Clinical studies in COVID-related olfactory disorders: Review of an institutional experience.

Objective: To share a single institutional experience with clinical research on COVID-related olfactory dysfunction (OD). Data Source/Method: Narrative review of published original data and ongoing clinical trials on COVID-related OD at Washington University from 2020 to 2023. Results: There were three new diagnostic-/patient-reported outcome measures developed and tested. We report five clinical trials of interventions for COVID-related olfactory disorders: combined Visual-Olfactory Training (VOLT) with patient-preferred scents versus standard olfactory training (VOLT trial), oral gabapentin versus placebo (Gabapentin for the Relief of Acquired Chemosensory Experience trial), nasal theophylline irrigations versus placebo (Smell Changes and Efficacy of Nasal Theophylline trial), stellate ganglion block (single-arm), and mindfulness-based stress reduction (MBSR) versus lifestyle intervention (MBSR trial). Conclusions: Initial intervention trials for COVID-related OD have shown potential for improving subjective and objective olfactory outcomes. However, there remains no gold standard treatment that definitively outperforms placebo in controlled trials. Therefore, continued investigation of novel therapeutic strategies for COVID-related OD is necessary to maximize olfactory outcomes for affected patients.

Tracheostomy Incidence and Complications: A National Database Analysis.

OBJECTIVE: To describe the incidence of tracheostomy-related complications and identify prognostic risk factors. STUDY DESIGN: Administrative database analysis. SETTING: Outpatient and inpatient insurance claims records obtained from a national database. METHODS: PearlDiver, a private analytics database of insurance claims from Medicare, Medicaid, and commercial insurance companies, was used to identify patients who underwent tracheostomies and associated complications between January 2010 and October 2021 by CPT and ICD-9/ICD-10 codes. RESULTS: A total of 198,143 tracheostomies were identified from PearlDiver, and at least 1 tracheostomy-related complication occurred within 90 days of the procedure in 22,802 (10.3%) of these cases. The proportion of tracheostomy-related complications was 2.3 times higher in 2019 compared to 2010 (95% confidence interval [CI]: 2.18-2.52). The risk of developing tracheostomy-complications was associated with the hospital region (highest in the Midwest as compared to the West [odds ratio [OR] = 1.32; 95% CI: 1.25-1.39]), provider specialty (highest for otolaryngologists as compared to nonsurgical physicians [OR = 2.22; 95% CI: 2.10-2.34]), insurance plan type (lowest for cash payment compared to Medicaid [OR = 0.70, 95% CI: 0.50-0.94]), and Elixhauser Comorbidity Index (ECI) (highest in patients with ECI of 7+ compared to 0-1 [OR = 2.96; 95% CI: 2.17-3.24]), but was not significantly associated with patient age (OR = 0.99; 95% CI: 0.99-0.99), or gender (OR = 1.04; 95% CI: 1.01-1.07). CONCLUSIONS: Complications after tracheostomy are common and sicker patients are at higher risk for complications. Identifying factors associated with increased risk for complications could help to improve patient and family counseling, guide quality improvement initiatives, and inform future studies on tracheostomy outcomes.

Mandibular Advancement vs Combined Airway and Positional Therapy for Snoring: A Randomized Clinical Trial.

