1 Department of Medicine, Metropolitan Hospital, Jaipur, Rajasthan, India
2 Department of Oncology, Department of Medicine, Mayo Clinic, Rochester, MN, USA
3 Department of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA
4 Department of Internal Medicine, North Alabama Medical Center, Florence, AL, USA
5 Department of Anesthesiology and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA
6 Department of Pulmonary & Critical Care Medicine & Pharmacology, Texas A&M University, TX, USA
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease (COVID-19) pandemic, which has led scientists all over the world to push for the identification of novel therapies for COVID-19. The lack of a vaccine and specific treatment has led to a surge of novel therapies and their publicity in recent times. Under these unprecedented circumstances, a myriad of drugs used for other diseases is being evaluated and repositioned to treat COVID-19 (example- Remdesivir, Baricitinib). While multiple trials for potential drugs and vaccines are ongoing, and there are many unproven remedies with little or no supporting evidence. Presently, discussions are revolving around the use of multivitamins (Vitamin, C, D, A), minerals (selenium, zinc), probiotics, flavonoids, polyphenols, and herbal remedies (curcumin, artemisinin, herbal drinks). Our review delves further into the details of some of these controversial therapies for COVID-19.
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* Address correspondence to this author at Department of Pulmonary & Critical Care Medicine & Pharmacology, Texas A&M University, TX, USA; E-mail: firstname.lastname@example.org
In December 2019, an outbreak of pneumonia of unknown etiology was reported by the Wuhan Municipal Health Commission, in Wuhan, Hubei Province in China. Subsequently, novel coronavirus SARS CoV-2 was identified as the cause of the 2019 coronavirus disease (COVID-19) [1World Health Organization. Johns Hopkins Coronavirus Resource Center 20202020 [Accessed June 10, 2020.]; Available from: https://www.who.int/news-room/detail/27-04-2020-who-timeline---covid-19]. As the disease rapidly spread across borders and was proven difficult to contain, the World Health Organization (WHO) declared COVID-19 as a pandemic on March 11th, 2020. On June 22, 2020, there were more than 9 Million positive patients worldwide, with >469,000 global deaths [2COVID-19 Map. Johns Hopkins Coronavirus Resource Center 2020 [Accessed June 22, 2020.]; Available from: https:// coronavirus.jhu.edu/map.html].
Typically, COVID-19 presents as fever, dry cough, and fatigue. It may also show other mild symptoms such as nasal congestion, headache, conjunctivitis, sore throat, diarrhea, anosmia, or discoloration of fingers or toes. Approximately 80% of the patients recover without needing hospital treatment; however, the remaining 20% may require hospitalization, some even advance to critical illness. Patients with pre-existing conditions such as hypertension, underlying chronic heart and lung diseases, diabetes, and cancer are at a higher risk of experiencing COVID-19 related complications, which could lead to a poorer prognosis [3World Health Organization. Question and answers hub 2020.https://www.who.int/emergencies/diseases/novel-coronavirus-2019/question-and-answers-hub]. It is a fact that the various vitamins, trace elements, herbal remedies, and probiotics enhance immunity during times when there is no definitive preventive or therapeutic cure for viral infections like COVID-19, especially in the pediatric age groups considering the lockdown states [4Wintergerst ES, Maggini S, Hornig DH. Contribution of selected vitamins and trace elements to immune function. Ann Nutr Metab 2007; 51(4): 301-23. [http://dx.doi.org/10.1159/000107673] [PMID: 17726308] -12Barazzoni R, Bischoff SC, Breda J, et al. ESPEN expert statements and practical guidance for nutritional management of individuals with SARS-CoV-2 infection. Clin Nutr 2020; 39(6): 1631-8. [http://dx.doi.org/10.1016/j.clnu.2020.03.022] [PMID: 32305181] ]. Emergency Use Authorization (EUA) was issued on March 28th, 2020, by the Food and Drug Administration (FDA), which was later withdrawn based on the newer data. This sanction was for the use of oral formulations of hydroxychloroquine sulfate and chloroquine phosphate when recommended for the treatment of COVID-19 by a health care professional [13Food and Drug Administration. Request for emergency use authorization for use of chloroquine phosphate or hydroxychloroquine sulfate supplied from the strategic national stockpile for treatment of 2019 Coronavirus Disease 2020. https://www.fda.gov/ media/136534/download.Published]. Likewise, the emergency use of antiviral drug Remdesivir for COVID-19 positive cases with the significant disease was warranted on May 1, 2020 [14Food and drug administration. Coronavirus (COVID-19) update: FDA issues emergency use authorization for potential COVID-19 treatment 2020. Available from: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-issues-emergency-use-authorization-potential-covid-19-treatment]. In this time of uncertainty in several countries, non-evidence-based novel therapies are deployed to improve patient outcomes.
