Pro-inflammatory markers associated with COVID-19-related persistent olfactory dysfunction.

INTRODUCTION: While localized inflammation has been implicated in the pathophysiology of acute coronavirus disease of 2019 (COVID-19) olfactory dysfunction (OD), persistent COVID-19 OD remains poorly understood with limited therapeutics. Our prospective study evaluated olfactory cleft (OC) biomarkers as predictors of persistent OD in mucus sampling. METHODS: COVID-19 subjects with persistent OD >3 months confirmed by psychophysical olfaction tests were compared to COVID-19 subjects with no OD and those with no prior infection. OC mucus samples were evaluated for 13 anti-viral and inflammatory biomarkers. Cohorts were compared using analysis of variance (ANOVA) and Mann-Whitney tests with multi-comparison adjustment. Viral RNA was assessed through RT-PCR using the COVID-19 N2 primer. RESULTS: Thirty-five samples were collected (20 COVID persistent OD, 8 COVID no OD, and 7 non-COVID no OD). Significant differences in IFN-λ1 (p = 0.007) and IFN-γ (p = 0.006) expression in OC mucus were found across all three groups, with the highest cytokine concentrations corresponding to COVID OD. IFN-α2 levels were elevated in COVID OD versus no OD (p = 0.026). Mean IFN-γ levels were the highest in COVID OD, but there were higher levels found in COVID no OD compared to non-COVID no OD (p = 0.008). No difference was seen in IL6. No N2 gene expression was detected in all cohorts. CONCLUSION: IFN pathway cytokines were found elevated in the olfactory microenvironment of COVID-19 persistent OD compared to those with no OD and no prior history of COVID-19 infection.

Fluorescent Guided Sentinel Lymph Mapping of the Oral Cavity with Fluorescent-Labeled Tilmanocept.

OBJECTIVE: With the shift toward utilization of sentinel lymph node biopsy (SLNB) in oral cavity cancer, improved techniques for intraoperative sentinel node identification are needed. This study investigates the feasibility of fluorescently labeled tilmanoscept in SLNB in an oral cancer rabbit model. METHODS: An animal study was designed using 21 healthy male New Zealand rabbits. Gallium-68-labeled tilmanocept labeled with IRDye800CW was injected submucosally into the buccal mucosa (n = 6) or lateral tongue (n = 7) followed by PET imaging. One hour after injection, SLNB was performed using fluorescence imaging followed by a bilateral neck dissection and sampling of non-nodal surrounding tissue. All tissues were measured for radioactivity and fluorescence. In addition, eight rabbits were injected with delayed SLNB performed 48 h after injection. RESULTS: Buccal injections all had ipsilateral SLN drainage and tongue injections exhibited 18.2% contralateral drainage. An average of 1.9 ± 1.0 SLN (range 1-5) were identified. In addition, an average of 16.9 ± 3.3 non-sentinel lymph nodes were removed per animal. SLNs had an average of 0.69 ± 0.60 percent-of-injected dose (%ID) compared with non-sentinel nodes with 0.012 ± 0.025 %ID and surrounding tissue with 0.0067 ± 0.015 %ID. There was 98.0% agreement between sentinel lymph nodes identified using fluorescence compared to radioactivity with Cohen's kappa coefficient of 0.879. In 48-h delayed SLNB, results were consistent with 97.8% agreement with radioactivity and Cohen's Kappa coefficient of 0.884. Fluorescence identified additional lymph nodes that were not identified by radioactivity, and with one false negative. CONCLUSION: Fluorescent-labeled Tc-99 m-tilmanocept represents a highly accurate adjunct to enhance SLNB for oral cavity cancer. LEVEL OF EVIDENCE: N/A Laryngoscope, 134:1299-1307, 2024.

Use of platelet-rich plasma for COVID-19-related olfactory loss: a randomized controlled trial.

