TCF1-LEF1 co-expression identifies a multipotent progenitor cell (TH2-MPP) across human allergic diseases.

Repetitive exposure to antigen in chronic infection and cancer drives T cell exhaustion, limiting adaptive immunity. In contrast, aberrant, sustained T cell responses can persist over decades in human allergic disease. To understand these divergent outcomes, we employed bioinformatic, immunophenotyping and functional approaches with human diseased tissues, identifying an abundant population of type 2 helper T (TH2) cells with co-expression of TCF7 and LEF1, and features of chronic activation. These cells, which we termed TH2-multipotent progenitors (TH2-MPP) could self-renew and differentiate into cytokine-producing effector cells, regulatory T (Treg) cells and follicular helper T (TFH) cells. Single-cell T-cell-receptor lineage tracing confirmed lineage relationships between TH2-MPP, TH2 effectors, Treg cells and TFH cells. TH2-MPP persisted despite in vivo IL-4 receptor blockade, while thymic stromal lymphopoietin (TSLP) drove selective expansion of progenitor cells and rendered them insensitive to glucocorticoid-induced apoptosis in vitro. Together, our data identify TH2-MPP as an aberrant T cell population with the potential to sustain type 2 inflammation and support the paradigm that chronic T cell responses can be coordinated over time by progenitor cells.

Nasal polyp antibody-secreting cells display proliferation signature in aspirin-exacerbated respiratory disease.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) causes nasal obstruction and olfactory dysfunction. Aspirin-exacerbated respiratory disease (AERD) is the triad of CRSwNP, asthma, and respiratory reactions to COX-1 inhibitors. Patients with AERD have elevated nasal IL-5 levels and high numbers of antibody-secreting cells (ASCs), including plasma cells and plasmablasts, in their polyp tissue; in addition, their nasal polyp (NP) IgE levels are correlated with disease severity and recurrence of nasal polyposis. OBJECTIVE: We sought to explore differences in the transcriptomic profile, activation markers, and IL-5Rα expression and function of NP ASCs from patients with AERD and CRSwNP. METHODS: NP tissue was collected from patients with AERD and CRSwNP and digested into single-cell suspensions. NP cells were analyzed for protein expression by mass cytometry. For IL-5Rα functional studies, plasma cells were purified and cultured in vitro with or without IL-5 and analyzed by bulk RNA sequencing. RESULTS: Compared with polyp tissue from patients with CRSwNP, polyp tissue from patients with AERD contained significantly more ASCs and had increased ASC expression of IL-5Rα. ASCs from patients with AERD expressed higher protein levels of B-cell activation and regulatory markers (CD40, CD19, CD32, and CD38) and the proliferation marker Ki-67. ASCs from patients with AERD also expressed more IL5RA, IGHE, and cell cycle- and proliferation-related transcripts (CCND2, MKI67, CDC25A, and CDC25B) than did ASCs from patients with CRSwNP. Stimulation of plasma cells from patients with AERD with IL-5 induced key cell cycle genes (CCND2 and PTP4A3), whereas IL-5 stimulation of ASCs from patients with CRSwNP induced few transcriptomic changes. CONCLUSION: NP tissue ASCs from patients with AERD express higher levels of functional IL-5Rα and markers associated with cell cycling and proliferation than do ASCs from patients with aspirin-tolerant CRSwNP.

Allergic inflammatory memory in human respiratory epithelial progenitor cells.