We aim to review these novels, yet controversial therapies that are being proposed and used in the treatment of COVID-19.
2.1. Vitamin C
Vitamin C (VC), also known as ascorbic acid, is known for its antioxidant properties. This characteristic of VC appears to play an essential role in modulating elevated levels of oxidative stress like infections and cancers. Infections lead to an activation of our immune system, which releases various oxidizing agents grouped as Reactive Oxygen Species (ROS). Though these ROS are useful to deactivate the microorganisms, they prove to be detrimental to the host cells [15Segal AW. How neutrophils kill microbes. Annu Rev Immunol 2005; 23: 197-223. [http://dx.doi.org/10.1146/annurev.immunol.23.021704.115653] [PMID: 15771570] ]. The duration of mechanical ventilation is reduced by 14% in a recent trial among 685 patients with the use of VC. Another multi-centric study confirmed the reduction in ventilation time by 25% with the dosage of 1-6g/day of VC in patients treated in critical care [16Hemilä 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(1): 15. [http://dx.doi.org/10.1186/s40560-020-0432-y] [PMID: 32047636] -18University of helsinki. Vitamin C can shorten the length of stay in the ICU, study finds 2019.https://www.sciencedaily.com/releases/2019/03
/190327123913.html]. With a pandemic like COVID-19, additional safe, cost-effective, and immune-supportive strategies, such as VC, may be warranted to protect individuals and populations against developing a severe disease [19Calder PC, Carr AC, Gombart AF, Eggersdorfer M. Optimal nutritional status for a well-functioning immune system is an important factor to protect against viral infections. Nutrients 2020; 12(4): 1181-0. [http://dx.doi.org/10.3390/nu12041181] ]. Thus, VC can be a potential prophylactic and therapeutic target for severe ARDS in COVID-19 patients [20Physicians Weekly. High-Dose IV Vitamin C on ARDS by COVID-19: A Possible Low-Cost Ally With a Wide Margin of Safety 2020.https://www.physiciansweekly.com/high-dose-iv-vitamin-c-on-ards-by-covid-19-a-possible-low-cost-ally-with-a-wide-margin-of-safety/]. Fowler et al. [21Fowler AA III, Truwit JD, Hite RD, et al. Effect of vitamin c infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: the citris-ali randomized clinical trial. JAMA 2019; 322(13): 1261-70. [http://dx.doi.org/10.1001/jama.2019.11825] [PMID: 31573637] ] and Wang et al. [22Wang Y, Lin H, Lin BW, Lin JD. Effects of different ascorbic acid doses on the mortality of critically ill patients: A meta-analysis. Ann Intensive Care 2019; 9(1): 58. [http://dx.doi.org/10.1186/s13613-019-0532-9] [PMID: 31111241] ] suggested that VC has a therapeutic role in critically ill patients. Studies conducted by Hemilä et al. [23Hemilä H. Vitamin C and SARS coronavirus. J Antimicrob Chemother 2003; 52(6): 1049-50. [http://dx.doi.org/10.1093/jac/dkh002] [PMID: 14613951] ] and Messina et al. [24Messina G, Polito R, Monda V, et al. Functional role of dietary intervention to improve the outcome of COVID-19: A hypothesis of work. Int J Mol Sci 2020; 21(9): 3104. [http://dx.doi.org/10.3390/ijms21093104] [PMID: 32354030] ] point towards the promising nature of VC in effectively improving the morbidity and mortality of patients in regard to COVID-19. With the rise of epidemics like COVID-19, additional safe, cost-effective, and immune-supportive strategies, such as VC, may be warranted to protect individuals and populations against developing a severe disease [21Fowler AA III, Truwit JD, Hite RD, et al. Effect of vitamin c infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: the citris-ali