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...

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BackgroundBudesonide irrigations (BIs) are commonly used to control inflammation in chronic rhinosinusitis (CRS). In 2016 we reported an analysis of long‐term BI with regard to hypothalamic‐pituitary‐adrenal axis function. We present a follow‐up analysis in a larger cohort of patients with longer follow‐up.MethodsPatients were candidates for stimulated cortisol testing after regularly performing BI for CRS at least daily for ≥6 months. We retrospectively evaluated all patients who received stimulated cortisol testing at our center between 2012 and 2022. We correlated cortisol levels with the use of BI and other forms of corticosteroids.ResultsWe analyzed 401 cortisol test results in 285 patients. The mean duration of use was 34 months. Overall, 21.8% of patients were hypocortisolemic (<18 ug/dL) at first test. In patients who used only BI, the rate of hypocortisolemia was 7.5%, whereas in patients who also used concurrent oral and inhaled corticosteroids, the rate was 40% to 50%. Lower cortisol levels were associated with male sex (p < 0.0001) and concomitant use of oral and inhaled steroids (p < 0.0001). Duration of BI use was not significantly associated with lower cortisol levels (p = 0.701), nor was greater dosing frequency (p = 0.289).ConclusionProlonged use of BI alone is not likely to cause hypocortisolemia in the majority of patients. However, concomitant use of inhaled and oral steroids and male sex may be associated with hypocortisolemia. Surveillance of cortisol levels may be considered in vulnerable populations who use BI regularly, particularly in patients using other forms of corticosteroids with known systemic absorption.