Since 2019, the world has faced a pandemic caused by a coronavirus called SARS-CoV-2. This betacoronavirus uses angiotensin-converting enzyme 2 (ACE2) to enter cells through its interaction with protein S.1 The disulfide bridges that form this interaction are fundamental, as is the equilibrium between the disulfide (SS) and thiol (-SH) groups.2

In the most severe forms of COVID-19, there is an excessive release of inflammatory mediators such as interleukin (IL)-1β, IL-2, IL-6, tumor necrosis factor (TNF)-α, and others. This is known as the “cytokine storm.”3,4 This leads to a massive release of free radicals, with the development of oxidative stress and a decrease in levels of glutathione, which plays an important role in tissue damage.5,6 Therefore, substances with an antioxidant effect have been proposed as treatment options, including ascorbic acid, zinc, vitamin D, and N-acetylcysteine (NAC).7–9

NAC is a precursor of glutathione derived from l-cysteine and has antioxidant action. There is extensive experience in its use in other diseases such as chronic obstructive pulmonary disease. It has been suggested for use in COVID-19 thanks to its multiple effects. Its mucolytic action is due to its capacity to break the disulfide bridges of the glycoprotein matrix. Its antioxidant effect is thanks to its capacity to replenish thiol and glutathione levels and to neutralize free radicals.10 Lastly, its anti-inflammatory action is due to its ability to inhibit cytokines such as IL-6 and promote lymphocyte proliferation (which is inversely affected by oxidative stress and low levels of glutathione.11,12

Spain was one of the countries most affected by the pandemic in the first wave (from January 31 to June 21, 2020). The worst months were March and April, which was also true in our center.13 Given the lack of a specific treatment for COVID-19, one of the adjuvant treatments proposed was NAC at a dose of 1200mg/day orally. This study aims to verify if the use of NAC had a positive impact on the progress of hospitalized patients and on reducing mortality due to COVID-19.

This study showed that the oral administration of NAC at a dose of 1200mg per day was associated with lower mortality in patients hospitalized due to COVID-19. The risk factors identified by means of logistic regression were age, greater radiological involvement, tobacco use, and presence of prior arrhythmia whereas treatment with NAC was a protective factor. In regard to asthma, the use of inhaled corticosteroids seemed to confer a certain degree of protection against SARS-CoV-2, as it reduced ACE2 receptor expression in the lungs.14,15

As shown in other studies, the use of NAC at high doses (≥1200mg/day) may have beneficial effects due to its antioxidant and anti-inflammatory action. This would help prevent production of oxygen free radicals and the cytokine storm in COVID-19.16,17 On the other hand, NAC may have a modulating role in ACE2 receptors, hindering the binding of SARS-CoV-2 to protein S and its entry into the cell.18 This effect is maintained even with the new variants, including Delta and Omicron.19 Findings have recently been published on its role in reducing inflammasomes in samples obtained through tracheal biopsy in severe patients with COVID-19 treated with NAC.20

The low cost of NAC and its good safety profile—with very few side effects even at high doses—make it possible to consider it as a treatment option. Nevertheless, there are contradictory results on its therapeutic effect. Most studies include only a small percentage of patients treated with NAC and the doses used as well as the duration and route of administration vary among the different works. A study conducted in Brazil on 135 severe patients who received intravenous NAC in two initial doses showed no differences in regard to progress and mortality.21 Other studies have reported improvements in mortality and inflammatory patterns, although findings were not statistically significant.22,23 A Greek study on 82 patients who received the same dose of NAC as in this study (1200mg/day orally) showed a reduction in mortality and the need for invasive mechanical ventilation.16 One of the studies with the largest number of cases included 2071 patients treated with NAC at a dose of 1800mg/day. It also showed lower mortality in those who received NAC, though there were no statistically significant differences in regard to the need for invasive mechanical ventilation.17 One of the difficulties is establishing the most suitable dose (in terms of safety and efficacy), considering that the effects of NAC are highly dependent on the dose administered. In general, a minimum NAC dose of 1200mg/day orally is recommended. In patients with severe disease and respiratory compromise, an intravenous NAC dose of 100mg/kg can be used for at least three days.24

Two meta-analyses have recently been published. The work by Paraskevas25 included eight studies and showed no significant differences in favor of NAC, though the authors recognize the low level of evidence (mainly due to the small number of patients) and the need for future research. The work by Chen26 also showed no differences in mortality, need for intubation, or length of hospital stay. However, the clinical trial by Panahi which included 250 patients and in which the treatment group received nebulized NAC did show benefits in the decrease in mortality and inflammatory parameters.27 At present, there are various clinical trials on the use of NAC in COVID-19 which will help clarify these issues.28

This study has several limitations. First, it is an observational study. Therefore, the results obtained must be confirmed by future randomized, controlled clinical trials. Second, patients were treated according to the protocols in force at the hospital, which included other drugs with a possible beneficial effect in COVID-19. To minimize this limitation, patients were divided into treatment subgroups according to whether they received NAC or not and this variable was used to adjust the multivariate analysis. Third, patients with the new Delta and Omicron variants were not included, though the available evidence shows that NAC may have the same effect on these variants.19,24 This study also had strengths. The sample included a large number of patients and it was homogeneous and representative of patients in the first wave, in which the effect of NAC could be studied as there were no specific treatments for these patients yet. The information collected was exhaustive and all data were reviewed and verified, especially data regarding treatment received. Grouping patients with similar treatments made it possible to note the effect of NAC. At present, thanks to the evolution of COVID-19, it is difficult to recruit a group of patients with these characteristics.

In conclusion, the use of NAC at high doses in patients with COVID-19 decreased mortality and was associated with more favorable progress. Future randomized clinical trials or prospective studies may help confirm the role of NAC in these patients. Until then, the low cost and good safety profile of NAC make it a reasonable choice as an associated treatment.

This work was conducted in accordance with the ethics code of the World Medical Association (Declaration of Helsinki). The study protocol was approved by the Drug Research Ethics Committee (DREC) of the Comprehensive Care Management of Alcázar de San Juan.

This research has received neither finantial support nor specific grants from agencies in the public, commercial, or non-profit sectors.

The authors declare that they do not have any conflicts of interest.