randomized clinical trial. JAMA 2019; 322(13): 1261-70. [http://dx.doi.org/10.1001/jama.2019.11825] [PMID: 31573637] -26Cheng RZ. Can early and high intravenous dose of vitamin C prevent and treat coronavirus disease 2019 (COVID-19)? Med Drug Discov 2020; 5100028 [http://dx.doi.org/10.1016/j.medidd.2020.100028] [PMID: 32328576] ]. Furthermore, previous evidences of VC to reduce the ICU stay and morbidity of patients in critical care with conditions like ARDS, sepsis, burns, trauma and respiratory failure, give an opportunity to investigate the role of VC in similar situations related to COVID-19 [27COVID-19 world news. Expert consensus on comprehensive treatment of coronavirus disease in shanghai 2019- COVID-19 world news 2020. Available from: https://covid19data.com/2020/03/04/
expert-consensus-on-comprehensive-treatment-of-coronavirus-disease-in-shanghai-2019/-35Hager DN, Hinson JS, Rothman RE. Vitamin C for Sepsis and Acute Respiratory Failure. JAMA 2020; 323(8): 791-2. [http://dx.doi.org/10.1001/jama.2019.21984] [PMID: 32096842] ]. Though the studies differ in doses used in the treatment of critical patients with the coronavirus, VC definitely seems to improve the outcomes (Table 1).
2.2. Vitamin D
The role of Vitamin D (VD) in providing immunity is unclear. The potential mechanisms include antiviral immunomodulation, induction of autophagy and apoptosis, and genetic or epigenetic regulation. Furthermore, the risk of viral infections can be reduced by VD. In addition, it has been observed in COVID-19 patients, that it works by enhancing the release of cytokines (pro-inflammatory) by the T helper type 2 cells, which will cause a diminution (anti-inflammatory) of the functioning of the T helper type 1 cells during various bacterial and viral crises [36Cantorna MT, Snyder L, Lin YD, Yang L. Vitamin D and 1,25(OH)2D regulation of T cells. Nutrients 2015; 7(4): 3011-21. [http://dx.doi.org/10.3390/nu7043011] [PMID: 25912039] , 37Kennel KA, Drake MT, Hurley DL. Vitamin D deficiency in adults: when to test and how to treat. Mayo Clin Proc 2010; 85(8): 752-7. [http://dx.doi.org/10.4065/mcp.2010.0138] [PMID: 20675513] ]. The high prevalence and outbreak of COVID during the winters raise the suspicion that there could be a relationship between VD deficiency and the infection leading to the high mortality rates in the elderly populations, who are known to produce lower amounts of VD, as compared to younger individuals when regularly exposed to sunlight [38Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395(10223): 497-506. [http://dx.doi.org/10.1016/S0140-6736(20)30183-5] [PMID: 31986264] ]. Various studies have suggested that there exists a relationship between VD deficiency and COVID-19, thus suggesting it might act as an aid to decrease the fatal nature of the virus. Nair et al. and Epidemiology Working Group for NCIP Epidemic Response, Chinese Center for Disease Control and Prevention interpret age as a risk factor for VD deficiency, which, if appropriately supplemented with VD, will improve COVID-19 outcomes. Similar studies report the association of low VD levels and positive blood cultures that might impact the severity of the condition [39Wimalawansa SJ. Global epidemic of CORONAVIRUS—COVID-19: What can we do to minimize risks. European J Biomed Pharma Sci -44Lee P, Eisman JA, Center JR. Vitamin D deficiency in critically ill patients. N Engl J Med 2009; 360(18): 1912-4. [http://dx.doi.org/10.1056/NEJMc0809996] [PMID: 19403914] ]. More studies need to define VD deficiency and groups prone to the deficit in relation to the coronavirus in order to prevent and cure it (Table 2).