Barrier tissue dysfunction is a fundamental feature of chronic human inflammatory diseases1. Specialized subsets of epithelial cells-including secretory and ciliated cells-differentiate from basal stem cells to collectively protect the upper airway2-4. Allergic inflammation can develop from persistent activation5 of type 2 immunity6 in the upper airway, resulting in chronic rhinosinusitis, which ranges in severity from rhinitis to severe nasal polyps7. Basal cell hyperplasia is a hallmark of severe disease7-9, but it is not known how these progenitor cells2,10,11 contribute to clinical presentation and barrier tissue dysfunction in humans. Here we profile primary human surgical chronic rhinosinusitis samples (18,036 cells, n = 12) that span the disease spectrum using Seq-Well for massively parallel single-cell RNA sequencing12, report transcriptomes for human respiratory epithelial, immune and stromal cell types and subsets from a type 2 inflammatory disease, and map key mediators. By comparison with nasal scrapings (18,704 cells, n = 9), we define signatures of core, healthy, inflamed and polyp secretory cells. We reveal marked differences between the epithelial compartments of the non-polyp and polyp cellular ecosystems, identifying and validating a global reduction in cellular diversity of polyps characterized by basal cell hyperplasia, concomitant decreases in glandular cells, and phenotypic shifts in secretory cell antimicrobial expression. We detect an aberrant basal progenitor differentiation trajectory in polyps, and propose cell-intrinsic13, epigenetic14,15 and extrinsic factors11,16,17 that lock polyp basal cells into this uncommitted state. Finally, we functionally demonstrate that ex vivo cultured basal cells retain intrinsic memory of IL-4/IL-13 exposure, and test the potential for clinical blockade of the IL-4 receptor α-subunit to modify basal and secretory cell states in vivo. Overall, we find that reduced epithelial diversity stemming from functional shifts in basal cells is a key characteristic of type 2 immune-mediated barrier tissue dysfunction. Our results demonstrate that epithelial stem cells may contribute to the persistence of human disease by serving as repositories for allergic memories.

Biologics versus endoscopic sinus surgery: Acute rhinosinusitis episodes and antibiotic use in chronic rhinosinusitis.

BACKGROUND: We sought to determine if chronic rhinosinusitis patients treated with endoscopic sinus surgery have fewer episodes of acute rhinosinusitis (ARS) post treatment compared to CRS patients treated with biologics alone. METHODS: We analyzed the electronic medical records of 213 adults with CRS who initiated treatment with either dupilumab or mepolizumab in calendar years 2016-2021 (CRS-biologics) group and a matched group with tissue eosinophilia who had undergone endoscopic sinus surgery (CRS-ESS) group. For each cohort, the medical record was reviewed to determine the number of ARS episodes for 12 months before and after treatment. Similarly, the number of antibiotic prescriptions was determined for each cohort in the 12 months after initiation of biologic therapy or ESS. RESULTS: There was no statistically significant difference in ARS episodes before initiation of between the CRS-biologic and CRS-ESS cohorts (0.38 versus 0.44 episodes per year, respectively; p = 0.323). In contrast, after initiation of therapy, the CRS-biologics group had a significantly reduced frequency of acute rhinosinusitis episodes versus the CRS-ESS group (0.11 versus 0.25 episodes per year; p = 0.001). Finally, the utilization of oral antibiotics in the 12 months after among those treated with biologics versus those treated with ESS was not significantly different (0.04 versus 0.08, respectively; p = 0.109). CONCLUSION: For CRS patients, treatment with dupilumab or mepolizumab significantly reduced the number of ARS episodes compared to CRS treated with ESS. Biologics appear to work as well as ESS in the control of ARS episodes after treatment for CRS.

Type 2 inflammation drives an airway basal stem cell program through insulin receptor substrate signaling.

BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a type 2 (T2) inflammatory disease associated with an increased number of airway basal cells (BCs). Recent studies have identified transcriptionally distinct BCs, but the molecular pathways that support or inhibit human BC proliferation and differentiation are largely unknown. OBJECTIVE: We sought to determine the role of T2 cytokines in regulating airway BCs. METHODS: Single-cell and bulk RNA sequencing of sinus and lung airway epithelial cells was analyzed. Human sinus BCs were stimulated with IL-4 and IL-13 in the presence and absence of inhibitors of IL-4R signaling. Confocal analysis of human sinus tissue and murine airway was performed. Murine BC subsets were sorted for RNA sequencing and functional assays. Fate labeling was performed in a murine model of tracheal injury and regeneration. RESULTS: Two subsets of BCs were found in human and murine respiratory mucosa distinguished by the expression of basal cell adhesion molecule (BCAM). BCAM expression identifies airway stem cells among P63+KRT5+NGFR+ BCs. In the sinonasal mucosa, BCAMhi BCs expressing TSLP, IL33, CCL26, and the canonical BC transcription factor TP63 are increased in patients with CRSwNP. In cultured BCs, IL-4/IL-13 increases the expression of BCAM and TP63 through an insulin receptor substrate-dependent signaling pathway that is increased in CRSwNP. CONCLUSIONS: These findings establish BCAM as a marker of airway stem cells among the BC pool and demonstrate that airway epithelial remodeling in T2 inflammation extends beyond goblet cell metaplasia to the support of a BC stem state poised to perpetuate inflammation.

