Highlights•

Low serum levels of H2S in COVID-19 pneumonia are associated with a poor prognosis

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Endogenous H2S production can be increased therapeutically by administering NAC

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NAC therapy was associated with improvement in SpO2/FiO2, CRP, and NEWS2 scale

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There were no significant differences in the clinical outcomes (IMV, mortality)

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NAC therapy was not associated with moderate and severe adverse events

KeywordsDear Editor,Despite numerous clinical studies conducted over the past year, we have to admit that today we still have a very limited list of effective drugs for the treatment of Novel coronavirus disease 2019 (COVID-19). Dexamethasone improves survival in hospitalized patients requiring supplemental oxygen or respiratory support (1Collaborative Group RECOVERY Horby P Lim WS Emberson JR Mafham M Bell JL Linsell L et al.Dexamethasone in Hospitalized Patients with Covid-19.), and in the presence of systemic inflammation, tocilizumab may provide additional benefits (2Collaborative Group RECOVERY Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.). Thus, there remains an unmet need for therapeutic interventions that prevent disease progression and improve prognosis in patients with COVID-19.Therefore, we read with great interest a recent article by Hasan et al. who reported data from a small retrospective cases series of COVID-19 patients that received an IL-17A inhibitor (secukinumab) (3Hasan MJ Rabbani R Anam AM Huq SMR. Secukinumab in severe COVID-19 pneumonia: Does it have a clinical impact?.). The authors demonstrated that this type of therapy, aimed at a new target, could reduce the severity of the cytokine storm and ultimately improve clinical outcomes in patients with severe COVID-19 pneumonia. The search for other targets of COVID-19 therapy is of undoubted interest.Bourgonje et al. described the potential role of hydrogen sulfide (H2S) as a fundamental host defense factor against SARS-CoV-2 infection (4Bourgonje AR Offringa AK van Eijk LE Abdulle AE Hillebrands JL van der Voort PHJ et al.N-Acetylcysteine and hydrogen sulfide in Coronavirus disease 2019.). Low serum levels of hydrogen sulfide (H2S) in patients with COVID-19 pneumonia have been shown to be negatively associated with inflammatory biomarkers such as IL-6 and C-reactive protein (CRP), and also associated with a poor prognosis (5Renieris G Katrini K Damoulari C Akinosoglou K Psarrakis C Kyriakopoulou M et al.Serum hydrogen sulfide and outcome association in pneumonia by the SARS-CoV-2 coronavirus.). Endogenous H2S production can be increased therapeutically by administering N-acetylcysteine (NAC), which can be seen as a potential treatment strategy for COVID-19 patients (4Bourgonje AR Offringa AK van Eijk LE Abdulle AE Hillebrands JL van der Voort PHJ et al.N-Acetylcysteine and hydrogen sulfide in Coronavirus disease 2019.). NAC may also replenish intracellular reduced glutathione (GSH) pools by providing L-cysteine, a precursor for GSH synthesis (6Meyer A Buhl R Kampf S Magnussen H. Intravenous N-acetylcysteine and lung glutathione of patients with pulmonary fibrosis and normals.). Moreover, NAC has shown the ability to restore the intracellular redox imbalance in vitro experiments (7Aldini G Altomare A Baron G Vistoli G Carini M Borsani L Sergio F. N-Acetylcysteine as an antioxidant and disulphide breaking agent: the reasons why.).To date, the published data on the efficacy of NAC therapy in COVID-19 are very scarce, and their results are rather controversial (8Ibrahim H Perl A Smith D Lewis T Kon Z Goldenberg R et al.Therapeutic blockade of inflammation in severe COVID-19 infection with intravenous N-acetylcysteine., 9Alamdari DH Moghaddam AB Amini S Keramati MR Zarmehri AM Alamdari AH Damsaz M Banpour H Yarahmadi A Koliakos G. Application of methylene blue -vitamin C -N-acetyl cysteine for treatment of critically ill COVID-19 patients, report of a phase-I clinical trial., 10de Alencar JCG Moreira CL Müller AD Chaves CE Fukuhara MA da Silva EA et al.Double-blind, randomized, placebo-controlled trial with N-acetylcysteine for treatment of severe acute respiratory syndrome caused by COVID-19.). Herein we describe the response to NAC therapy in a cohort of hospitalized patients with COVID-19 pneumonia.

This case-control study was conducted in the Pulmonology department of a university-affiliated hospital (Sechenov University) between April 12, 2020, and June 20, 2020. The study was approved by the Medical Ethical Committee (protocol number 08-20/1), and written informed consent was obtained from all patients.

We prospectively enrolled patients over 40 years old with additional high-risk criteria (≥65 years, cardiovascular comorbidities, diabetes, and BMI ≥ 30 kg/m2), with SARS-CoV-2 infection confirmed by real-time polymerase chain reaction, and radiological findings compatible with severe COVID-19 pneumonia. The exclusion criteria were as follows: need for immediate endotracheal intubation, chronic respiratory diseases, unstable hemodynamics, and pregnancy. According to the local protocol, all patients received hydroxychloroquine, azithromycin, corticosteroids, prophylactic low-molecular-weight heparin, and tocilizumab if indicated. The experimental group comprised patients who received NAC at a daily dose of 1200-1800 mg intravenously; the comparator arm was drawn from patients who did not receive NAC. All control patients had the same enrollment criteria described for the NAC group, and the measured parameters were collected prospectively on the same data chart, according to a standardized treatment procedure. Controls were matched to patients in the experimental group by age (within ±5 years), SpO2/FiO2 ratio (within ±20), and NEWS2 score (within ±1 point).

