By Steve Blechman

A most recent report on August 11, 2020 published in the Federation of American Society of Experimental Biology (FASEB) was entitled “Rationale for the use of N-acetylcysteine in both prevention and adjuvant therapy of COVID-19.” FASEB is a lead organization in Washington DC for recommending federal funding for research including the National Institutes of Health (NIH). FASEB members represent a total of greater than 80,000 scientists. The Federation also provides the FASEB journal a monthly scientific publication.

This was a very exciting report in the FASEB journal on the potential of the amino acid n-acetylcysteine (NAC) and COVID-19. The report said, “NAC may be proposed both in the prevention and in the therapy of COVID-19. In particular, the oral administration of NAC, at the dose of 600mg twice daily, may be proposed for preventive purposes aimed at attenuating the risk of developing COVID-19 and its severity during epidemic periods.” The conclusion of the report further says clearly, “The potential anti-COVID-19 mechanisms and properties of this thiol have to be substantiated in controlled clinical trials, some of which are now in progress!”

The Memorial Sloan Kettering Cancer Center is where one of those clinical trials is underway, according to the National Institutes of Health (NIH) U.S. National Library of Medicine, ClinicalTrials.gov website entitled “A study of N-acetylcysteine in Patients with COVID-19 infection.” The sponsor of this study is Memorial Sloan Kettering Cancer Center. The principal investigator is Santosha Vardhana, MD, Ph.D. Memorial Sloan Kettering and researchers are a leading cancer institution and research center in the world studying how the immune system responds to cancer. Also, the role of the immune system, coronavirus and COVID-19. This report was last updated June 1, 2020. The official title of the clinical trial is: “Phase II study of N-acetylcysteine in Severe or Critically Ill Patients With Refractory COVID-19 Infection,” according to the website. The clinical trial started on May 1, 2020 and the estimated primary completion date is May 2021. A brief summary of the study on the website says, “The study researchers think that a medication called N-acetylcysteine can fight the COVID-19 virus by boosting a type of cell in your immune system that attacks infections, by helping your immune system fight the virus. The researchers think that the infection will get better, which could allow the patient to be moved out of the critical care unit or go off a ventilator, or prevent them from moving into a critical care unit or going on a ventilator.” This study is the first to test N-acetylcysteine in people with severe COVID-19 infections. The researchers involved in this important new clinical trial are looking to see if N-acetylcysteine can repair lung tissue damage in COVID-19 patients.

N-acetylcysteine may be used in the future to improve T-cell therapeutic benefits (Cancer Res, October 15, 2015). Reactive oxygen species (ROS) free radicals cause DNA damage of T-cell lymphocytes (Immunity & Aging, February 21, 2013). T-cells (also called t-lymphocytes) are an important component of the immune system. T-cells recognize and kill virus-infected cells. “Now two studies reveal infected people harbor T-cells that target the virus – and may help them recover,” researchers said. N-acetylcysteine may supercharge T-cells in COVID-19 patients but also lower inflammation at the same time! (Journal Science, May 14, 2020). Research has shown that young children are less likely to get sick from the coronavirus. It might be because their immune systems can produce more T-cells faster than they are destroyed and depleted.

It was reported on April 21, in the journal Respiratory Medicine Case Reports, that a 48-year-old woman with COVID-19 pneumonia at NYU Langone Hospital-Brooklyn, NY made an amazing recovery with oral and intravenous glutathione plus oral N-acetylcysteine. This was very encouraging but remember this is only a case report and does not prove cause and effect! Further randomized controlled trials are needed and published in peer-reviewed journals to prove safety and efficacy in COVID-19 patients.

N-acetylcysteine is clearly the most effective and important antioxidant, anti-inflamatory and precursor of glutathione in the lungs! I was first to launch glutathione and N-acetylcysteine as a dietary supplement to the American market over 20 years ago, during my 27 years as Head of Product Development for Twin Laboratories, Inc. (TwinLab).

Research has shown that N-acetylcysteine (1200mg/1800mg daily) is much more cost effective and efficacious than oral glutathione for raising glutathione in the lungs, liver and other tissues, and therefore the preferred dietary supplement! I have been taking N-acetylcysteine daily for over 20 years.

Research has shown that N-acetylcysteine is also a donor and activator of hydrogen sulfide (H₂S) in the body. It was reported in a review in the American Journal of Physiology, Cell Physiology, June 19, 2020 that, “Hydrogen sulfide (H_²S) as a novel gasotransmitter has been shown to protect against lung damage via its anti-inflammation, anti-oxidative stress, anti-viral, pro-survival, anti-aging effects.” This review proposed, “H₂S as a potential defense against COVID-19. It is suggested that H₂S may block SARS-CoV-2 entry into the host cell by interfering with ACE2 and TMPRSS2, inhibit SARS-CoV-2 replication by attenuating virus assembly/release, and protect SARS-CoV-2 induced lung damage by suppressing immune response and inflammation development.” Also, “it is proposed that NAC may protect COVID-19-assoicated cytokine storm and acute respiratory distress syndrome.”