Rethinking the relationships between chronic rhinosinusitis and asthma severity.

BACKGROUND: Previous authors have endorsed the need for prospective studies on the effect of treatment of chronic rhinosinusitis on asthma outcomes. Although common pathophysiology for asthma and chronic rhinosinusitis (CRS) has been suggested with the unified airway theory, there is limited data to support the claim and our study does not support the theory. METHODS: This case-control study involved adult patients with a primary diagnosis of asthma in 2019 who were identified from the electronic medical records and divided into those with and without an associated CRS diagnosis. For each asthma encounter, the asthma severity classification, oral corticosteroid (OCS) use and oxygen saturation scores were tabulated and compared between asthma patients with CRS versus control patients after 1:1 matching on age and sex. We determined the association between asthma and chronic rhinosinusitis when evaluating proxies for disease severity: oral corticosteroid use, average oxygen saturation and minimum oxygen saturation. We identified 1321 clinical encounters for asthma associated with CRS and 1321 control encounters for asthma without CRS. RESULTS: OCS prescription rates at the asthma encounter were not statistically different between the groups (15.3 % and 14.6 %, respectively; p = 0.623). Asthma severity classification was higher in those with CRS versus those without (38.9 % and 25.7 % classified as severe, respectively; p < 0.001). We identified 637 asthma with CRS and 637 matched control patients. There was no significant difference in mean recorded O2 saturations between asthma patients with CRS versus control patients (mean O2 saturations, 97.2 % and 97.3 %, respectively; p = 0.816) nor in minimum oxygen saturation (96.8 % and 97.0 %, respectively; p = 0.115). CONCLUSION: Among patients with a primary diagnosis of asthma an increasing severity of asthma classification was significantly associated with an associated diagnosis of CRS. In contradistinction, the presence of CRS comorbidity in asthma patients was not associated with increased OCS use for asthma. Similarly, average oxygen saturation and minimum oxygen saturation did not seem differ according to CRS comorbidity. Our study does not support the unified airway theory that suggests a causative relationship between the upper and lower airway.

Associations between chronic pain, anxiety, and depression among adults in the United States.

OBJECTIVE: The objective of the study was to determine the associations of depression and anxiety with chronic pain among U.S. adults. SETTING: Nationally representative cross-sectional survey analysis. METHODS: The National Health Interview Survey for 2019 was analyzed with respect to the chronic pain module and embedded depression and anxiety scales (PHQ-8 and GAD-7). Univariate associations between the presence of chronic pain and depression and anxiety scores were determined. Similarly, associations between the presence of chronic pain and the adults' treating with medications for depression and anxiety were also determined. Odds ratios, adjusted for age and sex, were computed for these associations. RESULTS: Among 244.6 million sampled U.S. adults, 50.2 million (95% confidence interval, 48.2-52.2 million) reported chronic pain (20.5%, [19.9%-21.2%] of the population). Adults with chronic pain had elevated severity of depressive symptoms (PHQ-8 categories: none/minimal: 57.6%, mild: 22.3%, moderate: 11.4%, and severe: 8.7%) versus those without chronic pain (87.6%, 8.8%, 2.3%, and 1.2%; p < 0.001). Adults with chronic pain had elevated severity of anxiety symptoms (GAD-7 categories: none/minimal: 66.4%, mild: 17.1%, moderate: 8.5%, severe: 8.0%) versus those without chronic pain (89.0%, 7.5%, 2.1%, and 1.4%; p < 0.001). 22.4% and 24.5% of chronic pain sufferers were taking medication for depression and anxiety versus 6.6% and 8.5% of those without chronic pain, respectively (both p < 0.001). Adjusted odds ratios for the association of chronic pain with increasing severity of depression or anxiety and taking a depression or anxiety medication were 6.32 (5.82-6.85), 5.63 (5.15-6.15), 3.98 (3.63-4.37), and 3.42 (3.12-3.75), respectively. CONCLUSIONS: The presence of chronic pain in adults associated with significantly higher severity scores for both anxiety and depression as measured by validated surveys in a nationally representative sample. The same is true for the association between chronic pain and an adult taking medication for depression and/or anxiety. These data highlight the impact of chronic pain has on psychological well-being within the general population.

