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An overview on role of nutrition on COVID-19 immunity: Accumulative review from available studies

Open AccessPublished:November 08, 2022DOI:https://doi.org/10.1016/j.nutos.2022.11.001

      Summary

      The novel coronavirus infection (COVID-19) conveys a serious global threat to health and economy. A common predisposing factor for development to serious progressive disease is presence of a low-grade inflammation, e.g., as seen in diabetes, metabolic syndrome, and heart failure. Micronutrient deficiencies may also contribute to the development of this state. Therefore, the aim of the present study is to explore the role of the nutrition to relieve progression of COVID-19. According PRISMA protocol, we conducted an online databases search including Scopus, PubMed, Google Scholar and web of science for published literatures in the era of COVID-19 Outbreak regarding to the status of nutrition and COVID-19 until December 2021. There were available studies (80 studies) providing direct evidence regarding the associations between the status of nutrition and COVID-19 infection. Adequate nutritional supply is essential for resistance against other viral infections and also for improvement of immune function and reduction of inflammation. Hence, it is suggested that nutritional intervention which secures an adequate status might protect against the novel coronavirus SARS-CoV-2 (Severe Acute Respiratory Syndrome - coronavirus-2) and mitigate its course. We also recommend initiation of adequate nutritional supplementation in high-risk areas and/or soon after the time of suspected infection with SARS-CoV-2. Subjects in high-risk groups should have high priority for applying this nutritive adjuvant therapy that should be started prior to administration of specific and supportive medical measures.

      Keywords

      Introduction

      COVID-19 is a novel infectious disease due to infection by SARSCoV-2 (Severe Acute Respiratory Syndrome - coronavirus-2), a newly identified coronavirus, which spreads primarily between human hosts through respiratory droplets during close contacts. Besides, it could also develop after touching a contaminated surface with subsequent facial contact [
      • Xu Y.
      • Baylink D.J.
      • Chen C.-S.
      • Reeves M.E.
      • Xiao J.
      • Lacy C.
      • et al.
      The importance of vitamin d metabolism as a potential prophylactic, immunoregulatory and neuroprotective treatment for COVID-19.
      ]. SARS-CoV-2 is a single positive-stranded RNA enveloped virus containing ∼ 30kb with a nucleocapsid that undergoes membrane fusion or endocytosis for its entrance into the infected cells with subsequent development of enteric, respiratory, neurological and hepatic diseases in different species such as human being [
      • Cascella M.
      • Rajnik M.
      • Cuomo A.
      • Dulebohn S.C.
      • Di Napoli R.
      Stat Pearls. Treasure island (FL).
      ]. In severe cases, excessive activation of innate immune system, progressive inflammation and cytokine storm particularly in airways occurs leading to the development of cytokine release syndrome [
      • Shimabukuro-Vornhagen A.
      • Gödel P.
      • Subklewe M.
      • Stemmler H.J.
      • Schlößer H.A.
      • Schlaak M.
      • et al.
      Cytokine release syndrome.
      ,
      • Conti P.
      • Ronconi G.
      • Caraffa A.
      • Gallenga C.
      • Ross R.
      • Frydas I.
      • 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.
      ]. The contribution of clinical and subclinical micronutrient deficiencies to development of diminished immune function is suggested in patients with COVID-19 infection [
      • Hoffman R.
      Micronutrient deficiencies in the elderly–could ready meals be part of the solution?.
      ]. The role of nutritional management is suggested to be essential to diminish risk of severe infection [
      • Lipsitch M.
      • Swerdlow D.L.
      • Finelli L.
      Defining the epidemiology of Covid-19—studies needed.
      ]. Considering scant data on therapeutic and/or preventive efficiency of dietetics and nutrition in COVID-19 cases, in this narrative review we are going to discuss recently published data on the role of nutrition on immune system competency in COVID-19 patients.

      Methods

      Beast on PRISMA protocol [
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ], we did a literature search for the period COVID-19 Outbreak on Web of Science, PubMed, Scopus, Google scholar and Science Direct, and Medline with the keywords COVID 19, zinc, selenium, vitamins, mineral, deity, and nutrition until December, 2021 (Fig. 1). No restriction was considered for the time and language of publications. Papers evaluating nutrition status in cases with COVID-19 were eligible for inclusion. In this study, letters, comments, and short communications were excluded from the current study. Based on the information retrieved, we here discussed the role of the status of nutrition in the perspective of principles for implementing preventive measures against COVID-19.

      The status of nutrition and COVID-19

      Subclinical or clinical micronutrient deficiencies, such as vitamins and minerals deficiencies which often occurs in elder population, contribute to the development of age-related diseases including hypertension, diabetes, and coronary heart disease [
      • Bjørklund G.
      • Dadar M.
      • Pivina L.
      • Doşa M.D.
      • Semenova Y.
      • Aaseth J.
      The role of zinc and copper in insulin resistance and diabetes mellitus.
      ,
      • Farrokhian A.
      • Bahmani F.
      • Taghizadeh M.
      • Mirhashemi S.
      • Aarabi M.
      • Raygan F.
      • et al.
      Selenium supplementation affects insulin resistance and serum hs-CRP in patients with type 2 diabetes and coronary heart disease.
      ,
      • Holmberg S.
      • Rignell-Hydbom A.
      • Lindh C.H.
      • Jonsson B.A.
      • Thelin A.
      • Rylander L.
      High levels of vitamin D associated with less ischemic heart disease-a nested case-control study among rural men in Sweden.
      ]. These highly interacting metabolic diseases [
      • Grundy S.M.
      Metabolic syndrome: connecting and reconciling cardiovascular and diabetes worlds.
      ] are characterized by the presence of systemic low-grade inflammation [
      • Sanada F.
      • Taniyama Y.
      • Muratsu J.
      • Otsu R.
      • Shimizu H.
      • Rakugi H.
      • et al.
      Source of chronic inflammation in aging.
      ]. Pre-infectious signs of underlying inflammation, such as elevated plasma levels of C-reactive protein (CRP) in COVID-19 indicate to a common aggravating factor [
      • Zheng Y.-Y.
      • Ma Y.-T.
      • Zhang J.-Y.
      • Xie X.
      COVID-19 and the cardiovascular system.
      ]. Nutrients adequacy is vital for proper immune competence and their deficiency could be associated with inflammatory aggravation (Table 1). Dietary advice may not be alone enough to guarantee adequacy in some populations, including in elder subjects [
      • Maggini S.
      • Pierre A.
      • Calder P.C.
      Immune function and micronutrient requirements change over the life course.
      ] implying to seeking for supplementation in some populations.
      Table 1Association of nutrition status with COVID-19 and outcomes in recent studies
      Nutrition typeSample sizeOutcomeCountryReference
      vitamin A (research article)40 hospitalized patients and 47 age-matched convalescent as the control groupReduced plasma levels of vitamin A correlated significantly with higher levels of inflammatory markers (ferritin, C-reactive protein (CRP)) and markers of acute SARS-CoV-2 infection (reduced LDH, lymphocyte count). Significantly lower Vitamin A levels were observed in hospitalized patients compared with convalescent persons. Among hospitalized cases, significantly lower vitamin A levels were observed in critically ill patients than moderately ill patients. Plasma level of vitamin A below 0.2 mg/L was shown to be significantly related with the development of mortality and ARDS.GermanyTepasse et al. 2021 [
      • Tepasse P.-R.
      • Vollenberg R.
      • Fobker M.
      • Kabar I.
      • Schmidt H.
      • Meier J.A.
      • et al.
      Vitamin A plasma levels in COVID-19 patients: a prospective multicenter study and hypothesis.
      ]
      vitamin A (bioinformatics study)393 SARS-CoV-2-associated genes and 122 VA-pharmacological action genes.Mechanisms of action related with vitamin A functions against SARS-CoV-2 based on bioinformatics findings include inhibition of inflammatory reaction, enrichment of immunoreaction and biological processes associated with reactive oxygen species. Besides, seven core targets of vitamin A against COVID-19, including IL10, MAPK1, EGFR, MAPK14, ICAM1, PRKCB and CAT were identified. Based on this bioinformatics-based report, mechanisms of vitamin A and functions of anti-SARS-CoV-2 suggest vitamin A as a potent therapeutic option for COVID-19.ChinaLi et al. 2020 [
      • Li R.
      • Wu K.
      • Li Y.
      • Liang X.
      • Tse W.K.F.
      • Yang L.
      • et al.
      Revealing the targets and mechanisms of vitamin A in the treatment of COVID-19.
      ]
      vitamin B (review)Vitamin B helps in building and maintenance of healthy immune system, prevention or reduction of COVID-19 symptoms and treatment of SARS-CoV-2 infection. Poor nutritional status is a predisposing factor getting infections more easily. Thus, a balanced diet is essential for immuno-competence. Seeking for cost-effective and safe adjunct or therapeutic strategies to act as anti-thrombotic agents and suppress aberrant immune activation with its subsequent cytokine storm is essential. Adequate vitamin intake is fundamental for proper body function and also strengthening of immune system. Vitamin B particularly modulates immune response through downregulation of inflammation and pro-inflammatory cytokines, reduction of breathing difficulty and gastrointestinal discomforts, prevention of hypercoagulability, improvement of outcomes and reduction of hospital length of stay in COVID-19 patients.UAEShakoor et al. 2021 [
      • Shakoor H.
      • Feehan J.
      • Mikkelsen K.
      • Al Dhaheri A.S.
      • Ali H.I.
      • Platat C.
      • et al.
      Be well: A potential role for vitamin B in COVID-19.
      ]
      Vitamins (cohort)43 consecutive patients ≥50 yearAfter separate age or blood pressure adjustment in a multivariate analysis, intervention group retained protective significance. Fewer treated patients required oxygen therapy during their hospitalization than controls. DMB exposure was observed to be associated with odds ratios for intensive care support and oxygen therapy or both on multivariate and univariate analyses, respectively.SingaporeTan et al. 2020 [
      • Tan C.W.
      • Ho L.P.
      • Kalimuddin S.
      • Cherng B.P.Z.
      • Teh Y.E.
      • Thien S.Y.
      • et al.
      Cohort study to evaluate effect of vitamin D, magnesium, and vitamin B12 in combination on severe outcome progression in older patients with coronavirus (COVID-19).
      ]
      Vitamin C (review)21 studiesVitamin C has potent anti-inflammatory and anti-oxidant effects which diminishes chance of tissue damage related to oxidative stress and suppress significant inflammatory responses recognized as cytokine storm. By stimulating lymphocyte proliferation of and increasing production of interferon, vitamin C is able to improve host antiviral immune responses. Vitamin C consumption in critically ill patients and those with severe sepsis and or septic shock was seen in previous clinical trials to decrease vasopressor requirements, improve survival and decrease hospital length of stay. Treatment of COVID-19 patients using high dose of Intravenous (IV) vitamin C in the United States and China have demonstrated promising results. Indeed, no adverse effect was reported using short-term high dose of vitamin C.UKAbobaker et al. 2020 [
      • Abobaker A.
      • Alzwi A.
      • Alraied A.H.A.
      Overview of the possible role of vitamin C in management of COVID-19.
      ]
      Vitamin C (randomized placebo-controlled trial)308 adults diagnosed with COVID-19IV vitamin C exerts advantages in terms of availability, safety, stability and cost compared with other therapeutic modalities.ChinaLiu et al. 2020 [
      • Liu F.
      • Zhu Y.
      • Zhang J.
      • Li Y.
      • Peng Z.
      Intravenous high-dose vitamin C for the treatment of severe COVID-19: study protocol for a multicentre randomised controlled trial.
      ]
      Vitamin D (Systematic review)34 studiesIn our primary analysis on 31 peer-reviewed observational studies, a positive trend was observed between serum 25(OH)D level <20 ng/ml and not statistically significant enhanced risk of ICU admission, invasive or non-invasive ventilation, mortality, or SARS-CoV-2 positivity. In COVID-19 positive cases, mean 25(OH)D levels were 5.9 ng/ml significantly lower compared to COVID-19 negative patients, albeit there was very low certainty of the evidence. Only 32 clinical trial protocols were identified in which just three of them have published data to-date. The trials administer vitamin D doses of 357 to 60,000 IU/day, from one week to 12 months. Eight mega trials evaluate the efficacy of vitamin D in outpatient cases. A significant reduction in ICU admission using calcifediols vs. placebo revealed through a pilot trial with an unclear certainty of the evidence. Supplementation with daily cholecalciferol (60,000 IU) showed by another small trial to decrease fibrinogen levels without having any impact on CRP, D-dimer and procalcitonin levels compared to placebo. The third trial did not show any impact of supplementation with vitamin D on COVID-19 related outcomes.UKBassatne et al. 2021 [
      • Bassatne A.
      • Basbous M.
      • Chakhtoura M.
      • El Zein O.
      • Rahme M.
      • El-Hajj Fuleihan G.
      The link between COVID-19 and VItamin D (VIVID): A systematic review and meta-analysis.
      ]
      Vitamin D (Systematic review)9 studiesOf nine reviewed studies, seven (77.8%) demonstrated the correlation between vitamin D status and COVID-19 prognosis and mortality. Most articles demonstrated that plasma vitamin D status could determine the possibility of catching coronavirus and its mortality and severity. Thus, maintained of appropriate plasma levels of vitamin D through its supplementation or sunshine exposure is recommended to cope with the pandemic.EthiopiaYisak et al. 2021 [
      • Yisak H.
      • Ewunetei A.
      • Kefale B.
      • Mamuye M.
      • Teshome F.
      • Ambaw B.
      • et al.
      Effects of vitamin D on COVID-19 infection and prognosis: a systematic review.
      ]
      Vitamins and mineral (review)There were a few investigations which provide direct evidence regarding associations between vitamin D, selenium, zinc and COVID-19. Adequate supply of selenium, zinc, and vitamin D is necessary to resist other viral infections, to improve immune function, and reduce inflammation. Nutrition intervention securing an adequate status has been stated to protect against the novel coronavirus SARS-CoV-2 (Severe Acute Respiratory Syndrome - coronavirus-2) and mitigate the disease course of COVID-19 infection.NorwegianAlexander et al. 2020 [
      • Alexander J.
      • Tinkov A.
      • Strand T.A.
      • Alehagen U.
      • Skalny A.
      • Aaseth J.
      Early nutritional interventions with zinc, selenium and vitamin D for raising anti-viral resistance against progressive COVID-19.
      ]
      Vitamin D (review and correlation study)12 studiesThere was a significant negative correlation (P= 0.033) between COVID-19 cases per one million populations and mean vitamin D levels in European countries. However, in these countries the correlation between vitamin D and COVID-19 related death was not significant. There was an observed correlation between vitamin D and COVID-19 related severity and mortality in some retrospective studies, while other investigations observed no correlation after adjustment of other confounding variables. Several studies indicated to the roles of vitamin D in reducing the risk of pneumonia and acute viral respiratory tract infections including direct inhibition of viral replication or through anti-inflammatory or immunomodulatory approaches. Therefore, high risk patients for vitamin D deficiency during this global pandemic should be supplemented with vitamin D to maintain optimal levels of circulating 25(OH)D (75–125 nmol/L). Conclusively, there is not enough evidence regarding association between severity and mortality of COVID-19 infection and vitamin D levels. Thus, further cohort studies and randomized control trials are needed to test this hypothesis.BangladeshAli et al. 2020 [
      • Ali N.
      Role of vitamin D in preventing of COVID-19 infection, progression and severity.
      ]
      Vitamin D (review)Pervasive actions of vitamin D on different organ systems raised different probable interactions between it and mechanisms by which SARS-CoV-2 virus infects humans. By the way, for getting more conclusive results, further research is yet needed.USABilezikian et al. 2020 [
      • Bilezikian J.P.
      • Bikle D.
      • Hewison M.
      • Lazaretti-Castro M.
      • Formenti A.M.
      • Gupta A.
      • et al.
      Mechanisms in endocrinology: vitamin D and COVID-19.
      ]
      Vitamin D (review)47 studiesDeficiency in vitamin D contributes to acute respiratory distress syndrome with enhanced case fatality rate by age and chronic disease comorbidity and both are associated with lower concentration of 25(OH)D. In order to reduce infection risk, people at risk of infection by influenza and/or COVID-19, taking 10,000 IU/d of vitamin D3 for a few weeks to rapidly raise 25(OH) D concentrations, followed by 5000 IU/d is recommended. The goal should be to raise 25(OH) D concentrations above 40–60 ng/mL (100–150 nmol/L). For treatment of infected people with COVID-19, higher doses of vitamin D3 might be useful. Large population studies and randomized controlled trials should be conducted to asses these recommendations.USAGrant et al. 2020 [
      • Grant W.B.
      • Lahore H.
      • McDonnell S.L.
      • Baggerly C.A.
      • French C.B.
      • Aliano J.L.
      • et al.
      Evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths.
      ]
      Vitamin D (review)Vitamin D, a key regulator of renin-angiotensin system, is exploited by SARS-CoV-2 for its entrance into host cells. Furthermore, it modulates numerous immune mechanisms to contain virus including dampening SARS-CoV-2 entrance and replication, reduction of concentration of pro-inflammatory cytokines and enhancement of anti-inflammatory cytokines, increasing production of natural antimicrobial peptide and activating defensive cells such as macrophages with the ability to destroy SARS-CoV-2.IndiaKumar et al. 2020 [
      • Kumar R.
      • Haq A.
      • Wimalawansa S.J.
      • Sharma A.
      Putative roles of vitamin D in modulating immune response and immunopathology associated with COVID-19.
      ]
      Vitamin D (review)14 studiesVitamin D could reduce risk of COVID-19 and acute respiratory tract infections through several mechanisms through its interaction of cells. Among them, reducing viral survival and replication, reducing production of cytokines, maintenance of endothelial cell integrity and enhancement of angiotensin-converting enzyme 2 concentrations have been suggested. Inverse correlation of serum 25-hydroxyvitamin D concentrations with incidence and or severity of COVID-19 infection. It satisfies Hill's criteria for causality in a biological system, namely, consistency, strength of association, biological gradient, plausibility (e.g., mechanisms), temporality, and coherence despite of lacking experimental verification. Therefore, there is enough strong evidence about usage of vitamin D supplements to prevent or treat COVID-19 by people and physicians regarding their wide therapeutic window and safety.USAMercola et al. 2020 [
      • Mercola J.
      • Grant W.B.
      • Wagner C.L.
      Evidence regarding vitamin D and risk of COVID-19 and its severity.
      ]
      Vitamin D (review)A growing body of circumstantial evidence links vitamin D status and COVID-19 outcomes. Role of vitamin D in COVID-19 could be twofold by reducing inflammatory responses and supporting production of antimicrobial peptides in respiratory epithelium which makes development of COVID-19 symptoms less likely. Deregulation of inflammatory responses, especially renin– angiotensin system is the main feature of COVID-19 and its over activation brings poorer prognosis. Vitamin D is able to interact with a protein in ACE-2 pathway which is also exploited by SARS-CoV-2 as an entry receptor. While ACE-2 expression is downregulated by SARS-CoV-2, vitamin D promotes its expression.Mitchell et al. 2020 [
      • Mitchell F.
      Vitamin-D and COVID-19: do deficient risk a poorer outcome?.
      ]
      Vitamin D (review)Vitamin D exert dual role of initial controlling of viral replication and later dampening of hyper-inflammation which is consistent with observation of possible adverse impact of low levels of vitamin D or polymorphisms in Vitamin D receptor) on outcomes of COVID-19 cases.IndiaMohan et al. 2020 [
      • Mohan M.
      • Cherian J.J.
      • Sharma A.
      Exploring links between vitamin D deficiency and COVID-19.
      ]
      Vitamin D (review)15 studiesIt has been hypothesized that vitamin D supplementation could help in maintenance of sufficient vitamin D levels in COVID-19 patients as guideline recommended. This allows generation of a local high dose of 1,25(OH)2D3 in respiratory epithelia and immune cells by inflammation-up regulated 1α-hydroxylase (CYP27B1) in order to prohibit cytokine release syndrome and subsequent disease progression. Monitoring of serum calcium level is recommended and its mitigation using hydration or adjustment of the dose of applied vitamin D supplement is essential in the case of significant hypercalcemia.USAXu et al. 2020 [
      • Xu Y.
      • Baylink D.J.
      • Chen C.-S.
      • Reeves M.E.
      • Xiao J.
      • Lacy C.
      • et al.
      The importance of vitamin d metabolism as a potential prophylactic, immunoregulatory and neuroprotective treatment for COVID-19.
      ]
      Vitamin E (review)Lipid hydroperoxides will be formed due to reaction of oxygen with the cell membrane lipids using lipoxygenase with the help of peroxyl radicals. In order to prevent formation of hydroperoxides, vitamin E reacts with peroxyl radicals. Afterward, oxidized lipids will be detoxified by GPX4, glutathione, and other antioxidant agents to prohibit triggering of ferroptosis. Besides, vitamin E is able to compensate for detoxification induced by GPX4 deficiency. Indeed, induced neurodegeneration in the setting of vitamin E deficiency is said to be related to ferroptosis. Neural damage in COVID-19 cases might be partly inhibited by consumption of vitamin E through an anti-ferroptosis mechanism. Thus, toxic mechanisms behind iron serum levels such as ferroptosis should be inhibited using consumption of vitamin E through prohibition of peroxyl and lipoxygenase radicals. High dosage of Vitamin E supplement (500 mg/kg) could be used as a therapeutic medicine to prevent ferroptosis in COVID- 19 cases and diminish ferroptosis induced multiple organ damages including gut, kidney, heart, lung, liver, and nervous system. This could also lead to viral clearance and ablation of inflammation through modulation of T cells.IranTavakol et al. 2021 [
      • Tavakol S.
      • Seifalian A.M.
      Vitamin E at a high dose as an anti-ferroptosis drug and not just a supplement for COVID-19 treatment.
      ]
      Vitamin E (research article)60 pregnant women with COVID-19 infection and 36 age-matched pregnant women without any defined risk factors.A correlation analysis on pregnant women showed higher obstetric complication rate in COVID-19 group. Higher Afamin levels and lower vitamin E levels were observed in the COVID-19 group for the all trimesters, albeit this association was statistically noon-significant for Afamin levels which could support the role of enhanced oxidative stress in pathogenesis of COVID-19 infection and its relationship with the development of composite adverse perinatal outcomes. The values in the ROC curves with the best balance of sensitivity/specificity for vitamin E and afamin were 3.150μg/ml and 0.424 mg/l, respectively. A positive moderate statistically significant correlation was observed between regarding CRP and afamin levels.TurkeyErol et al. 2020 [
      • Erol S.A.
      • Tanacan A.
      • Anuk A.T.
      • Tokalioglu E.O.
      • Biriken D.
      • Keskin H.L.
      • et al.
      Evaluation of maternal serum afamin and vitamin E levels in pregnant women with COVID-19 and its association with composite adverse perinatal outcomes.
      ]
      Vitamin E (research article)in vitro and in vivoCytotoxicty is induced in aerosols generated reactive oxygen species exposed cells which subsequently lead to elicited inflammatory responses and epithelial barrier dysfunction. Parameters of acute toxicity due to aerosol inhalation were evaluated in a murine model. Infiltration of lymphocytes and neutrophils were accompanied by a significant increase in IL-6, G-CSF and eotaxin in bronchoalveolar lavage fluid. There was a significant increase in leukotrienes, eicosanoid inflammatory mediators, in mouse plasma. Increased plasma levels of hydroxyeicosatetraenoic acid and diverse eicosanoids were observed in e-cig users. The most significant toxicity and side effects were observed after exposure to e-cig cartridge aerosols compared to vitamin E acetate and medium-chain triglycerides. Indeed, we identified no impact associated with aerosol exposures from these evaluated cartridges. An induced in vitro cytotoxicity, inflammation and barrier dysfunction were observed following acute exposure to specific e-cig cartridges. Indeed, in vivo mouse exposure was associated with acute inflammation and elevated pro-inflammatory markers in pathogenesis of associated lung injury.USAMuthumalage et al. 2020 [
      • Muthumalage T.
      • Lucas J.H.
      • Wang Q.
      • Lamb T.
      • McGraw M.D.
      • Rahman I.
      Pulmonary Toxicity and Inflammatory Response of Vape Cartridges Containing Medium-Chain Triglycerides Oil and Vitamin E Acetate: Implications in the Pathogenesis of EVALI.
      ]
      Vitamin E (research article)138 COVID-19 patients and 138 population controls.Plasma levels of dephosphorylated-uncarboxylated Matrix Gla Protein (dp-ucMGP) were significantly different between survivors vs. non-survivors. Patients had significantly higher levels of dp-ucMGP compared to controls. Increased dp-ucMGP levels which indicates low vitamin K status reflected higher mortality risk based on Cox regression survival analysis. After adjustment for co-morbidities, the association became attenuated and statistically insignificant. Conclusively, low vitamin K status was found to be associated with mortality in COVID-19 patients in age- and sex-adjusted analyses, but not in analyses with additional adjustment for co-morbidities.DenmarkLinneberg et al. 2021 [
      • Linneberg A.
      • Kampmann F.B.
      • Israelsen S.B.
      • Andersen L.R.
      • Jørgensen H.L.
      • Sandholt H.
      • et al.
      The Association of Low Vitamin K Status with Mortality in a Cohort of 138 Hospitalized Patients with COVID-19.
      ]
      Vitamin E (research article)1270After Propensity score matching, 1270 patients remained in the study (635 on vitamin K antagonists (VKAs); 635 on direct-acting oral anticoagulants (DOACs). There was a similar risks and 30-day event-free survival including all-cause mortality, ICH/gastrointestinal bleeding and ICU admission/MV necessity in VKA-treated patients compared to patients on DOACs. In the VKA cohort, there was 43% higher risk of any venous or arterial thrombotic event was 43% higher. Thus, prior application of DOAC therapy at the time of diagnosis in outpatient COVID-19 cases with cardiometabolic diseases vs. VKA therapy.TriNetX (a global federated health research network)Rivera-Caravaca et al. 2021 [
      • Rivera-Caravaca J.M.
      • Harrison S.L.
      • Buckley B.J.
      • Fazio-Eynullayeva E.
      • Underhill P.
      • Marín F.
      • et al.
      Efficacy and safety of direct-acting oral anticoagulants compared to vitamin K antagonists in COVID-19 outpatients with cardiometabolic diseases.
      ]
      Vitamin E (research article)sixty-two COVID-19