N-acetylcysteine is a precursor of glutathione and as the body’s master antioxidant can improve lung function by decreasing inflammation in the lungs.

Air pollution, smoking, or vaping is a major source of reactive oxygen species (ROS) and free radicals in the lungs. The ROS can damage the lungs and can cause chronic obstruction pulmonary disease (COPD). A meta-analysis found that N-acetylcysteine can raise glutathione in the lungs and offers benefits in the treatments of COPD (Heart, Lung, March-April 2017). Air pollution and smoking can all increase the expression of the ACE2 receptor in the lungs that make it easier for the virus to enter the cell. “People with COVID-19 who live in the U.S. region with high levels of air pollution are more likely to die from the disease than people who live in less polluted areas, according to a new nationwide study from Harvard T.H. Chan School of Public Health (May 5, 2020). People that exercise outdoors especially when exposed to air pollution from automobile exhaust may benefit from NAC supplements. NAC should be taken with vitamin C. Vitamin C is an antioxidant and acts as a reducing agent and enhances the stability and function of NAC.

The Cleveland Clinic published a scientific review (June 2, 2020, Cleveland Clinic Journal of Medicine) entitled, “What is the role of supplementation with ascorbic acid, zinc, vitamin D, or N-acetylcysteine for prevention or treatment of COVID-19?” The review mentioned that zinc, vitamin D, and N-acetylcysteine (NAC) can lower proinflammatory cytokines such as interleukin-6 (IL-6), interleukin-1 (IL-1) and tumor necrosis factor (TNF). The authors outline “the biological plausibility, applicable clinical data and potential role of each of these agents.” The Cleveland Clinic Investigators continued that, “Several agents intended to supplement dietary intake or indigenous molecules may have a theoretical role in preventing or treating COVID-19.” Based on their scientific review, the authors further acknowledge that “ascorbic acid, zinc, vitamin D, and N-acetylcysteine have biologic plausibility for prevention and treatment of COVID-19 and are candidates for clinical trials evaluating patients with these indications.”

In conclusion, if you have shortness of breath especially during exercise, or tested positive for COVID-19, you can have your physician prescribe a simple ultrasound of your lungs to see if you have any damage or fibrosis. Unlike CT scans, ultrasound does not expose you to radiation. Research on N-acetylcysteine and other antioxidants and immune supplements discussed and reviewed in this article is very encouraging and promising, but more well-designed, randomized and controlled trials published in peer-reviewed journals are needed.

We need to learn to live with the virus, but we can’t let it control our lives. As always, I am eating very healthy, following the Mediterranean diet, and taking my immune support supplements (N-acetylcysteine, vitamin C, polyphenols, zinc, selenium, and vitamin D). As always, I am exercising daily, and coping better when dealing with daily stress with meditation and relaxation techniques. I also practice social distancing, use a face mask, and properly wash my hands. Why take a chance at my age of 67? Better safe than sorry!

There currently are no products or dietary supplements that are scientifically proven to treat or prevent the coronavirus, according to the U.S. Food and Drug Administration (FDA). By law, companies are not allowed to make claims on their product labels or ads that the product is intended to diagnose, treat, cure or prevent any disease.

©Published by from Advanced Research Media, Inc. 2020

©Reprinted with permission from Advanced Research Media, Inc.

References:

1. De Flora, S, Balansky, R, La Maestra, S. Rationale for the use of N-acetylcysteine in both prevention and adjuvant therapy of COVID-19. The FASEB Journal, August 11, 2020; 1-9. https://doi.org/10.1096/fj.202001807

2. N-acetylcysteine as a potential treatment for novel coronavirus disease 2019 Jorge-Aarón Rangel-Méndez and Rosa-Ester Moo-Puc Future Microbiology 0 0:0

3. Scheffel MJ, Scurti G, Simms P, et al. Efficacy of Adoptive T-cell Therapy Is Improved by Treatment with the Antioxidant N-Acetyl Cysteine, Which Limits Activation-Induced T-cell Death. Cancer Res. 2016;76(20):6006-6016. doi:10.1158/0008-5472.CAN-16-0587

4. Jun Wu et al. Tackle the free radicals damage in COVID-19. Nitric Oxide, September 2020. https://doi.org/10.1016/j.niox.2020.06.002.