Importance: Approximately 150 million individuals in the US snore in the absence of obstructive sleep apnea (primary snoring), but few studies have examined the efficacy of treatments for snoring or evaluated the effect of snoring in sleeping partners. Objective: To evaluate the efficacy of 2 treatments for primary snoring. Design, Setting, and Participants: This pilot randomized clinical trial that included a convenience sample of people who snore without sleep apnea and their sleeping partner who underwent 4 weeks of snoring treatment was conducted at an academic medical center between October 3, 2022, and July 3, 2023. Interventions: Fifty couples were randomized to either use a mandibular advancement device (MAD) or receive combined airway and positional therapy (CAPT; external nasal dilator, nasal saline lavage with mometasone, mouth taping, and lateral positional therapy). Main Outcome and Measure: Percentage of sleeping partners who reported that their partner's snoring was either very much improved or much improved (responder) on the Clinical Global Impression of Improvement scale. Results: A total of 42 dyads completed the study; 23 (55%) were randomized to MAD and 19 (45%) to CAPT. Among people who snore, 26 (62%) were female, and the mean (SD) age was 48 (14) years. Of 23 dyads randomized to MAD, 21 people who snore (91%) were rated by the sleeping partner as a responder, while 11 of the 19 dyads (58%) randomized to CAPT were rated by the sleeping partner as responder, resulting in a difference of 33 percentage points (95% CI, 8-58) and a number needed to treat of 3. Of the 10 participants who were withdrawn, 4 were withdrawn due to adverse effects of the treatment that were evenly distributed between the MAD (n = 2) and CAPT (n = 2) groups. Conclusion and Relevance: The results of this randomized clinical trial showed that the MAD may be more effective than CAPT for treating primary snoring, while both treatment options were found to reduce primary snoring. Physicians should have a patient-centered discussion to determine which treatment is best for individual patients with primary snoring, weighing convenience, adverse effects, and cost as factors. Trial Registration: ClinicalTrials.gov Identifier: NCT05756647.

Individual Patient Comorbidities and Effect on Cochlear Implant Performance.

OBJECTIVE: To examine the association between preoperative comorbidities and cochlear implant speech outcomes. STUDY DESIGN: Retrospective cohort. SETTING: Tertiary referral center. PATIENTS: A total of 976 patients who underwent cochlear implantation (CI) between January 2015 and May 2022. Adult patients with follow-up, preoperative audiologic data, and a standardized anesthesia preoperative note were included. EXPOSURE: Adult Comorbidity Evaluation 27 (ACE-27) based on standardized anesthesia preoperative notes. MAIN OUTCOME MEASURES: Postoperative change in consonant-nucleus-consonant (CNC) score, AzBio Sentence score in quiet, and AzBio + 10 dB signal-to-noise ratio (SNR). Sentence score of the implanted ear at 3, 6, and 12 months. RESULTS: A total of 560 patients met inclusion criteria; 112 patients (20%) had no comorbidity, 204 patients (36.4%) had mild comorbidities, 161 patients (28.8%) had moderate comorbidities, and 83 patients (14.8%) had severe comorbidities. Mixed model analysis revealed all comorbidity groups achieved a clinically meaningful improvement in all speech outcome measures over time. This improvement was significantly different between comorbidity groups over time for AzBio Quiet ( p = 0.045) and AzBio + 10 dB SNR ( p = 0.0096). Patients with severe comorbidities had worse outcomes. From preop to 12 months, the estimated marginal mean difference values (95% confidence interval) between the no comorbidity group and the severe comorbidity group were 52.3 (45.7-58.9) and 32.5 (24.6-40.5), respectively, for AzBio Quiet; 39.5 (33.8-45.2) and 21.2 (13.6-28.7), respectively, for AzBio + 10 dB SNR; and 43.9 (38.7-49.0) and 31.1 (24.8-37.4), respectively, for CNC. CONCLUSIONS: Comorbidities as assessed by ACE-27 are associated with CI performance. Patients with more severe comorbidities have clinically meaningful improvement but have worse outcome compared to patients with no comorbidities.

Preoperative Mobile Health Data Improve Predictions of Recovery From Lumbar Spine Surgery.

