Significance: Hydrogen sulfide (H 2 S) is one of the three main gasotransmitters that are endogenously produced in humans and are protective against oxidative stress. Recent findings from studies focusing on coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), shifted our attention to a potentially modulatory role of H 2 S in this viral respiratory disease. Recent Advances: H 2 S levels at hospital admission may be of importance since this gasotransmitter has been shown to be protective against lung damage through its antiviral, antioxidant, and anti-inflammatory actions. Furthermore, many COVID-19 cases have been described demonstrating remarkable clinical improvement upon administration of high doses of N-acetylcysteine (NAC). NAC is a renowned pharmacological antioxidant substance acting as a source of cysteine, thereby promoting endogenous glutathione (GSH) biosynthesis as well as generation of sulfane sulfur species when desulfurated to H 2 S. Critical Issues: Combining H 2 S physiology and currently available knowledge of COVID-19, H 2 S is hypothesized to target three main vulnerabilities of SARS-CoV-2: (i) cell entry through interfering with functional host receptors, (ii) viral replication through acting on RNA-dependent RNA polymerase (RdRp), and (iii) the escalation of inflammation to a potentially lethal hyperinflammatory cytokine storm (toll-like receptor 4 [TLR4] pathway and NLR family pyrin domain containing 3 [NLRP3] inflammasome). Future Directions: Dissecting the breakdown of NAC reveals the possibility of increasing endogenous H 2 S levels, which may provide a convenient rationale for the application of H 2 S-targeted therapeutics. Further randomized-controlled trials are warranted to investigate its definitive role. Antioxid. Redox Signal. 00, 000-000.

With the emerging mutations and new pandemic waves, there remains a need for an effective antiviral, administered safely and easily in the early treatment phase of SARS-CoV-2, despite the current roll-out of vaccines. For antiviral options in COVID-19 two studies deserve our attention: 1--Ten consecutive severe COVID-19 cases, on the ventilator as well ECMO support, all recovered completely and fairly rapidly by high doses of N-acetylcysteine (NAC) without any mortality. 2--Another study found that serum H2S level is a prognostic marker in COVID-19 pneumonia. A low serum level H2S at admission or a decrease during infection significantly increased the risk of death in COVID-19 patients (n = 74). Combining these two findings may give us even more options. Stepwise we explore how H2S works in viral respiratory diseases and we focus on the targets in COVID-19: the cell entry (ACE2 receptor), the virus replication (RdRp, nsp12), and the escalation of inflammation to a lethal cytokine storm (NLRP3 inflammasome). Finally, consider the question: How to administer H2S? Dissecting the degradation of NAC shows how the endogenous H2S level can be generated and with which drugs. Already 13 well-documented human cases have successfully supported this approach. The antiviral application of the endogenous H2S provides a pathway to reactivate the collapsed innate immunity as a treatment regimen for COVID-19, in early out-patient as well as later clinical situations. Further randomized controlled trials are warranted, with consideration of antiviral H2S for inclusion in one of the ANTICOV or WHO protocols.

Aim. To propose a new type of antiviral treatment for COVID-19, pending the rollout of the developed vaccines and bypassing vaccine resistance of the new upcoming mutated virus variants. Aiming for prophylaxis and early therapy, the search focused on small molecules or repurposed, safe, oral and inexpensive drugs, also suitable for low-income countries.Methods. A search in peer-reviewed literature for preclinical antiviral mechanisms highlighted at last two clinical studies for further detailed clinical analysis: 1) High dose N-acetylcysteine (NAC) was successfully applied in very severe COVID-19-pneumonia; 2) The discovery of serum level H2S (hydrogen sulfide) as a prognostic host factor.Results. Combining of these two findings resulted in a step-by-step approach with 3 perspectives that describes how H2S works in viral respiratory diseases, how H2S targets at least three vulnerabilities in the SARS-CoV-2 virus; finally, how H2S can be generated and with which drugs. More than 3 dozen successful, clinically well-documented applications have already been found.Conclusion. By using NAC as the H2S donor, the generated endogenous antiviral H2S reactivates the collapsed innate immunity, providing a therapy regimen for COVID-19. Further randomized controlled trials are warranted, considering antiviral H2S for inclusion in some master trial protocols.

No abstract

Correspondence regarding Klompas et al, in NEJM June 14, 2023; titled ''Strategic Masking to Protect Patients from All Respiratory Viral Infections'', a plea for structured use of masks to protect against future CoV2 and other types of viral infections in a hospital setting. We do not disagree with this, but we think that instead of a passive mask barrier, another active way can also achieve this goal, but more broadly. -The other respiratory viruses that Dr Klampos mentions are almost all of the 'single RNA enveloped' type. This is precisely the starting point of the proposed treatment method with an H2S donor, this has already been described by Dr Casola's group in some top journals (references 5,6,7). -In addition, NAC (very safe, known for a long time, cheap and available everywhere) has also been designated as an H2S donor. This makes global application possible, especially in low-income countries. [ref 12-18]. NAC effervescent tablets are cheaper than a medically suitable mask. This also invites to include NAC as a comparator in future RC trials. -This H2S supplementation for the restoration of innate immunity can be applied at different scales (cohorts): e.g. community, hospital, wards, barracks, cruise ships, prison, etc. Then staff and Clients/Patients can be treated combined in such a cohort.