IL-5Rα marks nasal polyp IgG4- and IgE-expressing cells in aspirin-exacerbated respiratory disease.

BACKGROUND: The cause of severe nasal polyposis in aspirin-exacerbated respiratory disease (AERD) is unknown. Elevated antibody levels have been associated with disease severity in nasal polyps, but upstream drivers of local antibody production in nasal polyps are undetermined. OBJECTIVE: We sought to identify upstream drivers and phenotypic properties of local antibody-expressing cells in nasal polyps from subjects with AERD. METHODS: Sinus tissue was obtained from subjects with AERD, chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP), CRS without nasal polyps, and controls without CRS. Tissue antibody levels were quantified via ELISA and immunohistochemistry and were correlated with disease severity. Antibody-expressing cells were profiled with single-cell RNA sequencing, flow cytometry, and immunofluorescence, with IL-5Rα function determined through IL-5 stimulation and subsequent RNA sequencing and quantitative PCR. RESULTS: Tissue IgE and IgG4 levels were elevated in AERD compared with in controls (P < .01 for IgE and P < .001 for IgG4 vs CRSwNP). Subjects with AERD whose nasal polyps recurred rapidly had higher IgE levels than did subjects with AERD, with slower regrowth (P = .005). Single-cell RNA sequencing revealed increased IL5RA, IGHG4, and IGHE in antibody-expressing cells from patients with AERD compared with antibody-expressing cells from patients with CRSwNP. There were more IL-5Rα+ plasma cells in the polyp tissue from those with AERD than in polyp tissue from those with CRSwNP (P = .026). IL-5 stimulation of plasma cells in vitro induced changes in a distinct set of transcripts. CONCLUSIONS: Our study identifies an increase in antibody-expressing cells in AERD defined by transcript enrichment of IL5RA and IGHG4 or IGHE, with confirmed surface expression of IL-5Rα and functional IL-5 signaling. Tissue IgE and IgG4 levels are elevated in AERD, and higher IgE levels are associated with faster nasal polyp regrowth. Our findings suggest a role for IL-5Rα+ antibody-expressing cells in facilitating local antibody production and severe nasal polyps in AERD.

Thymic stromal lymphopoietin controls prostaglandin D2 generation in patients with aspirin-exacerbated respiratory disease.