2.3. Vitamin A
Vitamin A (VA) is a fat-soluble compound, which plays an essential role in many physiological functions like embryonic development, vision, immunity, cellular differentiation, and proliferation [45Conaway HH, Henning P, Lerner UH, Vitamin A. Vitamin a metabolism, action, and role in skeletal homeostasis. Endocr Rev 2013; 34(6): 766-97. [http://dx.doi.org/10.1210/er.2012-1071] [PMID: 23720297] , 46Timoneda J, Rodríguez-Fernández L, Zaragozá R, et al. Vitamin A Deficiency and the Lung. Nutrients 2018; 10(9)E1132 [http://dx.doi.org/10.3390/nu10091132] [PMID: 30134568] ]. WHO stated in an article that VA supplementation improved the outcome of respiratory infections in nutritionally challenged children [47Who/Unicef. Global action plan for prevention and control of pneumonia (GAPP) 2009. Available from: https://www.who.int/maternal_child_adolescent/documents/fch_cah_nch_09_04/en/]. It is a fact that VA improves the clinical results in patients affected by measles associated pneumonia. However, some studies show that low doses of VA are associated with a low risk of respiratory infection [48Jee J, Hoet AE, Azevedo MP, et al. Effects of dietary vitamin A content on antibody responses of feedlot calves inoculated intramuscularly with an inactivated bovine coronavirus vaccine. Am J Vet Res 2013; 74(10): 1353-62. [http://dx.doi.org/10.2460/ajvr.74.10.1353] [PMID: 24066921] ]. Though these results have not been consistent, VA still does not have an established role in epidemics like COVID-19. VA seems to have an effective role in improving the morbidity of COVID-19 cases by alleviating the functions of neutrophils, natural killer cells, monocytes or macrophages, T cells, and B cells [49Market M, Angka L, Martel AB, et al. Flattening the COVID-19 curve with natural killer cell based immunotherapies. Front Immunol 2020; 11: 1512. [http://dx.doi.org/10.3389/fimmu.2020.01512] [PMID: 32655581] ]. Therefore, the role of VA in COVID-19 treatment remains inconclusive.
The European Micronutrients recommendations network of excellence (EURRECCA) has stated that selenium plays a crucial role in five significant functions like cognition individuals aged >50 years, viral load and onset of Acute Respiratory Distress Syndrome (AIDS) in Human Immunodeficiency Virus (HIV) positive patients, immune functions, male fertility, and cancer (particularly for persons at risk of prostate cancer) [50Hurst R, Collings R, Harvey LJ, et al. EURRECA-Estimating selenium requirements for deriving dietary reference values. Crit Rev Food Sci Nutr 2013; 53(10): 1077-96. [http://dx.doi.org/10.1080/10408398.2012.742861] [PMID: 23952089] ]. Supplementing a moderate dose of selenium can strengthen cellular immunity, humoral immunity, and nonspecific immunity. Thus, its deficiency can impair immunity and is a potential form of protection for the prevention and therapies of infections of the respiratory system [51Li Y, Zheng H, Luo Y. The function of selenium on the infection of respiratory system. Guangdong Trace Elements Science 2004; 11(9): 1-5.]. Selenium is known for its remarkable redox biology when it comes to neutralizing the release of the reactive oxygen species in the reaction to infections in the body. Numerous studies indicated the implication of its deficiencies with the evolution of various infections, cancers, neurodegenerative diseases, and cardiovascular diseases [50Hurst R, Collings R, Harvey LJ, et al. EURRECA-Estimating selenium requirements for deriving dietary reference values. Crit Rev Food Sci Nutr 2013; 53(10): 1077-96. [http://dx.doi.org/10.1080/10408398.2012.742861] [PMID: 23952089] ]. With the rise of infections like COVID-19, it is possible to say that selenium can have a protective and therapeutic role in improving morbidity rates. Selenium had improved effects after an influenza vaccine challenge [52Ivory K, Prieto E, Spinks C, et al. Selenium supplementation has beneficial and detrimental effects on immunity to influenza vaccine in older adults. Clin Nutr 2017; 36(2): 407-15. [http://dx.doi.org/10.1016/j.clnu.2015.12.003] [PMID: 26803169] ].
