With the appearance of the COVID-19 pandemic, a race for the discovery of effective
treatments to combat SARS-CoV-2 infection and its sequelae commenced. Some patients with
COVID-19 develop severe acute respiratory syndrome which is the main reason for death.
The aim of this study is to spearhead pharmacotherapeutic solutions for COVID-19 patients
in the intensive care which have proven to be the hardest to treat due to the high death
rate, the long-term allocation of patients in ICU, and the slow recovery that oftentimes
leads to residual symptoms and signs. The ever-increasing pressure on the health care
system requires finding an effective treatment that can benefit even advanced-stage
patients such as those in the intensive care unit.

It was not until recently that the published literature about hydrogen sulfide shifted
from revolving around its toxicity to its recognition as an endogenous gaseous signaling
molecule and its biological roles. Hydrogen Sulfide (H2S) is a novel gaseous signaling
molecule (gasotransmitter) that regulates a variety of physiological functions and
provides protection against organ damage (anti-inflammatory, prolonged survival,
cardioprotection, antioxidant, and more). H2S also displays beneficial roles in
preventing lung disorders such as pneumonia, lung injury (acute/ chronic), and chronic
obstructive pulmonary disease and limits viral replication. H2S has been shown to be
effective in reversing lung inflammation and improving pulmonary function in various
animal models. Based on preclinical data, cystathionine-γ-lyase (CSE)-derived H2S or
exogenously applied H2S may block Severe Acute Respiratory Syndrome Coronavirus-2
(SARS-CoV-2) entry into the host cells by interrupting Angiotensin-Converting Enzyme-2
(ACE2) and transmembrane protease serine-2 (TMPRSS2), inhibiting viral replication by
attenuating syncytium formation and virus assembly/release, and thus may protect
SARS-CoV-2-induced lung damage by suppressing the immune response and the development of
inflammation.

Lymphopenia is a key characteristic of COVID-19 patients. Serum H2S was positively
correlated with the lymphocyte count and is considered a predictor of mortality.
Additionally reduced H2S bioavailability has been suggested as an indicator of enhanced
pro-inflammatory responses and endothelial dysfunction. Both these conditions often
accompany severe COVID-19. Interleukin-6 (IL-6) has been proposed as the principle
pro-inflammatory cytokine involved in the cytokine storm that leads to severe lung
injury, respiratory failure, and death by COVID-19. A negative association between IL-6
and serum H2S has been shown to exist. The above-mentioned results led to further
evaluation of admission H2S levels as a marker of survival in a recent study. Results
showed that serum levels of H2S on day 1 lower than 150.44 micromolars (μM) had the best
tradeoff for sensitivity and specificity for death. Thus, administration of a H2S-donor
could be a potential remedy for COVID-19 by relieving the damage in lungs and other
organs.

Sodium thiosulfate (STS) is a H2S-donor with known safety and efficacy profile in humans
for other diseases, including calciphylaxis and cyanide poisoning. STS can be metabolized
to H2S and acts as a precursor for H2S signaling. Moreover, in patients presenting with
acute coronary syndrome, a phase 1 study was conducted, showing that STS was well
tolerated, even with concomitant use of blood pressure lowering drugs. Additionally, the
Groningen Intervention study for Preservation of cardiac function with Sodium thiosulfate
in ST-elevation myocardial infarction (GIPS-IV trial) is the first trial in humans
designed to test the hypothesis that STS provides protection against I/R injury in
patients presenting with ST-segment elevation myocardial infarction