Endogenous deficiency of glutathione as the most likely cause of serious manifestations and death
from novel coronavirus infection (COVID-19): a hypothesis based on literature data
and own observations
Alexey V. Polonikov, MD, PhD, Professor
Department of Biology, Medical Genetics and Ecology Kursk State Medical University
Research Institute for Genetic and Molecular Epidemiology. Kursk State Medical University
3, Karl Marx Street, 305041 Kursk, Russian Federation
Telephone/Fax: +7(4712) 58-81-47
Word count: 1225
Glutathione is a tripeptide consisting of cysteine, glycine, and glutamate, the most abundant
antioxidant preventing oxidative damage of cells from reactive oxygen species (ROS) . Maintenance
of highest (millimolar) concentrations of reduced glutathione (GSH) in most cell types highlights its
vital and multifunctional roles in the control of various biological processes such as detoxification of
foreign and endogenous compounds, protein folding, regeneration of vitamins C and E, antiviral action,
mitochondrial function, regulation of cellular proliferation, apoptosis and immune response [1,2].
Considering higher rates of serious illness and death from novel coronavirus SARS-CoV-2 infection
(COVID-19) among older people and those with comorbidity leading to severe pressure on health
services, there is an urgent need to identify effective drugs for disease prevention and treatment .
Despite a number of publications reporting beneficial effects of glutathione on human health including
antiviral defense, the key role of this powerful antioxidant in human physiology and pathology and also
a wide spectrum its clinical application remain underestimated.
Literature data analysis
In order to obtain scientific information regarding a possible link between glutathione deficiency
and viral infections, including novel coronavirus SARS-CoV-2 infection, its risk factors, mechanisms
and clinical manifestations, a literature search was performed across Pubmed and Google Scholar
publications (on April 15, 2020). Over a hundred original articles and reviews have been found and
analyzed. As expected, numerous studies reported that endogenous glutathione deficiency attributed to
its decreased biosynthesis and/or increased depletion, represents a significant contributor to the
pathogenesis of a wide range of human disorders through the mechanisms involving oxidative stress and
inflammation. Figure summarizes the most illustrative evidences from biomedical literature indicating
that glutathione deficiency is the most likely explanation for epidemiological findings on COVID-19
infection regarding the groups at higher risk for severe illness and death, and the restoration of this
deficiency can ameliorate clinical manifestations and prognosis significantly in such patients, as it has been
clearly demonstrated in other acute respiratory viral infections and pulmonary diseases. In particular, strong
evidence from human and animal studies points out the levels of endogenous glutathione are progressively
declined with aging making the cells in elderly more susceptible to oxidative damage caused by different
environmental factors including viral infections than in the young. The primary deficiency in endogenous
glutathione, found in many chronic diseases such as type 2 diabetes, obesity, cancer, cardiovascular,
respiratory and liver diseases, may shift per se redox homeostasis in COVID-19 patients towards
oxidative stress, thereby exacerbating inflammation in the lung and airways that may lead to acute
respiratory distress syndrome (ARDS), multiorgan failure and death. Numerious studies demonstrated
that the levels of reduced glutathione in males are lower than in females. This may be a reason why males
are more susceptible to oxidative stress and have often poor outcomes from COVID-19 infection than
females. Cigarette smoke is known deplete cellular glutathione pool in the airways, thereby exacerbating
oxidative damage and inflammation in the lung, more likely requiring intensive medical interventions.
Importantly, glutathione is known to protect host immune cells through its antioxidant mechanism and
provide the optimal functioning of cells of the immune system. Notably, there are evidences that glutathione
inhibits replication of various viruses at different stages of the viral life cycle, thereby decreasing viral load
and probably preventing the massive release of inflammatory cells into the lung (“cytokine storm”).
Antiviral efficiency of such treatment has been demonstrated by a study of Flora with co-workers 
showed that six-month preventive administration of N-acetylcysteine (NAC, precursor of glutathione),
significantly reduced the incidence of clinically apparent influenza and influenza-like episodes, especially in
elderly high-risk individuals. In addition, pathophysiological conditions such as lung cell injury and
inflammation found in patients with severe ARDS represents the targets for effective treatment by NAC
Own observations of COVID-19 cases
Our research team from Kursk State Medical University is involved in the project on genetics of
redox homeostasis in type 2 diabetes mellitus (T2D) since December, 2016 .In April 2020, four
patients from the control group, examined in February 2020, contacted with persons with COVID-19
confirmed diagnosis (3 patients were quarantined at home and 1 patient was hospitalized in Kursk
infectious hospital).Blood samples have been collected from the patients and used to measure total
plasma ROS and GSH levels immediately after blood sampling).All four cases were females, non-
smokers, without chronic diseases and with confirmed positive PCR-test for COVID-19.Description of
the cases is presented below.
