Dyspnea in Post-COVID Syndrome following Mild Acute COVID-19 Infections: Potential Causes and Consequences for a Therapeutic Approach.

Abstract

Dyspnea, shortness of breath, and chest pain are frequent symptoms of post-COVID syndrome (PCS). These symptoms are unrelated to organ damage in most patients  after mild acute COVID infection. Hyperventilation has been identified as a cause  of exercise-induced dyspnea in PCS. Since there is a broad overlap in  symptomatology with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS),  causes for dyspnea and potential consequences can be deduced by a stringent  application of assumptions made for ME/CFS in our recent review papers. One of  the first stimuli of respiration in exercise is caused by metabolic feedback via  skeletal muscle afferents. Hyperventilation in PCS, which occurs early on during  exercise, can arise from a combined disturbance of a poor skeletal muscle  energetic situation and autonomic dysfunction (overshooting respiratory  response), both found in ME/CFS. The exaggerated respiratory response aggravating  dyspnea does not only limit the ability to exercise but further impairs the  muscular energetic situation: one of the buffering mechanisms to respiratory  alkalosis is a proton shift from intracellular to extracellular space via the  sodium-proton-exchanger subtype 1 (NHE1), thereby loading cells with sodium. This  adds to two other sodium loading mechanisms already operative, namely glycolytic  metabolism (intracellular acidosis) and impaired Na(+)/K(+)ATPase activity. High  intracellular sodium has unfavorable effects on mitochondrial calcium and  metabolism via sodium-calcium-exchangers (NCX). Mitochondrial calcium overload by  high intracellular sodium reversing the transport mode of NCX to import calcium  is a key driver for fatigue and chronification. Prevention of hyperventilation  has a therapeutic potential by keeping intracellular sodium below the threshold  where calcium overload occurs.