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.

Chronic Fatigue Associated with Post-COVID Syndrome versus Transient Fatigue Caused by High-Intensity Exercise: Are They Comparable in Terms of Vascular Effects?

“…It seems likely that the above observation linking pathophysiology of transient fatigue caused by strenuous exercise and chronic post-COVID fatigue can originate from calcium homeostasis modification that leads to endothelial dysfunction. 7 , 8 , 13 , 14 …”

“…It seems likely that the above observation linking pathophysiology of transient fatigue caused by strenuous exercise and chronic post-COVID fatigue can originate from calcium homeostasis modification that leads to endothelial dysfunction. 7,8,13,14 In previous communications, we have suggested that the Hypoxia Sensitivity (HS) parameter can be used to predict severity of the acute phase of COVID-19 infection. 26,27 However, the present study indicates that this parameter now 2.…”

“…There is a broad overlap in symptomatology of post-COVID syndrome with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and it is assumed that both these pathologies can be linked to calcium homeostasis dysfunction. [7][8][9] It is likely that calcium homeostasis dysfunction may also affect regulation of adrenergic and muscarinic receptors with implications in post-COVID and chronic fatigue syndromes. 10 There is limited mechanistic knowledge explaining the pathophysiology of chronic fatigue associated with post-COVID.…”

The Challenge of Long COVID-19 Management: From Disease Molecular Hallmarks to the Proposal of Exercise as Therapy

“…These symptoms do not seem to be related to organ damage in patients affected by a mild form of COVID-19; instead, they are the consequence of respiratory organ dysfunctions, such as lung fibrosis, in previously hospitalized patients. Dyspnea induced by exercise is related to hyperventilation that can arise from an insufficient energetic supply and autonomic dysfunction [ 28 ]. However, in a different study, cardiopulmonary exercise testing was performed in patients aged 64 years affected by long COVID-19 and persistent dyspnea.…”

Correlation of respiratory muscle function and cardiopulmonary exercise testing in post-acute COVID-19 syndrome

“…Other pathophysiological mechanisms have recently been suggested to cause overshooting respiratory response in dyspneic patients after mild COVID-19, such as disturbance of skeletal muscle metabolism and autonomic dysfunction [ 5 ]. The latter may also explain the negative correlation between P0.1 and O 2 pulse in our data, as both ventilatory drive and ventricular stroke volume are subject to the influence of autonomic nervous regulation.…”