BACKGROUND: Prostaglandin (PG) D2 is the dominant COX product of mast cells and is an effector of aspirin-induced respiratory reactions in patients with aspirin-exacerbated respiratory disease (AERD). OBJECTIVE: We evaluated the role of the innate cytokine thymic stromal lymphopoietin (TSLP) acting on mast cells to generate PGD2 and facilitate tissue eosinophilia and nasal polyposis in patients with AERD. METHODS: Urinary eicosanoid levels were measured in aspirin-tolerant control subjects and patients with AERD. Nasal polyp specimens from patients with AERD and chronic rhinosinusitis were analyzed by using quantitative PCR, Western blotting, and immunohistochemistry. Human cord blood-and peripheral blood-derived mast cells were stimulated with TSLP in vitro to assess PGD2 generation. RESULTS: Urinary levels of a stable PGD2 metabolite (uPGD-M) were 2-fold higher in patients with AERD relative to those in control subjects and increased further during aspirin-induced reactions. Peak uPGD-M levels during aspirin reactions correlated with reductions in blood eosinophil counts and lung function and increases in nasal congestion. Mast cells sorted from nasal polyps expressed PGD2 synthase (hematopoietic PGD2 synthase) mRNA at higher levels than did eosinophils from the same tissue. Whole nasal polyp TSLP mRNA expression correlated strongly with mRNA encoding hematopoietic PGD2 synthase (r = .75), the mast cell-specific marker carboxypeptidase A3 (r = .74), and uPGD-M (r = 0.74). Levels of the cleaved active form of TSLP were increased in nasal polyps from patients with AERD relative to those in aspirin-tolerant control subjects. Recombinant TSLP induced PGD2 generation by cultured human mast cells. CONCLUSIONS: Our study demonstrates that mast cell-derived PGD2 is a major effector of type 2 immune responses driven by TSLP and suggests that dysregulation of this innate system contributes significantly to the pathophysiology of AERD.

Impaired E Prostanoid2 Expression and Resistance to Prostaglandin E2 in Nasal Polyp Fibroblasts from Subjects with Aspirin-Exacerbated Respiratory Disease.

Recurrent, rapidly growing nasal polyps are hallmarks of aspirin-exacerbated respiratory disease (AERD), although the mechanisms of polyp growth have not been identified. Fibroblasts are intimately involved in tissue remodeling, and the growth of fibroblasts is suppressed by prostaglandin E2 (PGE2), which elicits antiproliferative effects mediated through the E prostanoid (EP)2 receptor. We now report that cultured fibroblasts from the nasal polyps of subjects with AERD resist this antiproliferative effect. Fibroblasts from polyps of subjects with AERD resisted the antiproliferative actions of PGE2 and a selective EP2 agonist (P < 0.0001 at 1 µM) compared with nasal fibroblasts from aspirin-tolerant control subjects undergoing polypectomy or from healthy control subjects undergoing concha bullosa resections. Cell surface expression of the EP2 receptor protein was lower in fibroblasts from subjects with AERD than in fibroblasts from healthy control subjects and aspirin-tolerant subjects (P < 0.01 for both). Treatment of the fibroblasts with trichostatin A, a histone deacetylase inhibitor, significantly increased EP2 receptor mRNA in fibroblasts from AERD and aspirin-tolerant subjects but had no effect on cyclooxygenase-2, EP4, and microsomal PGE synthase 1 (mPGES-1) mRNA levels. Histone acetylation (H3K27ac) at the EP2 promoter correlated strongly with baseline EP2 mRNA (r = 0.80; P < 0.01). These studies suggest that the EP2 promotor is under epigenetic control, and one explanation for PGE2 resistance in AERD is an epigenetically mediated reduction of EP2 receptor expression, which could contribute to the refractory nasal polyposis typically observed in this syndrome.

Healthcare disparities in revisits for complications after adult tonsillectomy.

OBJECTIVE: Determine if disparities exist for revisit complications after adult tonsillectomy. METHODS: Cases of adult tonsillectomy were extracted from the state ambulatory surgery databases and linked to the state emergency department databases and inpatient databases for California, Iowa, Florida and New York for 2010 and 2011. Revisits within 14days for diagnoses of: post-tonsillectomy bleeding, acute pain and nausea/vomiting/dehydration were determined and analyzed for associations of these complications with age, sex, race, median household income and comorbidity score. RESULTS: Among 17,836 tonsillectomies (63.7% female; mean age, 29.0years), revisit rates for post-tonsillectomy bleeding, acute pain and fever/dehydration were 5.1, 2.8 and 1.5%, respectively. On multivariate analysis, only female sex was associated with a lower post-tonsillectomy bleeding rate (odds, 0.48, p<0.001). Decreasing household income, female sex, black and Hispanic race were associated with increased revisits for acute pain (odds, 1.21, 1.49, 2.03 and 1.32, p≤0.002). Female sex was associated with an increased odds of a revisit for FNVD (odds, 1.94, p<0.001). CONCLUSIONS: Significant disparities with respect to income and race exist in the incidence of revisits and potentially avoidable complications after adult tonsillectomy.