INTRODUCTION: The current study evaluated the use of platelet-rich plasma (PRP), an autologous blood product with supraphysiologic concentrations of growth factors, in the treatment of prolonged coronavirus disease 2019 (COVID-19)-related smell loss. METHODS: This multi-institutional, randomized controlled trial recruited patients with COVID-19 who had objectively measured smell loss (University of Pennsylvania Smell Identification Test [UPSIT] ≤ 33) between 6 and 12 months. Patients were randomized to three intranasal injections of either PRP or sterile saline into their olfactory clefts. The primary outcome measure was change in Sniffin' Sticks score (threshold, discrimination, and identification [TDI]) from baseline. The secondary end point measures included responder rate (achievement of a clinically significant improvement, ≥5.5 points TDI), change in individual TDI olfaction scores, and change in subjective olfaction via a visual analog scale. RESULTS: A total of 35 patients were recruited and 26 completed the study. PRP treatment resulted in a 3.67-point (95% CI: 0.05-7.29, p = 0.047) greater improvement in olfaction compared with the placebo group at 3 months and a higher response rate (57.1% vs 8.3%, odds ratio 12.5 [95% exact bootstrap confidence interval, 2.2-116.7]). There was a greater improvement in smell discrimination following PRP treatment compared with placebo but no difference in smell identification or threshold. There was no difference in subjective scores between PRP and placebo. No adverse effects were reported. CONCLUSION: Olfactory function following COVID-19 can improve spontaneously after 6 months and can improve to a greater extent with PRP injection. These data build on the promise of PRP to be a safe potential treatment option for patients with COVID-19-related smell loss, and larger-powered studies will help further assess its efficacy.

Role of sentinel lymph node biopsy for oral squamous cell carcinoma: Current evidence and future challenges.

Sentinel lymph node biopsy (SLNB) has been used across oncological specialties for prognostication, staging, and identification of occult nodal metastasis. Recent studies demonstrated the potential clinical utility of SLNB in oral cavity squamous cell carcinoma (OCSCC). Elective neck dissection is the current standard of care in early management of OCSCC with depth of invasion greater than 2-4 mm; however, majority of patients ultimately do not have nodal disease on final pathology. SLNB is an alternative procedure widely adopted in early cancer management in many oncological subspecialities. Several considerations such as depth of invasion, nodal mapping, histopathology methods, operator variability, postoperative complications, and advancement in preoperative and intraoperative imaging technology can guide the appropriate application to SLNB in OCSCC. The aim of this review is to discuss the current evidence for SLNB in the treatment of early stage OCSCC, imaging technologies that support SLNB procedures, and studies that are currently underway.

Persistent post-COVID-19 smell loss is associated with immune cell infiltration and altered gene expression in olfactory epithelium.

SARS-CoV-2 causes profound changes in the sense of smell, including total smell loss. Although these alterations are often transient, many patients with COVID-19 exhibit olfactory dysfunction that lasts months to years. Although animal and human autopsy studies have suggested mechanisms driving acute anosmia, it remains unclear how SARS-CoV-2 causes persistent smell loss in a subset of patients. To address this question, we analyzed olfactory epithelial samples collected from 24 biopsies, including from nine patients with objectively quantified long-term smell loss after COVID-19. This biopsy-based approach revealed a diffuse infiltrate of T cells expressing interferon-γ and a shift in myeloid cell population composition, including enrichment of CD207+ dendritic cells and depletion of anti-inflammatory M2 macrophages. Despite the absence of detectable SARS-CoV-2 RNA or protein, gene expression in the barrier supporting cells of the olfactory epithelium, termed sustentacular cells, appeared to reflect a response to ongoing inflammatory signaling, which was accompanied by a reduction in the number of olfactory sensory neurons relative to olfactory epithelial sustentacular cells. These findings indicate that T cell-mediated inflammation persists in the olfactory epithelium long after SARS-CoV-2 has been eliminated from the tissue, suggesting a mechanism for long-term post-COVID-19 smell loss.

Impact of COVID-19 versus chronic rhinosinusitis/rhinitis associated olfactory dysfunction on health utility and quality of life.

