My Cart

Close
 

CORONAVIRUS PANDEMIC: COVID-19 LUNG DAMAGE: New Clinical Trial Underway With N-acetylcysteine

Brian Turner

Posted on June 30 2020

By Steve Blechman

 

 

While virus cases surge, the coronavirus crisis has caused a severe acute respiratory syndrome posing a serious threat to the global public health. Covid-19 has killed over 500,000 people worldwide. “Almost all COVID-19 related serious consequences feature pneumonia” (Lancet May15, 2020) and many also have an inflammatory lung disease that damages the lungs called adult respiratory distress syndrome (ARDS). “Chest CT scans of the lungs showed bilateral round glass opacities in all patients.”

On June 22, 2020 an article appeared on Healthline.com entitled: Lifelong Lung Damage: the Serious COVID-19 complication that can hit people in their 20s. It was reported that, “severe cases of COVID-19 can cause lasting damage to the lungs that may necessitate surgery or even organ transplants.” It also says, “while the majority of COVID-19 deaths have occurred in people who are older, fibrosis cases show even young people who survived the disease can have lasting complications.” The article goes on to say that, “a 20-year old COVID-19 survivor in Chicago had a lung transplant that was necessary to treat a condition now being called post-COVID fibrosis.” While the Chicago patient is expected to make a full recovery, this is another serious long-term effect of the virus that the public needs to be made aware of.

An article appeared in The Wall Street Journal on Saturday/Sunday June 27th-28th, 2020 entitled: The Unknown Effects of COVID-19. It mentioned that, “sports are trying to restart next month. And the people who place the highest value on their hearts, lungs, and physical conditioning will have to live with uncertainty.” The article continues to say that, “this disease’s potential to attack the lungs is particularly alarming,” University of Southern California radiologist Ali Gholamrezanezhad said. “The unexpected lung damage would lead to reduced functional capacity.” He continued to say it means that when you’re walking or sitting, you don’t have shortness of breath, but as soon as you start running, you don’t have enough oxygen. “This can happen in young people.”

HOW DOES THE CORONAVIRUS VIRUS DAMAGE THE LUNGS?

When a virus particle enters your body through your nose, mouth or eyes, into your lungs, the immune system recognizes the virus and sends immune-signaling molecules called cytokines such as interleukin-6 (IL-6) and tumor necrosis factor (TNF). Normally these cytokines play a beneficial role by activating our innate immune response and certain white blood cells called macrophages, neutrophils and natural killer T cells that destroy and kill certain dangerous pathogens, bacteria and viruses. These white blood cells are like “killer, phagocytic Pac-Men” that release reactive oxygen species (ROS) free radicals and kill these bacteria and viruses. At the same time, these ROS free radical species damage normal tissues and cause inflammation and cell death. So, these white blood cells in fact are a two-edged sword – they kill dangerous viruses and bacteria or they can go haywire, causing severe inflammation, and cell damage in the lungs. Antioxidant supplements such as N-acetylcysteine (NAC) , vitamin C, polyphenols and selenium are potent scavengers of ROS and free radicals and help lower inflammation in the lungs and other organs and body tissues. NAC works best when combined synergistically with vitamin C and the mineral selenium. Vitamin C is an antioxidant and acts as a reducing agent and enhances the stability and function of NAC. Selenium also works with NAC by enhancing the function of glutathione in the body.

NEW CLINICAL TRIAL UNDERWAY ON N-ACETYLCYSTEINE

A very important new study is underway and reported by the National Institute 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.”

The summary continues to say, “The US Food and Drug Administration (FDA) has approved N-acetylcysteine to treat the liver side effects resulting from an overdose of the anti-inflammatory medication Tylenol® (acetaminophen). N-acetylcysteine is also used to loosen the thick mucus in the lungs of people with cystic fibrosis or chronic obstructive pulmonary disease (COPD). 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. 

MORE GOOD NEWS ON N-ACETYLCYSTEINE (NAC)

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 recently 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 recently reported in a review in the American Journal of Physiology, Cell Physiology, June 19, 2020 that, “hydrogen sulfide (H²S) 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 as well as mucus 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.

Recently, 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 to say 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 controlled trials published in peer-reviewed journals are needed. I like when NBA Commissioner Adam Silver said last week, as the NBA prepares to start working out again getting ready for the restart of the season at the Walt Disney World campus. “My ultimate conclusion is that we can’t outrun the virus and that this is what we’re going to be living with for the foreseeable future.”

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!

©Published by from Advanced Research Media, Inc. 2020

©Reprinted with permission from Advanced Research Media, Inc.

References: 

  1. 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 
  1. 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  
  1. 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 
  1. 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 
  1. Singh M, Das RR. Zinc for the common cold. Cochrane Database Syst Rev 2013; 2013(6):CD001364. doi:10.1002/14651858.CD001364.pub4
  1. 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 
  1. 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
  1. 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 
  1. 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
  1. 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
  1. 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.  
  1. 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
  1. 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 
  1. 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 
  1. 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
  1. 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 
  1. 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 
  1. 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 
  1. 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 
  1. 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 
  1. Covid-19 in Immune-Mediated Inflammatory Diseases - Case Series from New York. April 29, 2020. DOI: 10.1056/NEJMc2009567. 
  1. 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. 
  1. 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 
  1. 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
  1. 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 
  1. 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 
  1. 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
  1. 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 
  1. 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
  1. 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/ 
  1. 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 
  1. 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 
  1. 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 
  1. 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.  
  1. 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
  1. 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
  1. 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
  1. 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 
  1. 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
  1. 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 
  1. 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  
  1. 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 
  1. 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 
  1. N-Acetylcysteine Protection in COPD. Wu, Wenxin et al. CHEST, Volume 145, Issue 1, 193 – 194. January 2014 
  1. Gammoh, N.Z.; Rink, L. Zinc in Infection and Inflammation. Nutrients2017, 9, 624. 
  1. 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 
  1. 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 
  1. 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 
  1. 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 
  1. 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 
  1. 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 
  1. 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
  1. 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
  1. Vitamin D reduces respiratory tract infections frequency. Bhutta, Zulfiqar A. The Journal of Pediatrics, Volume 186, 209 – 212
  1. 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
  1. 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 
  1. 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
  1. 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 
  1. 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 
  1. 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 
  1. The pathogenesis and treatment of the ‘Cytokine Storm’ in COVID-19. Qing Ye, Bili Wang, Jianhua Mao. Journal of Infection. March 24, 2020. 
  1. 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
  1. 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
  1. 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
  1. 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 
  1. 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 
  1. 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 
  1. 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 
  1. 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
  1. 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 
  1. 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
  1. 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 
  1. 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
  1. 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
  1. 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 
  1. 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
  1. 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
  1. 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/ 
  1. 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
  1. 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
  1. 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
  1. 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
  1. 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 
  1. 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
  1. 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
  1. 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
  1. 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
  1. 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. 
  1. 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 
  1. 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
  1. 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.
  1. 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 
  1. 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
  1. 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
  1. 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
  1. 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
  1. 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
  1. 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 
  1. 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 
  1. 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 
  1. 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