Endogenous Deficiency of Glutathione as the Most Likely Cause of Serious Manifestations and Death in COVID-19 Patients

"The aim of this Viewpoint is to justify (1) the crucial roles of glutathione [GSH] in determining individual responsiveness to COVID-19 infection and disease pathogenesis and (2) the feasibility of using glutathione as a means for the treatment and prevention of COVID-19 illness...

What Is the Primary Cause of Severe COVID-19 Illness: Glutathione or Vitamin D Deficiency?

The novel hypothesis that vitamin D (VD) deficiency is responsible for severe manifestations and death in COVID-19 patients has been proposed and is actively being discussed by the scientific community. Several studies reported that glutathione levels positively correlate with active vitamin D. It has also been found that lower levels of l-cysteine (a rate-limiting precursor of GSH) and GSH correlated with lower vitamin D binding protein (VDBP) and VD levels in T2D patients. l-cysteine supplementation is known to improve GSH status through upregulation of expression of VDBP, vitamin D 25-hydroxylase, and vitamin D receptor, thereby increasing vitamin D levels and decreasing inflammatory biomarkers in diabetic rats... Taken together, these findings suggest that glutathione deficiency rather than vitamin D deficiency is a primary cause underlying biochemical abnormalities, including the decreased biosynthesis of vitamin D, and is responsible for serious manifestations and death in COVID-19 patients...

Hypothesis

Endogenous glutathione deficiency appears to be a crucial factor enhancing SARS-CoV-2-induced oxidative damage of the lung and, as a result, leads to serious manifestations, such as acute respiratory distress syndrome, multiorgan failure, and death in COVID-19 patients. When the antiviral activity of GSH is taken into account, individuals with glutathione deficiency seem to have a higher susceptibility for uncontrolled replication of SARS-CoV-2 virus and thereby suffer from an increasing viral load....

Since the antiviral effect of glutathione is nonspecific, there is reason to believe that glutathione is also active against SARS-CoV-2. Therefore, restoration of glutathione levels in COVID-19 patients would be a promising approach for the management of the novel coronavirus SARS-CoV-2. Notably, long-term oral administration of N-acetylcysteine has already been tested as an effective preventive measure against respiratory viral infections. (1) N-Acetylcysteine is widely available, safe, and cheap and could be used in an “off-label” manner. Moreover, parenteral injection of NAC or reduced glutathione (GSH is more bioavailable than NAC) could be an efficient therapy for COVID-19 patients with serious illness. Horowitz et al. just published a paper confirming this hypothesis: the authors reported the efficacy of glutathione therapy in relieving dyspnea associated with COVID-19 pneumonia."