      positive patients
      Vitamin K deficiency is suggested to be frequently observed in COVID-19 cases with more prevalence in males vs. females. Vitamin K deficiency in male patients is associated with greater circulatory levels of IL-6. Vitamin K deficiency is able to support both cytokine storm Through enhancement of proinflammatory cytokines including IL-6 which is involved in build-up of recruitment of inflammatory responses that recruit both humoral and cellular components. Moreover, it also contributes to events involved in vascular calcification associated with thrombosis and disseminate intravascular coagulation (DIC) as features of microvascular injury seen in COVID patients. These data introduce Vitamin K as a probable modifiable risk factor for development of a severe course of COVID-19 infection.ItalyAnastasi et al. 2020 [
      • Anastasi E.
      • Ialongo C.
      • Labriola R.
      • Ferraguti G.
      • Lucarelli M.
      • Angeloni A.
      Vitamin K deficiency and covid-19.
      ]
      Vitamin E (research article)135 hospitalized COVID-19 patients were compared with 184 historical controls.Elevated Dp-ucMGP was observed in COVID-19 cases compared to controls, with higher dp-ucMGP in infected cases with poor outcomes. In 82.1% of cases, prothrombin (PIVKA-II) was normal. There was a correlation between Dp-ucMGP and desmosines and scores of thoracic aorta and coronary artery calcification.NetherlandsDofferhoff et al. 2020 [
      • Dofferhoff A.S.
      • Piscaer I.
      • Schurgers L.J.
      • Visser M.P.
      • van den Ouweland J.M.
      • de Jong P.A.
      • et al.
      Reduced vitamin K status as a potentially modifiable risk factor of severe COVID-19.
      ]
      Vitamin E (review)Covid-19 results in significant extrahepatic vitamin K insufficiency leading to the development of impairment in activation of extrahepatic proteins such as endothelial anticoagulant protein S in the setting of normal hepatic procoagulant activity. This indicates to enhanced thrombogenicity in the setting of severe Covid-19 infection. VKA inhibits vitamin K recycling and exerts a greater impact on procoagulant activity during SARS-CoV- 2 infections rather than activation of extrahepatic vitamin K-dependent proteins. A genetic polymorphism in vitamin K epoxide reductase complex 1 which is known as Vitamin K epoxide reductase complex subunit 1 (VKORC1) −1639A, which is associated with low rates of vitamin K recycling is especially prevalent in East Asia. Allele carriage could be considered as being bioequivalent to consumption of low-dose VKA. VKORC1−1639A is speculated to confer protection against development of thrombotic complications related to Covid-19. Variations in its allele frequency could be partly responsible for differences in Covid-19 severity among East and West. Disparity in COVID-19 related morbidity and mortality between East and West that could be partly explained by variations in allelic distribution of a VKORC1 polymorphism involved in determination of vitamin K recycling rate. Since VKORC1−1639A allele has been demonstrated to be associated with reduced risk of thrombotic complications and/or death, it could support the important role of vitamin K metabolism in determination of Covid-19-related disease severity.NetherlandsJanssen et al. 2020 [
      • Janssen R.
      • Walk J.
      Vitamin K epoxide reductase complex subunit 1 (VKORC1) gene polymorphism as determinant of differences in Covid-19-related disease severity.
      ]
      Vitamin E (review)The vitamin K-dependent factors protein S (PROS1) and growth-arrest-specific gene 6 (GAS6) and their tyrosine kinase receptors TYRO3, MERTK, AXL and the TAM subfamily of receptor tyrosine kinases (RTK) are known as key regulators of vascular response to injury and inflammatory processes. The important role of the TAM receptor family is being recognized during SARS-CoV-2 infection and progression of COVID-19 disease. Altered serum levels of sAXL, GAS6, sMERTK, or PROS1 have been previously associated with progression of inflammatory diseases and fibrosis in lung, heart and liver. Changes of specific components in COVID-19 patients seems to be associated with clinical complications and disease severity. Thus, COVID-19 could be possibly benefited from TAM targeting.SpainTutusaus et al. 2020 [
      • Tutusaus A.
      • Marí M.
      • Ortiz-Pérez J.T.
      • Nicolaes G.A.
      • Morales A.
      • García de Frutos P.
      Role of Vitamin K-dependent factors protein S and GAS6 and TAM receptors in SARS-CoV-2 infection and COVID-19-associated immunothrombosis.
      ]
      Calcium (systematic review)25 studiesClinical data derived from 12 articles demonstrated hypocalcemia in 59% of COVID-19 patients. The results of meta-analysis demonstrated significant association between hypocalcemia and disease severity, mortality, admission to intensive care unit and number of hospitalization days. Indeed, a direct association was observed between low serum calcium levels and decreasing lymphocyte counts and increasing D-dimer levels.IranAlemzadeh et al. 2020 [
      • Alemzadeh E.
      • Alemzadeh E.
      • Ziaee M.
      • Abedi A.
      • Salehiniya H.
      The effect of low serum calcium level on the severity and mortality of Covid patients: A systematic review and meta-analysis.
      ]
      Calcium (review)20 studiesEvidence have indicated reduced mortality of COVID-19 through consumption of calcium channel blockers (CCBs), especially nifedipine and amlodipine. Indeed, hypocalcemia had strong positive association with severity of COVID-19. Effectiveness of CCBs as antiviral therapeutic approach and positive relationship between hypocalcemia and mortality have been shown for various viruses as well. It has been hypothesized that hypocalcemia indicates a host defense. In addition, hypocalcemia might include antiviral properties as the same with CCBs through its interference with metabolism of calcium in virus-infected cells. Calcium ions are central to replication of coronavirus and possible interference of hypocalcemia and CCBs with viral replication through reduction of intracellular calcium level has been suggested.USACrespi et al. 2021 [
      • Crespi B.
      • Alcock J.
      Conflicts over calcium and the treatment of COVID-19.
      ]
      Calcium (review)Calcium supplementation during SARS CoV-2 associated hyperactive stage of CaSR might induce injury to cardiorenal system. Besides, CaSR inhibition is also able to regulate enhanced levels of intracellular calcium, proinflammatory mechanisms, oxidative stress and cardio-renal cellular apoptosis with their subsequent adverse induction of high cytokine levels during COVID-19 infection.IndiaSingh et al. 2021 [
      • Singh Y.
      • Ali H.
      • Alharbi K.S.
      • Almalki W.H.
      • Kazmi I.
      Calcium sensing receptor hyperactivation through viral envelop protein E of SARS CoV2: A novel target for cardio-renal damage in COVID-19 infection.
      ]
      Zinc (review)Zinc should be prescribed as a preventative measure against COVID-19 infection and generally for support of immune health. Zinc should be considered as an adjunct therapy for COVID-19 based on its limited drug interactions and known safety. It also should be supplemented in the setting of acquired zinc deficiency during a viral infection and its related host immune response.USAJoachimiak et al. 2021 [
      • Joachimiak M.P.
      Zinc against COVID-19? Symptom surveillance and deficiency risk groups.
      ]
      Zinc (review)15 studiesZinc is a well-tolerated element with antiviral, anti-inflammatory, antioxidant and immunomodulatory properties. Its anti-viral properties are possibly mediated through inhibition of RNA virus RdRp which protects cells and tissues against oxidative damage and viral infection. Thus, zinc could be supplemented safely in COVID-19 cases.IndiaPal et al. 2021 [
      • Pal A.
      • Squitti R.
      • Picozza M.
      • Pawar A.
      • Rongioletti M.
      • Dutta A.K.
      • et al.
      Zinc and COVID-19: basis of current clinical trials.
      ]
      Zinc (review)Zinc could reduce risk of infection and optimize immune functions as an anti-inflammatory agent. Zinc supplementation could be a useful supplementation in order to diminish the global burden of infection in elder patients.BrazilAlmeida Brasiel et al. 2020 [
      • de Almeida Brasiel P.G.
      The key role of zinc in elderly immunity: A possible approach in the COVID-19 crisis.
      ]
      Zinc (review)Improvement of zinc status in COVID- 19 patients could conquer the infection and subsequently bolster their recovery. By adoption of this health-restoration strategy, other nutrients are also needed to be applied.AustraliaButters et al. 2020 [
      • Butters D.
      • Whitehouse M.
      COVID-19 and nutriceutical therapies, especially using zinc to supplement antimicrobials.
      ]
      Zinc and vitamins (review)Deficiency of one or more of vitamins C, D and zinc compromises immune responses, which makes persons prone to viral infections and a worse disease prognosis. Therefore, adequate intake of vitamin C, D and zinc during the COVID-19 pandemic could represent a promising approach based on high demands of these nutrients in cases with contact to the virus and those who are at the onset of inflammatory process.BrazilName et al. 2020 [
      • Souza A.C.R.
      • Vasconcelos A.R.
      • Prado P.S.
      • Pereira C.P.M.
      Zinc, Vitamin D and Vitamin C: perspectives for COVID-19 with a focus on physical tissue barrier integrity.
      ]
      Zinc (review)Chloroquine is able to induce zinc uptake into cell cytosol which enables inhibition of RNA-dependent RNA polymerase and ultimate halting of coronavirus replication in host cells. Chloroquine is widely prescribed as an anti-malarial agent without any doubt in its safety.USAShittu et al. 2020 [
      • Shittu M.O.
      • Afolami O.I.
      Improving the efficacy of Chloroquine and Hydroxychloroquine against SARS-CoV-2 may require Zinc additives-A better synergy for future COVID-19 clinical trials.
      ]
      Zinc (review)Certain indications implicate modulation of zinc status could be beneficial in COVID-19. In vitro experiments indicates antiviral properties of Zn2+ through inhibition of SARS-CoV RNA polymerase. This effect might indicate to the therapeutic efficiency of chloroquine which functions as zinc ionophore. Decreased activity of ACE2 which is known as SARS-C oV-2 receptor by Zn2+ is demonstrated through indirect evidence. Zinc could also improve antiviral immunity through up-regulated production of interferon α and enhancement of its antiviral properties. Zinc exert anti-inflammatory activity through modulation of regulatory T-cell functions and inhibition of NF-κB signaling that might limit cytokine storm in COVID-19. Improved Zinc status is also able to diminish the risk of bacterial co-infection through improvement of mucociliary clearance and respiratory epithelial barrier function and possessing antibacterial effects. Zinc status is tightly associated with risk factors of severe COVID-19 including immune deficiency, ageing, obesity, atherosclerosis and diabetes which are recognized risk groups for zinc deficiency. Thus, Zink could have protective effects such as adjuvant and preventive therapeutic measure of COVID-19 through reduction of inflammation, prevention of ventilator-induced lung damage, modulation of antibacterial and antiviral immunity and improvement of mucociliary clearance.RussiaSkalny et al. 2020 [
      • Skalny A.V.
      • Rink L.
      • Ajsuvakova O.P.
      • Aschner M.
      • Gritsenko V.A.
      • Alekseenko S.I.
      • et al.
      Zinc and respiratory tract infections: Perspectives for COVID-19.
      ]
      Zinc (review)17 studiesSeveral lines of evidence indicate to the benefits of supplementation with zinc. Zinc supplementation is associated with improved mucociliary clearance, preserved antiviral immunity, strengthened epithelial integrity, decreased viral replication, attenuated risk of hyper-inflammation, possessing anti-oxidative effects, minimized secondary infections and reduced lung damage. Patients with underlying chronic diseases, elder subjects, and most of the remaining COVID-19 risk groups would most likely be benefited. However, more investigation is required to test the impacts of zinc as a therapeutic option for the established disease. Indeed, preventive supplementation of cases from risk groups should be initiated due to the cost effectiveness, having little or no side effects, global availability and simple application of zinc.GermanyWessels et al. 2020 [
      • Wessels I.
      • Rolles B.
      • Rink L.
      The Potential Impact of Zinc Supplementation on COVID-19 Pathogenesis.
      ]
      Iron (review)13 studiesDuring COVID-19 infection, enhanced plasma iron levels is associated with higher amounts of generated reactive oxygen species which subsequently lead to oxidative stress and lung injury followed by declined lung function and lung fibrosis. Iron overload enhances viral replication and exert a fundamental role in severity of infection. Iron chelating agents such as Deferoxamine and Lactoferrin could diminish iron availability in serum and body tissues which could prevent lung injury and fibrosis related to COVID-19 infection. Indeed, recent nominate compounds with a potential as protease inhibition seems to be novel candidates for treatment of SARS-CoV-2 infection.ItalyCarota et al. 2021 [
      • Carota G.
      • Ronsisvalle S.
      • Panarello F.
      • Tibullo D.
      • Nicolosi A.
      • Li Volti G.
      Role of Iron Chelation and Protease Inhibition of Natural Products on COVID-19 Infection.
      ]
      Iron (review)Iron is an important player ensuring adequate immune responses and a number of interesting intersections have been highlighted from surveys on iron metabolism in COVID-19. While the functional implications of the action of iron in facing certain parasites, bacteria and the host have been established, this scenario is less clarified during viral infections. Furthermore, specific patterns related to hepcidin and iron regulation occur during various viral infections. Severe COVID-19 is characterized by significant functional iron deficiency and high hepcidin level, the former is possibly associated with impaired response to lymphocyte function and hypoxia.ItalyGirelli et al. 2021 [
      • Girelli D.
      • Marchi G.
      • Busti F.
      • Vianello A.
      Iron metabolism in infections: focus on COVID-19.
      ]
      Iron (review)Iron overload is implicated as a contributor in pathogenesis of COVID-19. Besides, several manifestations of COVID-19, such as hypercoagulation, immune dysfunction, inflammation and hyperferritinemia are reminiscent of iron overload. Although iron is vital for alive cells, free unbound iron which leads to iron dysregulation and overload is significantly reactive with potential toxic properties due to generation of reactive oxygen species (ROS). ROS react with and damage nucleic acids, cellular lipids, and proteins which consequently activate either acute and or chronic inflammatory processes during multiple clinical conditions. Furthermore, iron-catalyzed lipid injury exerts a direct causative impact on the newly identified nonapoptotic cell death pathway recognized as ferroptosis, which is immunogenic unlike apoptosis. It not only results in amplification of cell death but also promotes occurrence of reactions related to inflammation. Generally, iron chelators are safe and are able to protect patients in the clinical conditions induced by iron overload. Iron chelators also exert antiviral activities. Lactoferrin, as a naturally occurring iron chelator, possess immunomodulatory and anti-inflammatory properties which binds to several receptors in demand of coronaviruses to block their entry into host cells. Thus, iron chelators could be with high therapeutic value during this current COVID-19 pandemic.EgyptHabib et al. 2021 [
      • Habib H.M.
      • Ibrahim S.
      • Zaim A.
      • Ibrahim W.H.
      The role of iron in the pathogenesis of COVID-19 and possible treatment with lactoferrin and other iron chelators.
      ]
      Iron (review)Endolysosomal function could be considered as a target in COVID-19. Based on recent clinical data, patients on lysosomotropic drugs for the treatment of their underlying conditions would also be benefited from this therapeutic strategy to prevent SARS-CoV-2 infection and its transition to COVID-19. In these cellular settings, there are some obvious alterations in iron metabolism. Enhanced iron levels and/or dysregulated homeostasis of iron occur in various lung diseases such as pulmonary fibrosis. Fibrosis and declined lung function are observed in experimental and clinical investigations to be associated with accumulation of pulmonary iron level in a model of bleomycin-induced pulmonary fibrosis. Indeed, increased iron accumulation is observed in lung sections obtained from cases with idiopathic pulmonary fibrosis. Current antioxidant compounds of interest include enzymes (superoxide dismutases and GPXs), quercetin, minerals, melatonin, GSH, N-acetylcysteine, selenium, curcumin, vitamins B6, D, E, and C and natural polyphenols.FranceRochette et al. 2021 [
      • Rochette L.
      • Zeller M.
      • Cottin Y.
      • Vergely C.
      GDF15: an emerging modulator of immunity and a strategy in COVID-19 in association with iron metabolism.
      ]
      Iron (review)Hyper-ferritinemia is observed in COVID-19 patients as a response to inflammation. It could be associated with iron toxicity due to enhanced leakage of ferritin from damaged tissues releasing free iron. The linkage between hyper-ferritinemia and enhanced transferrin saturation reflects iron overload state. Thus, targeting intracellular iron overload seems an appropriate strategy in ongoing controlled clinical trials. We suggest application of approved ferroptosis inhibitors, iron chelators, erythropoietin and hepcidin modulators besides treatment of inflammatory state. This promising therapeutic strategy could be linked with specific targets of intra and extracellular mitochondria dysfunction or production of reactive species interactome and ferroptosis.FranceEdeas et al. 2020 [
      • Edeas M.
      • Saleh J.
      • Peyssonnaux C.
      Iron: Innocent bystander or vicious culprit in COVID-19 pathogenesis?.
      ]
      Iron (review)Presence of common aspects between iron chelation and COVID-19 is still unknown. It is reasonable to suggest the possible influence of iron chelation on production of pro-inflammatory cytokines and free radicals and production involved in the late phases of COVID-19 infection with subsequent development to acute lung injury and ARDS. Anti-fibrotic properties of iron chelators might be another mechanism of action which needs to be considered. The abovementioned considerations highlight COVID-19 as part of the spectrum of hyperferritinemic syndrome. Probable acute iron overload due to rapid synthesis of ferritin exceeded rate of iron incorporation and beneficial impacts of iron chelation therapy on inflammation and on fibrogenesis occur in the lungs indicate that iron chelation could improve the survival and long-term outcomes in critically ill COVID-19 patients.ItalyPerricone et al. 2020 [
      • Perricone C.
      • Bartoloni E.
      • Bursi R.
      • Cafaro G.
      • Guidelli G.M.
      • Shoenfeld Y.
      • et al.
      COVID-19 as part of the hyperferritinemic syndromes: the role of iron depletion therapy.
      ]
      Iron (review)Hydroxychloroquine (HCQ) and chloroquine (CQ) possible have: [
      • Xu Y.
      • Baylink D.J.
      • Chen C.-S.
      • Reeves M.E.
      • Xiao J.
      • Lacy C.
      • et al.
      The importance of vitamin d metabolism as a potential prophylactic, immunoregulatory and neuroprotective treatment for COVID-19.
      ] a direct antiviral property; [
      • Cascella M.
      • Rajnik M.
      • Cuomo A.
      • Dulebohn S.C.
      • Di Napoli R.
      Stat Pearls. Treasure island (FL).
      ] a possible ability to attenuate progression of COVID-19 to the development of severe forms by inflammatory mechanisms; [
      • Shimabukuro-Vornhagen A.
      • Gödel P.
      • Subklewe M.
      • Stemmler H.J.
      • Schlößer H.A.
      • Schlaak M.
      • et al.
      Cytokine release syndrome.
      ] a potential anti-thrombotic effect. Due to their minimal toxicity and complex action, we suggest treatment with CQ/HCQ CQ beyond 5–10 days in patients with COVID-19 based on the hypothesis that their application could be extended after ending high replication phase of Sars-Cov-2 and considering the possibility of infection reactivation.
      ItalyRoldan et al. 2020 [
      • Roldan E.Q.
      • Biasiotto G.
      • Magro P.
      • Zanella I.
      The possible mechanisms of action of 4-aminoquinolines (chloroquine/hydroxychloroquine) against Sars-Cov-2 infection (COVID-19): A role for iron homeostasis?.
      ]
