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.