BACKGROUND AND OBJECTIVES: Neurosurgeons and hospitals devote tremendous resources to improving recovery from lumbar spine surgery. Current efforts to predict surgical recovery rely on one-time patient report and health record information. However, longitudinal mobile health (mHealth) assessments integrating symptom dynamics from ecological momentary assessment (EMA) and wearable biometric data may capture important influences on recovery. Our objective was to evaluate whether a preoperative mHealth assessment integrating EMA with Fitbit monitoring improved predictions of spine surgery recovery. METHODS: Patients age 21-85 years undergoing lumbar surgery for degenerative disease between 2021 and 2023 were recruited. For up to 3 weeks preoperatively, participants completed EMAs up to 5 times daily asking about momentary pain, disability, depression, and catastrophizing. At the same time, they were passively monitored using Fitbit trackers. Study outcomes were good/excellent recovery on the Quality of Recovery-15 (QOR-15) and a clinically important change in Patient-Reported Outcomes Measurement Information System Pain Interference 1 month postoperatively. After feature engineering, several machine learning prediction models were tested. Prediction performance was measured using the c-statistic. RESULTS: A total of 133 participants were included, with a median (IQR) age of 62 (53, 68) years, and 56% were female. The median (IQR) number of preoperative EMAs completed was 78 (61, 95), and the median (IQR) number of days with usable Fitbit data was 17 (12, 21). 63 patients (48%) achieved a clinically meaningful improvement in Patient-Reported Outcomes Measurement Information System pain interference. Compared with traditional evaluations alone, mHealth evaluations led to a 34% improvement in predictions for pain interference (c = 0.82 vs c = 0.61). 49 patients (40%) had a good or excellent recovery based on the QOR-15. Including preoperative mHealth data led to a 30% improvement in predictions of QOR-15 (c = 0.70 vs c = 0.54). CONCLUSION: Multimodal mHealth evaluations improve predictions of lumbar surgery outcomes. These methods may be useful for informing patient selection and perioperative recovery strategies.

Smoking, Drinking, and Dietary Risk Factors for Head and Neck Cancer in Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Participants.

Importance: There is a paucity of large-scale prospective studies evaluating the risk of developing head and neck cancer (HNC) associated with smoking, drinking, and dietary habits. Objective: To determine the association of smoking, drinking, and dietary habits with the risk of developing HNC. Design, Setting, and Participants: A nested cohort survival analysis of Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial participants was performed. Participants were between 55 and 74 years of age and recruited at 10 centers across the US from November 1993 to July 2001. Participants who developed HNC were matched with controls based on demographics and family history of HNC for analysis of smoking habits; for the analysis of drinking and dietary habits, matching was performed on smoking status and duration in addition to demographics and family history of HNC. Data analysis was performed from January to November 2023. Exposures: Smoking, drinking, and dietary habits. Main Outcome and Measure: Diagnosis of HNC. Results: In total, 139 926 participants (51% female; mean [SD] age, 62.6 [5.4] years) were included in the analysis of smoking habits with a median (IQR) follow-up time of 12.1 (10.3-13.6) years, 571 of whom developed HNC. HNC risk associated with smoking increased the closer the proximity of the head and neck subsite to the lungs, with the greatest risk associated with smoking observed in laryngeal cancer (current smoker hazard ratio [HR], 9.36; 95% CI, 5.78-15.15 compared to a nonsmoker). For analysis of drinking and dietary habits, 94 466 participants were included in the analysis of smoking habits with a median (IQR) follow-up time of 12.2 (10.5-13.6) years, 264 of whom developed HNC. HNC risk increased with heavy drinking (HR, 1.85; 95% CI, 1.44-2.38) and decreased with consumption of whole grains (HR, 0.78; 95% CI, 0.64-0.94/oz per day), whole fruits (HR, 0.90; 95% CI, 0.82-0.98/cup per day), and overall healthy eating, as scored by Healthy Eating Index 2015 (HR, 0.87; 95% CI, 0.78-0.98/10 points). Conclusions and Relevance: In this nested cohort study, the risk of HNC associated with smoking was higher for subsites that were closer to the lungs; heavy drinking was associated with greater HNC risk, while healthy eating was associated with a modest reduction in HNC risk.

Prognostic Factors for Survival Using a Clinical Severity Staging System Among Patients With Acute Invasive Fungal Sinusitis.