5. Natural killer cell immunotypes related to COVID-19 disease severity by Christopher Maucourant, Iva Filipovic, Andrea Ponzetta, Soo Aleman, Martin Cornillet, Laura Hertwig, Benedikt Strunz, Antonio Lentini, Björn Reinius, Demi Brownlie, Angelica Cuapio Gomez, Eivind Heggernes Ask, Ryan M. Hull, Alvaro Haroun-Izquierdo, Marie Schaffer, Jonas Klingström, Elin Folkesson, Marcus Buggert, Johan K. Sandberg, Lars I. Eriksson, Olav Rooyackers, Hans-Gustaf Ljunggren, Karl-Johan Malmberg, Jakob Michaëlsson, Nicole Marquardt, Quirin Hammer, Kristoffer Strålin, Niklas K. Björkström, Karolinska Covid-19 Study Group. Science Immunology21 Aug 2020

6. Eylar E, Rivera-Quinones C, Molina C, Báez I, Molina F, Mercado CM. N-acetylcysteine enhances T cell functions and T cell growth in culture. Int Immunol. 1993;5(1):97-101. doi:10.1093/intimm/5.1.97

7. Arranz, Lorena & Fernández, Cesáreo & Rodriguez Perez, Antonio & Ribera, José & de la Fuente del MOral, Fátima. (2008). The glutathione precursor N-acetylcysteine improves immune function in postmenopausal women. Free Radical Biology and Medicine. 45. 1252-1262. 10.1016/j.freeradbiomed.2008.07.014.

8. W. Dröge, H.-P. Eck, S. Mihm. HIV-induced cysteine deficiency and T-cell dysfunction — a rationale for treatment with N-acetylcysteine. Immunology Today. 1992 https://doi.org/10.1016/0167-5699(92)90156-2.(http://www.sciencedirect.com/science/article/pii/0167569992901562)

9. Silvagno F, Vernone A, Pescarmona GP. The Role of Glutathione in Protecting against the Severe Inflammatory Response Triggered by COVID-19. Antioxidants (Basel). 2020;9(7):624. Published 2020 Jul 16. doi:10.3390/antiox9070624

10. Nasi A, McArdle S, Gaudernack G, et al. Reactive oxygen species as an initiator of toxic innate immune responses in retort to SARS-CoV-2 in an ageing population, consider N-acetylcysteine as early therapeutic intervention. Toxicol Rep. 2020;7:768-771. Published 2020 Jun 18. doi:10.1016/j.toxrep.2020.06.003

11. What is the role of supplementation with ascorbic acid, zinc, vitamin D, or N-acetylcysteine for prevention or treatment of COVID-19? Seth R. Bauer, Aanchal Kapoor, Mary Rath, Suma A. Thomas, Cleveland Clinic Journal of Medicine Jun 2020, DOI: 10.3949/ccjm.87a.ccc046

12. Hemilä H, Chalker E. Vitamin C for preventing and treating the common cold. Cochrane Database Syst Rev 2013; 2013(1). doi:10.1002/14651858.CD000980.pub4

13. Carr AC. Vitamin C administration in the critically ill: a summary of recent meta-analyses. Crit Care 2019; 23(1):265. doi:10.1186/s13054-019-2538-y

14. Velthuis AJW, van den Worm SHE, Sims AC, Baric RS, Snijder EJ, van Hemert MJ. Zn2+ inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture. PLoS Pathog 2010; 6(11). doi:10.1371/journal.ppat.1001176

15. Singh M, Das RR. Zinc for the common cold. Cochrane Database Syst Rev 2013; 2013(6):CD001364. doi:10.1002/14651858.CD001364.pub4

16. Grant WB, Lahore H, McDonnell SL, et al. Evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths. Nutrients 2020; 12(4):988. doi:10.3390/nu12040988

17. Martineau AR, Jolliffe DA, Hooper RL, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ 2017; 356. doi:10.1136/bmj.i658

18. Sadowska AM, Manuel-y-Keenoy B,De Backer WA. Antioxidant and anti-inflammatory efficacy of NAC in the treatment of COPD: discordant in vitro and in vivo dose-effects: a review. Pulm Pharmacol Ther 2007; 20(1):9-22. doi:10.1016/j.pupt.2005.12.00

19. Coronavirus Pandemic: Diet and Nutrition Battling the Deadly Cytokine Storm - The Latest Research! Steve Blechman. Advanced Molecular Labs. April 24, 2020 https://advancedmolecularlabs.com/blogs/news/coronavirus-pandemic-diet-and-nutrition-battling-the-deadly-cytokine-storm-the-latest-research

20. Kate J Claycombe-Larson, Travis Alvine, Dayong Wu, Nishan S Kalupahana, Naima Moustaid-Moussa, James N Roemmich, Nutrients and Immunometabolism: Role of Macrophage NLRP3, The Journal of Nutrition, nxaa085, https://doi.org/10.1093/jn/nxaa085

21. Calder, P.C.; Carr, A.C.; Gombart, A.F.; Eggersdorfer, M. Optimal Nutritional Status for a Well-Functioning Immune System Is an Important Factor to Protect against Viral Infections. Nutrients 2020, 12, 1181.

