A longitudinal study of olfactory dysfunction and parosmia in mild COVID-19 cases.

Background: COVID-19-related olfactory dysfunction (OD) can persist long after patients recover from acute infection, yet few studies have investigated the long-term progression of this complication. Moreover, existing studies are focused on hyposmia/anosmia but parosmia is becoming an increasingly recognized long-term symptom. Methods: We completed a longitudinal study about OD in individuals with mild cases of COVID-19. Participants completed a questionnaire and Brief Smell Identification Test (BSIT) one week, one month and one year after diagnosis. At one-year, participants completed an additional survey about parosmia. Results: We obtained questionnaires and psychophysical olfactory testing information from participants at one week (n=45), one month (n=38), and one year (n=33) post COVID-19 diagnosis. At one-year, 15.2% of participants had persistent OD and 66.7% of participants reported experiencing parosmia at some point following COVID-19 diagnosis. The mean onset of parosmia was 1.3 weeks (SD: 1.9 weeks) after diagnosis, although two patients reported delayed onset (>4 weeks after diagnosis). Eight patients (24.2%) reported ongoing parosmia one year after diagnosis. Of the patients whose parosmia resolved, the mean duration of symptoms was 7.2 weeks (SD: 7.3 weeks). Conclusion: Decreased sense of smell associated with COVID-19 infection has received significant recognition in both the media and in the medical literature. Symptoms of OD and parosmia were common in our patients with COVID-19. Hyposmia, anosmia, and parosmia, all decrease quality of life, necessitating continued research to understand the pathogenesis, course of symptoms, and possible treatment for these complications.

Sinonasal complications of severe acute respiratory syndrome coronavirus-2: A single center case series.

Background: The emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has resulted in an unprecedented global pandemic. Most infected patients are either asymptomatic or have mild upper respiratory infection symptoms. However, life-threatening sequelae have been observed. In this report, we reviewed nine cases of patients with severe complications from sinonasal disease in the setting of acute SARS-CoV-2 infection. Methods: IRB approval was obtained prior to study initiation. A retrospective chart review was performed of patients admitted to a tertiary hospital with complex sinonasal symptoms that required otolaryngologic evaluation and management in the setting of concomitant SARS-CoV-2 infection. Results: Nine patients, ranging from ages 3 to 71 years, with sinonasal disease and simultaneous SARS-CoV-2 infection were identified. Initial presentations ranged from asymptomatic infection to mild/moderate disease (nasal obstruction, cough) or more severe sequelae including epistaxis, proptosis, or neurologic changes. SARS-CoV-2 tests were positive from one to 12 days after symptom onset, with three patients receiving SARS-CoV-2-directed treatment. Complex disease presentations included bilateral orbital abscesses, suppurative intracranial infection, cavernous sinus thrombosis with epidural abscess, systemic hematogenous spread with abscess development in four distinct anatomic locations, and hemorrhagic benign adenoidal tissue. Eight of nine patients (88.8%) required operative intervention. Patients with abscesses also required prolonged, culture-directed antibiotic courses. Conclusion: Though most SARS-CoV-2 infections are asymptomatic and/or self-limited, there is significant morbidity and mortality in patients with severe disease sequela as outlined in our reported cases. This suggests early identification and treatment of sinonasal disease in this patient population is critical to minimizing poor outcomes. Further research on the pathophysiology of these atypical presentations is needed. Level of Evidence: 4 (Case Series).

Pharmacokinetic-based failure of a detergent virucidal for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) nasal infections: A preclinical study and randomized controlled trial.

BACKGROUND: The nose is the portal for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection, suggesting the nose as a target for topical antiviral therapies. The purpose of this study was to assess both the in vivo and in vitro efficacy of a detergent-based virucidal agent, Johnson and Johnson's Baby Shampoo (J&J), in SARS-CoV-2-infected subjects. METHODS: Subjects were randomized into three treatment groups: (1) twice daily nasal irrigation with J&J in hypertonic saline, (2) hypertonic saline alone, and (3) no intervention. Complementary in vitro experiments were performed in cultured human nasal epithelia. The primary outcome measure in the clinical trial was change in SARS-CoV-2 viral load over 21 days. Secondary outcomes included symptom scores and change in daily temperature. Outcome measures for in vitro studies included change in viral titers. RESULTS: Seventy-two subjects completed the clinical study (n = 24 per group). Despite demonstrated safety and robust efficacy in in vitro virucidal assays, J&J irrigations had no impact on viral titers or symptom scores in treated subjects relative to controls. Similar findings were observed administering J&J to infected cultured human airway epithelia using protocols mimicking the clinical trial regimen. Additional studies of cultured human nasal epithelia demonstrated that lack of efficacy reflected pharmacokinetic failure, with the most virucidal J&J detergent components rapidly absorbed from nasal surfaces. CONCLUSION: In this randomized clinical trial of subjects with SARS-CoV-2 infection, a topical detergent-based virucidal agent had no effect on viral load or symptom scores. Complementary in vitro studies confirmed a lack of efficacy, reflective of pharmacokinetic failure and rapid absorption from nasal surfaces.