Cysteinyl leukotriene overproduction in aspirin-exacerbated respiratory disease is driven by platelet-adherent leukocytes.

Cysteinyl leukotriene (cysLT) overproduction is a hallmark of aspirin-exacerbated respiratory disease (AERD), but its mechanism is poorly understood. Because adherent platelets can convert the leukocyte-derived precursor leukotriene (LT)A(4) to LTC(4), the parent cysLT, through the terminal enzyme LTC(4) synthase, we investigated the contribution of platelet-dependent transcellular cysLT production in AERD. Nasal polyps from subjects with AERD contained many extravascular platelets that colocalized with leukocytes, and the percentages of circulating neutrophils, eosinophils, and monocytes with adherent platelets were markedly higher in the blood of subjects with AERD than in aspirin-tolerant controls. Platelet-adherent subsets of leukocytes had higher expression of several adhesion markers than did platelet nonadherent subsets. Adherent platelets contributed more than half of the total LTC(4) synthase activity of peripheral blood granulocytes, and they accounted for the higher level of LTC(4) generation by activated granulocytes from subjects with AERD compared with aspirin-tolerant controls. Urinary LTE(4) levels, a measure of systemic cysLT production, correlated strongly with percentages of circulating platelet-adherent granulocytes. Because platelet adherence to leukocytes allows for both firm adhesion to endothelial cells and augmented transcellular conversion of leukotrienes, a disturbance in platelet-leukocyte interactions may be partly responsible for the respiratory tissue inflammation and the overproduction of cysLTs that characterize AERD.

Regional variation and factors associated with image guidance utilization during endoscopic sinus surgery in the ambulatory setting.

OBJECTIVE: Determine regional variation and factors associated with the use of image guidance (IG) during endoscopic sinus surgery (ESS) in the ambulatory surgery center setting. METHODS: All cases of ESS in 2010 were extracted from the state ambulatory surgery databases for New York, North Carolina, Florida, Iowa, and California. Current Procedural Terminology codes for individual sinusotomies and IG and International Classification of Diseases codes along with insurance and regional data were analyzed to determine factors that were associated with the use of IG during ESS. RESULTS: Among 36 646 ambulatory ESS procedures (mean age 46.0 years; 49.0% female), 6676 cases utilized IG (18.2%). Polyps were present in 27.9% of cases. North Carolina had the highest utilization rate for IG (26.0%), whereas Iowa had the lowest (12.8%). On multivariate analysis, use of IG was associated with state, insurance status, community setting, total ethmoidectomy, frontal sinusotomy, sphenoidotomy, and polyps (all P < .001), but not maxillary antrostomy (P = .197). The highest procedural odds ratio for IG use was noted for total ethmoidectomy (2.07), followed by frontal sinusotomy (1.97) and sphenoidotomy (1.26). CONCLUSION: Although IG is utilized in a relative minority of ESS cases, there is considerable regional variation in use. Factors other than complexity of surgery influence IG utilization as well.

Evolving Utilization of Topical Budesonide Following Endoscopic Sinus Surgery.

Topical budesonide irrigations are frequently prescribed after endoscopic sinus surgery (ESS) to manage mucosal inflammation. However, this off-label indication may conflict with health insurance formularies. We sought to quantify the relative frequency of postoperative budesonide prescriptions to determine if this could be considered common practice after ESS. We extracted and analyzed postoperative prescription data for patients undergoing ESS from 2016 to 2022 within our health care system. Overall, among 8157 ESS patients, 15.9% and 22.1% received topical budesonide prescriptions within 30 or 180 days postoperatively, respectively. On a year-over-year basis, budesonide prescription frequency increased significantly over time, culminating at 20.3% and 24.9% in 2022. Conversely, postoperative oral corticosteroid (OCS) prescriptions showed a decreasing frequency over the same time period (P < .001). Our results show topical budesonide irrigations are increasingly frequently prescribed after ESS and may offset postoperative OCS requirements. This argues for coverage of topical budesonide as a formulary medication after ESS.