22. Efficacy of glutathione therapy in relieving dyspnea associated with COVID-19 pneumonia: A report of 2 cases. Author links open overlay panel. Richard I.Horowitz. Phyllis R.Freeman. James Bruzzesec. Respiratory Medicine Case Reports. Volume 30, 2020, 101063. https://doi.org/10.1016/j.rmcr.2020.101063

23. University of Surrey. Link identified between dietary selenium and outcome of COVID-19 disease. ScienceDaily. ScienceDaily, 29 April 2020. www.sciencedaily.com/releases/2020/04/200429105907.htm

24. Margaret P Rayman, Ramy Saad, Kate Bennett, Ethan Will Taylor, Jinsong Zhang. Association between regional selenium status and reported outcome of COVID-19 cases in China. The American Journal of Clinical Nutrition, 2020; DOI: 10.1093/ajcn/nqaa095

25. Ilie PC, Stefanescu S, Smith L. The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality [published online ahead of print, 2020 May 6]. Aging Clin Exp Res. 2020;1‐4. doi:10.1007/s40520-020-01570-8

26. Gruber-Bzura BM. Vitamin D and Influenza-Prevention or Therapy? Int J Mol Sci. 2018;19(8):2419. Published 2018 Aug 16. doi:10.3390/ijms19082419

27. Ratih Wirapuspita Wisnuwardani, Stefaan De Henauw, Marika Ferrari, Maria Forsner, Frédéric Gottrand, Inge Huybrechts, Antonios G Kafatos, Mathilde Kersting, Viktoria Knaze, Yannis Manios, Ascensión Marcos, Dénes Molnár, Joseph A Rothwell, Azahara Iris Rupérez, Augustin Scalbert, Kurt Widhalm, Luis A Moreno, Nathalie Michels, Total Polyphenol Intake Is Inversely Associated with a Pro/Anti-Inflammatory Biomarker Ratio in European Adolescents of the HELENA Study, The Journal of Nutrition, nxaa064, https://doi.org/10.1093/jn/nxaa064

28. Bao B, Prasad AS, Beck FW, et al. Zinc decreases C-reactive protein, lipid peroxidation, and inflammatory cytokines in elderly subjects: a potential implication of zinc as an atheroprotective agent. Am J Clin Nutr. 2010;91(6):1634‐1641. doi:10.3945/ajcn.2009.28836

29. Silberstein M. Vitamin D: A simpler alternative to tocilizumab for trial in COVID-19? [published online ahead of print, 2020 Apr 23]. Med Hypotheses. 2020;140:109767. doi:10.1016/j.mehy.2020.109767

30. Aziz, M., Fatima, R. and Assaly, R. (2020), Elevated Interleukin‐6 and Severe COVID‐19: A Meta‐Analysis. J Med Virol. Accepted Author Manuscript. doi:10.1002/jmv.25948

31. Covid-19 in Immune-Mediated Inflammatory Diseases - Case Series from New York. April 29, 2020. DOI: 10.1056/NEJMc2009567.

32. Giovannini C, Filesi C, D'Archivio M, Scazzocchio B, Santangelo C, Masella R. Polifenoli e difese antiossidanti endogene: effetti sul glutatione e sugli enzimi ad esso correlati [Polyphenols and endogenous antioxidant defences: effects on glutathione and glutathione related enzymes]. Ann Ist Super Sanita. 2006;42(3):336‐347.

33. Margaret P Rayman, Ramy Saad, Kate Bennett, Ethan Will Taylor, Jinsong Zhang. Association between regional selenium status and reported outcome of COVID-19 cases in China. The American Journal of Clinical Nutrition, 2020; DOI: 10.1093/ajcn/nqaa095

34. University of Surrey. Link identified between dietary selenium and outcome of COVID-19 disease. ScienceDaily. ScienceDaily, 29 April 2020. www.sciencedaily.com/releases/2020/04/200429105907.htm

35. Jinsong Zhang, Ethan Will Taylor, Kate Bennett, Ramy Saad, Margaret P Rayman, Association between regional selenium status and reported outcome of COVID-19 cases in China, The American Journal of Clinical Nutrition, nqaa095, https://doi.org/10.1093/ajcn/nqaa095

36. The Possible Role of Vitamin D in Suppressing Cytokine Storm and Associated Mortality in COVID-19 Patients. Ali Daneshkhah, Vasundhara Agrawal, Adam Eshein, Hariharan Subramanian, Hemant Kumar Roy, Vadim Backman. medRxiv 2020.04.08.20058578; doi: https://doi.org/10.1101/2020.04.08.2005857

37. Thailand Medical News. BREAKING! COVID-19 Research: Russian Study Indicates That Glutathione Deficiency Affects COVID-19 Susceptibility, NAC Supplements Helps. Apr 26, 2020 https://www.thailandmedical.news/news/breaking-covid-19-research-russian-study-indicates-that-glutathione-deficiency-affects-covid-19-susceptibility,-nac-supplements-helps

38. Endogenous deficiency of glutathione as the most likely cause of serious manifestations and death in patients with the novel coronavirus infection (COVID-19): a hypothesis based on literature data and own observations. DO - 10.21626/vestnik. Polonikov, Alexey. 2020/04/25. ResearchGate

39. 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;10(7):1535‐1541. doi:10.1183/09031936.97.10071535

40. N-acetylcysteine: A rapid review of the evidence for effectiveness in treating COVID-19 by Dr Oliver Van Hecke, Dr Joseph Lee. CEBM. April 14, 2020 https://www.cebm.net/covid-19/n-acetylcysteine-a-rapid-review-of-the-evidence-for-effectiveness-in-treating-covid-19/