The primary objective was to assess the effect of NAC on arterial oxygen saturation to inspired oxygen fraction ratio (SpO2/FiO2) on Day 10. Clinical and laboratory data were recorded at admission and on day 10. We also analyzed the length of hospitalization and outcome of the disease, such as transfer to intensive care unit (ICU), need for non-invasive and invasive mechanical ventilation, and 28-day mortality.

A total of 24 consecutive patients were treated with NAC, and 22 patients were included in the control group. The baseline demographic, clinical and laboratory characteristics at baseline did not differ significantly between the groups (Table 1). The time between the symptom onset and NAC administration was 7.2 (6Meyer A Buhl R Kampf S Magnussen H. Intravenous N-acetylcysteine and lung glutathione of patients with pulmonary fibrosis and normals., 7Aldini G Altomare A Baron G Vistoli G Carini M Borsani L Sergio F. N-Acetylcysteine as an antioxidant and disulphide breaking agent: the reasons why., 8Ibrahim H Perl A Smith D Lewis T Kon Z Goldenberg R et al.Therapeutic blockade of inflammation in severe COVID-19 infection with intravenous N-acetylcysteine., 9Alamdari DH Moghaddam AB Amini S Keramati MR Zarmehri AM Alamdari AH Damsaz M Banpour H Yarahmadi A Koliakos G. Application of methylene blue -vitamin C -N-acetyl cysteine for treatment of critically ill COVID-19 patients, report of a phase-I clinical trial.) days. On day 1 of a study, 3 and 4 patients in NAC group and control groups, received noninvasive ventilation, and 16 and 13 patients, respectively, required oxygen supplementation via reservoir oxygen face mask.

Table 1Main characteristics of patients at baseline and on day 10 of the treatment, and clinical outcomes.

On Day 10, NAC therapy led to significant improvement in SpO2/FiO2 compared to the controls (Table 1). Furthermore, NAC administration markedly decreased the values of CRP and NEWS2 scale in comparison to the control group (Table 1). Duration of hospitalization was also significantly shorter in the NAC group (p=0.01). All other clinical outcomes (transfer to ICU, need for non-invasive or invasive mechanical ventilation, and 28-day mortality) did not differ between the groups (Table 1). There were no cases of adverse events leading to NAC discontinuation.Several studies also examined the efficacy of NAC in hospitalized patients with COVID-19. Ibrahim et al. have demonstrated that in respirator-dependent patients intravenous NAC elicited clinical improvement and reduced CRP and ferritin (8Ibrahim H Perl A Smith D Lewis T Kon Z Goldenberg R et al.Therapeutic blockade of inflammation in severe COVID-19 infection with intravenous N-acetylcysteine.). In another study by Alamdari et al., the administration of NAC in combination with high doses of methylene blue and vitamin C as a last therapeutic option resulted in a significant clinical response and recovery in four out of five critically ill patients with COVID-19 (9Alamdari DH Moghaddam AB Amini S Keramati MR Zarmehri AM Alamdari AH Damsaz M Banpour H Yarahmadi A Koliakos G. Application of methylene blue -vitamin C -N-acetyl cysteine for treatment of critically ill COVID-19 patients, report of a phase-I clinical trial.). At the same time, de Alencar et al. have shown that NAC administration in high doses did not affect the evolution of severe COVID-19 (10de Alencar JCG Moreira CL Müller AD Chaves CE Fukuhara MA da Silva EA et al.Double-blind, randomized, placebo-controlled trial with N-acetylcysteine for treatment of severe acute respiratory syndrome caused by COVID-19.). However, in this study, patients were not receiving systemic steroids. Thus, the role of NAC in COVID-19 is still controversial. Identifying a population that would likely benefit from NAC is the key question of the treatment of COVID-19. Presently several registered randomized control trials are evaluating the dose, efficacy, and safety of NAC therapy in COVID-19 (NCT04455243, NCT04374461, NCT04419025, NCT04458298).

Our study has several limitations. The case-control design cannot exclude a bias in the analysis of outcomes, and statistical analysis and interpretation of our study results are further limited by the small sample size.

Overall, our study demonstrated that NAC therapy provided a significant improvement in oxygenation parameters and reduction in CRP, NEWS2 scale, and length of hospitalization in hospitalized patients with COVID-19. These results need to be confirmed with further randomized prospective trials in a larger cohort.

Declaration of Competing Interest

The authors have no competing interest to declare.

Acknowledgments

The authors are grateful to Dr. Tatiana Gorbacheva and Dr. Inna Medvedeva for their help with the clinical management of our patients (University Clinical Hospital №4, Sechenov Moscow Medical University).

Funding

No funding was received for this work.

Ethical approval

The study was approved by the Medical Ethical Committee of Sechenov Moscow Medical University (protocol number 08-20/1).

CRediT authorship contribution statement

Sergey Avdeev: Conceptualization, Methodology, Validation, Resources, Data curation, Writing - original draft, Writing - review & editing, Supervision, Project administration. Viliya Gaynitdinova: Conceptualization, Investigation, Methodology, Validation, Data curation, Writing - original draft, Writing - review & editing. Zamira Merzhoeva: Investigation, Validation, Data curation, Writing - review & editing. Zelimkhan Berikkhanov: Investigation, Validation, Data curation, Writing - review & editing.

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Clin Infect Dis. 72: e736-e741https://doi.org/10.1093/cid/ciaa1443Article InfoPublication HistoryPublication stageIn Press Journal Pre-ProofIdentification

DOI: https://doi.org/10.1016/j.jinf.2021.07.003

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