Real-world effectiveness of mepolizumab in severe asthma and chronic rhinosinusitis in the United States: Impact of comorbidity and sinus surgery.

BACKGROUND: Trial data demonstrate that mepolizumab, a humanized anti-interleukin 5 monoclonal antibody, is effective for patients with severe asthma and comorbid chronic rhinosinusitis (CRS) with nasal polyps. This real-world, retrospective cohort study investigated mepolizumab for US patients with severe asthma and CRS with/without sinus surgery. METHODS: IQVIA PharMetrics Plus claims data from baseline and follow-up (12 months before and after mepolizumab initiation) were used to analyze three patient cohorts: cohort 1 (severe asthma only); cohort 2 (severe asthma + comorbid CRS without sinus surgery); and cohort 3 (severe asthma+comorbid CRS+sinus surgery), allowing for cross-cohort comparisons. RESULTS: The analysis included 495, 370, and 85 patients in cohort 1, cohort 2, and cohort 3, respectively. Systemic and oral corticosteroid use was lower for all cohorts after mepolizumab initiation. In cohort 3, asthma rescue inhaler and antibiotic use were lower during follow-up than baseline. Asthma exacerbations were reduced by 28% to 44% comparing follow-up versus baseline, with the largest reduction in cohort 3 (ratio of incidence rate ratio [RR] vs cohort 1: 0.76; p = 0.036). Reductions in oral corticosteroid claims were greater following mepolizumab initiation for cohort 3 versus cohort 1 (RR, 0.72; p = 0.011) and cohort 2 (RR, 0.70; p < 0.01). In cohorts 1 through 3, outpatient and emergency department visits were reduced by 1 to 2 and 0.4 to 0.6 visits annually, asthma-related and asthma exacerbation-related total costs were reduced by $387 to $2580 USD, and medical costs were reduced by $383 to $2438 USD during follow-up. CONCLUSIONS: Consistent with trial data, mepolizumab use in real-world practice shows benefits across comorbid patient cohorts with more a pronounced impact in those with severe asthma+comorbid CRS + sinus surgery.

Allergic rhinitis and keratoconus: a systematic review and meta-analysis.

BACKGROUND: The relationship between keratoconus and various allergic diseases has been a subject of controversy. OBJECTIVE: In the present study, a systematic review and meta-analysis was conducted to investigate the association between allergic rhinitis (AR) and keratoconus. METHODS: Relevant and eligible studies from PubMed, Web of Science, and Cochrane Library were systematically reviewed to evaluate the association between AR and keratoconus. Observational studies containing the number of patients with and without keratoconus and the number of patients with keratoconus diagnosed with or without AR were included. Two reviewers independently screened for eligible studies and extracted data from the included studies. A bivariate meta-analysis was conducted to compare the odds of keratoconus occurrence in patients with and without AR. The main outcome was the odds ratio of keratoconus occurrence in patients with AR. A sensitivity test was performed using the adjusted odds ratio reported in the included studies to validate the findings. RESULTS: Seven studies involving 775,574 participants were included in this meta-analysis. Among them, 29,082 patients had keratoconus. The pooled odds ratio of keratoconus occurrence in patients with AR was 1.71 (95% confidence interval [CI]: 1.36-2.15; P < 0.001; I2 = 96%), and the pooled adjusted odds ratio was 1.72 (95% CI: 1.23-2.40; P = 0.001; I2 = 97%). CONCLUSION: Patients with AR showed significantly higher odds of keratoconus occurrence than those without AR. Future studies are warranted to investigate the causal relationship and evaluate the cost-effectiveness of early screening using methods such as corneal topography and referral for keratoconus in patients with AR.