Importance: Despite the aggressive progression of fulminant acute invasive fungal sinusitis (AIFS), data on prognostic factors have been disparate, hindering the development of a staging system. A composite staging system may improve prognostication for patient counseling and conduct of clinical research. Objective: To identify prognostically important factors in AIFS and to incorporate the factors into a comprehensive Functional Severity Staging System and Clinical Severity Staging System. Design, Setting, and Participants: This retrospective cohort study included adult patients diagnosed with pathology-proven AIFS from June 1, 1992, to December 31, 2022, at Washington University Medical Center and Barnes-Jewish Hospital, a tertiary care center in St Louis, Missouri. Data were analyzed from April to July 2023. Main Outcome and Measures: Sequential sequestration and conjunctive consolidation was used to develop a composite staging system to predict 6-month overall survival. Results: Of 71 patients with pathology-proven AIFS over the 30-year period, the median (range) age of the cohort was 56 (19-63) years, and there were 47 (66%) male patients. The median (range) follow-up time was 2 (0-251) months. There were 28 patients alive within 6 months, for a 39% survival rate. Symptoms, comorbidity burden, and presence and duration of severe neutropenia were associated with 6-month survival and were consolidated into a 3-category Clinical Severity Staging System with 6-month survival of 75% for stage A (n = 16), 41% for stage B (n = 27), and 18% for stage C (n = 28). The discriminative power of the composite staging system was moderate (C statistic, 0.63). Conclusion and Relevance: This cohort study supports the clinical importance of symptomatology, comorbidity burden, and prolonged severe neutropenia at the time of AIFS presentation. The composite clinical staging system may be useful for clinicians when counseling patients with AIFS and conducting clinical research.

Implications of Preoperative Depression for Lumbar Spine Surgery Outcomes: A Systematic Review and Meta-Analysis.

Importance: Comorbid depression is common among patients with degenerative lumbar spine disease. Although a well-researched topic, the evidence of the role of depression in spine surgery outcomes remains inconclusive. Objective: To investigate the association between preoperative depression and patient-reported outcome measures (PROMs) after lumbar spine surgery. Data Sources: A systematic search of PubMed, Cochrane Database of Systematic Reviews, Embase, Scopus, PsychInfo, Web of Science, and ClinicalTrials.gov was performed from database inception to September 14, 2023. Study Selection: Included studies involved adults undergoing lumbar spine surgery and compared PROMs in patients with vs those without depression. Studies evaluating the correlation between preoperative depression and disease severity were also included. Data Extraction and Synthesis: All data were independently extracted by 2 authors and independently verified by a third author. Study quality was assessed using Newcastle-Ottawa Scale. Random-effects meta-analysis was used to synthesize data, and I2 was used to assess heterogeneity. Metaregression was performed to identify factors explaining the heterogeneity. Main Outcomes and Measures: The primary outcome was the standardized mean difference (SMD) of change from preoperative baseline to postoperative follow-up in PROMs of disability, pain, and physical function for patients with vs without depression. Secondary outcomes were preoperative and postoperative differences in absolute disease severity for these 2 patient populations. Results: Of the 8459 articles identified, 44 were included in the analysis. These studies involved 21 452 patients with a mean (SD) age of 57 (8) years and included 11 747 females (55%). Among these studies, the median (range) follow-up duration was 12 (6-120) months. The pooled estimates of disability, pain, and physical function showed that patients with depression experienced a greater magnitude of improvement compared with patients without depression, but this difference was not significant (SMD, 0.04 [95% CI, -0.02 to 0.10]; I2 = 75%; P = .21). Nonetheless, patients with depression presented with worse preoperative disease severity in disability, pain, and physical function (SMD, -0.52 [95% CI, -0.62 to -0.41]; I2 = 89%; P < .001), which remained worse postoperatively (SMD, -0.52 [95% CI, -0.75 to -0.28]; I2 = 98%; P < .001). There was no significant correlation between depression severity and the primary outcome. A multivariable metaregression analysis suggested that age, sex (male to female ratio), percentage of comorbidities, and follow-up attrition were significant sources of variance. Conclusions and Relevance: Results of this systematic review and meta-analysis suggested that, although patients with depression had worse disease severity both before and after surgery compared with patients without depression, they had significant potential for recovery in disability, pain, and physical function. Further investigations are needed to examine the association between spine-related disability and depression as well as the role of perioperative mental health treatments.