      Selenium (review)Oxidative stress is a unique feature of COVID-19 disease which is associated with immunopathological disorder seen in cases with severe COVID-19. Selenium exerts a fundamental role in strengthening of immunity, preventing viral infections, reducing oxidative stress and supporting critical illness. Selenium deficiency is associated with hyperinflammation and oxidative stress observed in critical and severe COVID-19 illness.AustraliaKhatiwada et al. 2021 [
      • Khatiwada S.
      • Subedi A.
      A Mechanistic Link Between Selenium and Coronavirus Disease 2019 (COVID-19).
      ]
      Selenium (review)31 studiesSelenium is an essential trace element for proper functioning of immune system. Impaired immune responses and predisposition to autoimmune disease (AID) especially for thyroid gland could be induced by severe Selenium deficits. Active immune system by elevated cytokine levels suppresses biosynthesis of hepatic selenoprotein and secretion of selenoprotein P into the circulation leading to diminished metabolism of Selenium and suppressed Selenium status. An acute or chronic severe Selenium deficiency perturbs immune system irrespective of its cause (e.g., infection, poor nutrition, pregnancy, cancer, trauma, surgery). Clinical settings with low Selenium status are overlapping with known triggers of AID indicating to the presence of a direct causal interrelation. Benefits of supplemental Selenium are recognized for the thyroid but not yet for the other prevalent AID, such as type 1 diabetes mellitus or rheumatoid arthritis. Avoidance of severe Selenium deficiency might diminish risks of AID that alleviate symptoms of disease, both for prevention and treatment. Therefore, substitution of selenium is recommended strongly for acute or chronic deficiency, while supplementation of healthy persons by sufficiently high baseline levels is not a warranty.GermanySchomburg et al. 2021 [
      • Schomburg L.
      Selenium Deficiency Due to Diet, Pregnancy, Severe Illness, or COVID-19—A Preventable Trigger for Autoimmune Disease.
      ]
      Selenium (review)Disrupted antioxidant defense is shown in severe acute respiratory syndrome caused by SARSCoV infection. Selenium exerts a fundamental role in reduction of produced ROS in response to different viral infections. Selenoprotein enzymes are important for fighting against oxidative stress due to excessive production of ROS. Selenium also plays a role in inhibition of NF-κB activation which alleviates inflammation. Selenoproteins could inhibit responses related to type I interferon during viral infections which modulates oxidative burst in macrophages and proliferation of T cells with subsequent inhibition of viral transcriptional activators. Potential virally encoded selenoproteins have been recognized through computational analysis performed in various viral genomes such as Japanese encephalitis virus, HIV-1 and hepatitis C virus. The relationship between these potential virally encoded selenoproteins with different disease phenotypes highlights their biological role in pathogenesis of COVID-19. It could also help in better understanding impacts of an apparent selenium deficiency in the host cell through over translation of viral selenoproteins on host cell defense mechanisms against COVID-19 infection. Trials on selenium for the treatment of COVID-19 will provide new horizons for the treatment of COVID-19 due to the presence of unequivocal proof regarding the involvement of selenium in antioxidant related mechanisms. Indeed, improvement in lung antioxidant capacity of ARDS patients has been shown using infusion of intravenous sodium selenite.IndiaTomo et al. 2021 [
      • Tomo S.
      • Saikiran G.
      • Banerjee M.
      • Paul S.
      Selenium to selenoproteins–role in COVID-19.
      ]
      Selenium (review)36 studiesEnvironments with selenium deficiency favor replication, virulence and mutation of RNA viruses. Selenium status could influence SARS-CoV-2 like other RNA viruses. Selenium induces activity of antioxidant selenoenzymes that possibly rebalance host responses. Selenium plays a role as a NF-kB inhibitor in progression of COVID-19 and functions as an anti-inflammatory and immunomodulatory micronutrient. Besides, it could reduce impacts of SARS-CoV-2 on vascular endothelial cells and platelet aggregation. Oxidative state is a common feature of COVID-19 especially in obese and elder patients who are at risk for the development of severe outcomes. Selenium has an important roles to play by reduction of oxidative stress.FranceHiffler et al. 2020 [
      • Hiffler L.
      • Rakotoambinina B.
      Selenium and RNA virus interactions: Potential implications for SARS-CoV-2 infection (COVID-19).
      ]
      Selenium (review)There is a long story behind selenium in reduction of incidence and severity of different viral infections. Significantly higher selenium level was observed in serum samples of survivors vs. non-survivors of COVID-19 infection. Indeed, there was a significant positive linear relationship between the cure rate of COVID-19 in Chinese people and regional selenium status. Furthermore, the cure rate raised to beyond the selenium intake needed for optimization of selenoproteins which suggest that possibly selenoproteins are not the whole story. Significant reduction in expression level of a number of selenoproteins that control ER stress and increase in IL-6 expression was observed in SARS-CoV-2 infected cells in culture suggesting a potential association between the reduced expression of selenoprotein and COVID-19-related inflammation. The synthetic redox-active selenium compound, ebselen, could strongly inhibit main SARS-CoV-2 protease which enables maturation of viruses within host cells. This observation indicates that formed redox-active selenium species at high selenium intake could possibly inhibit SARS-CoV-2 proteases. Through interference with human selenoprotein system, SARS-CoV-2 could evade an adequate host response.ChinaZhang et al. 2020 [
      • Zhang J.
      • Saad R.
      • Taylor E.W.
      • Rayman M.P.
      Selenium and selenoproteins in viral infection with potential relevance to COVID-19.
      ]
      Amino acids (research article)30 control and 112 COVID-19 patientsThere was a significant difference regarding 20 amino acids when compared to the control group in COVID-19 patient groups with different levels of severity. Branched-chain amino acids showed alteration in correlation with each other, and l-phenylalanine and l-2-aminobutyric acid were suggested to be potential biomarkers for COVID-19. Thus, l-2-aminobutyric acid could afford prognostic information regarding disease course.TurkeyAtila et al. 2021 [
      • Atila A.
      • Alay H.
      • Yaman M.E.
      • Akman T.C.
      • Cadirci E.
      • Bayrak B.
      • et al.
      The serum amino acid profile in COVID-19.
      ]
      Amino acids (research article)46 severe and 19 mild COVID-19 patients and 27 controlsIn hypoxic conditions, there was an association between modified metabolic profiles and altered amino acid catabolism. Besides, there was an increase in three α-hydroxyl acids of amino acid origin with disease severity in correlation with clinical markers of lung injury and changed oxygen saturation levels. We speculate maintenance NAD recycling through enzymatic conversion of α-keto-acids to α- hydroxyl-acids in the setting of altered oxygen levels indicating to the potential relevance of supplementation with amino acids during SARS-CoV-2 infection.MexicoPáez-Franco et al. 2021 [
      • Páez-Franco J.C.
      • Torres-Ruiz J.
      • Sosa-Hernández V.A.
      • Cervantes-Díaz R.
      • Romero-Ramírez S.
      • Pérez-Fragoso A.
      • et al.
      Metabolomics analysis reveals a modified amino acid metabolism that correlates with altered oxygen homeostasis in COVID-19 patients.
      ]
      Amino acids (review)Overnutrition/excess serum amino acid profile during obesity has been associated with inflammation and reprogramming of translational machinery through hyperactivation of amino acid sensor mammalian target of rapamycin (mTOR), which is exploited by SARS-CoV-2 for its replication. Indeed, activation of general control nonderepressible 2 (GCN2) dependent amino acid starvation sensing pathway prevents intestinal inflammation through suppressing production of interleukin-1 beta and reactive oxygen species (ROS). While activation of GCN2 is able to mitigate susceptibility to dengue infection, enhanced GCN2 deficiency is associated with viremia and inflammation-related pathologies. These findings display role of amino acid sensing pathway in controlling viral infections and inflammation. The current fact is aggravated COVID-19 infection through activation of obesity/excess amino acids/mTOR pathway and activation of amino acid starvation sensor GCN2 could possibly have an opposite effect.IndiaPhilips et al. 2021 [
      • Philips A.M.
      • Khan N.
      Amino acid sensing pathway: A major check point in the pathogenesis of obesity and COVID-19.
      ]
      Amino acids (review)Impaired angiotensin-converting enzyme-2 (ACE2) which is cellular anchor of SARS-CoV-2 results in GI disturbance. During infection it is postulated to be internalized to dwindle expression of sodium-dependent neutral amino acid transporter (B◦AT1) in intestinal cells (Nisoli et al., 2020). Hartnup disorder, an inherited defect in B◦AT1 amino acid transporter, which is encoded by mutated SLC6A19 gene shares numerous psychiatric symptoms with COVID-19 (Nisoli et al., 2020). Impaired uptake of amino acid reduces neurotransmitter levels which could invite psychiatric symptoms. Tryptophan catabolites (TRYCATs) exerts pleiotropic effects during physiological and psychiatric health. It also regulates presentations of depressive disorders (Rao et al., 2008); which postulates a link for psychoneuroimmunomodulation in COVID-19 (Soni et al., 2020b). Precursor amino acid therapy was associated with huge success in management of pain and management of psychosomatic disorders (Rao et al., 2008). Attempts made for management of COVID-19 encompass both physiological and mental well-being (Tandon, 2020). Thus, psychiatric symptoms in COVID-19 infected cases patients are contributing to physiological injuries triggered by SARS-CoV-2-infection. Nutritional deficiency mainly at the level and ratio of amino acids might change the neurotransmitters balance in provoking depression, anxiety, and mood alterations in COVID-19 patients. A supplementation with conditional amino acids could improve mental well-being, immunity and therapeutic outcomes of COVID-19.IndiaSoni et al. 2020 [
      • Soni V.K.
      • Sharma K.
      • Mehta A.
      • Ratre Y.K.
      • Kumar S.
      • Shukla D.
      • et al.
      A physiological link for psychiatric symptoms in COVID-19: Role of amino acid deficiency.
      ]
      Coenzyme Q10 (review)Modulated mitochondrial dynamics and metabolism with lower levels of Coenzyme Q10 (CoQ10) in viral infections highlights dysfunction in mitochondrial bioenergetics with CoQ10 deficit as the main pathobiochemical impacts of SARS-Cov-2 virus resulting in reduction in its endogenous biosynthesis. The mechanism could pass through virus induced oxidative stress leading to mutation of one or more of the nine COQ genes resulting in the development of primary CoQ10 deficiency.SlovakiaGvozdjakova et al. 2020 [
      • Gvozdjakova A.
      • Klauco F.
      • Kucharska J.
      • Sumbalova Z.
      Is mitochondrial bioenergetics and coenzyme Q10 the target of a virus causing COVID-19?.
      ]
      omega-3 (review)Administration of I.V. omega-3 PUFA will reduce inflammatory mediators which is indicative for beneficial clinical effects. Simultaneous monitoring of pro-resolving and pro-inflammatory mediators will facilitate understanding possible failure of resolution of inflammation in COVID-19.SwedenArnardottir et al. 2021 [
      • Arnardottir H.
      • Pawelzik S.-C.
      • Öhlund Wistbacka U.
      • Artiach G.
      • Hofmann R.
      • Reinholdsson I.
      • et al.
      Stimulating the resolution of inflammation through omega-3 polyunsaturated fatty acids in COVID-19: rationale for the COVID-Omega-F Trial.
      ]
      omega-3 (review)Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have immunomodulation effects and are also able to improve mood disorders. Strengthening baseline immunity could facilitate prevention of psychiatric sequelae and fatal outcomes in COVID-19 infected cases or prevent relapse of pre-pandemic psychiatric disorders. Therefore, a balanced healthy diet might be what is required for improvement of our immunity and it is needed to evaluate if n-3 PUFAs are possible nutraceutical for maintenance of our mental.TaiwanChang et al. 2020 [
      • Chang J.P.-C.
      • Pariante C.M.
      • Su K.-P.
      Omega-3 fatty acids in the psychological and physiological resilience against COVID-19.
      ]
      omega-3 (review)Omega-3 fatty acids (FA) has several benefits and taking it as a supplement could prevent viral entry through altered composition of fat component in cellular bilipid membrane. Omega-3 FAs, such as Docosahexaenoic Acid (DHA) and Eicosapentaenoic Acid (EPA) and exert their functions by their incorporation in cell membrane and influence of clumping of toll-like receptors with subsequent prevention of signals activating NF-κB in order to ameliorate COVID-19 complications through production of production of fewer pro-inflammatory mediators. EPA and DHA are precursors of resolvins E and D particles reducing proinflammatory mediators which subsequently reduce recruitment of pulmonary neutrophils and increase apoptosis by macrophages. As a result, production of broncho-alveolar IL-6 and lung inflammation are decreased. Omega-3 FA is involved in enhancement of phagocytic capacity of macrophages in the setting of altered composition of bilipid layer of cell membrane. Omega-3 FAs is also involved in modulation of both innate and acquired immunity and mediating inflammatory processes. Understanding association between omega-3 FA-enriched diet and clinical outcomes could be more complex than previously speculated while treating COVID-19 patients.USAHathaway et al. 2020 [
      • Hathaway III, D.
      • Pandav K.
      • Patel M.
      • Riva-Moscoso A.
      • Singh B.M.
      • Patel A.
      • et al.
      Omega 3 fatty acids and COVID-19: a comprehensive review.
      ]
      omega-3 (review)Although well documented in vivo and in vitro assays demonstrated benefits of omega-3 fatty acids to decrease severity of COVID-19, the risk of high supplementation doses previous or during infection with SARS-CoV-2 must be investigated. Regarding consequences of oxidative stress, cytokines storm, and antiviral drugs on progression of cardiovascular diseases, more investigations on supplementation with omega-3 fatty acids should be performed on survivors of SARS-CoV-2 infection, since health status of these individuals could be improved using proper and controlled supplementation.BrazilRogeroa et al. 2020 [
      • Rogero M.M.
      • Leão MdC.
      • Santana T.M.
      • de Mb Pimentel M.V.
      • Carlini G.C.
      • da Silveira T.F.
      • et al.
      Potential benefits and risks of omega-3 fatty acids supplementation to patients with COVID-19.
      ]
      omega-3 (review)Increased dietary omega-3 LC-PUFAs level or as a pharmaco nutrient in addition to artificial nutrition is speculated to diminish the impact of inflammation induced by viral infection such as Covid-19. The mentioned biochemical mechanisms reinforced by animal, clinical and epidemiological data suggest acceleration of revery, reduction of hospitalization, ICU length of stay and reduction of mortality of novel coronavirus SARS-Cov-2 using nutritional supplementation. Omega-3 long-chain (LC)-PUFAs are able to play a central role to prevent cytokine storm at least through reduction of the intensity of inflammation and mortality risk in patients with Covid-19. For general population and primary prevention, at least nutritional recommendation is 500 mg/day for EPAþ DHA and 2.2 g/day for α-linolenic acid (ALA). For secondary prevention, and for symptomatic cases or those with positive Covid-19 infection, the optimal doses for both omega-3 LC-PUFAs and ALA are yet unknown. It is also crucial to meet nutritional recommendation of 2.2g/day of ALA. Regarding omega-3 LC-PUFAs, enteral nutrition enriched with 3.5 g/day EPA and DHA should be prescribed in Covid-19 cases not in a bolus form. Higher amounts of omega-3 LC-PUFAs, up to 9 g/day in the form of fish oil, are safe for administration. It seems that all fatty acids of the omega-3 family seem to play a role. Omega-3 DPA, EPA and DHA are direct substrates for synthesis of pro-resolution mediator. ALA is the initial precursor of these LC-PUFAs by successive desaturation and elongation. Although the overall ALA to DHA conversion is weak, ALA might exert its own impacts on resolution of inflammation.FranceWeill et al. 2020 [
      • Weill P.
      • Plissonneau C.
      • Legrand P.
      • Rioux V.
      • Thibault R.
      May omega-3 fatty acid dietary supplementation help reduce severe complications in Covid-19 patients?.
      ]
      Probiotic (research article)lycocin F and lactococcine G extracted from Lactococcus lactis and from Lactobacillus plantarum, respectively which have high affinities for binding to viral proteins. Manipulation of their sequences are also associated with elimination of side effects. In some instances, their affinities for attachment to SARSCoV- 2 proteins are increased. These two discovered drugs seem to be optimal for treatment of COVID-19 infection.IranBalmeh et al. 2021 [
      • Balmeh N.
      • Mahmoudi S.
      • Fard N.A.
      Manipulated bio antimicrobial peptides from probiotic bacteria as proposed drugs for COVID-19 disease.
      ]
      Probiotic (review)46 studiesProbiotics are attractive vehicles for nasal or oral mucosal delivery of therapeutic molecules. Mucosal administration of therapeutic molecules could induce an immune response mediated through specific mucosal IgA and serum IgG antibodies accompanied by mucosal cell-mediated immune responses that effectively concur to neutralize and eradicate infections. Application of probiotics as live delivery vectors, promotes prospective investigations to evaluate efficacy of genetically modified probiotics against SARSCoV- 2 infection. New emerging horizons in development of vaccine technology re-emphasizes into the contribution of adjuvants accompanied by optimization of codon usage during designing a synthetic gene, expression level, and inoculation dose in order to elicit potent and specific protective immune responses. Mucosal immunization, mainly through nasal route using a probiotic-based vaccine might strongly prohibit SARS-CoV-2 infection.IranTaghinezhad-S et al. 2021 [
      • Taghinezhad-S S.
      • Mohseni A.H.
      • Bermúdez-Humarán L.G.
      • Casolaro V.
      • Cortes-Perez N.G.
      • Keyvani H.
      • et al.
      Probiotic-Based Vaccines May Provide Effective Protection against COVID-19 Acute Respiratory Disease.
      ]
      Probiotic (research article)200 frontline medical staffOur data indicates significantly diminished the incidence of respiratory tract infections by about 64.8%, shortened work absent days by 95.5%, reduced time being under medication, reduced time experiencing symptoms of respiratory tract infection and oral ulcer by 78% using administration of oropharyngeal probiotic while no history of antibiotic and anti-viral medicine consumption in the probiotic group. Medical staff under treatment by Bactoblis demonstrated sustained protection against respiratory tract infections with extremely low incidence rate of being suffered from respiratory tract infections at 10th day of administrated probiotic.ChinaWang et al. 2021 [
      • Wang Q.
      • Lin X.
      • Xiang X.
      • Liu W.
      • Fang Y.
      • Chen H.
      • et al.
      Oropharyngeal probiotic ENT-K12 prevents respiratory tract infections among frontline medical staff fighting against COVID-19: a pilot study.
      ]
      Probiotic (review)The nutritional and immunity enhancing probiotics which operate gut homeostasis must be paid more research attention. A healthy lifestyle, regular physical exercise, and probiotics supplementation are prominent players for induction of immunity. The specific probiotics roles for stimulation of IgA antibodies, enhancement of natural killer cells function, and control of mucosal barrier inflammation made a big interest in generation of novel probiotics for strengthening of immunity to fight against COVID-19 viruses.Saudi ArabiaAl-Ansari et al. 2020 [
      • Alansari M.M.
      • Sahlah S.A.
      • AlHumaid L.
      • Singh A.R.
      Probiotic lactobacilli: Can be a remediating supplement for pandemic COVID-19. A review.
      ]
