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

Klaus J Wirth,Carmen Scheibenbogen

doi:10.3390/medicina58030419

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.

Highlights

Dyspnea, shortness of breath, and chest pain are frequent symptoms of the postCOVID syndrome (PCS) [1–3]
Recent studies in PCS suggest that there is a broad overlap in symptomatology with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which in the majority of patients may be a post-infectious disease, mostly after viral infections [4–10]
In PCS, stimulation of the respiratory center may be further enhanced by dysautonomia, resulting in a significant hyperventilation that leads to hypocapnia and respiratory alkalosis [28]

Summary

Introduction

Shortness of breath, and chest pain are frequent symptoms of the postCOVID syndrome (PCS) [1–3]. Recent studies in PCS suggest that there is a broad overlap in symptomatology with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which in the majority of patients may be a post-infectious disease, mostly after viral infections [4–10]. Both syndromes present with a confusing variety of symptoms with mental and muscular fatigue, cognitive impairment, exertion intolerance with post-exertional malaise (PEM), chronic muscle pain, and headaches, as described for ME/CFS [11]

Hyperventilation as the Cause of Dyspnea in Post-COVID Syndrome Patients with Mild

The Potential Causes of Hyperventilation

Possible Consequences of Hyperventilation and Respiratory Alkalosis on Muscular

Differential Mechanisms of Dyspnea following Mild and Severe COVID-19

Conclusions and Therapeutic Implication