Identifying Predictors of Treatment Response in Meniere's Disease: A Clinical Severity Staging System.

OBJECTIVE: Identify clinically important factors associated with conservative treatment response in Meniere's disease and incorporate these factors into a composite clinical severity staging system. STUDY DESIGN: Retrospective cohort. SETTING: Tertiary academic medical center. METHODS: Adult patients newly diagnosed with Meniere's disease between January 1, 2016 and December 31, 2019 were eligible. Patients with previous treatment for Meniere's disease, prior otologic surgery, or a lack of follow-up data were excluded. Treatment-responsive patients were managed with only conservative therapies (eg, dietary modifications, diuretics) and unresponsive patients underwent more intensive therapies (eg, intratympanic procedures, surgical interventions). RESULTS: Of 78 patients included in the study, 49 (63%) were responsive to conservative therapies and 29 (37%) were not. Responsive patients had higher proportions of no or mild vertigo (24%, 95% confidence interval [CI]: 3.1%-45.8%) and none or mild comorbidity (27%, 95% CI: 9.2%-44.7%) and a lower proportion of hearing loss (19%, 95% CI: 5.6%-32.4%) compared to unresponsive patients. Conjunctive consolidation of these 3 factors was performed to develop a three-stage system with a treatment response gradient ranging from 100% to 64% to 18% for stage 1 (n = 11), stage 2 (n = 56), and stage 3 (n = 11), respectively. CONCLUSIONS: This study identified decreased vertigo severity, reduced comorbidity burden, and absence of hearing loss as factors associated with conservative treatment response in Meniere's disease. A composite clinical severity staging system including these 3 factors can be used to optimize treatment selection and promote patient-centered management of Meniere's disease.

Longitudinal Analysis of Early Hearing Detection and Intervention Program Performance.

OBJECTIVES: Early hearing detection and intervention (EHDI) is a newborn hearing screening system created to detect infants with hearing loss (HL) and intervene to reduce language and communication impairment. Early hearing detection (EHD) consists of three sequential stages: identification, screening, and diagnostic testing. This study longitudinally reviews each stage of EHD in each state and proposes a framework to improve utilization of EHD data. DESIGN: A retrospective public database review was conducted, accessing publicly available data from the Centers for Disease Control and Prevention. Summary descriptive statistics were utilized to generate a descriptive study of EHDI programs in each U.S. state from 2007 to 2016. RESULTS: Data over 10 years from 50 states as well as Washington, DC were included in this analysis, creating up to 510 data points per analysis. Hundred percent (85 to 105) (median [min to max]) of newborns were identified by and entered EHDI programs. Ninety-eight percent (51 to 100) of identified infants completed screening. Of the infants who screened positive for HL, the proportion that received diagnostic testing was 55% (1 to 100). The overall proportion of infants who failed to complete EHD was 3% (1 to 51). Of the infants who fail to complete EHD 70% (0 to 100) are from missed screenings, 24% (0 to 95) are from missed diagnostic testing, and 0% (0 to 93) are from missed identification. Although there are more infants missed at screening, it was estimated, with limitations, that there is an order of magnitude more infants with HL among those who did not complete diagnostic testing compared with those who did not complete screening. CONCLUSIONS: Analysis demonstrates high completion rates at both identification and screening stages, whereas the diagnostic testing stage demonstrates low and highly variable completion rates. The low completion rates at diagnostic testing create a bottleneck in the EHD process and the large variability impedes the comparison of HL outcomes across states. Analysis also demonstrates that among all stages of EHD, whereas the largest number of infants are missed at screening, the largest number of children with HL are likely missed at diagnostic testing. Therefore, a focus by individual EHDI programs on addressing causes of low diagnostic testing completion rates would yield the greatest increase in the identification of children with HL. Potential causes of low diagnostic testing completion rates are further discussed. Finally, a new vocabulary framework is proposed to facilitate further study of EHD outcomes.

Optimization of diagnostic and procedural codes to identify patients with acute invasive fungal sinusitis.