1.-Patient-M.-(age-34), BMI-23.8 kg/m2. Symptoms (fever-38°C, mild myalgia) appeared on the
8th-day after contact with a COVID-19 positive patient and disappeared on the 6th-day of disease
without treatment. GSH-0.712 μmol/L, ROS-2.075 μmol/L, ROS/GSH-ratio-2.9.
2.-Patient P.-(age-47), BMI 21.0-kg/m2. Symptoms (fever-37.3°C, mild fatigue) appeared on the
10th-day after contact with a COVID-19 positive patient and disappeared on the 4th-day of disease
without treatment. GSH-0.933 μmol/L, ROS-1.143 μmol/L, ROS/GSH-ratio-1.2.
3.-Patient C.-(age-44), BMI 22.5-kg/m2, family history (FH) for diabetes. First symptoms such as
fever 37.7°C and air hunger appeared on the 4th-day after contact with a COVID-19 positive patient.
Daily fever between 37.1 and 38.5°C, dry cough, hoarseness, significant myalgia and fatigue are
persisting to date for 13-days. GSH-0.079- (!)-μmol/L, ROS-2.73-μmol/L, ROS/GSH ratio-34.6-(!).
4.-Patient-R.-(age 56), BMI-33.0-kg/m2, PH for diabetes. Symptoms (fever 39°C, severe dry
cough, dyspnea, significant fatigue and tachycardia) appeared on the 7th-day after contact with a
COVID-19 positive patient, and she was hospitalized with characteristic radiological signs of COVID-
19 pneumonia. Clinical symptoms are persisting to date for 11 days. GSH-0.531-μmol/L, ROS-3.677-
(!) μmol/L, ROS/GSH-ratio-6.9-(!).
Based on the literature findings and own observations, a conclusion can be drawn that glutathione
deficiency is the most plausible explanation of why people with established risk factors have severe
clinical manifestations of COVID-19 infection and increased risk of death. Glutathione deficiency
appears to be a common disorder attributed to both environmental and genetic factors including those
determining an individual susceptibility to chronic diseases and possibly related with changes in age-
and sex-dependent gene expression. Apparently, glutathione deficiency formation takes a long time and
occurs predominantly in a winter-spring season associated with an insufficient consumption of fresh
vegetables and fruits, natural sources of glutathione . In this regard, a decreased consumption of fresh
vegetables and fruits may explain established racial difference in the rate of severe manifestations and
death from COVID-19 infection with lower rate among Japanese and Koreans consuming a lot of plant
foods and higher rate among African Americans having a limited access to such healthy foods.
The antiviral effect of glutathione is clearly non-specific, since GSH is known to inhibit replication of
various types of viruses, and therefore there is reason to believe that glutathione is also active against the
novel coronavirus infection. Our observations demonstrate that patients with moderate-to-severe COVID-
19-infection have lower levels of glutathione, higher ROS levels, and greater ROS/GSH ratio than
patients with a mild illness suggesting that coronavirus SARS-CoV-2 cannot actively replicate at higher
levels of cellular glutathione, and a lower viral load is manifested by milder clinical symptoms. This
makes glutathione a promising drug for etiological treatment of various viral infections. Therefore, oral
administration of N-acetylcysteine as a preventive measure against viral infections , as well as
intravenous injection of NAC or reduced glutathione (GSH is highly bioavailable) in patients with
serious illness may be effective options against novel coronavirus SARS-CoV-2 infection. However,
clinical trials are needed to objectively assess an efficacy of N-acetylcysteine and reduced glutathione
for both the treatment and prevention of this novel viral infection.
Conflict of interests: not declared
1. Forman HJ, Zhang H, Rinna A. Glutathione: overview of its protective roles, measurement, and
biosynthesis. Mol Aspects Med. 2009;30(1-2):1-12.
2. Pizzorno J. Glutathione! Integr Med (Encinitas). 2014;13(1):8-12.
3. Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic Treatments for
Coronavirus Disease 2019 (COVID-19): A Review. JAMA. 2020. doi:10.1001/jama.2020.6019.
4. De Flora S, Grassi C, Carati L. Attenuation of influenza-like symptomatology and improvement
of cell-mediated immunity with long-term N-acetylcysteine treatment. Eur Respir J. 1997;10(7):1535-
5. Azarova I, Bushueva O, Konoplya A, Polonikov A. Glutathione S-transferase genes and the risk
of type 2 diabetes mellitus: Role of sexual dimorphism, gene-gene and gene-smoking interactions in
disease susceptibility. J Diabetes. 2018;10(5):398-407.
6. Minich DM, Brown BI. A Review of Dietary (Phyto)Nutrients for Glutathione Support.