Dietary zinc deficiency in developing countries is widespread and often exacerbated by acute and chronic infections. It is a necessary component of numerous metalloproteins, including those critical for DNA replication and cell division, and is crucial for maintaining immunological integrity, predominantly cellular immunity and antioxidant activity. It is also associated with growth, impaired immunity, learning disabilities, and anorexia [54Cuevas LE, Koyanagi A. Zinc and infection: a review. Ann Trop Paediatr 2005; 25(3): 149-60. [http://dx.doi.org/10.1179/146532805X58076] [PMID: 16156979] ]. Studies show that children with Zinc deficiency are at an increased risk of respiratory tract infections. Many mechanisms have been implicated in the role of zinc deficiency in causing an increased susceptibility to Acute Respiratory Infections (ARI’s). Zinc plays a vital barrier role in the cohesiveness of respiratory epithelial cells and controls the secretion of pro-inflammatory cytokines. Improved immunity has been confirmed with high dose Zinc supplementation for Torque Teno Virus (TTV) [55Iovino L, Mazziotta F, Carulli G, et al. High-dose zinc oral supplementation after stem cell transplantation causes an increase of TRECs and CD4+ naïve lymphocytes and prevents TTV reactivation. Leuk Res 2018; 70: 20-4. [http://dx.doi.org/10.1016/j.leukres.2018.04.016] [PMID: 29747074] ].
It is reported that Zinc supplementation could play a key role in preventing ARI in developing countries. It is supposed to lower the duration of respiratory tract infections, the number of episodes, the severity of bronchiolitis, and pneumonia [56Nair BT, Bhunia R, Sharma KK. Role of zinc supplementation in acute respiratory tract infections in children aged 2 to 60 months. International Journal of Contemporary Pediatrics 2017; 4(5) [http://dx.doi.org/10.18203/2349-3291.ijcp20173780] ]. But, this effect was minimal when other cases specific filters were applied [57Roth DE, Richard SA, Black RE. Zinc supplementation for the prevention of acute lower respiratory infection in children in developing countries: meta-analysis and meta-regression of randomized trials. Int J Epidemiol 2010; 39(3): 795-808. [http://dx.doi.org/10.1093/ije/dyp391] [PMID: 20156999] ]. Hence, the role of zinc in pandemics like COVID is unclear.
“Probiotics” are live microorganisms that are supposed to be beneficial to the health and well-being of an individual when ingested or applied to the body. The Food and Agriculture Organization of the United Nations (FAO) and the World Health Organization (WHO) have described probiotics as “live microorganisms which confer a health benefit on the host when administered in adequate amounts” [58Food And Agriculture Organization Of The United Nations. Health and Nutrition Properties of Probiotics in Food including Powder Milk with Live Lactic Acid Bacteria 2001.http://www.fao.org/3/a-a0512e.pdf]. The most commonly used probiotics are Lactobacilli and Bifidobacteria strains, and the yeast Saccharomyces boulardii. Some reports contemplate the use of probiotics in COVID-19. In a recent study, Trompette et al. stated that improving the diet quality in a susceptible COVID-19 individual could mitigate the risk of significant infection and complications [59Trompette A, Gollwitzer ES, Pattaroni C, et al. Dietary fiber confers protection against flu by shaping Ly6c- patrolling monocyte hematopoiesis and CD8+ T cell metabolism. Immunity 2018; 48(5): 992-1005.e8. [http://dx.doi.org/10.1016/j.immuni.2018.04.022] [PMID: 29768180] ]. Morrow et al. [60Morrow LE, Kollef MH, Casale TB. Probiotic prophylaxis of ventilator-associated pneumonia: A blinded, randomized, controlled trial. Am J Respir Crit Care Med 2010; 182(8): 1058-64. [http://dx.doi.org/10.1164/rccm.200912-1853OC] [PMID: 20522788] ] conducted randomized controlled trials and reported that critically ill patients on mechanical ventilation if given probiotics (i.e., live Bacillus subtilis, Lactobacillus rhamnosus GG, and Enterococcus faecalis) developed significantly less ventilator-associated pneumonia compared with the patients who were on placebo [60Morrow LE, Kollef