      Probiotic (research article)Binding energies for Plantaricin W for residual binding protein (RBP), polymerase and ACE2 were -11.1, -14.64, and -12.68, respectively comparatively very high with other compounds. Plantaricin W, D, and JLA-9 were able to block the residues (THR556, ALA558) surrounding the deep grove catalytic site (VAL557) of RdRp making them more therapeutically active for COVID-19. Molecular dynamics studies would strengthen the stability of the complexes of plantaricin w and SARS-CoV-2 RdRp enzyme, RBD of spike protein, and human ACE2 receptor.Saudi ArabiaAnwar et al. 2020 [
      • Anwar F.
      • Altayb H.N.
      • Al-Abbasi F.A.
      • Al-Malki A.L.
      • Kamal M.A.
      • Kumar V.
      Antiviral effects of probiotic metabolites on COVID-19.
      ]
      Diet (review)Administration of very low-calorie ketogenic diet could be considered in severely obese cases as an effective adjuvant treatment or preventive measure for both rapid weight loss and also rehabilitation during COVID-19 infection. Administration of high fat ketogenic diet (HFKD) in hospitalization period or delicate cases such as cases after positive ventilation and intensive care unit is a challenging hypothesis. Limiting intake of carbohydrate and promotion of ketone formation could lead to amelioration of respiratory parameters. Moreover, HFKDs have strong anti-inflammatory properties and could be helpful in reduction of viral replication. However, numerous studies are old with small sample size without specific addressing of ketosis which highlights the importance of novel clinical trials.ItalyGangitano et al. 2021 [
      • Gangitano E.
      • Tozzi R.
      Ketogenic Diet as a Preventive and Supportive Care for COVID-19 Patients.
      ]
      Diet (review)22 studiesDiet, prebiotics and probiotics are primary modulators to maintain gut biodiversity and to support immune responses. Nutritional strategies with the aim to restore a beneficial gut microbiome might facilitate suppression of viral infection in elders and those with underlying comorbidities. Besides, large-scale international randomized clinical trials are required to identify an association between dietary probiotic remedies, gut microbiome, predisposition to SARS-CoV-2 infection, and severity of COVID-19 infection.PolandJabczyk et al. 2021 [
      • Jabczyk M.
      • Nowak J.
      • Hudzik B.
      Diet, Probiotics and Their Impact on the Gut Microbiota during the COVID-19.
      ]
      Diet (review)A healthy and well-balanced diet exert beneficial impacts on conditions predisposing patients to COVID-19 and its complications. A diet with high antioxidant, immunomodulatory and anti-inflammatory potential might prophylactically mitigate severity of COVID-19. Thus, more investigations are required to evaluate specific components of diet to prevent COVID-19 and also improve infection parameters during illness. In the case of hospitalized COVID-19 patients, cases in intensive care units and in critical condition, assessment of their nutritional status and implementation of rapid and proper nutritional care is recommended. Nutritional support requires adequate intake of all essential nutrients particularly n-3 fatty acids, proteins, microelements (zinc and selenium) and vitamins especially C and D and caloric value based on patient's requirements.PolandSkrajnowska et al. 2021 [
      • Skrajnowska D.
      • Brumer M.
      • Kankowska S.
      • Matysek M.
      • Miazio N.
      • Bobrowska-Korczak B.
      Covid 19: Diet Composition and Health.
      ]
      Diet (review)Different players are involved in extension and severity of COVID-19 infection including early and fast education, public preparedness for pandemics, trained immunity of population, public hygiene and rapid adaptation and organization of the hospitals. Diet is only one of the possible causes of the COVID-19 Which still requires further assessment.GermanyBousqu et al. 2020 [
      • Bousquet J.
      • Anto J.M.
      • Iaccarino G.
      • Czarlewski W.
      • Haahtela T.
      • Anto A.
      • et al.
      Is diet partly responsible for differences in COVID-19 death rates between and within countries?.
      ]
      Diet (review)23 studiesA diet with positive impacts on immune function should have adequate protein levels especially arginine, glutamine, and branched-chain amino acids; high fiber content such as whole grains, high amounts of micronutrients including vitamin A, C, D, B and E, iron, selenium, zinc and phytochemicals, high levels of omega-3 vs. lower saturated, trans fat, and omega-6 fatty acids and low amounts of refined sugars. However, as shown well for dietary fiber, an excessive anti-inflammatory response may also reduce the immune response and increase susceptibility to infection. There are controversial reports about vitamin A, in which supplementation with carotenoid might be merely detrimental for asbestos-exposed workers and smokers. Supplementation with selenium should also be considered carefully due to its narrow therapeutic window and its possible side-effects particularly in diabetic cases. While anti-inflammatory constituents of diet could be beneficial during hyper-inflammation phase such as cytokine storm of COVID-19, too strong suppression of immune system and inflammation using high doses of antioxidants and or isolated anti-inflammatory compounds during healthier conditions seems dangerous. Strengthening of immune system during COVID-19 crisis is the output of reduced oxidative stress and inflammation. This topic is highly complex and indicates to seeking for simultaneous determination of individual marker and a nutrient signature in different ways such as using nutrigenomics tools (i.e., metabolomics fingerprinting). This approach might clarify unnoticed associations between nutrients, their metabolites inflammation, oxidative stress, and the immune system. Besides, confounding factors such as environmental pollutants and medication should also be taken into account. It is also of great importance of control low-grade chronic inflammation associated with chronic diseases such as obesity, auto-immune, diabetes, and cardiovascular diseases (CVD) possibly through management of nutritional deficiencies and promotion of appropriate nutritional status, which could improve immune response during infection phases.LuxembourgIddir et al. 2020 [
      • Iddir M.
      • Brito A.
      • Dingeo G.
      • Fernandez Del Campo S.S.
      • Samouda H.
      • La Frano M.R.
      • et al.
      Strengthening the immune system and reducing inflammation and oxidative stress through diet and nutrition: considerations during the COVID-19 crisis.
      ]
      Diet (review)Adequate management of metabolic disorders is essential to reduce risk of severe COVID-19. We should seek for avoidance of deleterious consequences of and positive energy balance physical inactivity through maintenance of exercise levels and physical activity in a safe home environment and applying a healthy diet. It is also beneficial for people without metabolic disorders to prevent deleterious impacts of positive energy balance and physical inactivity, which could lead to the development of metabolic syndrome and its related comorbidities. Avoidance of overeating through applying a healthy balanced diet based on carbohydrates with a low glycemic index such as legumes, healthy fats, vegetables or fruits, protein enriched foods with lower fat percentage is of great value. Besides, restricted calorie intake in the setting of diminished activity or physical inactivity is beneficial. These nutritional recommendations should be accompanied by appropriate daily physical activity program advised by sports science specialists to prohibit metabolic-related health issues. The items need to be considered in this program include coordination, mobility, resistance, and balance and aerobic. The training frequency is recommended to be performed 5–7 days per week with at least 2–3 days with resistance training.SpainMartinez-Ferranet al. 2020 [
      • Martinez-Ferran M.
      • de la Guía-Galipienso F.
      • Sanchis-Gomar F.
      • Pareja-Galeano H.
      Metabolic impacts of confinement during the COVID-19 pandemic due to modified diet and physical activity habits.
      ]
      Diet (review)57 studiesThe signs and symptoms of respiratory infections due to COVID-19 could be categorized in the field of Zato al-rieh that can mainly be matched with pneumonia. Some medicinal materia medica and nutrients have been introduced based on the described criteria for the treatment of acute respiratory infections including Rosa Damas Cena, Honey, Cydonia oblonga, Raisin, Citrus sinensis, Malus domestica, D.Carota, Crocus sativus, Citrus medica, Camellia Sinensis, Punica granatum, Anethum graveolens dhi, Coriandrum sativum, Urtica dioica, Petroselinum Crispum, Sesamum indicum, Allium sativumIranMoslemifard et al. 2020 [
      • Moslemifard M.
      Hospital diet for COVID-19, an acute respiratory infectious disease: An evidence-based Protocol of a Clinical Trial.
      ]
      Diet (review)Multiple mechanisms exist which highlight the impacts of ketone bodies during significant viral infections such as COVID-19. Administration of exogenous ketones into critical patients to target complications respiratory viruses could be considered as a possible therapy. In order to prevent infection by Sars-Cov 2 infection and its adverse outcomes in obese cases, especially in this current prolonged pandemic emergency, ketogenic diet (KD)-induced increased endogenous ketone bodies might represent a valuable strategy. Furthermore, prevention and or modification of risk status associated with serious COVID-19 including hyperglycemia, obesity, high glycemic variability, hypertension and insulin resistance is mandatory considering novel infection routs in the absence of vaccination and functional pharmacological therapies. This could be achieved using a nutritional strategy aimed to diminish systemic and hepatic insulin resistance and chronic inflammation, improve cardiovascular health, nutritional status, glucose homeostasis, immune response and blood pressure control and induce fat mass loss. Adoption of a personalized and well-structured KD regimen could help a progressive rehabilitation and nutritional education in obese cases which provides an effective strategy to modify lifestyle behavior, support a long-term management of body weight and reduce risk factors for the development of potentially severe complications associated with Sars-Cov2 infection. Well- designed multicentric investigations on the incidence of severe COVID-19 among obese cases who followed or not a planned protocol of KD might help in confirmation of such hypothesis.ItalyPaoli et al. 2020 [
      • Paoli A.
      • Gorini S.
      • Caprio M.
      The dark side of the spoon-glucose, ketones and COVID-19: a possible role for ketogenic diet?.
      ]
      Diet (review)Large body of evidence support the role of commensal microbiota in human health. Diet plays a crucial role in modulation of gut microbiota resulting in the development of symbiosis or dysbiosis. People should be informed about the benefits of daily consumption of a balanced diet that could be prescribed or improved by food industries or nutritional biologists. A balanced diet like those prepared by dieticians in hostels and hospitals of educational institutions could also be defined for general public, migrants and economically weaker subpopulation of society in order to prevent malnutrition. Besides, intermittent fasting or a fasting-mimicking diet could also be an important advisory, for restoration of beneficial gut microbiota and promotion of overall health.IndiaRishi et al. 2020 [
      • Rishi P.
      • Thakur K.
      • Vij S.
      • Rishi L.
      • Singh A.
      • Kaur I.P.
      • et al.
      Diet, gut microbiota and COVID-19.
      ]
      Nutration (review)Nutrition is an important determining factor for immune response. Good nutrition is essential for supporting immune responses. Immunity could be impaired in elders especially obese, malnourished and frail ones and those who use low amounts of micronutrients. These immune impairments due to nutritional inadequacy leads to susceptibility to infection which allows infections to get more severe and or even fatal. Nutritional inadequacy facilitates dysregulated oxidative stress and inflammation contributing to the development of frailty and poor outcome following infection. Adverse impacts of poor nutrition on immune system and its inflammatory component could explain partly higher risk of poor outcomes following infection with SARS-CoV-2 as observed in elders and those who love with obesity. The role of good nutrition in promotion of diverse gut microbiota which supports immune system should not be neglected and the impacts of aging and obesity on gut microbiota should also be considered. Good nutrition ensures good responses to vaccination, too. Therefore, attention should be paid on addressing current nutritional inadequacies (obesity, general undernutrition frailty, micronutrient insufficiency or deficiency) which are widespread in general population for better supporting of immune responses.UKCalder et al. 2021 [
      • Calder P.C.
      Nutrition and immunity: lessons for COVID-19.
      ]
      Nutration (review)The COVID-19 lockdown resulted in unhealthy dietary alterations and increased body weight of the population which implies to physical inactivity and obesity as risk factors for COVID-19. Indeed, hospitalized COVID-19 patients manifested malnutrition and deficiencies in selenium, omega-3, iron, medium and long-chain fatty acids and vitamin C, B12 which highlights the potential health impacts of vitamin D and C interventions.SpainClemente-Suárez et al. 2021 [
      • Clemente-Suárez V.J.
      • Ramos-Campo D.J.
      • Mielgo-Ayuso J.
      • Dalamitros A.A.
      • Nikolaidis P.A.
      • Hormeño-Holgado A.
      • et al.
      Nutrition in the Actual COVID-19 Pandemic. A Narrative Review.
      ]
      Nutration (review)The COVID-19 pandemic resulted in alterations in food supply. In many countries, special programs are currently implemented to increase food safety and availability. This altered food availability due to the pandemic is a worldwide phenomenon and its severity is dependent to economic status and affluence of that country. It induces serious implications especially in third world countries due to delayed food distribution, impaired food access, income losses to purchase food. This has acute serious health implications and considering deleterious impacts of past pandemics on human health and growth, prediction of current COVID-19 pandemic is reasonable which will induce global nutritional deficiencies with long-lasting negative impacts on human health. There is no evidence regarding transmission of COVID-19 virus through foods or food packages. The importance of appropriate precautionary equipment in the food industry and application of appropriate personal protective measures, disinfectants and hand hygiene are not negligible. Personal nutritional status could modulate positively or negatively inflammatory processes and infectious disease through alteration of immune system. Malnutrition in elderly and disadvantaged populations leaves these populations predisposed to COVID-19 infections with severe clinical symptoms and poorer outcomes. Although severity of clinical symptoms and infectivity rates of a coronavirus infection could be modulated, strong viral transmission could likely be fully prevented through following a healthy diet or supplementation of diet with nutraceuticals. The impact of zinc, and vitamin D status in COVID-19 patients on viral transmission and its related clinical symptoms is still unclear and needs further research. COVID-19 has a significant impact on some populations through changed eating behaviors. The impact of lockdowns and social isolation on eating habits during the COVID-19 pandemic era should not be underestimated since it has acute effects with possible long-term deleterious impacts on population health. Poor nutritional choices over extended periods of time could have enhanced plasma risk factors for the development of diabetes, cardiovascular disease and cancer.CanadaRodriguez-Leyva et al. 2021 [
      • Rodriguez-Leyva D.
      • Pierce G.N.
      The Impact of Nutrition on the COVID-19 Pandemic and the Impact of the COVID-19 Pandemic on Nutrition.
      ]
      Nutrition (review)Nutritional risk is a highly prevalent event in hospitalized COVID-19 cases with a multi-factorial etiology which is likely due to affliction of older patient population and higher prevalence of comorbidities and altered energy intake due to enhanced requirement of energy and protein due to hypermetabolism, mechanical ventilation, fever, muscle mass loss, weight and diminished nutrient intake related to reduced appetite, mechanical ventilation, dyspnea and gastrointestinal intolerance. Thus, screening or assessing nutritional risk in hospitalized COVID-19 cases through validated screening/assessment tools is recommended by most expert guidance. Since the preferred route of feeding is oral intake, parenteral Nutrition (PN) or enteral Nutrition (EN) should be prescribed soon after ICU admission within 12–48 h, based on the source of expert guidance in the case of contraindications. Furthermore, hospitalized patients might not be able to receive timely nutritional interventions due to uncontrolled hypoxemia, uncontrolled shock needing vasopressor support, uncontrolled hypoxemia, acidosis or hypercapnia, feeding contraindications such as significant gastrointestinal symptoms and difficulty in assessment of patient's nutritional risks which all could lead to the development of poor outcomes. In order to prevent potential exposure to SARS-CoV-2 cluster care is recommended and screening of underlying malnutrition by other family, healthcare professionals and/or caregivers is essential. In the case of experiencing contraindications to nutrition such as enhanced vasopressor support or gastrointestinal intolerance, prioritizing patient stabilization is important while considering PN or enteral trophic feeding. After patient stabilization, trophic EN could be initiated by slow progression to the goal nutritional requirements. A standard, protein enriched, polymeric isosmotic EN formula is advised by ASPEN/SCCM; although a higher protein formula may be more appropriate to meet protein requirements in this population. In critically ill hospitalized COVID-19 cases, formulas enriched with DHA and EPA may beneficial through exertion of immunomodulatory effects. Despite lack of clinical evidence providing specific recommendations for nutritional interventions in COVID-19 cases, experience derived from guidelines and clinicians associated with similar disease states could be beneficial until availability of more clinical data. By emerging more data derived from this population, specific guidelines and recommendations can be updated. Recent publications demonstrate higher nutritional risk in critically and severely COVID-19 patients who are hospitalized or admitted to ICU. Poorer clinical outcomes are seen in cases with increased nutritional risk in these populations. Therefore, rapid assessment, recognition and treatment of poor nutritional status is fundamental to improve clinical outcomes in critically and severely ill COVID-19 patients.USAThomas et al. 2021 [
      • Thomas S.
      • Alexander C.
      • Cassady B.A.
      Nutrition risk prevalence and nutrition care recommendations for hospitalized and critically-ill patients with COVID-19.
      ]
      Nutrition (review)60 studiesNo miracle food, cure or supplement to treat or prevent COVID-19 is yet available. During the pandemic, application of healthy eating habits is the most appropriate nutritional recommendation.MalaysiaAbdul Rahim et al. 2020 [
      • Rahim N.C.A.
      • Singh J.S.M.
      • Pardi M.
      • Zainuddin A.A.
      • Salleh R.
      Analysis of Available Nutrition Recommendations to Combat COVID-19: A Scoping Review.
      ]
      Nutrition (review)39 studiesThe impacts of selenium, zinc, omega-3 fatty acids and vitamins D, C, E on the immune system and their possible benefits for suffered COVID-19 cases are presented, especially in vulnerable elder population with a disproportionate burden of related morbidity and mortality. All of the above-mentioned nutrients have a feasible role to support COVID-19 patients. Consumption of higher dosage of zinc and vitamins C and D could exert positive effects during COVID-19 infection. Given the negligible risk of supervised nutritional supplementation which weights against its possible benefits, ensuring adequate intake of these minerals and key vitamins in both at risk of, and or suffered from COVID-19 patients.UAEShakoor et al. 2020 [
      • Shakoor H.
      • Feehan J.
      • Al Dhaheri A.S.
      • Ali H.I.
      • Platat C.
      • Ismail L.C.
      • et al.
      Immune-boosting role of vitamins D, C, E, zinc, selenium and omega-3 fatty acids: Could they help against COVID-19?.
      ]

