N-acetylcysteine: A rapid review of the evidence for effectiveness in treating COVID-19

April 14, 2020

Dr Oliver Van Hecke, Dr Joseph Lee

On behalf of the Oxford COVID-19 Evidence Service Team
Centre for Evidence-Based Medicine, Nuffield Department of Primary Care Health Sciences
University of Oxford
Correspondence to oliver.vanhecke@phc.ox.ac.uk; joseph.lee@phc.ox.ac.uk

VERDICT

• N-acetylcysteine (NAC) has been proposed for use in the therapy and/or prevention of several respiratory diseases and of diseases involving an oxidative stress including COVID-19.
• A search on 3rd April 2020 did not reveal any COVID-specific evidence for NAC, so we have fallen back on evidence in other acute respiratory disorders.
• Clinical trial evidence for the use of NAC as an antioxidant in influenza and other acute viral respiratory tract infections is very limited and therefore difficult to draw any concrete conclusions without further trial evidence.

An old drug repurposed?

N-acetylcysteine (NAC) was introduced in the 1960s as a mucolytic drug for chronic respiratory diseases. It has a well-established safety profile and is still commonly used orally at doses of 600mg/day as a mucolytic. In hospital settings, it is also used as an antidote for paracetamol overdose (IV formulation at doses of up to 150mg/kg) and in nebulized format in patients with acute bronchopulmonary disease (pneumonia, bronchitis, tracheobronchitis). Acetylcysteine makes bronchial mucous less viscous. In vitro, cysteine derivatives act by breaking disulphide bridges between macromolecules, which leads to a reduction in mucus viscosity.(1)

However, at higher doses (≥1200mg), acetylcysteine also acts as an antioxidant through complex mechanisms which can combat conditions of oxidative stress. Acetylcysteine is a derivative of the natural amino acid cysteine, which serves as a substrate for the synthesis of glutathione (GSH) in the body which an antioxidant effect. This reduces the formation of proinflammatory cytokines, such as IL-9 and TNF-α and also has vasodilator properties by increasing cyclic GMP levels and by contributing to the regeneration of endothelial-derived relaxing factor. It is this potential antioxidant mechanism that has sparked interest with the current COVID-19 pandemic and whether this might be useful in community settings.

We therefore aimed to conduct a rapid review of NAC with specific emphasis on its potential for early administration in the community for patients at greater risk of severe COVID-19.

NAC and its antioxidant properties

NAC appears to support the synthesis of glutathione (GSH) under conditions when the demand
for GSH is increased, during oxidative stress. GSH is a critical molecule in resisting oxidative stress with the enzyme glutathione reductase (GR) recycling oxidized glutathione back to the reduced form. GSH levels decrease with age and due to certain disease states e.g Type 2 Diabetes Mellitus, cardiovascular disease.(2) Oral NAC increases GSH levels by providing the liver with an increased supply of cysteine promoting an increase in GSH synthesis, and therefore reduce oxidative stress. Based on a small case series (n=198) patients with COVID-19 had a noticeable increase of glutathione reductase (GR) levels occurring in around 40% of COVID-19 patients.(3)

Several studies addressed the question about the anti-viral activity of NAC against influenza A strains.(4,5) In-vitro and in-vivo experiments show that NAC enhances GSH levels which reduce viral load by inhibiting viral replication in a number of viruses e.g. influenza A (H3N2 and H5N1). However, these models suggest any therapeutic efficacy of NAC is likely to be strain dependent. The protective effect of NAC alone appeared as weak or null in some models with a variation in its efficacy depending on the infecting viral strain.

High dose NAC administration (1.2 g daily) is not recommended in healthy individuals who are not exposed to extreme oxidative stress. NAC might actually act as a pro-oxidant and might lower GSH and increase the amount of oxidized GSH.

Limited clinical trial data to justify its use in COVID-19

Most of the clinical studies where NAC has been used (either alone or in combination with another drug) tend to focus on its use as a mucolytic in two population subgroups: paediatric populations at lower doses where its antioxidant effects are less evident (6) with studies dating mainly from the 1970s and 1980s of low quality evidence; or in patients with chronic bronchitis where treatment periods were lengthy (12±24 weeks) at doses of 400±600 mg/day where NAC reduced the risk of exacerbations and improves symptoms in patients with chronic bronchitis compared with placebo (11 trials, 2,011 participants).(7)

Clinical trial evidence for the use of NAC as an antioxidant in influenza and other acute viral respiratory tract infections is limited and relate to isolated small clinical trials. A small RCT (n=262) in the 1990s showed that NAC (600 mg twice daily for 6 months) attenuated the (self-reported) severity of influenza (A/H1N1 virus) influenza and influenza-like episodes (evaluated by the length of time in bed), particularly in elderly high-risk persons, compared to placebo.(8) There were no deaths and no cases of hospitalisation in either group.