KEY POINTS: Acute invasive fungal sinusitis (IFS) is a rare disease with high mortality There is no designated International Classification of Diseases code for IFS We propose a novel method to identify IFS using optimized codes complemented by medications.

Validation of a Novel Allergy-Specific Domain for the 22-Item Sino-Nasal Outcomes Test.

OBJECTIVES: To develop and assess the validity of a novel allergy-specific domain for the 22-item sino-nasal outcomes test (SNOT-22), to provide a new tool that efficiently quantifies the impact of allergic rhinitis (AR) concurrent with chronic rhinosinusitis. STUDY DESIGN: Prospective validation study. SETTING: Tertiary care hospital and community-based clinic. METHODS: Proposed items were developed based on clinician and patient input, and further assessed via factor analysis and for internal consistency (n = 1987). Items were then additionally assessed for convergent and discriminant validity (n = 415), applying data from concurrent completions of the Nasal Obstruction and Septoplasty Effectiveness Scale (NOSE), Mini-Rhinoconjunctivitis Quality-of-Life Questionnaire (MiniRQLQ), and validated global health assessments. Assessments of intra-rater reliability, responsiveness to change, and qualitative input were also performed. RESULTS: Factor analysis demonstrated that proposed allergy items mapped to a single domain. Items were internally consistent (Cronbach α: 0.80 within domain, 0.91 within all SNOT). In assessments of convergent validity, domain scores were associated with MiniRQLQ (Spearman's ρ: 0.46, 95% confidence interval [CI]: 0.30-0.59) and NOSE scores (0.36, 95% CI: 0.27-0.44). The novel items also discriminated among clinical states: a 1-point increase in domain score was associated with an 8.32 (95% CI: 5.43-12.75) increase in the odds of prompting a visit for allergy-related symptoms and a 1.52 (95% CI: 1.13-2.05) increase in the odds of positive allergy testing. Intra-rater reliability was substantial (Cohen's κ: 0.8, 95% CI: 0.8-0.9), and responsiveness to change was demonstrated (mean difference: -0.6, 95% CI: -0.8 to -0.4). CONCLUSIONS: This novel domain is a valid, efficient measure of AR alongside rhinosinusitis.

Validation of Minimal Clinically Important Difference (MCID) for University of Pennsylvania Smell Identification Test (UPSIT).

BACKGROUND: The University of Pennsylvania Smell Identification Test is widely used to measure change in olfactory function, but a minimal clinically important difference (MCID) has not been well-established. A study published in 1997 regarding patients with head trauma reported an MCID of 4 but did not detail the methods used in the calculation. OBJECTIVE: To validate the MCID for UPSIT in patients with postviral, sinusitis, and procedure-associated olfactory loss. METHODS: This was a secondary analysis of prospectively collected data from 5 clinical research studies related to olfactory function. Three studies included subjects with COVID-19-related olfactory dysfunction, one with chronic sinusitis subjects, and one with subjects undergoing transsphenoidal surgery. All subjects had completed a baseline and follow-up UPSIT, baseline and follow-up Clinical Global Impression-Severity (CGI-Severity), and a follow-up CGI-Improvement. Both distribution- and anchor-based methods were used to determine the MCID of UPSIT. Distribution-based method calculated MCID using half standard deviation of baseline UPSIT and delta UPSIT scores. Clinical-anchor method determined MCID by comparing delta UPSIT scores between consecutive CGI-I clinical categories ranging from very much better to very much worse. RESULTS: The study population comprised 295 subjects. Subjects had a mean (SD) baseline UPSIT score of 27 (7.5), and follow-up score of 28 (7.9), and a mean UPSIT change of 0.6 (5.8). Half the baseline UPSIT SD was 3.75 and half the delta UPSIT SD was 2.9. With the anchor-based approach, an MCID of 4 was defined as clinically meaningful by exploring the relationship between delta UPSIT and CGI-Improvement. Using a more conservative approach based on the MCID values identified from both methods, we determined that a change of 4 or greater is the appropriate MCID for UPSIT. CONCLUSION: Investigators in the future should use 4 as MCID for UPSIT and report the percentage of study subjects who achieve a clinically meaningful difference. LEVEL OF EVIDENCE: III.