Background: Olfactory dysfunction (OD) is associated with both post-viral and inflammatory etiologies such as COVID-19 and chronic rhinosinusitis/rhinitis (CRS/R) respectively, to result in reduced quality of life (QoL). However, the former typically induces a sudden-onset OD while the latter has a gradual presentation. This study aims to establish and compare health utility values (HUVs) and olfactory-specific QoL measurements between patients with COVID-19 and CRS/R related OD. Methods: This prospective study surveyed COVID-19 and CRS/R patients with self-reported OD using HUV assessments (EuroQol-visual analog scale [EQ-VAS], EuroQol-5 dimension [EQ-5D], time trade-off [TTO]) and olfactory and sinonasal QoL measures (questionnaire of olfactory disorders -negative and positive statements [QOD-NS + PS] and sino-nasal outcome test [SNOT-22]). A subgroup of subjects completed objective olfactory testing. Intergroup mean scores were compared using Mann-Whitney U tests. Results: One hundred eleven subjects were enrolled: mean age ± SD (43.0 ± 15.4 years), 55.9% female. CRS/R was associated with lower HUVs as measured by EQ-VAS (CRS/R: 0.67 ± 0.18 vs. COVID-19: 0.74 ± 0.19, p = .03) and worse SNOT-22 scores in both overall (CRS/R: 49.03 ± 21.04 vs. COVID-19: 27.58 ± 18.45, p < .001) and subgroup analysis of objectively confirmed OD subjects (CRS/R: 52.40 ± 22.78 vs. COVID-19: 29.84 ± 21.10, p = .01). On the other hand, COVID-19 has greater burden on olfactory-specific QoL (QOD-NS + PS, COVID-19: 23.19 ± 13.73 vs. CRS/R: 17.25 ± 11.38, p = .04). Both groups demonstrated a similar decrease in health using the EQ-5D assessment. Conclusion: CRS/R associated OD has a more severe impact on general health and sinonasal specific QoL outcomes, while COVID-19 associated OD has a greater burden on olfactory-specific QoL. Level of evidence: Level 2c.

Persistent post-COVID-19 smell loss is associated with inflammatory infiltration and altered olfactory epithelial gene expression.

Most human subjects infected by SARS-CoV-2 report an acute alteration in their sense of smell, and more than 25% of COVID patients report lasting olfactory dysfunction. While animal studies and human autopsy tissues have suggested mechanisms underlying acute loss of smell, the pathophysiology that underlies persistent smell loss remains unclear. Here we combine objective measurements of smell loss in patients suffering from post-acute sequelae of SARS-CoV-2 infection (PASC) with single cell sequencing and histology of the olfactory epithelium (OE). This approach reveals that the OE of patients with persistent smell loss harbors a diffuse infiltrate of T cells expressing interferon-gamma; gene expression in sustentacular cells appears to reflect a response to inflammatory signaling, which is accompanied by a reduction in the number of olfactory sensory neurons relative to support cells. These data identify a persistent epithelial inflammatory process associated with PASC, and suggests mechanisms through which this T cell-mediated inflammation alters the sense of smell.

Clinical factors associated with lower health scores in COVID-19-related persistent olfactory dysfunction.