In a small RCT in China (n=39) with patients hospitalised with community-acquired pneumonia, the addition of high dose NAC (1200mg/d for 10 days) to usual care suggested an improvement in oxidative stress parameters, inflammatory factors but not radiological changes compared to usual care only. No clinical outcomes were reported.(9)

CONCLUSIONS
Preclinical data suggests that N-acetylcysteine and its antioxidant properties may have purpose for use in the therapy and/or prevention of acute viral respiratory infections including influenza. However, the therapeutic efficacy of NAC is likely to be strain-dependent. Clinical trial evidence for the use of NAC as an antioxidant in influenza and other acute viral respiratory tract infections is very limited. It is therefore difficult to draw any concrete conclusions without evidence from larger trials. We did not find any COVID-specific evidence for the use of N-acetylcysteine.

Disclaimer:  the article has not been peer-reviewed; it should not replace individual clinical judgement and the sources cited should be checked. The views expressed in this commentary represent the views of the authors and not necessarily those of the host institution, the NHS, the NIHR, or the Department of Health and Social Care. The views are not a substitute for professional medical advice.

AUTHORS
Joseph Lee is a General Practitioner and doctoral researcher based at the Nuffield Department of Primary Care Health Sciences, University of Oxford.
Oliver van Hecke is a General Practitioner and NIHR Academic Clinical Lecturer based at the Nuffield Department of Primary Care Health Sciences, University of Oxford.

SEARCH TERMS
We searched Pubmed and Google Scholar on 4 April 2020 using the search terms *N-acetylcysteine, AND coronavirus, SARS-Cov-2, 2019-NCov, and COVID-19; and broader search terms N-acetylcysteine AND bronchitis OR common cold OR influenza OR pneumonia OR SARS OR MERS OR severe respiratory infections OR acute respiratory infections OR “Respiratory Tract Infections”[Mesh]). In addition, we included reviews of the existing literature on this topic. We provide a narrative summary of the current literature. 

REFERENCES

1. Medici TC, Radielovic P. Effects of drugs on mucus glycoproteins and water in bronchial secretion. Journal of International Medical Research 1979;7(5):434‐
2. Teskey G, Abrahem R, Cao R, et al. Glutathione as a Marker for Human Disease. Adv Clin Chem. 2018;87:141–159. doi:10.1016/bs.acc.2018.07.004
3. Cao M, Zhang D, Wang Y, et al. Clinical Features of Patients Infected with the 2019 Novel Coronavirus (COVID-19) in Shanghai, China. (preprint) medRxiv 2020.03.04.20030395; doi: https://doi.org/10.1101/2020.03.04.20030395
4. Geiler J, Michaelis M, Naczk P, et al. N-acetyl-L-cysteine (NAC) inhibits virus replication and expression of pro-inflammatory molecules in A549 cells infected with highly pathogenic H5N1 influenza A virus. Biochem Pharmacol. 2010 Feb;79(3): 413–20.
5. Ghezzi P, Ungheri D. Synergistic combination of N-acetylcysteine and ribavirin to protect from lethal influenza viral infection in a mouse model.
6. Chalumeau M, Duijvestijn YC. Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho-pulmonary disease. Cochrane Database Syst Rev. 2013 May 31;(5):CD003124.
7. Stey C, Steurer J, Bachmann S, et al. The effect of oral N-acetylcysteine in chronic bronchitis: a quantitative systematic review. Eur Respir J. 2000 Aug;16(2):253-62.
8. De Flora S, Grassi C, Carati L. Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment. Eur Respir J. 1997 Jul;10(7):1535–41.
9. Zhang Q, Ju Y, Ma Y, et al. N-acetylcysteine improves oxidative stress and inflammatory response in patients with community acquired pneumonia: A randomized controlled trial. Medicine (Baltimore). 2018 Nov;97(45):e13087.