41. De Rosa SC, Zaretsky MD, Dubs JG, et al. N-acetylcysteine replenishes glutathione in HIV infection. Eur J Clin Invest. 2000;30(10):915‐929. doi:10.1046/j.1365-2362.2000.00736.x

42. Shu Y, Wu M, Yang S, Wang Y, Li H. Association of dietary selenium intake with telomere length in middle-aged and older adults [published online ahead of print, 2020 Jan 31]. Clin Nutr. 2020;S0261-5614(20)30037-6. doi:10.1016/j.clnu.2020.01.014

43. McCarty MF, DiNicolantonio JJ. Nutraceuticals have potential for boosting the type 1 interferon response to RNA viruses including influenza and coronavirus [published online ahead of print, 2020 Feb 12]. Prog Cardiovasc Dis. 2020;. doi:10.1016/j.pcad.2020.02.007

44. Ungheri D, Pisani C, Sanson G, et al. Protective effect of n-acetylcysteine in a model of influenza infection in mice. Int J Immunopathol Pharmacol. 2000;13(3):123‐128.

45. Prasad AS, Beck FW, Bao B, et al. Zinc supplementation decreases incidence of infections in the elderly: effect of zinc on generation of cytokines and oxidative stress. Am J Clin Nutr. 2007;85(3):837‐844. doi:10.1093/ajcn/85.3.837

46. Glutathione Fine-Tunes the Innate Immune Response toward Antiviral Pathways in a Macrophage Cell Line Independently of Its Antioxidant Properties. Diotallevi Marina, Checconi Paola et al. Frontiers in Immunology. September 17, 2017 https://www.frontiersin.org/article/10.3389/fimmu.2017.01239

47. The Role of N-Acetyl Cysteine in Pulmonary Tuberculosis. Resti Yudhawati, Nitya Prasanta. January 2020. Journal of Respiration https://e-journal.unair.ac.id/JR/article/download/17303/9706

48. Nair MP, Mahajan S, Reynolds JL, et al. The flavonoid quercetin inhibits proinflammatory cytokine (tumor necrosis factor alpha) gene expression in normal peripheral blood mononuclear cells via modulation of the NF-kappa beta system. Clin Vaccine Immunol. 2006;13(3):319‐328. doi:10.1128/CVI.13.3.319-328.2006

49. Leyva-López N, Gutierrez-Grijalva EP, Ambriz-Perez DL, Heredia JB. Flavonoids as Cytokine Modulators: A Possible Therapy for Inflammation-Related Diseases. Int J Mol Sci. 2016;17(6):921. Published 2016 Jun 9. doi:10.3390/ijms17060921

50. Cheng SC, Huang WC, S Pang JH, Wu YH, Cheng CY. Quercetin Inhibits the Production of IL-1beta-Induced Inflammatory Cytokines and Chemokines in ARPE-19 Cells via the MAPK and NF-κB Signaling Pathways. Int J Mol Sci. 2019;20(12):2957. Published 2019 Jun 17. doi:10.3390/ijms20122957

51. Nair MP, Mahajan S, Reynolds JL, et al. The flavonoid quercetin inhibits proinflammatory cytokine (tumor necrosis factor alpha) gene expression in normal peripheral blood mononuclear cells via modulation of the NF-kappa beta system. Clin Vaccine Immunol. 2006;13(3):319‐328. doi:10.1128/CVI.13.3.319-328.2006

52. Hemilä H, Chalker E. Vitamin C Can Shorten the Length of Stay in the ICU: A Meta-Analysis. Nutrients. 2019;11(4):708. Published 2019 Mar 27. doi:10.3390/nu11040708

53. Bucca C, Rolla G, Arossa W, et al. Effect of ascorbic acid on increased bronchial responsiveness during upper airway infection. Respiration. 1989;55(4):214‐219. doi:10.1159/000195737

54. N-Acetylcysteine Protection in COPD. Wu, Wenxin et al. CHEST, Volume 145, Issue 1, 193 – 194. January 2014

55. Gammoh, N.Z.; Rink, L. Zinc in Infection and Inflammation. Nutrients2017, 9, 624.

56. Hirano T, Murakami M, Fukada T, Nishida K, Yamasaki S, Suzuki T. Roles of zinc and zinc signaling in immunity: zinc as an intracellular signaling molecule. Adv Immunol. 2008;97:149‐176. doi:10.1016/S0065-2776(08)00003-5

57. Changes in cytokine production and T cell subpopulations in experimentally induced zinc-deficient humans. F. W. Beck, A. S. Prasad, J. Kaplan, J. T. Fitzgerald, and G. J. Brewer. American Journal of Physiology-Endocrinology and Metabolism 1997 272:6, E1002-E1007

58. Prasad AS. Effects of zinc deficiency on Th1 and Th2 cytokine shifts. J Infect Dis. 2000;182 Suppl 1:S62‐S68. doi:10.1086/315916

