The coronavirus SARS-CoV-2 is the causative agent of the ongoing severe acute respiratory disease pandemic COVID-19. Tissue and cellular tropism is one key to understanding the pathogenesis of SARS-CoV-2. We investigate the expression and subcellular localization of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), within the upper (nasal) and lower (pulmonary) respiratory tracts of human donors using a diverse panel of banked tissues. Here, we report our discovery that the ACE2 receptor protein robustly localizes within the motile cilia of airway epithelial cells, which likely represents the initial or early subcellular site of SARS-CoV-2 viral entry during host respiratory transmission. We further determine whether ciliary ACE2 expression in the upper airway is influenced by patient demographics, clinical characteristics, comorbidities, or medication use, and show the first mechanistic evidence that the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs) does not increase susceptibility to SARS-CoV-2 infection through enhancing the expression of ciliary ACE2 receptor. These findings are crucial to our understanding of the transmission of SARS-CoV-2 for prevention and control of this virulent pathogen.

We investigated the expression and subcellular localization of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), within the upper (nasal) and lower (pulmonary) respiratory tracts of healthy human donors. We detected ACE2 protein expression within the cilia organelle of ciliated airway epithelial cells, which likely represents the initial or early subcellular site of SARS-CoV-2 viral entry during respiratory transmission. We further determined whether ACE2 expression in the cilia of upper respiratory cells was influenced by patient demographics, clinical characteristics, co-morbidities, or medication use, and found no evidence that the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs) increases ACE2 protein expression.Coronavirus disease 2019 is an ongoing pandemic infection caused by the positivesense RNA virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 1 . The high transmissibility of the virus, along with case fatality estimates ranging from 1% to above 5%, has raised concerns worldwide. Patients with comorbid conditions including hypertension, diabetes, and pulmonary disease are highly represented among hospitalized patients with COVID-19 disease, suggesting the presence of risk factors that may determine susceptibility to SARS-CoV-2 infection [2][3][4][5] .A molecular connection between SARS-CoV-2 and hypertension, in particular, is suggested by the discovery that ACE2 is the major essential receptor for SARS-CoV-2 6,7 . ACE2 plays an important role in the renin-angiotensin-aldosterone system (RAAS), which consists of a cascade of vasoactive peptides that maintain blood pressure and electrolyte homeostasis. ACE2 converts vasoconstrictor peptides, angiotensin (Ang) II and Ang I, into the vasodilator peptides, Ang (1-7) and Ang (1-9), respectively 8 . These actions counterbalance the enzymatic effect of the related ACE, which generates angiotensin II from angiotensin I. ACEI and ARBs are commonly used antihypertensive drugs that target components of the RAAS. Several recent correspondences have raised concerns that ACEI and ARBs may increase expression of ACE2 and thereby elevate the risk of infection by SARS-CoV-2, thus potentially explaining why hypertension is a common comorbidity in patients with COVID-19 9-12 . This hypothesis is also rooted in human and rodent studies showing upregulation of ACE2 mRNA in the heart, kidney, and urine after ACEI/ARB administration [13][14][15] . Notably, however, the effects of ACEI and ARBs on the expression of ACE2 in the respiratory tract are currently unknown. Given SARS-CoV-2 causes respiratory infections, whether ACE2 expression is altered in the airway of patients taking ACEI or ARBs is a critical question that needs to be addressed to support continued clinical use of these antihypertensive drugs.We first determined the expression patterns of the ACE2 protein in the upper and lower respiratory tract. Gene expression analyses have identified ACE2 expression in the nasopharynx, oral muc...