MH, Casale TB. Probiotic prophylaxis of ventilator-associated pneumonia: A blinded, randomized, controlled trial. Am J Respir Crit Care Med 2010; 182(8): 1058-64. [http://dx.doi.org/10.1164/rccm.200912-1853OC] [PMID: 20522788] ]. There is also an indication that probiotic strains maintain equilibrium between pro-inflammatory and immunoregulatory cytokines, which aid in viral clearance while reducing immune response-mediated lung damage, which might be of particular interest in preventing ARDS, a significant complication of COVID-19. An RCT with Lactobacillus Plantarum DR7 diminished plasma pro-inflammatory cytokines (IFN-π, TNF-α) in middle-aged adults (30 to 60 years of age) and boosted anti-inflammatory cytokines (IL-4, IL-10) in young adults (30 years of age), supplemented by reduction of plasma peroxidation and oxidative stress compared with placebo [61Chong HX, Yusoff NAA, Hor YY, et al. Lactobacillus plantarum DR7 improved upper respiratory tract infections via enhancing immune and inflammatory parameters: A randomized, double-blind, placebo-controlled study. J Dairy Sci 2019; 102(6): 4783-97. [http://dx.doi.org/10.3168/jds.2018-16103] [PMID: 30954261] ]. This finding might be helpful, as it shows to inhibit the cytokine storm occurring in COVID-19 patients. Lactobacillus acidophilus and Bacillus clausii in the animal study did not show any reduction in the expression of coronavirus receptors in the murine small intestine when compared with the control and the post-Salmonella infection models. Feng et al. conducted animal studies and found that coronaviruses receptors could increase in the presence of both invasive bacteria and their counterpart, probiotics (Lactobacillus acidophilus and Bacillus clausii) in the murine small intestine with control and post-salmonella infection models [62Feng ZW. The small intestine, an underestimated site of SARS-CoV-2 infection: From red queen effect to probiotics. Preprints 2020; 2020030161.]. Due to a lack of substantial data, further clinical trials are warranted to understand the effect of probiotics in COVID-19.
2.7. PUFA and Omega-3
Polyunsaturated Fatty Acids (PUFA) are classified into two classes, the Omega-6 (N-6) family of PUFA (e.g., linoleic acid, arachidonic acid) and the Omega-3 (N-3) family (e.g., alpha-linolenic acid, Eicosapentaenoic Acid (EPA), Docosahexaenoic Acid (DHA). Such distinct groups of fatty acids have been extensively studied to understand their effects on cardiovascular and metabolic health, and cancer [63Mozaffarian D. Dietary fat 2020.https://www.uptodate.com/contents
/dietary-fat]. It is recognized that ω-3 PUFAs have anti-inflammatory properties and play an essential role in the body’s inflammation resolution [64Sansbury BE, Spite M. Resolution of acute inflammation and the role of resolvins in immunity, thrombosis, and vascular biology. Circ Res 2016; 119(1): 113-30. [http://dx.doi.org/10.1161/CIRCRESAHA.116.307308] [PMID: 27340271] ]. In several lung infections, the administration of PUFA can improve the patient’s outcome in acute pneumonia. Sharma et al. reported in their study that the dietary supplementation of ω-3 PUFA supplementation exerts an overall beneficial effect against acute experimental pneumonia. This mechanism is operative through the up-regulation of nonspecific and specific host immune defenses [65Sharma S, Chhibber S, Mohan H, Sharma S. Dietary supplementation with omega-3 polyunsaturated fatty acids ameliorates acute pneumonia induced by Klebsiella pneumoniae in BALB/c mice. Can J Microbiol 2013; 59(7): 503-10. [http://dx.doi.org/10.1139/cjm-2012-0521] [PMID: 23826960] ]. Jones et al. concluded the susceptibility of poxvirus infection of mice was not affected by dietary fats utilization [66Jones GJB, Roper RL. The effects of diets enriched in omega-3 polyunsaturated fatty acids on systemic vaccinia virus infection. Sci Rep 2017; 7(1): 15999. [http://dx.doi.org/10.1038/s41598-017-16098-7] [PMID: 29167527] ]. Dushianthan et al. [67Dushianthan A, Cusack R, Burgess VA, Grocott MP, Calder PC. Immunonutrition for acute respiratory distress syndrome (ARDS) in adults. Cochrane Database Syst Rev 2019; 