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

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 can explain the CFTR inactivation, which may distinguish COVID-19 disease from other viral infections and may explain the pulmonary edema as shown by us for meningococcal septicemia in which elevated sweat chloride levels and reduced chloride channel function on nasal potential difference measurement in the respiratory epithelium in children in vivo were associated with pulmonary edema (15). Like meningococcal septicemia, COVID-19 is associated with a cytokine storm involving the same inflammatory mediators, and they have previously been shown to cause reduced CFTR function (13).

Future investigations need to use exhaled breath condensate in ventilated patients with SARS-CoV-2-induced acute respiratory distress syndrome (ARDS) for measurement of chloride levels corrected by putting into ratio to a reference molecule or ion as outlined previously (14) and comparing patients with and without pulmonary edema in coronavirus disease. A reduction of chloride levels would confirm the hypothesis of a reduced CFTR function as was demonstrated in patients with cystic fibrosis (16).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the author.

AUTHOR CONTRIBUTIONS

M.E. drafted manuscript; edited and revised manuscript; and approved final version of manuscript.