BACKGROUND: Patients with persistent COVID-19 olfactory dysfunction (OD) commonly report parosmia. Understanding the impact of COVID-19 OD and parosmia is critical to prioritizing research and interventions. In this study we investigate the impact of parosmia and other clinical and disease characteristics on health state utility values (HUVs) for those with persistent COVID-19 OD. METHODS: Patients with a history of COVID-19 diagnosis and persistent OD were recruited from a tertiary medical center and a social media support forum for chemosensory dysfunction. Clinical characteristics and disease-specific symptoms were obtained along with self-reported history of smell function and presence of parosmia. HUVs were calculated using indirect (EuroQol 5-Dimension [EQ-5D]) and direct (VAS) measures. RESULTS: Our study included 286 subjects (75.52% women) with persistent COVID-19-related OD. Results (mean ± standard deviation) of HUVs based on EQ-5D and VAS were 0.81 ± 0.14 and 0.73 ± 0.21, respectively. Mean self-reported smell function (on a 0-10 scale) was 9.67 ± 1.25 pre-COVID-19, 0.93 ± 2.34 at diagnosis, and 3.39 ± 2.32 at most current assessment. A total of 89.16% of the subjects reported parosmia and 24.13% sought medical care for anosmia. Seeing an MD for OD (p < 0.001), female gender (EQ-5D only, p = 0.002), a history of chronic pain (p < 0.05) and depression/anxiety (EQ-5D only, p < 0.001) predicted worse health. Parosmia and persistent symptoms, such as shortness of breath, were associated with lower EQ-5D and VAS scores, but did not independently predict poorer health scores on multivariable analysis. CONCLUSION: Persistent COVID-19 OD results in health states comparable to other chronic diseases.

Discordance Between Subjective and Objective Measures of Smell and Taste in US Adults.

OBJECTIVE: Examine the rates and factors associated with under- and overreporting of subjective changes in smell or taste as compared with objective measures. STUDY DESIGN: Cross-sectional analysis. SETTING: National Health and Nutrition Examination Survey (2013-2014). METHODS: We examined participants ≥40 years old who completed subjective questionnaires (smell, n = 3510; taste, n = 3089), validated objective 8-odor pocket smell tests, and NaCl/quinine taste tests. Over- and underreporting was determined by the difference in subjective and objective results. Univariate and multivariate logistic regression analyses incorporated sampling weights. RESULTS: A majority of participants correctly classified impairment: smell (73.7%; 95% CI, 71.2%-76.1%) and taste (78.3%; 95% CI, 75.6%-80.7%). Age ≥65 years (odds ratio, 2.23; P = .001) was associated with underreporting impairment, and persistent cold symptoms (odds ratio, 2.15; P = .001) were associated with overreporting smell impairment. Smoke, onion, and natural gas scents were incorrectly identified more frequently by individuals aged ≥65 years after Bonferroni correction. No factors were associated with under- and overreporting taste impairment. CONCLUSION: Although the concordance rate between subjective and objective assessment of smell and taste impairment remains high, we found that older age was associated with incorrect report of impairment. This suggests that the subjective perception of smell varies across demographical and clinical factors, and it is important to not overlook such factors in clinical practice. Potentially using a simplified odor assessment regularly in the clinical setting may aid in early detection and intervention.

Smell and Taste Impairment in a Nationwide Sample of US Adults With Chronic Rhinosinusitis Symptoms.

OBJECTIVE: To estimate the prevalence of objectively confirmed olfactory and gustatory dysfunction in US adults reporting chronic rhinosinusitis (CRS) symptoms in a nationally representative database. STUDY DESIGN: Cross-sectional epidemiologic analysis. SETTING: Data were analyzed from the smell and taste component of the 2013-2014 NHANES data set (National Health and Nutrition Examination Survey). METHODS: Individuals reporting the presence of ≥2 cardinal CRS symptoms (nasal blockage, sinus pain, discolored mucus, and dysosmia) were identified as patients with a potential diagnosis of CRS. Associations were examined between the presence of CRS symptoms and both self-reported and objectively measured smell and taste. RESULTS: One-third (33%) of adults who have ≥2 CRS symptoms report subjective olfactory impairment, though only 18% of these adults have quantifiable olfactory dysfunction on objective testing. Of these adults, 27% report subjective taste impairment, but just 17% have quantifiable gustatory dysfunction on objective testing. The presence of ≥2 CRS symptoms was not significantly associated with objective olfactory or gustatory dysfunction, although the individual symptoms of subjective dysosmia and discolored mucus were associated with objectively confirmed olfactory dysfunction. CONCLUSION: The prevalence of objective olfactory and gustatory dysfunction was higher among adults reporting the presence of ≥2 CRS symptoms, but the differences were not statistically significant. Specific sinonasal symptoms, including discolored mucus and subjective smell dysfunction, were significantly associated with objective smell impairment.