Increasing Prevalence of Voice Disorders in the USA: Updates in the COVID Era.

OBJECTIVE: To estimate the current prevalence of voice disorders among adults in the United States; to determine the association of individual factors with voice disorders. METHODS: The 2022 National Health Interview Survey (NHIS) was analyzed to identify adults reporting voice problems in the past 12 months. Demographics were assessed, as well as the duration, severity, and resolution of the voice problem. The relationship between voice problems, gender, lost workdays, and long COVID was investigated. A comparison to the 2012 NHIS was made to determine changes in voice disorder prevalence. RESULTS: 29.9 million Americans (95%CI[28.3-31.5]) annually report a voice problem, representing 12.2% of the population (95%CI[11.7-12.8%]). Overall, 26.8% and 13.2% reported the severity of their voice problem as moderate or severe, respectively. Only 5.1% (95%CI[4.3-6.0%]) of respondents sought treatment. Most voice problems were resolved within 1 week (53.0%,95%CI[50.9-55.1%]). Females were more likely than males to report a voice problem (14.4% vs. 10.0%,95%CI[13.7-15.1] and [9.3-10.7], respectively). The 17.6 million Americans with long COVID symptoms were more likely to have voice complaints than those without (21.1% vs. 11.6%,95%CI[18.9-23.5%] and [11.1-12.1%], respectively). Lost workdays were not significantly higher for those with voice disorders compared to those without (17.1 vs. 12.9 days,95%CI[12.0-22.1] and [11.0-14.8], respectively). CONCLUSIONS: Voice problems affect approximately 1 in 8 adults in the U.S. annually, demonstrating an alarming increased prevalence since 2012 using the same survey methodology. Relatively few individuals seek care for their voice problem, despite significant self-reported impact. Further study is required regarding the impact of COVID and changes in voice use patterns on voice disorders. LEVEL OF EVIDENCE: 3 Laryngoscope, 2024.

Diagnostic Yield of Patients Undergoing Evaluation of Possible Superior Canal Dehiscence.

OBJECTIVE: To characterize the diagnostic yield of patients undergoing evaluation for superior canal dehiscence syndrome (SCDS), and identify alternative conditions diagnosed in patients suspected of, but not ultimately diagnosed with, SCDS. METHODS: Diagnostically undifferentiated adult patients suspected of having SCDS were identified between 2016 and 2021 at a tertiary academic medical system. Patients were categorized by diagnostic testing, radiographic superior semicircular canal (SSC) abnormality, symptoms, evaluating clinician specialty, operative intervention, and diagnosis. Differences among groups were assessed for statistical significance. RESULTS: Of 1242 candidate patients, 477 met inclusion criteria-evaluation by a clinician with SCDS on their differential diagnosis prior to diagnostic imaging. The mean (SD) age was 53.0 (15.0) years and 70.6% were female. A total of 364 patients underwent subsequent diagnostic imaging, and among these, 164 (45.1%) had a radiographic SSC abnormality with 99 (27.2%) receiving a diagnosis of SCDS (two cases of "near dehiscence syndrome"). One third (33.3%) of patients with SCDS underwent operative repair. Most clinicians with the initial suspicion for SCDS were otolaryngologists (90.6%), who had greater diagnostic yield than clinicians from other specialties (22.2% vs. 6.7%, p = 0.012). Patients not diagnosed with SCDS alternatively received 21 unique diagnoses and 52.1% (138/265) were not definitively diagnosed with any condition. CONCLUSIONS: This study characterizes the diagnostic incidence, or yield, of newly identified radiographic SSC abnormalities (45.1%) and SCDS (27.2%) among people suspected of having SCDS. Considerable overlap in presentation between SCDS and other conditions exists, and there is need for improvement in efficiently diagnosing patients with SCDS and audio-vestibular complaints in general. LEVEL OF EVIDENCE: III Laryngoscope, 2024.