Stellate Ganglion Block for the Treatment of COVID-19-Induced Olfactory Dysfunction: A Prospective Pilot Study.

OBJECTIVE: The objective of this study was to explore the safety and feasibility of stellate ganglion blocks (SGBs) to treat persistent COVID-19-induced olfactory dysfunction (OD). Secondarily, the goal was to determine effect sizes to plan a future randomized clinical trial. STUDY DESIGN: Prospective case series. SETTING: Quaternary Care Academic Medical Center. METHODS: In this single-arm pilot trial, adult participants with a COVID-19 diagnosis ≥ 12 months prior to enrollment with OD underwent bilateral SGBs. Subjects were followed for 1 month after completion of SGB. The primary outcome measure was the change in the Clinical Global Impression-Improvement Scale for smell loss. Secondary outcome measures included changes in the University of Pennsylvania Smell Identification Test (UPSIT) and Olfactory Dysfunction Outcomes Rating (ODOR). RESULTS: Twenty participants were enrolled with a mean (SD) age of 46 (11) years and a mean (SD) duration of OD of 21 (5) months. At 1 month, 10 (50%) participants experienced at least slight subjective improvement in their OD, 11 (55%) attained a clinically meaningful improvement in smell identification using the UPSIT, and 7 (35%) achieved a clinically meaningful improvement in olfactory-specific quality of life (QoL) measured by the ODOR. The median difference between UPSIT scores at baseline and 1 month was 6 (95% confidence interval: 3-11), exceeding the minimal clinically important difference of 4. There were no serious adverse events. CONCLUSION: Sequential SGBs for COVID-19-associated OD were safe and associated with modest improvements in subjective olfaction, odor identification, and olfactory-specific QoL. A placebo-controlled trial is warranted to determine the efficacy of SGBs for COVID-19-associated OD.

Preexisting tumor-resident T cells with cytotoxic potential associate with response to neoadjuvant anti-PD-1 in head and neck cancer.

About 50% of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) experience recurrences after definitive therapy. The presurgical administration of anti-programmed cell death protein 1 (PD-1) immunotherapy results in substantial pathologic tumor responses (pTR) within the tumor microenvironment (TME). However, the mechanisms underlying the dynamics of antitumor T cells upon neoadjuvant PD-1 blockade remain unresolved, and approaches to increase pathologic responses are lacking. In a phase 2 trial (NCT02296684), we observed that 45% of patients treated with two doses of neoadjuvant pembrolizumab experienced marked pTRs (≥50%). Single-cell analysis of 17,158 CD8+ T cells from 14 tumor biopsies, including 6 matched pre-post neoadjuvant treatment, revealed that responding tumors had clonally expanded putative tumor-specific exhausted CD8+ tumor-infiltrating lymphocytes (TILs) with a tissue-resident memory program, characterized by high cytotoxic potential (CTX+) and ZNF683 expression, within the baseline TME. Pathologic responses after 5 weeks of PD-1 blockade were consistent with activation of preexisting CTX+ZNF683+CD8+ TILs, paralleling loss of viable tumor and associated tumor antigens. Response was associated with high numbers of CD103+PD-1+CD8+ T cells infiltrating pretreatment lesions, whereas revival of nonexhausted persisting clones and clonal replacement were modest. By contrast, nonresponder baseline TME exhibited a relative absence of ZNF683+CTX+ TILs and subsequent accumulation of highly exhausted clones. In HNSCC, revival of preexisting ZNF683+CTX+ TILs is a major mechanism of response in the immediate postneoadjuvant setting.

Efficacy of Gabapentin For Post-COVID-19 Olfactory Dysfunction: The GRACE Randomized Clinical Trial.