1(1)CD012041 [http://dx.doi.org/10.1002/14651858.CD012041.pub2] [PMID: 30677127] ] examined the effects of omega-3 fatty acids and antioxidants in adults with ARDS (a significant complication in COVID-19). The study showed an ambiguity in regards to the consumption of omega-3 and other antioxidants and their benefits towards the improvement of ICU length of stay and duration of ventilator days. They further concluded that the intervention of omega-3 usage produced a minuscule or no difference in all-cause mortality [67Dushianthan A, Cusack R, Burgess VA, Grocott MP, Calder PC. Immunonutrition for acute respiratory distress syndrome (ARDS) in adults. Cochrane Database Syst Rev 2019; 1(1)CD012041 [http://dx.doi.org/10.1002/14651858.CD012041.pub2] [PMID: 30677127] ]. Considering the scarcity of data on hand, we have to rely on the results of ongoing trials to establish the role of ω-3 supplementation in ARDS and COVID-19.
Table 1 Summary of the evidence outlining the effects of Vitamin C use in COVID-19.
Table 2 Summary of the evidence outlining the potential role of Vitamin D in COVID-19.
Table 3 Summary of the evidence for the use of Flavonoids and Polyphenols in COVID-19.
2.8. Polyphenols, Flavonoids, and Herbal Drinks
Polyphenols are natural plant compounds and are generally involved in the defense against ultraviolet radiation or pathogenic aggression. Over the last decade, the possible health benefits of dietary plant polyphenols as an antioxidant have been of great interest. The main classes of polyphenols are phenolic acids, flavonoids, lignans, and stilbenes. Out of these, one of the most prominent phenols is the class flavonoids. The benefit of continuing the use of polyphenols against cancer growth, cardiovascular disorders, diabetes, osteoporosis, and neurodegenerative diseases was implied in recent epidemiological studies. Their key role in being anti-inflammatory, anti-mutagenic, antioxidant, and anti-carcinogenic is diverse [68Panche AN, Diwan AD, Chandra SR. Flavonoids: An overview. J Nutr Sci 2016; 5e47 [http://dx.doi.org/10.1017/jns.2016.41] [PMID: 28620474] ]. The summary of the use of flavonoids and polyphenols in COVID-19 is exhibited in Table 3. Bhowmick et al. [69Bhowmick D, Nandi R, Kumar D. Evaluation of flavonoids as 2019-ncov cell entry inhibitor through molecular docking and pharmacological analysis 2020. Preprint from ChemRxiv 2020; 05 [http://dx.doi.org/10.26434/chemrxiv.12071508.v1] ], and Adem et al. [70Adem SE, Sarfraz I, Rasul A, Ali M. Identification of potent COVID-19 Main Protease (Mpro) inhibitors from natural polyphenols: An in silico strategy unveils a hope against CORONA. Preprints 2020; 2020030333. [http://dx.doi.org/10.20944/preprints 202003.0333.v1] ] reported the binding of flavonoids and polyphenols to the receptors of SARS-CoV-2, subsequently inhibiting it at a molecular level. They also proposed the affinity of flavonoids towards the ACE-2 receptor [69Bhowmick D, Nandi R, Kumar D. Evaluation of flavonoids as 2019-ncov cell entry inhibitor through molecular docking and pharmacological analysis 2020. Preprint from ChemRxiv 2020; 05 [http://dx.doi.org/10.26434/chemrxiv.12071508.v1] , 70Adem SE, Sarfraz I, Rasul A, Ali M. Identification of potent COVID-19 Main Protease (Mpro) inhibitors from natural polyphenols: An in silico strategy unveils a hope against CORONA. Preprints 2020; 2020030333. [http://dx.doi.org/10.20944/preprints 202003.0333.v1] ]. Ang et al. [71Ang L, Lee HW, Kim A, Lee JA, Zhang J, Lee MS. Herbal medicine for treatment of children diagnosed with COVID-19: A review of guidelines. Complement Ther Clin Pract 2020; 39101174 [http://dx.doi.org/10.1016/j.ctcp.2020.101174] [PMID: 32379639] ] reported the use of Armeniacae semen, which was the most frequently used herbal supplement reducing the hyper-responsiveness on the airways for the treatment of pediatric COVID-19 in the Chinese population [71Ang L, Lee HW, Kim A, Lee JA, Zhang J, Lee MS. Herbal medicine for treatment of children diagnosed with COVID-19: A review of guidelines. Complement Ther Clin Pract 2020; 39101174 [http://dx.doi.org/10.1016/j.ctcp.2020.101174] [PMID: 32379639] ].