COVID-19 related olfactory dysfunction prevalence and natural history in ambulatory patients.

BACKGROUND: Evidence regarding prevalence of COVID-19 related Olfactory dysfunction (OD) among ambulatory patients is highly variable due to heterogeneity in study population and measurement methods. Relatively few studies have longitudinally investigated OD in ambulatory patients with objective methods. METHODS: We performed a longitudinal study to investigate OD among COVID-19 ambulatory patients compared to symptomatic controls who test negative. Out of 81 patients enrolled, 45 COVID-19 positive patients and an age- and sex-matched symptomatic control group completed the BSIT and a questionnaire about smell, taste and nasal symptoms. These were repeated at 1 month for all COVID-19 positive patients, and again at 3 months for those who exhibited persistent OD. Analysis was performed by mixed-effects linear and logistic regression. RESULTS: 46.7% of COVID-19 patients compared to 3.8% of symptomatic controls exhibited OD at 1-week post diagnosis (p<0.001). At 1 month, 16.7%, (6 of 36), of COVID-19 patients had persistent OD. Mean improvement in BSIT score in COVID-19 patients between 1-week BSIT and 1 month follow-up was 2.0 (95% CI 1.00 - 3.00, p<0.001). OD did not correlate with nasal congestion (r= -0.25, 95% CI, -0.52 to 0.06, p=0.12). CONCLUSIONS: Ambulatory COVID-19 patients exhibited OD significantly more frequently than symptomatic controls. Most patients regained normal olfaction by 1 month. The BSIT is a simple validated and objective test to investigate the prevalence of OD in ambulatory patients. OD did not correlate with nasal congestion which suggests a congestion-independent mechanism of OD.

Pharmacokinetic-based failure of a detergent virucidal for SARS-COV-2 nasal infections.

The nose is the portal for SARS-CoV-2 infection, suggesting the nose as a target for topical antiviral therapies. Because detergents are virucidal, Johnson and Johnson's Baby Shampoo (J&J) was tested as a topical virucidal agent in SARS-CoV-2 infected subjects. Twice daily irrigation of J&J in hypertonic saline, hypertonic saline alone, or no intervention were compared (n = 24/group). Despite demonstrated safety and robust efficacy in in vitro virucidal assays, J&J irrigations had no impact on viral titers or symptom scores in treated subjects relative to controls. Similar findings were observed administering J&J to infected cultured human airway epithelia using protocols mimicking the clinical trial regimen. Additional studies of cultured human nasal epithelia demonstrated that lack of efficacy reflected pharmacokinetic failure, with the most virucidal J&J detergent components rapidly absorbed from nasal surfaces. This study emphasizes the need to assess the pharmacokinetic characteristics of virucidal agents on airway surfaces to guide clinical trials.

SARS-CoV-2 infection of the oral cavity and saliva.

Despite signs of infection-including taste loss, dry mouth and mucosal lesions such as ulcerations, enanthema and macules-the involvement of the oral cavity in coronavirus disease 2019 (COVID-19) is poorly understood. To address this, we generated and analyzed two single-cell RNA sequencing datasets of the human minor salivary glands and gingiva (9 samples, 13,824 cells), identifying 50 cell clusters. Using integrated cell normalization and annotation, we classified 34 unique cell subpopulations between glands and gingiva. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral entry factors such as ACE2 and TMPRSS members were broadly enriched in epithelial cells of the glands and oral mucosae. Using orthogonal RNA and protein expression assessments, we confirmed SARS-CoV-2 infection in the glands and mucosae. Saliva from SARS-CoV-2-infected individuals harbored epithelial cells exhibiting ACE2 and TMPRSS expression and sustained SARS-CoV-2 infection. Acellular and cellular salivary fractions from asymptomatic individuals were found to transmit SARS-CoV-2 ex vivo. Matched nasopharyngeal and saliva samples displayed distinct viral shedding dynamics, and salivary viral burden correlated with COVID-19 symptoms, including taste loss. Upon recovery, this asymptomatic cohort exhibited sustained salivary IgG antibodies against SARS-CoV-2. Collectively, these data show that the oral cavity is an important site for SARS-CoV-2 infection and implicate saliva as a potential route of SARS-CoV-2 transmission.

Quantification of Aerosol Particle Concentrations During Endoscopic Sinonasal Surgery in the Operating Room.