Objectives/Hypothesis: We sought to report the long-term, symptom-focused, prospective outcomes in empty nose syndrome (ENS) patients after undergoing inferior meatus augmentation procedure (IMAP) through use of four validated questionnaires: Empty Nose Syndrome 6-Item Questionnaire (ENS6Q), 22-item Sino-Nasal Outcome Test (SNOT-22), Generalized Anxiety Disorder 7-Item Scale (GAD-7), and Patient Health Questionnaire-9 (PHQ-9).Study Design: Prospective case series.Methods: A single-center prospective case series was performed for patients diagnosed with ENS who underwent IMAP between July 2017 and February 2020. Diagnosis of ENS was based on the following criteria: 1) reported discomfort with nasal breathing and/or paradoxical nasal obstruction after inferior turbinate reduction, 2) a positive ENS6Q score of at least 11, and 3) a positive cotton test. Questionnaire responses were recorded prior to surgery as well as 1, 3, 6, and 12 months postoperatively.Results: Seventeen eligible patients were included. Mean ENS6Q scores were significantly reduced at all postoperative time points (p < .0001, p < .0001, p < .0001, p = .0003). Of the six ENS6Q subdomains, five (suffocation, dryness, sense of diminished airflow, nasal crusting, and nasal burning) were significantly reduced 1-year postoperatively (p < .0001, p = .0004, p = .0136, p = .0114, p = .0080, respectively). SNOT-22 scores were significantly reduced at all time points (p = .0021, p = .0227, p = .0004, and p = .0025). Of the SNOT-22 subdomains, the sleep subdomain was significantly reduced 1-year postoperatively (p = .0432). Low baseline GAD-7 and PHQ-9 scores were recorded at 7 and 9.4, respectively, and although scores at all postoperative time points were reduced, there was no statistical significance.Conclusion: IMAP via implant of cadaveric rib cartilage provides significant, long-term improvements in ENS-specific and general sinonasal symptoms.

Background Empty nose syndrome ENS is a controversial upper airway disorder most commonly associated with tissue loss from the inferior turbinates The inferior meatus augmentation procedure IMAP has been shown to effectively reduce ENS symptoms in a durable manner but the precise mechanisms that may govern this symptomatic improvement remain unknown Methods Five patients with ENS who underwent bilateral IMAP via submucosal costal cartilage implant were assessed Pre-implant and months post-implant computed tomography CT imaging for each ENS patient was analyzed in a blinded fashion using computational fluid dynamics CFD modeling to investigate intrapatient changes in airflow parameters Results Following surgery ENS patients have significantly improved symptoms as indexed by Empty Nose Syndrome -Item Questionnaire ENS Q scoring pre-implant ± mean ± standard deviation confidence interval CI to post-implant ± CI to Cohen's d = p = Using CFD a significant shi in nasal airflow patterns was observed where airflow deviates away from the middle meatus upon hitting the implant pre-implant ± CI to post-implant ± CI to d = p < toward the inferior meatus pre-implant ± CI to post-implant ± CI to d = p < No significant changes were found in nasal resistance pre-implant ± CI to Pa*s/mL post-implant ± CI toPa*s/mL In addition the improvement of ENS Q scoring significantly correlated with percent reduction in aberrant airflow through the middle meatus R = p = Conclusion This study supports our prior working hypothesis that disordered vectors of nasal airflow congregate in the middle meatus contribute to ENS symptoms not nasal resistance Moreover these data illuminate a paradoxical but consistent restoration of nasal airflow to the inferior meatus following the replacement of turbinate tissue volume in the inferior meatus via IMAP surgery potentially due to the Coandȃ effect © 2020 ARS-AAOA, LLC.

Background: Empty nose syndrome (ENS) remains a controversial disease primarily associated with inferior turbinate tissue loss. Co on placement into the inferior meatus o en alleviates ENS symptoms within minutes, but the physiologic explanation for this phenomenon is unknown. Computational fluid dynamics (CFD) was employed to evaluate the mechanisms of altered nasal airflow conferred by co on testing. Methods:Six ENS patients (12 sides) with pre-existing sinus computed tomography (CT) imaging were enrolled a er marked symptomatic improvement (decrease in score on the Empty Nose Syndrome 6-Item Questionnaire [ENS6Q] of >7 points) with office-based co on testing. The fashioned co on plug was labeled in situ with iohexol contrast spray, and sinus CT was immediately obtained to detect co on contouring in the inferior meatus. CT imaging from pre-and post-co on placement was analyzed using comparative CFD techniques. Results:A er co on placement, significant symptomatic improvement and reduced ENS6Q scores (16.8 ± 4.1 to 3.1 ± 2.4; p < 0.001) were recorded. Using CFD, co on placement produced an expected 21% increase in upper airway resistance (p < 0.05). However, a significant shi in the nasal airflow distribution was also detected, with a transition of airflow vectors away from a middle meatus jetstream (−41%; p < 0.002). Conclusion:Objective CFD assessment confirmed that the co on test not only increases nasal resistance, but also restores airflow distribution to the inferior meatus in symptomatic ENS patients. These results highlight the potential efficacy of co on test in ENS patients and further bolster the utility of this tool in identifying appropriate candidates for the inferior meatus augmentation procedure. C 2020 ARS-AAOA, LLC.