4.3 H2S as a potential biomarker in determining final outcome of COVID-19 infection
Although there is currently no studies on effect of H2S on COVID-19-associated nephropathy, recent clinical study in a cohort of patients with COVID-19 pneumonia showed that circulating H2S level was significantly higher along with increased lymphocyte count and reduced serum interleukin-6 (IL-6; an inflammatory marker) in survivors of the disease compared to healthy controls and those who died of the disease (Renieris et al., 2020). This observation suggests that H2S could be a potential biomarker to determine the final outcome of pneumonia caused by COVID-19. It is important to note that IL-6 is considered a major pro-inflammatory mediator in the cytokine-storm syndrome that causes respiratory failure and COVID-19-associated mortality (Gubernatorova et al., 2020). There are studies including ours, showing that H2S is a potent inhibitor of pro-inflammatory pathway by inhibiting pulmonary and renal IL-6 and several other pro-inflammatory mediators such as IL-2, tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), intercellular adhesion molecule-1 (ICAM-1) and NF-κB while simultaneously increasing the levels of anti-inflammatory cytokines (Lobb et al., 2014; Zhang et al., 2016). Therefore, the findings by Renieris et al. (2020) may suggest that the increased serum H2S level in the COVID-19 survivors could be due to increased endogenous H2S production from the lungs and perhaps the kidneys and other tissues to suppress production of IL-6 and other pro-inflammatory mediators which are yet to be investigated. This is in agreement with the a study by Li and colleagues (2015) who observed reduced endogenous H2S production and downregulation of CSE mRNA and protein expression (H2S-producing enzyme) in airway epithelial cells infected with respiratory syncytial virus, the virus commonly associated with upper and lower respiratory tract infections in children of which there is no vaccine or effective treatment. Further evidence of the involvement of H2S in virus-induced respiratory condition was reported when increased viral replication and airway inflammation was observed in CSE knockout mice infected with respiratory syncytial virus compared to wild-type mice (Ivanciuc et al., 2016). Interestingly, treatment with the H2S donor, GYY4137, markedly reduced the viral replication of not only respiratory syncytial virus but also human metapneumovirus and Nipah virus, which correlated with decreased production of pro-inflammatory mediators and improvement in airway dysfunction (Ivanciuc et al., 2016). These findings provide strong evidence of the antiviral property of H2S, which could be a potential therapeutic agent against COVID-19. In addition, administration of NAC to 10 patients with severe COVID-19 significantly improved clinical and biochemical parameters (Ibrahim et al., 2020) as well as clinical improvement in two critically ill COVID-19 patients with multisystem organ dysfunction, who were treated with intravenous administration of NAC (75 mg/kg over 4 hours, then 35 mg/kg over 16 hours, followed by 17 mg/kg over 24 hours on day 2) along with low-dose hydroxychloroquine (Puyo et al., 2020). This finding is supported by another case of a severely ill COVID-19 patient who was cured and discharged following administration of NAC inhalation solution (Liu et al., 2020). However, a recent double-blind, randomized controlled trial in which intravenous administration of NAC (14 g/kg in the first 4 hours and 7 g/kg in the next 16 hours) to severe COVID-19 patients in late stage of the disease showed no clinical benefits compared to placebo group (de Alencar et al., 2021). This contradictory result could be attributable to differences in the dose of NAC and treatment regimen, synergistic effect with hydroxychloroquine, and the timing of NAC administration, as the latter study administered NAC later than 7–10 days after the onset of COVID-19 symptoms compared to the former study. It further suggests that the aforementioned factors are crucial in the treatment of COVID-19 patients with NAC or other H2S donors, and should be matched with concurrent medical treatments. These clinical outcomes have led to conduction of several clinical trials with NAC to determine the most appropriate timing of administration in various stages of COVID-19. In the face of the potential positive role of H2S in COVID-19 cases, Dominic et al. (2021) recently refuted the report of Renieris et al. (2020) by showing low circulating H2S levels in Caucasian and African American COVID-19 patients compared to healthy controls and fatal cases. This conflicting finding could be due to important determinants such as age, race, sex, comorbidities (e.g. diabetes and hypertension) and stage of COVID-19 infection, which were not reported in the former study. Another important factor for consideration is the differences in the method of serum H2S measurement, as H2S decay was so fast in the latter study and may not have been very accurate. Besides, the authors of the latter study did not include high performance liquid chromatography (a new method of H2S quantification in biological systems) in their serum H2S measurement, which their counterparts in the former study did, although both studies used the common monobromobimane method of H2S measurement. This discrepancy in the two studies requires additional investigations, and should take into consideration all important determining factors of H2S, to establish the exact role of H2S in determining the final outcome of COVID-19 infection.
The pathological characteristics of COVID-19 also includes coagulopathy, during which there is progression of thrombosis and generation of DIC with increased platelet–leukocyte aggregates, which promote coagulation and vascular inflammation in the glomeruli of critically ill patients, and partly accounts for COVID-19-related mortality (Pfister et al., 2021). Hence, inhibiting platelet–leukocyte aggregates is a therapeutic interest in COVID-19 patients, especially those with kidney conditions. Emerging evidence using animal and human whole blood shows that H2S donors such as NaHS and GYY4137 inhibit the coagulation system by preventing DIC formation and platelet-leukocyte aggregation, and facilitate thrombolysis, leading to impairment in thrombus stability (Lu et al., 2015; Grambow et al., 2017). Therefore, these findings about the thrombolytic or anti-thrombotic property of H2S could advance its potential clinical utility by COVID-19 patients.