      Vitamins

      Vitamin A

      Vitamin A impacts on cellular immunity in different ways. Vitamin A has shown to exert a central function in the process of development and differentiation of dendritic cells (DCs) which are potent antigen-presenting cells activating T-cells. DCs express three isotypes of retinoic acid receptors and, therefore, directly respond to vitamin A status [
      • Manicassamy S.
      • Ravindran R.
      • Deng J.
      • Oluoch H.
      • Denning T.L.
      • Kasturi S.P.
      • et al.
      Toll-like receptor 2–dependent induction of vitamin A–metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits autoimmunity.
      ]. DCs drive differentiation of T-cells into either pro-inflammatory effector T-cells or anti-inflammatory regulating T-cells (Treg) following receptor activation to maintain homeostasis between pro-inflammatory and anti-inflammatory stimuli [
      • Ruane D.
      • Brane L.
      • Reis B.S.
      • Cheong C.
      • Poles J.
      • Do Y.
      • et al.
      Lung dendritic cells induce migration of protective T cells to the gastrointestinal tract.
      ]. Vitamin A is involved in migration of effector T-cells to inflammatory sites during infective processes through induction of leukocyte-homing receptors such as α47 integrin and CCR9 [
      • Iwata M.
      • Hirakiyama A.
      • Eshima Y.
      • Kagechika H.
      • Kato C.
      • Song S.-Y.
      Retinoic acid imprints gut-homing specificity on T cells.
      ]. It also initiates production of pro-inflammatory cytokines such as interferon-gamma in order to resolve viral infection [
      • Hall J.A.
      • Cannons J.L.
      • Grainger J.R.
      • Dos Santos L.M.
      • Hand T.W.
      • Naik S.
      • et al.
      Essential role for retinoic acid in the promotion of CD4+ T cell effector responses via retinoic acid receptor alpha.
      ]. Vitamin A drives humoral immune responses which crucially promotes maturation of B-cells with subsequent antibody responses during viral clearance [
      • Chen Q.
      • Ross A.C.
      Retinoic acid promotes mouse splenic B cell surface IgG expression and maturation stimulated by CD40 and IL-4.
      ,
      • Ma Y.
      • Chen Q.
      • Ross A.C.
      Retinoic acid and polyriboinosinic: polyribocytidylic acid stimulate robust anti-tetanus antibody production while differentially regulating type 1/type 2 cytokines and lymphocyte populations.
      ]. Vitamin A promotes differentiation of anti-inflammatory Treg cells and their extravasation into the inflammation site so as to limit pro-inflammatory stimuli [
      • Kang S.G.
      • Lim H.W.
      • Andrisani O.M.
      • Broxmeyer H.E.
      • Kim C.H.
      Vitamin A metabolites induce gut-homing FoxP3+ regulatory T cells.
      ]. Taken together, both anti-inflammatory and pro-inflammatory cellular immune responses could be promoted using vitamin A [
      • Tepasse P.-R.
      • Vollenberg R.
      • Fobker M.
      • Kabar I.
      • Schmidt H.
      • Meier J.A.
      • et al.
      Vitamin A plasma levels in COVID-19 patients: a prospective multicenter study and hypothesis.
      ].

      Vitamin B1

      Thiamine could improve functioning of immune system and diminish the risk of kidney disease, cardiovascular disease, type-2 diabetes, aging-related disorders, mental disorders, cancer, and neurodegenerative disorders [
      • Shakoor H.
      • Feehan J.
      • Mikkelsen K.
      • Al Dhaheri A.S.
      • Ali H.I.
      • Platat C.
      • et al.
      Be well: A potential role for vitamin B in COVID-19.
      ]. Thiamine deficiency impacts on cardiovascular system leading to the development of neuro-inflammation, increasing general inflammation and aberrant antibody responses [
      • Mikkelsen K.
      • Apostolopoulos V.
      Vitamin B1, B2, B3, B5, and B6 and the immune system.
      ]. Since T-cells and antibodies are required for elimination of SARS-CoV-2 virus, thiamine deficiency is potentially able to result in development of inadequate antibody responses with subsequent development of severe COVID-19 symptoms. Indeed, thiamine acts as an inhibitor of anhydrase isoenzyme [
      • Özdemir Z.Ö.
      • Şentürk M.
      • Ekinci D.
      Inhibition of mammalian carbonic anhydrase isoforms I, II and VI with thiamine and thiamine-like molecules.
      ]. High-doses of thiamine is potentially able to limit hypoxia and reduce following hospitalization at early stages of COVID-19. By the way, further research is needed to determine if high-doses of thiamine could improve COVID-19 control [
      • Shakoor H.
      • Feehan J.
      • Mikkelsen K.
      • Al Dhaheri A.S.
      • Ali H.I.
      • Platat C.
      • et al.
      Be well: A potential role for vitamin B in COVID-19.
      ].

      Vitamin B2

      Riboflavin in association with UV light result in irreversible injury to nucleic acids such as RNA and DNA pathogens disabling replication of microbial pathogens. Riboflavin and UV light are effective against the MERS-CoV virus indicating to their efficacy against SARS-CoV-2 [
      • Ragan I.
      • Hartson L.
      • Pidcoke H.
      • Bowen R.
      • Goodrich R.
      Pathogen reduction of SARS-CoV-2 virus in plasma and whole blood using riboflavin and UV light.
      ]. Thus, riboflavin-UV reduces SARS-CoV-2 infectious titer below the detection limit in human blood [
      • Shakoor H.
      • Feehan J.
      • Mikkelsen K.
      • Al Dhaheri A.S.
      • Ali H.I.
      • Platat C.
      • et al.
      Be well: A potential role for vitamin B in COVID-19.
      ], and plasma and platelet products [
      • Keil S.D.
      • Ragan I.
      • Yonemura S.
      • Hartson L.
      • Dart N.K.
      • Bowen R.
      Inactivation of severe acute respiratory syndrome coronavirus 2 in plasma and platelet products using a riboflavin and ultraviolet light-based photochemical treatment.
      ]. Vitamin B2 could diminish transmission of COVID-19 and other pathogens in blood products of critically ill COVID-19 cases [
      • Shakoor H.
      • Feehan J.
      • Mikkelsen K.
      • Al Dhaheri A.S.
      • Ali H.I.
      • Platat C.
      • et al.
      Be well: A potential role for vitamin B in COVID-19.
      ].

      Vitamin B3

      Niacin functions as a building block for NAD and NADP, two essential elements during chronic systemic inflammation [
      • Boergeling Y.
      • Ludwig S.
      Targeting a metabolic pathway to fight the flu.
      ]. NAD+ acts as a coenzyme in different metabolic pathways in which its enhanced levels are needed for treatment of various pathophysiological conditions. At early stages if inflammation NAD+ is released providing immunomodulatory properties in order to diminish pro-inflammatory cytokines such as IL-6, IL-1β, and TNF-α [
      • Shakoor H.
      • Feehan J.
      • Mikkelsen K.
      • Al Dhaheri A.S.
      • Ali H.I.
      • Platat C.
      • et al.
      Be well: A potential role for vitamin B in COVID-19.
      ]. Recently, it has been advocated that IL-6 reduction could relieve the inflammatory storm in the setting of COVID-19 infection [
      • Liu B.
      • Li M.
      • Zhou Z.
      • Guan X.
      • Xiang Y.
      Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)?.
      ]. Besides niacin diminishes neutrophil infiltration with subsequent anti-inflammatory properties incases with ventilator-induced lung damage. Nicotinamide and niacin administration were associated with prohibited lung injury in hamsters [
      • Nagai A.
      • Matsumiya H.
      • Hayashi M.
      • Yasui S.
      • Okamoto H.
      • Konno K.
      Effects of nicotinamide and niacin on bleomycin-induced acute injury and subsequent fibrosis in hamster lungs.
      ]. Moreover, nicotinamide decreased viral replication (human immunodeficiency virus, vaccinia virus, hepatitis B virus and enteroviruses) with subsequent enforcement of defense mechanisms. Considering the immune strengthening and lung protective roles of niacin, it could be prescribed as an adjunct treatment in COVID-19 patients [
      • Mehmel M.
      • Jovanović N.
      • Spitz U.
      Nicotinamide riboside—the current State of research and therapeutic uses.
      ,
      • Zhang L.
      • Liu Y.
      Potential interventions for novel coronavirus in China: A systematic review.
      ].

      Vitamin B5

      Pantothenic acid has various properties including triglyceride and cholesterol-lowering properties and are involved in different processes such as wound healing, improvement of mental health and decreasing inflammation [
      • Mikkelsen K.
      • Apostolopoulos V.
      Vitamin B1, B2, B3, B5, and B6 and the immune system.
      ]. Even though the available studies regarding the impacts of pantothenic acid on the immune system are scant, this filed of investigation is open for further studies [
      • Shakoor H.
      • Feehan J.
      • Mikkelsen K.
      • Al Dhaheri A.S.
      • Ali H.I.
      • Platat C.
      • et al.
      Be well: A potential role for vitamin B in COVID-19.
      ].

      Vitamin B6

      Pyridoxal 5′ -phosphate (PLP), active form of pyridoxine, is an essential cofactor in various inflammatory pathways [
      • Shakoor H.
      • Feehan J.
      • Mikkelsen K.
      • Al Dhaheri A.S.
      • Ali H.I.
      • Platat C.
      • et al.
      Be well: A potential role for vitamin B in COVID-19.
      ]. There is an inverse relationship between PLP and plasma TNF-α and IL-6 in chronic inflammatory conditions. Enhanced utilization of PLP during inflammation leads to B6 depletion, indicating to the possible B6 deficiency in COVID-19 cases with high inflammation [
      • Shakoor H.
      • Feehan J.
      • Mikkelsen K.
      • Al Dhaheri A.S.
      • Ali H.I.
      • Platat C.
      • et al.
      Be well: A potential role for vitamin B in COVID-19.
      ]. In elderly, cases with cardiovascular diseases and type-2 diabetes who are at higher risk for COVID-19 infection with poor outcomes, low PLP levels have been observed [
      • Shakoor H.
      • Feehan J.
      • Mikkelsen K.
      • Al Dhaheri A.S.
      • Ali H.I.
      • Platat C.
      • et al.
      Be well: A potential role for vitamin B in COVID-19.
      ,
      • Merigliano C.
      • Mascolo E.
      • Burla R.
      • Saggio I.
      • Vernì F.
      The relationship between vitamin B6, diabetes and cancer.
      ]). Enhanced risk of coagulopathy and dysregulation of immune responses have also been observed in COVID-19 infected patients [
      • Shakoor H.
      • Feehan J.
      • Mikkelsen K.
      • Al Dhaheri A.S.
      • Ali H.I.
      • Platat C.
      • et al.
      Be well: A potential role for vitamin B in COVID-19.
      ]. In a recent study, modulated COVID-19 symptoms have been observed using PLP supplementation through decreasing pro-inflammatory cytokines, regulating immune responses, preventing hypercoagulability and maintaining endothelial integrity [
      • Desbarats J.
      Pyridoxal 5'-phosphate to mitigate immune dysregulation and coagulopathy in COVID-19.
      ]. In fact, PLP diminishes abnormalities in platelet aggregation and clot formation [
      • Van Wyk V.
      • Luus H.
      • Heyns AdP.
      The in vivo effect in humans of pyridoxal-5′-phosphate on platelet function and blood coagulation.
      ]. Recently, it has been revealed upregulated IL-10 as a powerful immunosuppressive and anti-inflammatory cytokine using vitamin B6 (as well as B2 and B9), which is able to deactivate monocytes and macrophages and monocytes and prohibit T cells and antigen-presenting cells [
      • Mikkelsen K.
      • Prakash M.D.
      • Kuol N.
      • Nurgali K.
      • Stojanovska L.
      • Apostolopoulos V.
      Anti-tumor effects of vitamin B2, B6 and B9 in promonocytic lymphoma cells.
      ]. Excessive secretion of pro-inflammatory cytokines and exaggerated T cell responses are common in COVID-19 patients. Possible contribution of PLP in dampening inflammation and cytokine storm in some COVID-19 patients [
      • Shakoor H.
      • Feehan J.
      • Mikkelsen K.
      • Al Dhaheri A.S.
      • Ali H.I.
      • Platat C.
      • et al.
      Be well: A potential role for vitamin B in COVID-19.
      ].

      Vitamin B9

      Folate is vital for protein and DNA synthesis and is fundamental for adaptive immune response. Furin is an enzyme related to viral and bacterial infections and is considered as a promising target for infection treatment. Recently, furin inhibition by folic acid with subsequent prevention of binding by SARS-CoV-2 spike protein and prohibited cell entry and following virus turnover has been noted. Thus, folic acid could be applied for earlier management of COVID-19-related respiratory disease [
      • Sheybani Z.
      • Dokoohaki M.H.
      • Negahdaripour M.
      • Dehdashti M.
      • Zolghadr H.
      • Moghadami M.
      • et al.
      The role of folic acid in the management of respiratory disease caused by COVID-19.
      ]. Stable and strong binding affinities against the SARS-CoV-2 by folic acid and its derivatives 5-methyl tetrahydrofolic acid and tetrahydrofolic acid have been illustrated using structure-based molecular docking [
      • Kumar V.
      • Kancharla S.
      • Jena M.K.
      In silico virtual screening-based study of nutraceuticals predicts the therapeutic potentials of folic acid and its derivatives against COVID-19.
      ]. Thus, folic acid might be applied as a therapeutic approach for management of COVID-19.

      Vitamin B12

      Vitamin B12 is fundamental for myelin synthesis, cellular growth, red blood cell synthesis, and rapid synthesis of DNA. Active vitamin B12 forms are adenosyl-, hydroxo-, and methylcobalamin. Vitamin B12 acts as regulator of gut microbiota and its low levels elevates homocysteine, and methylmalonic acid leading to enhanced production of reactive oxygen species, oxidative stress and inflammation [
      • Mikkelsen K.
      • Stojanovska L.
      • Prakash M.
      • Apostolopoulos V.
      The effects of vitamin B on the immune/cytokine network and their involvement in depression.
      ]. Hyperhomocysteinemia is associated with activated platelet and coagulation cascades, endothelial dysfunction, megaloblastic anemia, decreased immune responses and disruption of myelin sheath integrity [
      • Shakoor H.
      • Feehan J.
      • Mikkelsen K.
      • Al Dhaheri A.S.
      • Ali H.I.
      • Platat C.
      • et al.
      Be well: A potential role for vitamin B in COVID-19.
      ,
      • Nemazannikova N.
      • Mikkelsen K.
      • Stojanovska L.
      • Blatch G.L.
      • Apostolopoulos V.
      Is there a link between vitamin B and multiple sclerosis?.
      ]. SARS-CoV-2 is able to interfere with vitamin B12 metabolism which could impair proliferation of intestinal microbes. Thus, symptoms of vitamin B12 deficiency such as elevated lactate dehydrogenase and oxidative stress, coagulation cascade activation, hyperhomocysteinemia, vasoconstriction and pulmonary and renal vasculopathy are possibly close to COVID-19 infection [
      • Shakoor H.
      • Feehan J.
      • Mikkelsen K.
      • Al Dhaheri A.S.
      • Ali H.I.
      • Platat C.
      • et al.
      Be well: A potential role for vitamin B in COVID-19.
      ]. Besides, B12 deficiency can lead to gastrointestinal, respiratory, and central nervous system disorders [30]. Recently, methylcobalamin supplements have demonstrated to potentially diminish COVID-19-related organ damages [
      • dos Santos L.M.J.
      Can vitamin B12 be an adjuvant to COVID-19 treatment?.
      ]. COVID-19 patients who received supplemental vitamin B12, vitamin D and magnesium showed reduced severity of COVID-19 symptoms and diminished intensive care support and need for oxygen [
      • Tan C.W.
      • Ho L.P.
      • Kalimuddin S.
      • Cherng B.P.Z.
      • Teh Y.E.
      • Thien S.Y.
      • et al.
      A cohort study to evaluate the effect of combination Vitamin D, Magnesium and Vitamin B12 (DMB) on progression to severe outcome in older COVID-19 patients.
      ].