59. Shen Y, Cai W, Lei S, Zhang Z. Effect of high/low dose N-acetylcysteine on chronic obstructive pulmonary disease: a systematic review and meta-analysis. COPD. 2014;11(3):351‐358. doi:10.3109/15412555.2013.85831

60. Fowdar K, Chen H, He Z, et al. The effect of N-acetylcysteine on exacerbations of chronic obstructive pulmonary disease: A meta-analysis and systematic review. Heart Lung. 2017;46(2):120‐128. doi:10.1016/j.hrtlng.2016.12.004

61. Cazzola M, Calzetta L, Facciolo F, Rogliani P, Matera MG. Pharmacological investigation on the anti-oxidant and anti-inflammatory activity of N-acetylcysteine in an ex vivo model of COPD exacerbation. Respir Res. 2017;18(1):26. Published 2017 Jan 24. doi:10.1186/s12931-016-0500-y

62. Santus P, Corsico A, Solidoro P, Braido F, Di Marco F, Scichilone N. Oxidative stress and respiratory system: pharmacological and clinical reappraisal of N-acetylcysteine. COPD. 2014;11(6):705‐717. doi:10.3109/15412555.2014.898040

63. De Backer J, Vos W, Van Holsbeke C, et al. Effect of high-dose N-acetylcysteine on airway geometry, inflammation, and oxidative stress in COPD patients. Int J Chron Obstruct Pulmon Dis. 2013;8:569‐579. doi:10.2147/COPD.S49307

64. Vitamin D reduces respiratory tract infections frequency. Bhutta, Zulfiqar A. The Journal of Pediatrics, Volume 186, 209 – 212

65. N-Acetyl-l-cysteine (NAC) inhibit mucin synthesis and pro-inflammatory mediators in alveolar type II epithelial cells infected with influenza virus A and B and with Respiratory Syncytial Virus (RSV) Mata, Manuel, Morcillo, Esteban et al. 2011/05/25. Biochemical pharmacology. 10.1016/j.bcp.2011.05.014

66. Schrauzer GN, Sacher J. Selenium in the maintenance and therapy of HIV-infected patients [published correction appears in Chem Biol Interact 1995 Feb;94(2):167]. Chem Biol Interact. 1994;91(2-3):199‐205. doi:10.1016/0009-2797(94)90040-x

67. N-Acetylcysteine: A New Approach to Anti-HIV Therapy. Mario Roederer, Stephen W. Ela, Frank J.T. Staal, Leonore A. Herzenberg, and Leonard A. Herzenberg. AIDS Research and Human Retroviruses 1992 8:2, 209-217

68. Kent L. Erickson, Edward A. Medina, Neil E. Hubbard, Micronutrients and Innate Immunity, The Journal of Infectious Diseases, Volume 182, Issue Supplement_1, September 2000, Pages S5-S10, https://doi.org/10.1086/315922

69. Assimakopoulos SF, Marangos M. N-acetyl-cysteine may prevent COVID-19-associated cytokine storm and acute respiratory distress syndrome [published online ahead of print, 2020 Apr 22]. Med Hypotheses. 2020;140:109778. doi:10.1016/j.mehy.2020.109778

70. Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033‐1034. doi:10.1016/S0140-6736(20)30628-0

71. The pathogenesis and treatment of the ‘Cytokine Storm’ in COVID-19. Qing Ye, Bili Wang, Jianhua Mao. Journal of Infection. March 24, 2020.

72. Wu W, Li R, Li X, et al. Quercetin as an Antiviral Agent Inhibits Influenza A Virus (IAV) Entry. Viruses. 2015;8(1):6. Published 2015 Dec 25. doi:10.3390/v8010006

73. Hemilä H, Chalker E. Vitamin C may reduce the duration of mechanical ventilation in critically ill patients: a meta-regression analysis. J Intensive Care. 2020;8:15. Published 2020 Feb 7. doi:10.1186/s40560-020-0432-y

74. Zinc-hydroxychloroquine Found Effective In Some COVID-19 Patients: Study. May 11, 2020. Barrons. Agence France Presse. https://www.barrons.com/news/zinc-hydroxychloroquine-found-effective-in-some-covid-19-patients-study-01589234407?tesla=y

75. Bernard GR, Wheeler AP, Arons MM, et al. A trial of antioxidants N-acetylcysteine and procysteine in ARDS. The Antioxidant in ARDS Study Group. Chest. 1997;112(1):164‐172. doi:10.1378/chest.112.1.164

76. Hydroxychloroquine and azithromycin plus zinc vs hydroxychloroquine and azithromycin alone: outcomes in hospitalized COVID-19 patients. Philip Carlucci, Tania Ahuja, Christopher M Petrilli, Harish Rajagopalan, Simon Jones, Joseph Rahimian. medRxiv 2020.05.02.20080036; doi: https://doi.org/10.1101/2020.05.02.20080036

