The significance of a lack of rhinorrhea in severe coronavirus 19 lung disease

Abstract

TO THE EDITOR: In their article, Abdel Hameid et al. (1) propose that SARS-CoV-2 may through G protein-coupled receptor signaling via the cAMP/PKA pathway stimulate CFTR activity, thus leading to excessive chloride secretion in the airways and alveolar type II cells leading to alveolar pulmonary edema. To understand the pathophysiology of respiratory epithelial chloride transport in SARS-CoV-2 infection of the respiratory tract, one needs to carefully analyze the clinical features: it is striking that rhinorrhea is a common feature of CFTR activation, as evident in patients given CFTR activators like ivacaftor (2) or 5 phosphodiesterase inhibitors and in upper respiratory tract infections with influenza (in 91%) for which the authors quote research showing CFTR activation in the mouse model and rhinoviruses (in 82%) in ex vivo human nasal mucosa (3-7). The authors mentioned the example of diarrhea in cholera-associated CFTR activation. CFTR activation in the upper respiratory tract should cause rhinorrhea. The authors' proposed mechanism of CFTR activation may apply to endemic coronaviruses where rhinorrhea is observed in up to 90% of patients (8-10). Rhinorrhea is observed in only a small minority of patients with severe SARS-CoV-2 lung disease [<10% in reviews (11, 12)].Patients with features of severe pulmonary edema did not have rhinorrhea. The absence of rhinorrhea is a pointer to CFTR inactivation as the mechanism in the pathogenesis of SARS-CoV-2-induced pulmonary edema. The mechanism and other clinical features supporting this hypothesis have previously been outlined (13, 14): G protein-coupled receptors are hereby stimulated by proinflammatory cytokines like TNF, and this stimulation then activates mitogen-activated protein kinase-kinase-kinase (MAPKKK) by phosphorylation. This is followed by a chain of phosphorylation reactions via mitogen-activated protein kinase-kinase (MAPKK), mitogen-activated protein kinase (MAPK), and MAPK-activated protein kinase-2 (MAPKAP kinase-2). MAPKAP kinase-2 stabilizes tristetraprolin (TTP), a protein that destabilizes CFTR mRNA by binding to AU-rich sequences. MAPKAP kinase-2 can also stabilize TTP mRNA and, thus, contribute to the degradation of CFTR mRNA by TTP (13), leading to reduced CFTR levels on the respiratory cell surface.The difference from the clinical picture in endemic coronaviruses in COVID-19 is the more severe systemic inflammatory response with significantly elevated TNF levels that

Reply to Eisenhut

“…In line with a lack of generalized CFTR activation, clinical studies show little or no rhinorrhea in patients with COVID-19 ( 21 ), albeit rhinorrhea presents a common feature (in ∼25% of cases) in patients with cystic fibrosis receiving CFTR modulators ( 22 ). As such, these findings argue against a systemic activation of CFTR in patients with COVID-19 ( 1 ). This conclusion is, however, based on the assumption that changes in CFTR abundance and function in response to SARS-CoV-2 infection will be quantitatively and qualitatively similar between different cell types and/or tissues.…”

“…TO THE EDITOR: We read with great interest the Letter to the Editor by Eisenhut ( 1 ) regarding our recently published perspective ( 2 ). The pathophysiology of complex disease processes like pulmonary edema is commonly multifactorial, involving different players including inciting agent(s) and/or event(s), airway/alveolar and/or endothelial barriers, various cell types, transporters, or inflammatory cytokines to name a few ( 3 – 6 ).…”

Call for Papers: “In It for the Long Haul: Understanding the Lasting Impact of COVID-19 on Lung Health and Disease”

“…These insights include a substantial body of findings published in the American Journal of Physiology-Lung Cellular and Molecular Physiology ( AJP-Lung ) under the 2020 Call for Papers “The Pathophysiology of COVID-19 and SARS-CoV-2 Infection” ( 1 ). To date, 47 manuscripts have been published by AJP-Lung under this Call, spanning the development of new models of coronavirus and SARS-CoV-2 infection ( 2 , 3 ), mechanistic investigations of COVID-19 pathogenesis ( 4 , 5 ), human biomarker discovery ( 6 ), and even discussions of unexpected clinical observations in patients with COVID-19 ( 7 ).…”