Association Between Olfactory Dysfunction and Mortality in US Adults.

Importance: A study of olfactory dysfunction and mortality in a large national cohort will aid in better understanding their association when accounting for multiple relevant factors and possible underlying mechanisms. Objective: To investigate the association of olfactory dysfunction with all-cause 5-year mortality in US adults. Design, Setting, and Participants: This cohort study included participants 40 years or older from the 2013-2014 National Health and Nutritional Examination Survey who had data on olfaction and mortality (n = 3503). Olfaction was assessed by self-report and objective test (8-odor Pocket Smell Test). Mortality was determined by linking with the National Death Index through February 24, 2019. Data were analyzed from July 1 to September 30, 2019. Main Outcomes and Measures: Olfaction and 5-year mortality. Cox proportional regression models were used to examine the associations between olfaction and mortality while adjusting for demographics and medical comorbidities. Multivariate models were further adjusted for depression and cognitive assessments. Results: Among the 3503 participants (1831 women [52.3%]; mean [SD] age, 59.0 [12.0] years), the prevalence of olfactory dysfunction was 13.5% (95% CI, 11.0%-16.0%) based on results of an objective smell test and 21.6% (95% CI, 18.9%-24.2%) based on self-report. Risk of mortality increased by 18% (95% CI, 7%-29%) per 1-point decrease in smell test score in a multivariate model. The association was significant among adults 65 years or older in association with binary (hazard ratio [HR], 1.95; 95% CI, 1.19-3.21) and linear (HR, 1.19; 95% CI, 1.08-1.31) measures of objective olfactory dysfunction, but not among adults aged 40 to 64 years. There was no association between self-reported olfactory dysfunction and mortality. The association between objective olfactory dysfunction and mortality remained after further adjusting for cognitive assessment battery and depression among older adults (HR, 1.18; 95% CI, 1.01-1.37). Conclusions and Relevance: These findings suggest that objective olfactory dysfunction is associated with increased mortality among older adults. In addition to its effect on quality of life, the association of olfactory dysfunction with mortality has implications for physical and cognitive health.

Integration and Sustainability of Electronic Surgical Logbooks in Sub-Saharan Africa.

BACKGROUND: Countries in Sub-Saharan Africa lack adequate surgical workforces to achieve safe and affordable care for their populations. The Global Surgery movement highlights the urgent need to address this situation. Interventions include not only financial, material and infrastructural support, but also collaborative information flow to support surgical training. In 2015, an electronic logbook was launched for surgical trainees across Sub-Saharan Africa. OBJECTIVES: To assess the integration and context sustainability of surgical e-logbooks in Sub-Saharan Africa. METHODS: In January 2019, a survey analysis of surgical trainees was employed using quantitative and qualitative methods. Participants (active trainees and recent fellows) completed an anonymous internet-based questionnaire evaluating end-user feedback, perceptions and self-reported compliance. Multi-point Likert Scale measures and free-text thematic analysis were used. RESULTS: 358 (68.19%) eligible individuals across 21 Sub-Saharan countries and seven surgical specialties voluntarily participated. The e-resource demonstrated integration into local curricula with the majority of users maintaining activity and reporting moderate-high compliance. Context appropriateness measures were high with 203 (69.76%) deeming it convenient to use. The principle obstacle to compliance was internet connectivity (74, 25.96%), while behavioural factors including supervisor engagement were implicated. The e-logbook demonstrated future sustainability with the majority (243, 78.14%) of participants intent on maintaining usage beyond completion of surgical training. CONCLUSIONS: We describe the successful integration and sustainability of electronic surgical logbooks for trainees across Sub-Saharan Africa. However context-appropriate resources are essential for Low- and Middle-Income Countries. Internet connectivity may hinder the achievement of several Global Surgery objectives in Sub-Saharan Africa.