Curcumin is a chemical with potent anti-inflammatory and antioxidant properties, popularly found in turmeric. These novel compounds have been proposed as an adjunctive therapy on social media. Jena et al. depicted the role of curcumin and catechin in binding to the S-protein at the location where host cell binding is known to occur. Similarly, they documented the attachment of these molecules to ACE2 sites that served as a viral entry medium. The study concluded that curcumin has the potential to block the entry of viral protein by inhibiting the host cell receptor and virus binding [73Jena A, Kanungo N, Nayak V, Chainy GBN, Dandapat J. Catechin and Curcumin interact with corona (2019-nCoV/SARS-CoV2) viral S protein and ACE2 of human cell membrane: Insights from Computational study and implication for intervention 2020.].
On 14th April 2020, MGC pharmaceuticals announced the approval from the Human Research Ethics Committee ('Ethics Committee') of Nazareth Hospital EMMS in Israel to implement a Phase II placebo-controlled clinical trial to determine the safety and efficacy of a natural anti-infective formulation ('ArtemiC' or 'Product') in patients infected with COVID-19 [74Ltd MP. Ethics committee approval received for phase ii clinical trial on patients diagnosed with COVID-19 2020.https://wcsecure.
2.10. Colloidal Silver
Colloidal silver is composed of small silver particles in a liquid marketed as a dietary supplement claiming to have antiviral properties. There is, however, a shortage of evidence to support arguments related to its benefits. In reality, colloidal silver can be hazardous to one's health. Zachar et al. [75Zachar O. Formulations for COVID-19 early stage treatment via silver nanoparticles inhalation delivery at home and hospital science open preprints 2020.https://www.scienceopen.com/hosted-
document?doi=10.14293/S2199-1006.1.SOR-.PPHBJEO.v1] concluded that successful Minimum Inhibitory Concentration (MIC) was achieved in both the bronchial tree and the alveoli after investigating its effect in specific locations of the respiratory system during viral and bacterial infections. They concluded that successful MIC was achieved in both the bronchial tree and the alveoli. This approach was proposed as a first-line treatment to suppress the progression of the SARS-COV-2 infection in the respiratory system [75Zachar O. Formulations for COVID-19 early stage treatment via silver nanoparticles inhalation delivery at home and hospital science open preprints 2020.https://www.scienceopen.com/hosted-
document?doi=10.14293/S2199-1006.1.SOR-.PPHBJEO.v1]. Further studies are needed to support this hypothesis.
Nutrition and immunity go hand in hand and are known to have a direct relationship in reducing the risk and severity of any infection. Various macro and micronutrients have been implicated to affect morbidity and mortality positively when supplemented during the episodes of infection. Since the COVID-19 pandemic constitutes higher mortality due to respiratory failure, these nutrients may have a beneficial but not completely validated role as a prophylactic and therapeutic treatment. However, there is insufficient data to prove an association between COVID-19 and the benefits of nutrition. There is also a clear need to study the beneficial effects’ applicability on the whole population or only on the groups that are nutritionally challenged. Robust nutritional surveys and blinded randomized clinical studies are needed to investigate the potential effects of such therapies on COVID-19.
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