      Vitamin C

      Vitamin C (VC), is a common necessary nutrient with antioxidant properties. Despites its role in metabolism of human body including collagen biosynthesis and repair, iron absorption, energy transformation, adrenal catecholamine and steroid production [
      • Liu F.
      • Zhu Y.
      • Zhang J.
      • Li Y.
      • Peng Z.
      Intravenous high-dose vitamin C for the treatment of severe COVID-19: study protocol for a multicentre randomised controlled trial.
      ], it also has antimicrobial properties and immunomodulatory functions especially in high concentrations [
      • Mousavi S.
      • Bereswill S.
      • Heimesaat M.M.
      Immunomodulatory and antimicrobial effects of vitamin C.
      ]. Its role in immunomodulation passes through prohibition of nuclear factor kappa-B (NFκB) activation as a primary proinflammatory transcription factor playing a fundamental role in overall immunity, including genetic regulation of cytokines, chemokines, inflammatory mediators, adhesion molecules, and apoptosis inhibitors [
      • Sen C.K.
      • Packer L.
      Antioxidant and redox regulation of gene transcription.
      ]. Vitamin C is able to inhibit production of tumor necrosis factor alpha (TNF-α) and IL-6 through a dose dependent manner [
      • Liu F.
      • Zhu Y.
      • Zhang J.
      • Li Y.
      • Peng Z.
      Intravenous high-dose vitamin C for the treatment of severe COVID-19: study protocol for a multicentre randomised controlled trial.
      ]. It also diminishes GM-CSF signaling responses [
      • Cárcamo J.M.
      • Bórquez-Ojeda O.
      • Golde D.W.
      Vitamin C inhibits granulocyte macrophage–colony-stimulating factor–induced signaling pathways.
      ], acts as a regulator of cytokine redox-signal transduction in host defense cells and possibly have a role in controlling inflammatory responses. Besides, vitamin C at high doses could regulate proliferation and functioning of B cells, T cells and natural killer (NK) cells [
      • Liu F.
      • Zhu Y.
      • Zhang J.
      • Li Y.
      • Peng Z.
      Intravenous high-dose vitamin C for the treatment of severe COVID-19: study protocol for a multicentre randomised controlled trial.
      ]. It might facilitate progression of cytokine storm and improve the host's immunity. Moreover, vitamin C could inhibit oxidative stress with fundamental role in innate immune response against viral respiratory infection and contribute to the development of barrier dysfunction and lung injury [
      • Liu F.
      • Zhu Y.
      • Zhang J.
      • Li Y.
      • Peng Z.
      Intravenous high-dose vitamin C for the treatment of severe COVID-19: study protocol for a multicentre randomised controlled trial.
      ]. Oxidative stress could also be involved in pathogenesis of COVID-19 [
      • Delgado-Roche L.
      • Mesta F.
      Oxidative stress as key player in severe acute respiratory syndrome coronavirus (SARS-CoV) infection.
      ]. Furthermore, vitamin C is able to repair oxidative damage in human bronchial epithelium through modulating regeneration of reactive oxygen species (ROS) and inflammatory expression with subsequent prevention of ROS-induced lung damage [
      • Liu F.
      • Zhu Y.
      • Zhang J.
      • Li Y.
      • Peng Z.
      Intravenous high-dose vitamin C for the treatment of severe COVID-19: study protocol for a multicentre randomised controlled trial.
      ]. Vitamin C could indeed regulate clearance of alveolar fluid by enhancement of lung epithelial barrier functioning through transcriptional and epigenetic enhancement of protein channels which regulates alveolar fluid clearance [
      • Fisher B.J.
      • Kraskauskas D.
      • Martin E.J.
      • Farkas D.
      • Wegelin J.A.
      • Brophy D.
      • et al.
      Mechanisms of attenuation of abdominal sepsis induced acute lung injury by ascorbic acid.
      ,
      • Bharara A.
      • Grossman C.
      • Grinnan D.
      • Syed A.
      • Fisher B.
      • DeWilde C.
      • et al.
      Intravenous vitamin C administered as adjunctive therapy for recurrent acute respiratory distress syndrome.
      ]. Vitamin C might reduce symptoms related to acute respiratory distress syndrome (ARDS) which improves respiratory function. The antiviral effects of vitamin C passes through inhibition of replication of poliovirus type 1, herpes simplex virus 1, and influenza A virus [
      • Furuya A.
      • Uozaki M.
      • Yamasaki H.
      • Arakawa T.
      • Arita M.
      • Koyama A.H.
      Antiviral effects of ascorbic and dehydroascorbic acids in vitro.
      ]. Intravenous vitamin C (IVC) achieves higher plasma concentration compared to oral vitamin C attributed to losses during tissue transport, intestinal absorption and renal reabsorption [
      • Padayatty S.J.
      • Sun H.
      • Wang Y.
      • Riordan H.D.
      • Hewitt S.M.
      • Katz A.
      • et al.
      Vitamin C pharmacokinetics: implications for oral and intravenous use.
      ]. The safety and efficacy of intravenous high-dose vitamin C (HIVC) in critically ill cases have been evaluated through several clinical trials. A recent meta-analysis on cardiac surgery trials demonstrated shortened duration of mechanical ventilation in ICU patients and ICU length of stay after using vitamin C [
      • Hemilä H.
      • Chalker E.
      Vitamin C can shorten the length of stay in the ICU: a meta-analysis.
      ]. Indeed, vitamin C effects were significantly greater in patients with more severe illness [
      • Liu F.
      • Zhu Y.
      • Zhang J.
      • Li Y.
      • Peng Z.
      Intravenous high-dose vitamin C for the treatment of severe COVID-19: study protocol for a multicentre randomised controlled trial.
      ]. Vitamin C significantly reduced levels of circulating injury biomarkers and scores of multi-organ failure in patients with ARDS or sepsis in a phase I trial using IVC [
      • Syed A.A.
      • Knowlson S.
      • Sculthorpe R.
      • Farthing D.
      • DeWilde C.
      • Farthing C.A.
      • et al.
      Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis.
      ]. The impacts were greater in high-dose group (200 mg/kg) vs. low-dose group (50 mg/kg). Moreover, no difference was reported regarding primary outcome of inflammation biomarkers and organ failure scores in a study conducted on patients with ARDS and sepsis, while a significant reduction in both 28-day mortality and long-term prognosis were also observed using 50 mg/kg IVC at patients undergoing mechanical ventilation. In a case report [
      • Fowler III, A.A.
      • Kim C.
      • Lepler L.
      • Malhotra R.
      • Debesa O.
      • Natarajan R.
      • et al.
      Intravenous vitamin C as adjunctive therapy for enterovirus/rhinovirus induced acute respiratory distress syndrome.
      ], administration of HIVC (200 mg/kg) was showed to successfully treat virus-induced ARDS in patients experienced a rapid recovery without any long-term sequelae after being on extracorporeal membrane oxygenation [
      • Liu F.
      • Zhu Y.
      • Zhang J.
      • Li Y.
      • Peng Z.
      Intravenous high-dose vitamin C for the treatment of severe COVID-19: study protocol for a multicentre randomised controlled trial.
      ].

      Vitamin D

      Vitamin D, a steroid hormone which is endogenously produced by ultraviolet radiation on skin or exogenously from food or dietary supplements. Its insufficiency is a public health issue affecting over a billion people worldwide at all life stages [
      • Holick M.F.
      The vitamin D deficiency pandemic: Approaches for diagnosis, treatment and prevention.
      ]. There is a potential link between vitamin D deficiency and numerous diseases such as systemic infection [
      • Ali N.
      Role of vitamin D in preventing of COVID-19 infection, progression and severity.
      ]. Since vitamin D has an immune modulatory role, its insufficiency affects immune functions [
      • Greiller C.L.
      • Martineau A.R.
      Modulation of the immune response to respiratory viruses by vitamin D.
      ]. Vitamin D increases innate immunity through secretion of antiviral peptides [
      • Wang T.-T.
      • Dabbas B.
      • Laperriere D.
      • Bitton A.J.
      • Soualhine H.
      • Tavera-Mendoza L.E.
      • et al.
      Direct and indirect induction by 1, 25-dihydroxyvitamin D3 of the NOD2/CARD15-defensin β2 innate immune pathway defective in Crohn disease.
      ,
      • Gombart A.F.
      • Borregaard N.
      • Koeffler H.P.
      Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1, 25-dihydroxyvitamin D3.
      ] with the ability to improve mucosal defenses. In clinical studies, low serum levels of vitamin D were associated with development of acute respiratory tract infections such as epidemic influenza [
      • Ali N.
      Role of vitamin D in preventing of COVID-19 infection, progression and severity.
      ]. A recent meta-analysis on eight observational studies demonstrated a 64% enhanced risk of community-acquired pneumonia in cases with a serum vitamin D concentration <50 nmol/l [
      • Zhou Y.-F.
      • Luo B.-A.
      • Qin L.-L.
      The association between vitamin D deficiency and community-acquired pneumonia: A meta-analysis of observational studies.
      ]. Vitamin D insufficiency has been hypothesized to diminish respiratory immune function with subsequent increased risk of COVID-19 severity and mortality. Correlation between vitamin D levels and COVID-19 mortality and severity has been determined through some retrospective studies [
      • Ali N.
      Role of vitamin D in preventing of COVID-19 infection, progression and severity.
      ]. Antiviral effects of vitamin D with the ability to directly hinder viral replication besides its immunomodulatory and anti-inflammatory properties have been demonstrated recently [
      • Teymoori-Rad M.
      • Shokri F.
      • Salimi V.
      • Marashi S.M.
      The interplay between vitamin D and viral infections.
      ]. In some patients, SARS-CoV-2 seems to primarily apply immune evasion process flowed by cytokine storm and hyper reaction [
      • Guo Y.-R.
      • Cao Q.-D.
      • Hong Z.-S.
      • Tan Y.-Y.
      • Chen S.-D.
      • Jin H.-J.
      • et al.
      The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak–an update on the status.
      ], as a known pathogenic process involved in development of acute respiratory disease syndrome (ARDS) [
      • Jakovac H.
      COVID-19 and vitamin D—Is there a link and an opportunity for intervention?.
      ]. SARS-CoV-2 applies angiotensin converting enzyme 2 as host receptor for its entrance into intestinal and alveolar epithelial cells [
      • Xiao F.
      • Tang M.
      • Zheng X.
      • Liu Y.
      • Li X.
      • Shan H.
      Evidence for gastrointestinal infection of SARS-CoV-2.
      ]. Subsequent dysregulation of renin–angiotensin system might result in excessive cytokine production leading to prospective fatal ARDS [
      • Jakovac H.
      COVID-19 and vitamin D—Is there a link and an opportunity for intervention?.
      ]. Nutrient such as vitamin D demonstrated substantial roles in immune function. However, scant data are available regarding the role of vitamin D in prevention of COVID-19 infection and fatality [
      • Ali N.
      Role of vitamin D in preventing of COVID-19 infection, progression and severity.
      ].

      Vitamin E

      Vitamin E is a lipophilic antioxidant [
      • Gagné A.
      • Wei S.Q.
      • Fraser W.D.
      • Julien P.
      Absorption, transport, and bioavailability of vitamin e and its role in pregnant women.
      ,

      Balandeh E, Karimian M, Behjati M, Mohammadi AH. Serum Vitamins and Homocysteine Levels in Obsessive-Compulsive Disorder: A Systematic Review and Meta-Analysis. Neuropsychobiology.1–14.

      ] which amplifies immune system and supplies integrity of T-cell membranes. It also diminishes the course of influenza virus infection [
      • BourBour F.
      • Mirzaei Dahka S.
      • Gholamalizadeh M.
      • Akbari M.E.
      • Shadnoush M.
      • Haghighi M.
      • et al.
      Nutrients in prevention, treatment, and management of viral infections; special focus on Coronavirus.
      ]. The glutathione preserves membrane integrity through elimination of electrophiles derived from lipid peroxidation and inhibits protein cysteine oxidation. The main underlying mechanism related to antiferroptosis effect of vitamin E is reduction of ferric iron center in 15-lipoxygenase to inactive ferrous (Fe2+) leading to 15-lipoxygenase inhibition [
      • Tavakol S.
      • Seifalian A.M.
      Vitamin E at a high dose as an anti-ferroptosis drug and not just a supplement for COVID-19 treatment.
      ]. Lipoxygenase result in formation of lipid hydroperoxides using peroxyl radicals, while reaction of vitamin E with peroxyl radicals leads to prevention of lipid hydroperoxides formation. Afterward, GPX4, glutathione and other antioxidant agents are involved in detoxification of lipids to prohibit triggering of ferroptosis. Besides, vitamin E compensates for detoxification made by GPX4 in its deficiency. Indeed, alpha-tocopherol hydroquinone is a more potent antioxidant compared to alpha-tocopherol [
      • Hinman A.
      • Holst C.R.
      • Latham J.C.
      • Bruegger J.J.
      • Ulas G.
      • McCusker K.P.
      • et al.
      Vitamin E hydroquinone is an endogenous regulator of ferroptosis via redox control of 15-lipoxygenase.
      ]. Furthermore, neurodegeneration due to vitamin E deficiency is associated with ferroptosis. The neural damages in COVID-19 patients might be partly prohibited using vitamin E through an anti-ferroptosis mechanism. Thus, vitamin E is able to prevent toxic mechanisms behind iron serum levels such as ferroptosis through prohibition of peroxyl and lipoxygenase radicals. High doses of vitamin E (500 mg/kg) might act as a therapeutic medicine to inhibit ferroptosis and reduce ferroptosis injury to multiple organ such as liver, lung, heart, gut, nervous system and kidney in COVID-19 cases. It also leads to ablation of inflammation and viral clearance through modulation of T cells [
      • Tavakol S.
      • Seifalian A.M.
      Vitamin E at a high dose as an anti-ferroptosis drug and not just a supplement for COVID-19 treatment.
      ].

      Vitamin K

      Recently, anti-inflammatory actions of vitamin K, mediated through reduction of COX2, PGE2, and IL-6, have been focused [
      • Suleiman L.
      • Négrier C.
      • Boukerche H.
      Protein S: A multifunctional anticoagulant vitamin K-dependent protein at the crossroads of coagulation, inflammation, angiogenesis, and cancer.
      ]. Inflammatory cytokines, including C-reactive protein and IL-6 are increased in the setting of vitamin K deficiency due to intestinal malabsorption or interaction with medicines such as prolonged antibiotic therapy or anticoagulant. Besides anti-inflammatory actions, diminished coronary calcification and reduced risk of cardiovascular diseases have been reported to be associated with high intake of vitamin K [
      • Shioi A.
      • Morioka T.
      • Shoji T.
      • Emoto M.
      The inhibitory roles of vitamin K in progression of vascular calcification.
      ]. Furthermore, vitamin K supplementation in experimental animal models was associated with a 50% reduction in rate of atherosclerotic calcification due activation of a specific matrix Gla protein (MGP) with the ability to remove abnormal accumulation from the arteries [
      • Torii S.
      • Ikari Y.
      • Tanabe K.
      • Kakuta T.
      • Hatori M.
      • Shioi A.
      • et al.
      Plasma phylloquinone, menaquinone-4 and menaquinone-7 levels and coronary artery calcification.
      ]. Vitamin K deficiency is clinically a frequent complication observed in admitted patients in adult intensive care units (ICU) with an incidence as high as 25% [
      • Dahlberg S.
      • Schurgers L.
      • Schött U.
      • Kander T.
      Vitamin K deficiency in critical ill patients; a prospective observational study.
      ]. Low vitamin K status in COVID-19 patients was associated with poor disease outcome. Moreover, increased blood levels of desmosines, a biomarker of degradation of elastic fibers in the lung, was seen in the setting of low vitamin K status [
      • Piscaer I.
      • van den Ouweland J.M.
      • Vermeersch K.
      • Reynaert N.L.
      • Franssen F.M.
      • Keene S.
      • et al.
      Low vitamin K status is associated with increased elastin degradation in chronic obstructive pulmonary disease.
      ], indicative to the enhanced rate of elastic fiber degradation possibly due to low vitamin K status during severe COVID-19. Over degradation of lung's elastic fibers could be related to lack of activated MGP, which is recognized to prevent calcification and following degradation of extracellular matrix proteins including elastic fibers [
      • Piscaer I.
      • Wouters E.F.
      • Vermeer C.
      • Janssens W.
      • Franssen F.M.
      • Janssen R.
      Vitamin K deficiency: the linking pin between COPD and cardiovascular diseases?.
      ]. MGP is known as the strongest inhibitor of calcification in arterial vessel walls that subsequently inhibit arterial calcification [
      • Piscaer I.
      • van den Ouweland J.M.
      • Vermeersch K.
      • Reynaert N.L.
      • Franssen F.M.
      • Keene S.
      • et al.
      Low vitamin K status is associated with increased elastin degradation in chronic obstructive pulmonary disease.
      ]. MGP is highly expressed in the lungs [
      • Linneberg A.
      • Kampmann F.B.
      • Israelsen S.B.
      • Andersen L.R.
      • Jørgensen H.L.
      • Sandholt H.
      • et al.
      The Association of Low Vitamin K Status with Mortality in a Cohort of 138 Hospitalized Patients with COVID-19.
      ]. Degraded lung's elastic fibers stimulate their calcification [
      • Basalyga D.M.
      • Simionescu D.T.
      • Xiong W.
      • Baxter B.T.
      • Starcher B.C.
      • Vyavahare N.R.
      Elastin degradation and calcification in an abdominal aorta injury model: role of matrix metalloproteinases.
      ]. Local synthesis of MGP is stimulated by rising calcium level of extracellular matrix which prevents calcification of elastic fibers [
      • Piscaer I.
      • Wouters E.F.
      • Vermeer C.
      • Janssens W.
      • Franssen F.M.
      • Janssen R.
      Vitamin K deficiency: the linking pin between COPD and cardiovascular diseases?.
      ]. MGP is synthesized as dp-ucMGP which requires activation through vitamin K-dependent carboxylation to protect elastic fibers in extracellular matrix from calcification. These processes create or facilitate a pre-morbid vitamin K deficiency during severe disease course with enhanced vitamin K demands. Vitamin K is also required for carboxylation of antithrombotic proteins such as protein C and S in addition to carboxylation of prothrombotic proteins [
      • Caluwé R.
      • Verbeke F.
      • De Vriese A.S.
      Evaluation of vitamin K status and rationale for vitamin K supplementation in dialysis patients.
      ]. Protein C and prothrombotic proteins are exclusively hepatic proteins, while about half of protein S is synthesized extrahepatically and subsequently activated by vitamin K. Indeed, synthesis and activation of MPG is primarily extrahepatically [
      • Linneberg A.
      • Kampmann F.B.
      • Israelsen S.B.
      • Andersen L.R.
      • Jørgensen H.L.
      • Sandholt H.
      • et al.
      The Association of Low Vitamin K Status with Mortality in a Cohort of 138 Hospitalized Patients with COVID-19.
      ]. During vitamin K deficiency such as acute illness with enhanced vitamin K usage, vitamin K is used primarily for hepatic carboxylation of prothrombotic coagulation factors and to a lesser extent for extrahepatic carboxylation of vitamin K-dependent proteins such as antithrombotic protein S and MGP [
      • Dofferhoff A.S.
      • Piscaer I.
      • Schurgers L.J.
      • Visser M.P.
      • van den Ouweland J.M.
      • de Jong P.A.
      • et al.
      Reduced vitamin K status as a potentially modifiable risk factor of severe COVID-19.
      ]. This could induces a prothrombotic state with enhanced blood clotting in peripheral tissues as could be observed in COVID-19 patients [
      • Janssen R.
      • Visser M.P.
      • Dofferhoff A.S.
      • Vermeer C.
      • Janssens W.
      • Walk J.
      Vitamin K metabolism as the potential missing link between lung damage and thromboembolism in Coronavirus disease 2019.
      ].

      Minerals

      Calcium

      Calcium is a vital ion for cellular processes and metabolic and signaling pathways playing a fundamental role in viral survival and virulence [
      • Torres B.
      • Alcubilla P.
      • González-Cordón A.
      • Inciarte A.
      • Chumbita M.
      • Cardozo C.
      • et al.
      Impact of low serum calcium at hospital admission on SARS-CoV-2 infection outcome.
      ]. Hypocalcemia is prominent in COVID-19 patients with a direct relationship with enhanced likelihood of hospitalization, ventilation, admission to ICU, longer hospitalizations, increased D-dimer levels, disease severity and increased mortality in COVID-19 patients [
      • Alemzadeh E.
      • Alemzadeh E.
      • Ziaee M.
      • Abedi A.
      • Salehiniya H.
      The effect of low serum calcium level on the severity and mortality of Covid patients: A systematic review and meta-analysis.
      ]. Since there are some limitations in published surveys in this regards [
      • Martha J.W.
      • Wibowo A.
      • Pranata R.
      Hypocalcemia is associated with severe COVID-19: A systematic review and meta-analysis.
      ], a comprehensive study is essential in this area. Therefore, development of hypocalcemia during SARS-CoV-2 infection with severe clinical course, is not unexpected. Thus, degree of hypocalcemia could be a robust indicator of disease intensity and should be considered by physicians during the treatment process [
      • Alemzadeh E.
      • Alemzadeh E.
      • Ziaee M.
      • Abedi A.
      • Salehiniya H.
      The effect of low serum calcium level on the severity and mortality of Covid patients: A systematic review and meta-analysis.
      ].