77. Horowitz RI, Freeman PR, Bruzzese J. Efficacy of glutathione therapy in relieving dyspnea associated with COVID-19 pneumonia: A report of 2 cases [published online ahead of print, 2020 Apr 21]. Respir Med Case Rep. 2020;30:101063. doi:10.1016/j.rmcr.2020.101063

78. Aditya Arya & Vivek Dhar Dwivedi (2020) Synergistic effect of vitamin D and remdesivir can fight COVID-19, Journal of Biomolecular Structure and Dynamics, DOI: 10.1080/07391102.2020.1773929

79. Meltzer, D., et al. (2020). Association of Vitamin D Deficiency and Treatment with COVID-19 Incidence medRxiv preprint. doi: https://doi.org/10.1101/2020.05.08.20095893. http://medrxiv.org/cgi/content/short/2020.05.08.20095893

80. Rahman MT, Idid SZ. Can Zn Be a Critical Element in COVID-19 Treatment? [published online ahead of print, 2020 May 26]. Biol Trace Elem Res. 2020;1‐9. doi:10.1007/s12011-020-02194-9

81. Speeckaert, M.M., Delanghe, J.R. Association between low vitamin D and COVID-19: don’t forget the vitamin D binding protein. Aging Clin Exp Res (2020). https://doi.org/10.1007/s40520-020-01607-y A Study of N-acetylcysteine in Patients With COVID-19 Infection. Clinical Trials.gov. Last update June 1, 2020. Phase II https://clinicaltrials.gov/ct2/show/NCT04374461 Alveolar macrophage dysfunction and cytokine storm in the pathogenesis of two severe COVID-19 patients. Chaofu Wangi et al. EBioMedicine The Lancet Date: July 2020. https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(20)30208-5/fulltext Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Chaolin Huang et al. The Lancet. Date: 15–21 February 2020

82. Guan WJ, Ni ZY, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020;382(18):1708-1720. doi:10.1056/NEJMoa2002032

83. Spagnolo P, Balestro E, Aliberti S, et al. Pulmonary fibrosis secondary to COVID-19: a call to arms? [published online ahead of print, 2020 May 15]. Lancet Respir Med. 2020;S2213-2600(20)30222-8. doi:10.1016/S2213-2600(20)30222-8

84. Assimakopoulos SF, Marangos M. N-acetyl-cysteine may prevent COVID-19-associated cytokine storm and acute respiratory distress syndrome [published online ahead of print, 2020 Apr 22]. Med Hypotheses. 2020;140:109778. doi:10.1016/j.mehy.2020.109778

85. Sanguinetti, C.M. N-acetylcysteine in COPD: why, how, and when?. Multidiscip Respir Med11, 8 (2015). https://doi.org/10.1186/s40248-016-0039-2

86. Zhang Q, Ju Y, Ma Y, Wang T. N-acetylcysteine improves oxidative stress and inflammatory response in patients with community acquired pneumonia: A randomized controlled trial. Medicine (Baltimore). 2018;97(45):e13087. doi:10.1097/MD.0000000000013087

87. Mata M, Morcillo E, Gimeno C, Cortijo J. N-acetyl-L-cysteine (NAC) inhibit mucin synthesis and pro-inflammatory mediators in alveolar type II epithelial cells infected with influenza virus A and B and with respiratory syncytial virus (RSV). Biochem Pharmacol. 2011;82(5):548-555. doi:10.1016/j.bcp.2011.05.014

88. N-acetylcysteine: A rapid review of the evidence for effectiveness in treating COVID-19. April 14, 2020. Dr Oliver Van Hecke, Dr Joseph Lee. https://www.cebm.net/covid-19/n-acetylcysteine-a-rapid-review-of-the-evidence-for-effectiveness-in-treating-covid-19/

89. Lifelong Lung Damage: The Serious COVID-19 Complication That Can Hit People in Their 20s. Written by Meagan Drillinger on June 22, 2020. Healthline. https://www.healthline.com/health-news/lifelong-lung-damage-the-serious-covid-19-complication-that-can-hit-people-in-their-20s

90. Nobody in Sports Knows the Long-Term Effects of Covid-19. June 26, 2020. Ben Cohen & Louis Radnofsky. Wall Street Journal https://www.wsj.com/articles/covid-long-term-effects-sports-athletes-nba-bubble-11593161922

91. H2S as a potential defence against COVID-19? Guangdong Yang. American Journal of Physiology-Cell Physiology 0 0:0 https://journals.physiology.org/doi/abs/10.1152/ajpcell.00187.2020

92. Gargani L, Soliman-Aboumarie H, Volpicelli G, Corradi F, Pastore MC, Cameli M. Why, when, and how to use lung ultrasound during the COVID-19 pandemic: enthusiasm and caution [published online ahead of print, 2020 Jun 9]. Eur Heart J Cardiovasc Imaging. 2020;jeaa163. doi:10.1093/ehjci/jeaa163

93. Çinkooğlu A, Bayraktaroğlu S, Savaş R. Lung Changes on Chest CT During 2019 Novel Coronavirus (COVID-19) Pneumonia. Eur J Breast Health. 2020;16(2):89-90. Published 2020 Apr 1. doi:10.5152/ejbh.2020.010420