BACKGROUND: Recent indirect evidence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) transmission during endoscopic endonasal procedures has highlighted the dearth of knowledge surrounding aerosol generation with these procedures. As we adapt to function in the era of Coronavirus Disease 2019 (COVID-19) a better understanding of how surgical techniques generate potentially infectious aerosolized particles will enhance the safety of operating room (OR) staff and learners. OBJECTIVE: To provide greater understanding of possible SARS-CoV-2 exposure risk during endonasal surgeries by quantifying increases in airborne particle concentrations during endoscopic sinonasal surgery. METHODS: Aerosol concentrations were measured during live-patient endoscopic endonasal surgeries in ORs with an optical particle sizer. Measurements were taken throughout the procedure at six time points: 1) before patient entered the OR, 2) before pre-incision timeout during OR setup, 3) during cold instrumentation with suction, 4) during microdebrider use, 5) during drill use and, 6) at the end of the case prior to extubation. Measurements were taken at three different OR position: surgeon, circulating nurse, and anesthesia provider. RESULTS: Significant increases in airborne particle concentration were measured at the surgeon position with both the microdebrider (p = 0.001) and drill (p = 0.001), but not for cold instrumentation with suction (p = 0.340). Particle concentration did not significantly increase at the anesthesia position or the circulator position with any form of instrumentation. Overall, the surgeon position had a mean increase in particle concentration of 2445 particles/ft3 (95% CI 881 to 3955; p = 0.001) during drill use and 1825 particles/ft3 (95% CI 641 to 3009; p = 0.001) during microdebrider use. CONCLUSION: Drilling and microdebrider use during endonasal surgery in a standard operating room is associated with a significant increase in airborne particle concentrations. Fortunately, this increase in aerosol concentration is localized to the area of the operating surgeon, with no detectable increase in aerosol particles at other OR positions.

Quantification of Aerosol Concentrations During Endonasal Instrumentation in the Clinic Setting.

OBJECTIVE: Recent anecdotal reports and cadaveric simulations have described aerosol generation during endonasal instrumentation, highlighting a possible risk for transmission of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) during endoscopic endonasal instrumentation. This study aims to provide a greater understanding of particle generation and exposure risk during endoscopic endonasal instrumentation. STUDY DESIGN: Prospective quantification of aerosol generation during office-based nasal endoscopy procedures. METHODS: Using an optical particle sizer, airborne particles concentrations 0.3 to 10 microns in diameter, were measured during 30 nasal endoscopies in the clinic setting. Measurements were taken at time points throughout diagnostic and debridement endoscopies and compared to preprocedure and empty room particle concentrations. RESULTS: No significant change in airborne particle concentrations was measured during diagnostic nasal endoscopies in patients without the need for debridement. However, significant increases in mean particle concentration compared to preprocedure levels were measured during cold instrumentation at 2,462 particles/foot3 (95% CI 837 to 4,088; P = .005) and during suction use at 2,973 particle/foot3 (95% CI 1,419 to 4,529; P = .001). In total, 99.2% of all measured particles were ≤1 µm in diameter. CONCLUSION: When measured with an optical particle sizer, diagnostic nasal endoscopy with a rigid endoscope is not associated with increased particle aerosolization in patient for whom sinonasal debridement is not needed. In patients needing sinonasal debridement, endonasal cold and suction instrumentation were associated with increased particle aerosolization, with a trend observed during endoscope use prior to tissue manipulation. Endonasal debridement may potentially pose a higher risk for aerosolization and SARS-CoV-2 transmission. Appropriate personal protective equipment use and patient screening are recommended for all office-based endonasal procedures. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:E1415-E1421, 2021.

Numerical evaluation of spray position for improved nasal drug delivery.

Topical intra-nasal sprays are amongst the most commonly prescribed therapeutic options for sinonasal diseases in humans. However, inconsistency and ambiguity in instructions show a lack of definitive knowledge on best spray use techniques. In this study, we have identified a new usage strategy for nasal sprays available over-the-counter, that registers an average 8-fold improvement in topical delivery of drugs at diseased sites, when compared to prevalent spray techniques. The protocol involves re-orienting the spray axis to harness inertial motion of particulates and has been developed using computational fluid dynamics simulations of respiratory airflow and droplet transport in medical imaging-based digital models. Simulated dose in representative models is validated through in vitro spray measurements in 3D-printed anatomic replicas using the gamma scintigraphy technique. This work breaks new ground in proposing an alternative user-friendly strategy that can significantly enhance topical delivery inside human nose. While these findings can eventually translate into personalized spray usage instructions and hence merit a change in nasal standard-of-care, this study also demonstrates how relatively simple engineering analysis tools can revolutionize everyday healthcare. Finally, with respiratory mucosa as the initial coronavirus infection site, our findings are relevant to intra-nasal vaccines that are in-development, to mitigate the COVID-19 pandemic.