      Zinc

      Zinc, as the second most abundant trace element after iron in human body, is a common element for both prophylactic and curative applications in COVID-19 clinical studies. Zinc is fundamental for multiple cellular purposes such as maintenance of immune health. In fact, “Zinc proteome” is believed to possess around 3000 proteins [
      • Maret W.
      Zinc and the zinc proteome. Metallomics and the Cell.
      ] including about 750 Zinc finger transcription factors which are deeply implicated in inflammation and homeostasis. The history of zinc deficiency identification in human goes back to more than 56 years ago. Zinc deficiency has been associated to hypogonadism, immune dysfunction, growth retardation, and cognitive impairment [
      • Pal A.
      • Squitti R.
      • Picozza M.
      • Pawar A.
      • Rongioletti M.
      • Dutta A.K.
      • et al.
      Zinc and COVID-19: basis of current clinical trials.
      ]. Zinc also plays a fundamental role in antiviral immunity [
      • Gupta S.
      • Read S.A.
      • Shackel N.A.
      • Hebbard L.
      • George J.
      • Ahlenstiel G.
      The role of micronutrients in the infection and subsequent response to hepatitis C virus.
      ,
      • Read S.A.
      • Obeid S.
      • Ahlenstiel C.
      • Ahlenstiel G.
      The role of zinc in antiviral immunity.
      ]. There are specialized reviews regarding essential role of zinc in both human health maintenance (including zinc transporters and homeostasis) and in nonviral/viral diseases [
      • Pal A.
      • Squitti R.
      • Picozza M.
      • Pawar A.
      • Rongioletti M.
      • Dutta A.K.
      • et al.
      Zinc and COVID-19: basis of current clinical trials.
      ]. Although abundant clinical trials are going on against COVID- 19 pandemic, there is still scientific curiosity about these trials [
      • Rahman M.T.
      • Idid S.Z.
      Can Zn be a critical element in COVID-19 treatment?.
      ].

      Iron

      COVID-19 is manifested by various complications as well as biochemical and physiological alterations. These include hemoglobin damage, hyper coagulation state and dysregulation of iron homeostasis including iron overload that is likely a key factor in pathogenesis of COVID-19 [
      • Habib H.M.
      • Ibrahim S.
      • Zaim A.
      • Ibrahim W.H.
      The role of iron in the pathogenesis of COVID-19 and possible treatment with lactoferrin and other iron chelators.
      ,
      • Colafrancesco S.
      • Priori R.
      • Alessandri C.
      • Astorri E.
      • Perricone C.
      • Blank M.
      • et al.
      sCD163 in AOSD: a biomarker for macrophage activation related to hyperferritinemia.
      ]. Liu et al. (2020) indicated hemoglobin attack as the key pathogenic molecular step in COVID-19 leading to porphyrin dissociation from iron and subsequent releasing of iron into the circulation [
      • Habib H.M.
      • Ibrahim S.
      • Zaim A.
      • Ibrahim W.H.
      The role of iron in the pathogenesis of COVID-19 and possible treatment with lactoferrin and other iron chelators.
      ]. Therefore, hemoglobin loses its oxygen binding capacity which hinders its delivery to major organs that subsequently is coupled with development of rapid multi-organ failures. Besides, the released free iron into circulation might lead to iron overload resulting in oxidative damage to the lung and other organs. Iron overload could lead to inflammation and dysfunction of immune system [
      • Moreira A.C.
      • Mesquita G.
      • Gomes M.S.
      Ferritin: an inflammatory player keeping iron at the core of pathogen-host interactions.
      ,
      • Cassat J.E.
      • Skaar E.P.
      Iron in infection and immunity.
      ]. These dictate enhanced uptake and storage of iron in iron-binding proteins. Moreover, it is supported by enhanced ferritin level in COVID-19 patients [
      • Habib H.M.
      • Ibrahim S.
      • Zaim A.
      • Ibrahim W.H.
      The role of iron in the pathogenesis of COVID-19 and possible treatment with lactoferrin and other iron chelators.
      ]. Iron overload results in blood hyper viscosity with diffuse and recurrent micro and macro circulatory thrombosis that could explain unexpected deterioration and subsequent death in some instances [
      • Habib H.M.
      • Ibrahim S.
      • Zaim A.
      • Ibrahim W.H.
      The role of iron in the pathogenesis of COVID-19 and possible treatment with lactoferrin and other iron chelators.
      ,
      • Gardenghi G.
      Pathophysiology of worsening lung function in COVID-19.
      ].

      Selenium

      Selenium (Se) exerts a fundamental and complex role in the immune system, especially in oxidative stress processes via NADPH, Thioredoxin, and TrxR [
      • Rayman M.P.
      Food-chain selenium and human health: emphasis on intake.
      ,
      • Avery J.C.
      • Hoffmann P.R.
      Selenium, selenoproteins, and immunity.
      ]. Furthermore, Se deficiency is associated with susceptibility to viral RNA infections and poor outcomes. In addition, obesity (BMI > 30 kg/m2) is now identified as major risk factors for severe COVID-19 [
      • Hiffler L.
      • Rakotoambinina B.
      Selenium and RNA virus interactions: Potential implications for SARS-CoV-2 infection (COVID-19).
      ]. This important risk factor could contribute to the development of uncontrolled epidemic in Mexico and USA where 30% and 42% of the population are obese, respectively [
      • Chiappetta S.
      • Sharma A.M.
      • Bottino V.
      • Stier C.
      COVID-19 and the role of chronic inflammation in patients with obesity.
      ,
      Control CfD, Prevention
      Overweight and obesity: data and statistics.
      ] with a relatively younger average age of hospital admission due to COVID-19 infection compared to European cohorts [
      • Hernández-Garduño E.
      Obesity is the comorbidity more strongly associated for Covid-19 in Mexico. A case-control study.
      ]. Worse outcomes of COVID-19 [
      • Kass D.A.
      • Duggal P.
      • Cingolani O.
      Obesity could shift severe COVID-19 disease to younger ages.
      ] are characterized to oxidative stress and an underlying low-grade inflammation such as metabolic syndrome and obesity [
      • Hiffler L.
      • Rakotoambinina B.
      Selenium and RNA virus interactions: Potential implications for SARS-CoV-2 infection (COVID-19).
      ]. Adipose tissue, a distinct endocrine organ, is capable of synthesizing enormous cytokines such as TNF-alpha, IL-6 and IL-8 [
      • Coppack S.W.
      Pro-inflammatory cytokines and adipose tissue.
      ]. Obesity is characterized by enhanced infiltration of macrophages in adipose tissue as a SARS-Cov-2 reservoir [
      • Ryan P.
      • Caplice N.
      Is adipose tissue a reservoir for viral spread, immune activation and cytokine amplification in COVID-19.
      ]. These macrophages can be locally activated by the virus resulting in production of deleterious reactive oxygen/nitrogen species if not counterbalanced by redox homeostasis [
      • Hiffler L.
      • Rakotoambinina B.
      Selenium and RNA virus interactions: Potential implications for SARS-CoV-2 infection (COVID-19).
      ]. Notably, Se attenuates expression of pro-inflammatory genes in the macrophages [
      • Vunta H.
      • Belda B.J.
      • Arner R.J.
      • Channa Reddy C.
      • Vanden Heuvel J.P.
      • Sandeep Prabhu K.
      Selenium attenuates pro-inflammatory gene expression in macrophages.
      ]. The miR-185–5p which is a Se sensitive microRNA was recognized to control feedback expression of selenoproteins in obese cases through regulation of six of eight Glutathione Peroxidase [
      • Matoušková P.
      • Hanousková B.
      • Skálová L.
      MicroRNAs as potential regulators of glutathione peroxidases expression and their role in obesity and related pathologies.
      ]. Indeed, obesity is associated with reduction of Glutathione Peroxidase 3 (GPx 3) activity in adipose tissue [
      • Langhardt J.
      • Flehmig G.
      • Klöting N.
      • Lehmann S.
      • Ebert T.
      • Kern M.
      • et al.
      Effects of weight loss on glutathione peroxidase 3 serum concentrations and adipose tissue expression in human obesity.
      ]. Hauffe et al. demonstrated enhanced GPx3 activity and insulin receptors/sensitivity in adipose tissue of obese mice following sodium selenite supplementation [
      • Hauffe R.
      • Stein V.
      • Chudoba C.
      • Flore T.
      • Rath M.
      • Ritter K.
      • et al.
      GPx 3 dysregulation impacts adipose tissue insulin receptor expression and sensitivity.
      ]. Furthermore, obesity is usually accompanied by impaired cardiovascular functioning including arterial stiffness and endothelial cell dysfunction favoring endothelial infection by SARSCoV- 2 [
      • Blokhin I.O.
      • Lentz S.R.
      Mechanisms of thrombosis in obesity.
      ]. Besides, cardiac changes and prothrombotic propensity in obesity are parallel with enhanced rate of cardiovascular events in COVID-10 cases admitted in intensive care unit [
      • Hiffler L.
      • Rakotoambinina B.
      Selenium and RNA virus interactions: Potential implications for SARS-CoV-2 infection (COVID-19).
      ]. These pathologies exhibit inflammation and oxidative stress along with low Se level and endothelial dysfunction [
      • Hiffler L.
      • Rakotoambinina B.
      Selenium and RNA virus interactions: Potential implications for SARS-CoV-2 infection (COVID-19).
      ,
      • Larvie D.Y.
      • Doherty J.L.
      • Donati G.L.
      • Armah S.M.
      Relationship between selenium and hematological markers in young adults with normal weight or overweight/obesity.
      ], and the above mentioned relationships between RNA viruses and Se suggest a possible joint between Se and SARS-CoV-2 infection. Indeed, older subjects are consistently more vulnerable to COVID- 19 infection with atypical clinical manifestations and enhanced risk of significant complications and mortality compared to healthy adults [
      • Nikolich-Zugich J.
      • Knox K.S.
      • Rios C.T.
      • Natt B.
      • Bhattacharya D.
      • Fain M.J.
      SARS-CoV-2 and COVID-19 in older adults: what we may expect regarding pathogenesis, immune responses, and outcomes.
      ,
      • Godaert L.
      • Proye E.
      • Demoustier-Tampere D.
      • Coulibaly P.S.
      • Hequet F.
      • Dramé M.
      Clinical characteristics of older patients: the experience of a geriatric short-stay unit dedicated to patients with COVID-19 in France.
      ]. Average case fatality ratio for subjects older than 60 years driven from international data is reported to be of 4–5%, and this value for subjects > 80 years is probably up to 14.8% [
      • Hiffler L.
      • Rakotoambinina B.
      Selenium and RNA virus interactions: Potential implications for SARS-CoV-2 infection (COVID-19).
      ,
      • Williamson E.
      • Walker A.J.
      • Bhaskaran K.
      • Bacon S.
      • Bates C.
      • Morton C.E.
      • et al.
      Open SAFELY: factors associated with COVID-19-related hospital death in the linked electronic health records of 17 million adult NHS patients.
      ]. Numerous factors could explain this including aging related frailty, multiple chronic co-morbidities and blunted immune response along with a degree of malnutrition [
      • Hiffler L.
      • Rakotoambinina B.
      Selenium and RNA virus interactions: Potential implications for SARS-CoV-2 infection (COVID-19).
      ]. Furthermore, senescent fibroblasts are four times more prone to oxidative stress compared to young cells and use more Se [
      • Ghneim H.K.
      Selenium concentrations for maximisation of thioredoxin reductase 2 activity and upregulation of its gene transcripts in senescent human fibroblasts.
      ]. Indeed, addition of high concentration of Se to these cells is associated with over activity of Glutathione Peroxidase and reduced amounts of reactive oxygen species [
      • Ghneim H.K.
      Selenium concentrations for maximisation of thioredoxin reductase 2 activity and upregulation of its gene transcripts in senescent human fibroblasts.
      ]. Low or borderline levels of Se in old ages influences longevity and mortality rate [
      • Hiffler L.
      • Rakotoambinina B.
      Selenium and RNA virus interactions: Potential implications for SARS-CoV-2 infection (COVID-19).
      ]. Se deficiency was reported in 71% of Sweden elders admitted to Intensive Care Unit [
      • Broman L.M.
      • Bernardson A.
      • Bursell K.
      • Wernerman J.
      • Fläring U.
      • Tjäder I.
      Serum selenium in critically ill patients: Profile and supplementation in a depleted region.
      ]. Se supplementation was associated with significantly reduced infection in institutionalized elderly subjects [
      • Girodon F.
      • Lombard M.
      • Galan P.
      • Brunet-Lecomte P.
      • Monget A.-L.
      • Arnaud J.
      • et al.
      Effect of micronutrient supplementation on infection in institutionalized elderly subjects: a controlled trial.
      ]. Besides, Se supplementation for 4 years in Swedish elderly peoples diminished risk of cardiovascular mortality by more than 40%, the long-lasting effect even 12 years later [
      • Hiffler L.
      • Rakotoambinina B.
      Selenium and RNA virus interactions: Potential implications for SARS-CoV-2 infection (COVID-19).
      ].

      Amino acids

      Amino acids are essential for synthesis of numerous important molecules such as hormones and neurotransmitters which ensure proper metabolic functioning and immune responses against diseases through being used in cellular redox status, lymphocyte proliferation, gene expression, production of lymphokines, cytokines, antibodies and cytotoxic substances and activation of natural killer cells, B and T lymphocytes, and macrophages; various diseases including malignancies (hepatocellular, breast, lung and colon cancer, cervical squamous epithelium cell carcinoma, cervical intraepithelial neoplasia and renal cell carcinoma), kidney diseases, metabolic diseases (metabolic syndrome, diabetes mellitus, nasal polyposis, and sepsis [
      • Atila A.
      • Alay H.
      • Yaman M.E.
      • Akman T.C.
      • Cadirci E.
      • Bayrak B.
      • et al.
      The serum amino acid profile in COVID-19.
      ]. Insufficient data is available regarding the way that serum amino acid profile through which plays a significant role in making immune responses in SARS-CoV-2 infection. Increase and decrease in amino acid levels could be a possible significant prognostic factors in some diseases [
      • Atila A.
      • Alay H.
      • Yaman M.E.
      • Akman T.C.
      • Cadirci E.
      • Bayrak B.
      • et al.
      The serum amino acid profile in COVID-19.
      ,
      • Du X.
      • Li Y.
      • Wang Y.
      • You H.
      • Hui P.
      • Zheng Y.
      • et al.
      Increased branched-chain amino acid levels are associated with long-term adverse cardiovascular events in patients with STEMI and acute heart failure.
      ]. Clinical healing could develop through replacement of decreased amino acids in significant diseases as demonstrated in some clinical studies [
      • Atila A.
      • Alay H.
      • Yaman M.E.
      • Akman T.C.
      • Cadirci E.
      • Bayrak B.
      • et al.
      The serum amino acid profile in COVID-19.
      ]. Detection of both cytokines and amino acid profiles might be beneficial for estimation of possible organ damages and development of diverse therapeutic strategies [
      • Atila A.
      • Alay H.
      • Yaman M.E.
      • Akman T.C.
      • Cadirci E.
      • Bayrak B.
      • et al.
      The serum amino acid profile in COVID-19.
      ,
      • Wang T.J.
      • Larson M.G.
      • Vasan R.S.
      • Cheng S.
      • Rhee E.P.
      • McCabe E.
      • et al.
      Metabolite profiles and the risk of developing diabetes.
      ]. Previous studies have also focused on the importance of serum amino acids during infections such as COVID-19 [
      • Atila A.
      • Alay H.
      • Yaman M.E.
      • Akman T.C.
      • Cadirci E.
      • Bayrak B.
      • et al.
      The serum amino acid profile in COVID-19.
      ]. Determining amino acid profile in such acute conditions is fundamental for both patient diagnosis and supplementation [
      • Cengiz M.
      • Uysal B.B.
      • Ikitimur H.
      • Ozcan E.
      • Islamoğlu M.S.
      • Aktepe E.
      • et al.
      Effect of oral L-Glutamine supplementation on Covid-19 treatment.
      ]. Thus, new investigations focusing on serum amino acid profile and its alterations are required [
      • Atila A.
      • Alay H.
      • Yaman M.E.
      • Akman T.C.
      • Cadirci E.
      • Bayrak B.
      • et al.
      The serum amino acid profile in COVID-19.
      ].

      Coenzyme Q10

      Frederick Loring Crane discovered Coenzyme Q10 (CoQ10) in 1957. CoQ10 is located within the inner membrane of mitochondria and is an integral part of mitochondrial respiratory chain transporting electrons from complex I and complex II to complex III. It is also the key part of ATP production in mitochondria. FL Crane demonstrated its effects through a plasma membrane to autism [
      • Gvozdjakova A.
      • Klauco F.
      • Kucharska J.
      • Sumbalova Z.
      Is mitochondrial bioenergetics and coenzyme Q10 the target of a virus causing COVID-19?.
      ,
      • Teske B.F.
      • Sun I.
      • Gvozdjakova A.
      • Low H.
      • Crane F.L.
      Plasma membrane CoQ, porin, and redox control of autism.
      ]. CoQ10 is primarily synthetized endogenously from tyrosine in the endoplasmic reticulum by mevalonate pathway using vitamins C, B2, B6 B9, and B12 and transported into plasma by low-density lipoproteins [
      • Gvozdjakova A.
      • Klauco F.
      • Kucharska J.
      • Sumbalova Z.
      Is mitochondrial bioenergetics and coenzyme Q10 the target of a virus causing COVID-19?.
      ]. Since now, there are nine known genes to be involved in endogenous biosynthesis of CoQ10 known as “COQ genes” of coenzyme Q2-polyprenyltransferase (COQ2), coenzyme Q4 (COQ4), coenzyme Q6-monooxygenase (COQ6), coenzyme Q7-hydroxylase (COQ7), coenzyme Q8A (COQ8A), coenzyme Q8B (COQ8B), coenzyme Q9 (COQ9), prenyl diphosphate synthase, subunit 1 and 2 (PDSS1, PDSS2). Biosynthesis of CoQ10 involves several metabolic reactions including decarboxylation, methylation and hydroxylation [
      • Laredj L.N.
      • Licitra F.
      • Puccio H.M.
      The molecular genetics of coenzyme Q biosynthesis in health and disease.
      ]. Its low levels might be due to impaired endogenous synthesis of CoQ10 or mutation of one or more COQ genes or its over utilization. Significantly lower serum levels of CoQ10 were observed in cases with chronic kidney disease, acute influenza infection, infertile men, in patients with cardiomyopathy and in endomyocardial biopsies of post heart transplantation samples [
      • Gvozdjakova A.
      • Klauco F.
      • Kucharska J.
      • Sumbalova Z.
      Is mitochondrial bioenergetics and coenzyme Q10 the target of a virus causing COVID-19?.
      ,
      • Turner A.J.
      • Hiscox J.A.
      • Hooper N.M.
      ACE2: from vasopeptidase to SARS virus receptor.
      ]. CoQ10 has the potential to reduce fatigue and pain in fibromyalgia patients [
      • Cordero M.D.
      • Alcocer-Gómez E.
      • de Miguel M.
      • Culic O.
      • Carrión A.M.
      • Alvarez-Suarez J.M.
      • et al.
      Can coenzyme q10 improve clinical and molecular parameters in fibromyalgia?.
      ]. There is a significant association observed between CoQ10, IL-2 and TNF-alpha in patients with septic shock [
      • Donnino M.W.
      • Cocchi M.N.
      • Salciccioli J.D.
      • Kim D.
      • Naini A.B.
      • Buettner C.
      • et al.
      Coenzyme Q10 levels are low and may be associated with the inflammatory cascade in septic shock.
      ]. Lower levels of CoQ10 due to statin therapy may also induce mitochondrial dysfunction, myopathy, fatigue and myalgia [
      • Gvozdjakova A.
      • Klauco F.
      • Kucharska J.
      • Sumbalova Z.
      Is mitochondrial bioenergetics and coenzyme Q10 the target of a virus causing COVID-19?.
      ]. Suggested roles of CoQ10 in cardiovascular disease have been discovered by another research group [
      • Gvozdjakova A.
      • Klauco F.
      • Kucharska J.
      • Sumbalova Z.
      Is mitochondrial bioenergetics and coenzyme Q10 the target of a virus causing COVID-19?.
      ,
      • Gvozdjákova A.
      • Takahashi T.
      • Singh R.
      • De Meester F.
      • Wilson D.W.
      • Crane F.L.
      New roles of coenzyme Q10 in cardiovascular diseases, discovered by a single group.
      ]. Targeted therapy with CoQ10 for mitochondrial disturbances has also documented [
      • Gvozdjáková A.
      • Cornelissen-Guillaume G.G.
      • Singh R.B.
      Recent advances in mitochondrial medicine and Coenzyme Q10.
      ]. Beneficial impacts of CoQ10 pass through its antioxidant activity, and its impacts on production of cytokine by human peripheral blood mononuclear cells (PMBC) could modulate human immune functions. Incubation of PMBC with variable dosages of CoQ10 for 24 hours was associated with reduced secretion of TNF-alpha and IL-2 in those cells [
      • Bessler H.
      • Bergman M.
      • Blumberger N.
      • Djaldetti M.
      • Salman H.
      Coenzyme Q10 decreases TNF-α and IL-2 secretion by human peripheral blood mononuclear cells.
      ] Therefore, CoQ10 diminishes inflammatory cytokines and biomarkers [
      • Fan L.
      • Feng Y.
      • Chen G.-C.
      • Qin L.-Q.
      • Fu C-l
      • Chen L.-H.
      Effects of coenzyme Q10 supplementation on inflammatory markers: a systematic review and meta-analysis of randomized controlled trials.
      ].