94. Huan Han, Qingfeng Ma, Cong Li, Rui Liu, Li Zhao, Wei Wang, Pingan Zhang, Xinghui Liu, Guosheng Gao, Fang Liu, Yingan Jiang, Xiaoming Cheng, Chengliang Zhu & Yuchen Xia (2020) Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors, Emerging Microbes & Infections, 9:1, 1123-1130, DOI: 10.1080/22221751.2020.1770129

95. Özakıncı H, Sak SD. Lung Pathology in COVID-19 Disease: We Must Be Aware!. Turk Thorac J. 2020;21(3):217-218. doi:10.5152/TurkThoracJ.2020.20049

96. Face masks – a sustainable measure to mitigate COVID-19. S.K. Jindal et al. International Union Against Tuberculosis and Lung Disease. June 2020. https://www.ingentaconnect.com/content/iuatld/ijtld/2020/00000024/00000006/art00025;jsessionid=3s1qejfeuqhru.x-ic-live-02

97. Volpicelli, G., Lamorte, A. & Villén, T. What’s new in lung ultrasound during the COVID-19 pandemic. Intensive Care Med (2020). https://doi.org/10.1007/s00134-020-06048-9

98. Conti P, Ronconi G, Caraffa A, et al. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies. Journal of Biological Regulators and Homeostatic Agents. 2020 Mar;34(2). DOI: 10.23812/conti-e.

99. Severe air pollution links to higher mortality in COVID-19 patients: The “double-hit” hypothesis.: Antonio Frontera,Lorenzo Cianfanelli,Konstantinos Vlachos,Giovanni Landoni,George Cremona. Journal of Infection. Elsevier. Available online 21 May 2020 https://www.journalofinfection.com/article/S0163-4453(20)30285-1/fulltext

100. Leung CC, Cheng KK, Lam TH, Migliori GB. Mask wearing to complement social distancing and save lives during COVID-19. Int J Tuberc Lung Dis. 2020;24(6):556-558. doi:10.5588/ijtld.20.0244

101. Air Pollution and Covid-19: The Role of Particulate Matter in the Spread and Increase of Covid-19's Morbidity and Mortality Silvia Comunian Res Public Health . 2020 Jun 22;17(12):E4487. doi: 10.3390/ijerph17124487.

102. Jakovac H. COVID-19 and vitamin D-Is there a link and an opportunity for intervention?. Am J Physiol Endocrinol Metab. 2020;318(5):E589. doi:10.1152/ajpendo.00138.2020

103. Kaur, G., Lungarella, G. & Rahman, I. SARS-CoV-2 COVID-19 susceptibility and lung inflammatory storm by smoking and vaping. J Inflamm 17, 21 (2020). https://doi.org/10.1186/s12950-020-00250-8

104. Jain A. COVID-19 and lung pathology. Indian J Pathol Microbiol [serial online] 2020 [cited 2020 Jun 30];63:171-2. Available from: http://www.ijpmonline.org/text.asp?2020/63/2/171/282688

105. Aigner C, Dittmer U, Kamler M, Collaud S, Taube C. COVID-19 in a lung transplant recipient. J Heart Lung Transplant. 2020;39(6):610-611. doi:10.1016/j.healun.2020.04.004

106. Smith, M.J., Hayward, S.A., Innes, S.M. and Miller, A.S.C. (2020), Point‐of‐care lung ultrasound in patients with COVID ‐19 – a narrative review. Anaesthesia. doi:10.1111/anae.15082

107. Vetrugno, L, Bove, T, Orso, D, et al. Our Italian experience using lung ultrasound for identification, grading and serial follow‐up of severity of lung involvement for management of patients with COVID‐19. Echocardiography. 2020; 37: 625– 627. https://doi.org/10.1111/echo.14664

108. Fowdar K, Chen H, He Z, et al. The effect of N-acetylcysteine on exacerbations of chronic obstructive pulmonary disease: A meta-analysis and systematic review. Heart Lung. 2017;46(2):120-128. doi:10.1016/j.hrtlng.2016.12.004

109. Scheffel MJ, Scurti G, Simms P, et al. Efficacy of Adoptive T-cell Therapy Is Improved by Treatment with the Antioxidant N-Acetyl Cysteine, Which Limits Activation-Induced T-cell Death. Cancer Res. 2016;76(20):6006-6016. doi:10.1158/0008-5472.CAN-16-0587

110. Marthandan S, Hyland P, Pawelec G, Barnett Y. An investigation of the effects of the antioxidants, ebselen or N-acetyl cysteine on human peripheral blood mononuclear cells and T cells. Immun Ageing. 2013;10(1):7. Published 2013 Feb 21. doi:10.1186/1742-4933-10-7

111. T cells found in COVID-19 patients ‘bode well’ for long-term immunity. Mitch Leslie. May. 14, 2020. ScienceMag https://www.sciencemag.org/news/2020/05/t-cells-found-covid-19-patients-bode-well-long-term-immunity