Importance: The COVID-19 pandemic affected millions of people and has become a dominant etiology of olfactory dysfunction (OD). No interventions with definitive clinical utility exist. Gabapentin represents a potential therapy for COVID-19-induced OD. Objective: To evaluate the efficacy of oral gabapentin on olfactory function and olfaction-related quality of life in patients with COVID-19-induced OD. Design, Setting, and Participants: This pilot double-blinded, placebo-controlled randomized clinical trial (RCT) was conducted at Washington University School of Medicine in St Louis from January 7, 2022, to February 3, 2023. Adults with at least 3 months of OD after COVID-19 infection were eligible for inclusion. Participants with a history of other causes of OD or contraindications to gabapentin were excluded. Intervention: Patients were randomized 1:1 to oral gabapentin or placebo. All patients underwent titration to a maximum tolerable dose, which was maintained during an 8-week fixed-dose (FD) phase then tapered off. Participants were monitored for 4 weeks following cessation of study medication. Main Outcomes and Measures: Outcomes were assessed following the 8-week FD phase and 4 weeks after taper completion. The primary outcome measure was the response rate determined by subjective improvement in OD on the Clinical Global Impression of Improvement (CGI-I) after the FD phase. Other subjective and objective measures of olfactory function were also assessed as secondary outcome measures. Results: Sixty-eight participants were enrolled (34 randomized to each arm), a total of 44 participants completed the FD period and 20 (45.4%) reported response to treatment with at least slight improvement in olfaction from baseline. Of those randomized, 51 (75%) were women and 56 were White (82%) with a mean (SD) age of 43 (13.5) years. Baseline demographic features including age, sex, and race and ethnicity were not significantly different between the groups. Of the 18 participants in the gabapentin group, 8 (44%) were responders and of the 26 participants in the placebo group, 12 (46%) reported response to treatment (percent difference, 1.7%; 95% CI, -31.6% to 28.2%). Mixed-model analysis of all secondary outcome measures demonstrated no clinically meaningful or statistically significant difference between the gabapentin and placebo groups throughout the trial. There were no serious adverse events. Conclusions and Relevance: In this randomized clinical trial, gabapentin was not associated with statistically significant or clinically meaningful benefit over placebo and likely is not an efficacious therapy for COVID-19-induced OD. Trial Registration: ClinicalTrials.gov Identifier: NCT05184192.

Development and Validation of the Parosmia Olfactory Dysfunction Outcomes Rating (DisODOR).

OBJECTIVE: Develop and validate a quality-of-life (QoL) outcome measure for patients with dysosmia. STUDY DESIGN: Cross-sectional survey study. SETTING: Otolaryngology clinics, research registries, and Facebook support groups. METHODS: A 59-item pilot survey with questions addressing parosmia concerns was developed using input from subjects with parosmia and clinical expertise from Otolaryngologists. After item reduction, the Parosmia Olfactory Dysfunction Outcomes Rating (DisODOR) was reduced to its final 29 items. DisODOR maximum score is 116 (each item score 0-4) with higher scores indicating a higher degree of dysfunction from smell distortion. DisODOR was validated using participants with parosmia persisting >3 months after severe acute respiratory syndrome coronavirus 2 (cases) and healthy controls. Reliability, face and content validity, internal consistency, convergent validity, discriminative validity, sensitivity to change, and the minimal clinically important difference (MCID) were assessed. RESULTS: A total of 134 cases and 20 controls completed DisODOR. The mean (SD) age was 45.9 (12.2) for cases and 29.6 (8.9) for controls. The mean score difference between cases and controls was 45.0 (95% confidence interval, 40.5-49.5) displaying good discriminative validity. DisODOR showed strong test-retest reliability (r = .942) with high internal consistency (Cronbach's α = .971). DisODOR had a moderate correlation with SNOT-22 scores (r = .619) indicating good convergent validity. There is an excellent association with the global impression of severity categories (η2 = 0.447). Based on the distribution method, the MCID is 15. CONCLUSION: DisODOR is a valid, reliable QoL instrument for parosmia that can be used to measure the functional impact and QoL impairment for parosmia patients. DisODOR is sensitive to change and thus can be used in studies investigating treatments for parosmia.