Upregulation of ACE/ACE2 Balance in Nasal Mucosa: A Working Hypothesis to Explain the Absence of Nasal Inflammatory Symptoms in COVID-19 Disease

We read with interest the article by Sayin et al, debating the significance of the paucity of nasal symptomatology, except for anosmia, in COVID-19. ¹ However, the authors didn’t provide any pathophysiological mechanism for this low incidence of sneezing, rhinorrhea, nasal obstruction, and sinusitis-like manifestations of the usual viral rhinitis in COVID-19. We, herein, take an opportunity to explain these differences based on our “epithelial-endothelial cross-talk hypothesis” of COVID-19 pneumonia. ²

Bradykinin is believed to have a major role in generating the usual local symptoms of upper respiratory tract infections. ³ However, in severe acute respiratory syndrome and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we believe that bradykinin formation is largely inhibited due to the upregulation of ACE-Ang II-AT1R pathways. It has been shown that SARS-CoV-2 spike protein binds with membranous angiotensin-converting enzyme 2 (ACE2) of ciliated nasal epithelial cells and sustentacular cells in olfactory epithelium and can result in downregulation and shedding of ACE2 on the airway epithelium. This can possibly result in relative upregulation of ACE-Ang II-AT1R activity in nasal mucosa. Undoubtably, this effect in the nasal mucosa should be less pronounced than at the alveolar capillary ultrastructure due to less pronounced epithelial–endothelial cross talk. Note, on immunohistochemistry, ACE has been localized on the endothelial cells of the fenestrated capillaries in the superficial lamina propria, beneath the basement membrane, of the ciliated, pseudostratified, columnar epithelium of human nasal mucosa, and in the nasal epithelial lining fluid. ⁴ Although the precise role of ACE in mucosal health and disease is unknown, based on their observations, Ohkubo et al proposed that ACE may participate in the respiratory inflammatory diseases by limiting the levels of inflammatory peptides such as bradykinin and substance P, thus suggested its protective role against viral rhinitis. ⁴ Hence, there is possibility that the indirect upregulation of ACE-Ang-II pathways in the nasal mucosa can promote bradykinin degradation and cause vasoconstriction; thus, minimizing nasal congestion in SARS-CoV-2 infection. Also, as SARS-CoV-2 can replicate to high levels without inducing substantial host cell damage, ⁵ direct injury to the ciliated nasal mucosal cells as a result of infective process is minimal. This is in contrast to the previous coronaviruses that accounts for 15% to 30% of common cold and carries a greater potential to produce significant nasal epithelial disruption by direct infective process, ⁶ thus cause extensive bradykinin formation from tissue injury. Further, as SARS-CoV-2 inhibits innate immune response, ⁷ the immune-mediated indirect injury of nasal epithelium is minimal.

Our arguments are further supported by the fact that asthma did not increase the risk of developing severe COVID-19. ⁸ This is in contrast to H1NI pneumonia, wherein asthma was the strongest risk predictor. Further, wheezing is uncommon in patients with COVID-19 pneumonia. ⁹ If “bradykinin storm” is believed to be the pathophysiological explanation of COVID-19 disease, wheeze and nasal symptoms of rhinorrhea, congestion, and sinusitis should be common.

Our hypothesis is also supported by the recent publication of Navarra et al reporting “excessive nasal dryness” and/or a continual sensation of having had a “nasal douche” in 61.8% and 51.5% of the COVID-19 patients. ¹⁰ We believe that the hypothesis of ACE-AngII-AT1R upregulation mediated mechanisms can support these symptoms as well.