      Omega-3

      Polyunsaturated fatty acids (PUFA) are substrates for anti-inflammatory, pro-inflammatory, and specialized pro-resolving lipid mediators (SPM) [
      • Chiang N.
      • Serhan C.N.
      Specialized pro-resolving mediator network: an update on production and actions.
      ]. Omega-6 PUFA arachidonic acid (AA) is substrate for cyclooxygenase and lipoxygenase pathways leading to generation of leukotrienes and prostaglandins, respectively, which all called as eicosanoids. In contrast, docosahexaenoic acid (DHA) and omega-3 PUFA eicosapentaenoic acid (EPA) act as substrate for pro-resolving SPM. PUFA can also be metabolized into respective epoxides by cytochrome (CYP) P450 epoxygenases which regulate inflammatory reaction. Decreased omega-6 PUFA and enhanced omega-3 PUFA represent a probable mean to skew immune response toward modulation of inflammation [
      • Arnardottir H.
      • Pawelzik S.-C.
      • Öhlund Wistbacka U.
      • Artiach G.
      • Hofmann R.
      • Reinholdsson I.
      • et al.
      Stimulating the resolution of inflammation through omega-3 polyunsaturated fatty acids in COVID-19: rationale for the COVID-Omega-F Trial.
      ]. Thus, AA is able to give rise to pro-resolving lipoxins favored by CYP450-derived AA epoxides [
      • Hammock B.D.
      The Overlooked Storm in Coronavirus Disease 2019 (COVID-19)? Eicosanoids.
      ]. Indeed, anti-inflammatory actions of adrenic acid which is another omega-6 PUFA has been recently ascribed [
      • Brouwers H.
      • Jónasdóttir H.S.
      • Kuipers M.E.
      • Kwekkeboom J.C.
      • Auger J.L.
      • Gonzalez-Torres M.
      • et al.
      Anti-Inflammatory and proresolving effects of the Omega-6 polyunsaturated fatty Acid Adrenic Acid.
      ]. A general nutritional state in favor of inflammation is made in the setting of low omega-3 to omega-6 ratio [
      • Arnardottir H.
      • Pawelzik S.-C.
      • Öhlund Wistbacka U.
      • Artiach G.
      • Hofmann R.
      • Reinholdsson I.
      • et al.
      Stimulating the resolution of inflammation through omega-3 polyunsaturated fatty acids in COVID-19: rationale for the COVID-Omega-F Trial.
      ] and ratios of respective lipid mediators such as resolvin to leukotriene ratio [
      • Thul S.
      • Labat C.
      • Temmar M.
      • Benetos A.
      • Bäck M.
      Low salivary resolvin D1 to leukotriene B4 ratio predicts carotid intima media thickness: a novel biomarker of non-resolving vascular inflammation.
      ]. Omega-3 PUFA reduces relative availability of AA for synthesis of pro-inflammatory eicosanoid and formation of leukotriene [
      • Artiach G.
      • Carracedo M.
      • Plunde O.
      • Wheelock C.E.
      • Thul S.
      • Sjövall P.
      • et al.
      Omega-3 polyunsaturated fatty acids decrease aortic valve disease through the Resolvin E1 and ChemR23 axis.
      ] which all results in diminished eicosanoid storm in COVID-19 [
      • Arnardottir H.
      • Pawelzik S.-C.
      • Öhlund Wistbacka U.
      • Artiach G.
      • Hofmann R.
      • Reinholdsson I.
      • et al.
      Stimulating the resolution of inflammation through omega-3 polyunsaturated fatty acids in COVID-19: rationale for the COVID-Omega-F Trial.
      ].

      Probiotics

      Entry point of SARS-CoV-2 is often the respiratory passage, leading to significant acute respiratory illness. Its impacts on gastrointestinal system are well known. Affinity of SARS-CoV-2 to the respiratory and gastrointestinal epithelium is due to the receptor angiotensin-converting enzyme-2 (ACE-2) in lungs alveolar epithelial type II cells and brush border of gut enterocytes [
      • Hoffmann M.
      • Kleine-Weber H.
      • Schroeder S.
      • Krüger N.
      • Herrler T.
      • Erichsen S.
      • et al.
      SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.
      ]. Presence of SARS-CoV-2 viral RNA in fecal samples of COVID-19 cases [
      • Ahlawat S.
      • Sharma K.K.
      Immunological co-ordination between gut and lungs in SARS-CoV-2 infection.
      ] is a clue toward their gut inhabitation. Gut co-infection impairs gut physiology that eliminates ‘‘Good bacteria” to make an imbalance between good and bad bacteria (dysbiosis) [
      • Alansari M.M.
      • Sahlah S.A.
      • AlHumaid L.
      • Singh A.R.
      Probiotic lactobacilli: Can be a remediating supplement for pandemic COVID-19. A review.
      ]. Further complications might shoot up, unless this gut dysbiosis induced by COVID-19 is set by probiotic supplementation [
      • Tiwari S.K.
      • Dicks L.M.
      • Popov I.V.
      • Karaseva A.
      • Ermakov A.M.
      • Suvorov A.
      • et al.
      Probiotics at war against viruses: what is missing from the picture?.
      ]. The entrance of SARSCoV-2 into the gut along with respiratory tract invasion infects gut epithelium which impacts on its integrity and gut microbiome [
      • Jin X.
      • Lian J.-S.
      • Hu J.-H.
      • Gao J.
      • Zheng L.
      • Zhang Y.-M.
      • et al.
      Epidemiological, clinical and virological characteristics of 74 cases of coronavirus-infected disease 2019 (COVID-19) with gastrointestinal symptoms.
      ]. The sentinel cells, dendritic cells, mast cells and macrophages promote first-line defense following viral entry. Viruses bind with sentinel cells’ receptors through specific receptor binding molecules also known as pathogen-associated molecular pattern [PAMPs]. Since PAMPs are virus specific, their receptors in sentinel cells need to be complimentary [
      • Alansari M.M.
      • Sahlah S.A.
      • AlHumaid L.
      • Singh A.R.
      Probiotic lactobacilli: Can be a remediating supplement for pandemic COVID-19. A review.
      ]. Masked PAMPs in the setting of COVID-19 infection leads to escape of viruses from surveillance of sentinel cells. Besides, virus recognizing lymphocytes [B-cells, T-cells and natural killer (NK) cells] which secret antibodies against viruses are diminished sharply and affect immunity [
      • Yang D.
      • Chu H.
      • Hou Y.
      • Chai Y.
      • Shuai H.
      • Lee A.C.-Y.
      • et al.
      Attenuated interferon and proinflammatory response in SARS-CoV-2–infected human dendritic cells is associated with viral antagonism of STAT1 phosphorylation.
      ]. However, probiotics are able to stimulate cytokines and other factors with the capacity to trigger innate and adaptive immunity (Anwar et al., 2020). Macrophages and T helper cells initiate uncontrolled release of cytokines due to SARS-CoV-2 infection. Cytokine storm results in heavy inflammation-associated acute respiratory distress syndrome, which is most often fatal [
      • Taghizadeh-Hesary F.
      • Akbari H.
      The powerful immune system against powerful COVID-19: A hypothesis.
      ]. Probiotic supplementation might be useful due to the ability to induce Th1 and Th2 cells and promote anti-inflammatory actions and subsequently diminishes lungs' viral load [
      • Vlasak R.
      • Luytjes W.
      • Spaan W.
      • Palese P.
      Human and bovine coronaviruses recognize sialic acid-containing receptors similar to those of influenza C viruses.
      ]. Moreover, supplementation with probiotics along with zinc and vitamin D diminishes Th1/Th17 T cells and production of pro-inflammatory cytokines, such as TNFa, IFNc, IL-1, IL-6 and IL-8 induced by Th2 cells and inflammation in ling and gut in the setting of COVID-19 infection [
      • Yeager C.L.
      • Ashmun R.A.
      • Williams R.K.
      • Cardellichio C.B.
      • Shapiro L.H.
      • Look A.T.
      • et al.
      Human aminopeptidase N is a receptor for human coronavirus 229E.
      ]. The gut probiotics consortium is often low among the older and immune-compromised patients and those cases enduring severe impact of COVID-19 disease [
      • Viana S.D.
      • Nunes S.
      • Reis F.
      ACE2 imbalance as a key player for the poor outcomes in COVID-19 patients with age-related comorbidities–Role of gut microbiota dysbiosis.
      ]. Probiotic anti-inflammatory properties could regulate the above mentioned inflammatory reactions through co-supplementation of personalized functional foods with probiotics [
      • Antunes A.E.
      • Vinderola G.
      • Xavier-Santos D.
      • Sivieri K.
      Potential contribution of beneficial microbes to face the COVID-19 pandemic.
      ]. As a therapeutic solution for COVID-19, attention is mainly focused on appliance of effective nutritional therapy. Probiotics are highlighted by several recent reviews as an adjunct alternative among other available therapies for the treatment of this novel coronavirus [
      • Alansari M.M.
      • Sahlah S.A.
      • AlHumaid L.
      • Singh A.R.
      Probiotic lactobacilli: Can be a remediating supplement for pandemic COVID-19. A review.
      ]. Besides, some probiotics weaken viral replication through playing role in purine management that could help in treatment of COVID-19 [
      • Morais A.H.
      • Passos T.S.
      • Maciel B.L.
      • da Silva-Maia J.K.
      Can probiotics and diet promote beneficial immune modulation and purine control in coronavirus infection?.
      ]. Secretion of protein p40 by probiotic L. rhamnosus GG has been proved by several experimental studies, which reduces IFNc, IL-6, TNF, and chemoattractant preventing inflammation in gut epithelium [
      • Yan F.
      • Cao H.
      • Cover T.L.
      • Washington M.K.
      • Shi Y.
      • Liu L.
      • et al.
      Colon-specific delivery of a probiotic-derived soluble protein ameliorates intestinal inflammation in mice through an EGFR-dependent mechanism.
      ]. A cocktail, f L. casei L. reuteri, L. acidophilus, and other probiotics stimulated dendritic cell and down-regulated Th1 cells, Th2 cells and other factors inducing gut and lung inflammation through gut-lung axis link [
      • Yang D.
      • Chu H.
      • Hou Y.
      • Chai Y.
      • Shuai H.
      • Lee A.C.-Y.
      • et al.
      Attenuated interferon and proinflammatory response in SARS-CoV-2–infected human dendritic cells is associated with viral antagonism of STAT1 phosphorylation.
      ]. Since development of COVID-19 vaccines takes time, alternative measures including immunity-boosting nutritional strategies including probiotics and prebiotics seems beneficial. Probiotics regulate gut–lung axis and produce numerous antiviral offensive and defensive mechanisms through innate and adaptive immunity [
      • Tiwari S.K.
      • Dicks L.M.
      • Popov I.V.
      • Karaseva A.
      • Ermakov A.M.
      • Suvorov A.
      • et al.
      Probiotics at war against viruses: what is missing from the picture?.
      ]. A review of gastrointestinal disorders in COVID-19 cases emphasizes requirements for glorify gut using probiotics to resolve gut dysbiosis as a major impact of COVID-19 [
      • Alansari M.M.
      • Sahlah S.A.
      • AlHumaid L.
      • Singh A.R.
      Probiotic lactobacilli: Can be a remediating supplement for pandemic COVID-19. A review.
      ].

      Diet

      Nutrition might play a role in immune defense against COVID-19. Differences in dietary status in European countries could explain partly some of the differences observed in COVID-19 across Europe [
      • Bousquet J.
      • Anto J.M.
      • Iaccarino G.
      • Czarlewski W.
      • Haahtela T.
      • Anto A.
      • et al.
      Is diet partly responsible for differences in COVID-19 death rates between and within countries?.
      ]. Foods containing potent antioxidants are mainly consumed in low-death rate regions including European countries, Taiwan and Korea [
      • Bousquet J.
      • Anto J.M.
      • Iaccarino G.
      • Czarlewski W.
      • Haahtela T.
      • Anto A.
      • et al.
      Is diet partly responsible for differences in COVID-19 death rates between and within countries?.
      ]. Another considered factor could be food availability. Alterations in food availability has particularly changed alimentary habits—promoting sugar-enriched, vitamin deficient foods—and has become one of the reasons leaded to obesity epidemic. These foods came from centralized farms located in selected world's areas are distributed around planet and elongate the supply chain of food. Enhanced rate of insulin resistance and metabolic syndrome are health outcomes of long supply chain of food [
      • Santulli G.
      • Pascale V.
      • Finelli R.
      • Visco V.
      • Giannotti R.
      • Massari A.
      • et al.
      We are what we eat: impact of food from short supply chain on metabolic syndrome.
      ]. Thus, short supply of food is more common in rural areas which have lower death toll and better toleration of COVID-19 pandemic. These considerations could partly explain lower death rates in Southern Italy vs. Northern parts [
      • Bousquet J.
      • Anto J.M.
      • Iaccarino G.
      • Czarlewski W.
      • Haahtela T.
      • Anto A.
      • et al.
      Is diet partly responsible for differences in COVID-19 death rates between and within countries?.
      ].

      Nutrition

      Nutritional intervention for COVID-19 has been recently discussed extensively. Possible therapeutic impacts of certain food properties with the ability to treat COVID-19 have been discussed. Most available data are derived from case studies, observational studies, reviews, systematic reviews, clinical trials, laboratory diagnosis, and general nutritional guidelines [
      • Rahim N.C.A.
      • Singh J.S.M.
      • Pardi M.
      • Zainuddin A.A.
      • Salleh R.
      Analysis of Available Nutrition Recommendations to Combat COVID-19: A Scoping Review.
      ]. Presently, no definite recommendations are available in terms of nutritional therapeutic and medical guidelines to treat COVID-19. The public shared nutrition remedies for prevention or treatment of this virus are without any support from evidence-based studies. Most worldwide dietitian association societies have emphasized on getting healthy eating habits and there are general guidelines for preparation and storage of foods. No specific food has been noted by the American, Canada and Australia Dietetics Association to prevent and cure COVID-19 infection. These guidelines specify good hygiene throughout lockdown and quarantine periods. UNICEF [
      • Rahim N.C.A.
      • Singh J.S.M.
      • Pardi M.
      • Zainuddin A.A.
      • Salleh R.
      Analysis of Available Nutrition Recommendations to Combat COVID-19: A Scoping Review.
      ] and WHO [
      • Zakay-Rones Z.
      • Varsano N.
      • Zlotnik M.
      • Manor O.
      • Regev L.
      • Schlesinger M.
      • et al.
      Inhibition of several strains of influenza virus in vitro and reduction of symptoms by an elderberry extract (Sambucus nigra L.) during an outbreak of influenza B Panama.
      ] encourage healthy eating guidelines throughout lockdown and quarantine period of COVID-19. The Food and Drug Association (FDA) has also noticed that COVID-19 is not foodborne. For critically ill patients, ESPEN and ASPEN provided nutrition recommendations derived from convincing evidence-based guidelines [
      • Rahim N.C.A.
      • Singh J.S.M.
      • Pardi M.
      • Zainuddin A.A.
      • Salleh R.
      Analysis of Available Nutrition Recommendations to Combat COVID-19: A Scoping Review.
      ]. Medical nutrition therapy focuses mainly on the malnutrition pre- and post- COVID-19 diagnosis. Thus, being aware of personal nutritional habits and following balanced and healthy dietary habits containing high amounts of vitamins, antioxidants and minerals is essential during this period. Several investigations showed the boosting of immune functions using micronutrients with antioxidant properties derived from vegetables and fruits such as beta-carotene, vitamin C and vitamin E. This pandemic has emphasized on getting healthy life and good nutrition and a healthy life as the key element for strengthening immunity [
      • Rahim N.C.A.
      • Singh J.S.M.
      • Pardi M.
      • Zainuddin A.A.
      • Salleh R.
      Analysis of Available Nutrition Recommendations to Combat COVID-19: A Scoping Review.
      ]. Although consumption of a well-balanced diet could ensure normal functioning of immune system, no specific food, nutrient or supplement will ‘boost’ it beyond its average level. Thus, prevention and minimization of symptoms during severe illness phases is more effective than its treatments [
      • Rahim N.C.A.
      • Singh J.S.M.
      • Pardi M.
      • Zainuddin A.A.
      • Salleh R.
      Analysis of Available Nutrition Recommendations to Combat COVID-19: A Scoping Review.
      ].

      Impact of nutrition on the susceptibility of COVID-19 and its long-term consequences

      Sufficient intake of vitamins is an essential factor COVID-19 patients. Vitamins have diverse properties including immune-modulatory, anti-microbial, antioxidant and anti-inflammatory properties which could be useful for the prevention of diseases and infections (mainly viral infections). Although their anti-inflammatory and immunomodulatory properties are noticeable, some unique antiviral mechanisms [
      • Toledano J.M.
      • Moreno-Fernandez J.
      • Puche-Juarez M.
      • Ochoa J.J.
      • Diaz-Castro J.
      Implications of Vitamins in COVID-19 Prevention and Treatment through Immunomodulatory and Anti-Oxidative Mechanisms.
      ]. Vitamin D is supposed to develop (IFN)-based therapy and CD8+ T cells’ responses against viral infections [
      • Xu Y.
      • Baylink D.J.
      • Chen C.-S.
      • Reeves M.E.
      • Xiao J.
      • Lacy C.
      • et al.
      The importance of vitamin d metabolism as a potential prophylactic, immunoregulatory and neuroprotective treatment for COVID-19.
      ]. The vitamin is leading to the synthesis of antimicrobial peptides, induction of autophagy, blockage of viral entrance, suppression of Toll-like receptors and induction of virus specific CD8+ T cells. Sufficient vitamin D level results in under expression of dipeptidyl peptidase 4 (DPP-4 or CD26) which interacts with the S1 domain of spike glycoprotein taking part in adhesion of SARS-CoV-2 to epithelial cells [
      • Toledano J.M.
      • Moreno-Fernandez J.
      • Puche-Juarez M.
      • Ochoa J.J.
      • Diaz-Castro J.
      Implications of Vitamins in COVID-19 Prevention and Treatment through Immunomodulatory and Anti-Oxidative Mechanisms.
      ]. Another important fact is inhibitory role of SARS-CoV-2 by its prominent binding to spike protein. B9 and B12 directly prevent pathogenicity of SARS-CoV-2 by binding to non-structural protein 3 (NSP3) and furin, respectively. Furin-mediated cleavage of viral spike is essential for its entry into the host cell. Viral NSP3 encodes; NTPase, N-terminal proteinase (in charge of polyprotein cleavage), and C-terminal helicase [
      • Pandya M.
      • Shah S.
      • Dhanalakshmi M.
      • Juneja T.
      • Patel A.
      • Gadnayak A.
      • et al.
      Unravelling Vitamin B12 as a potential inhibitor against SARS-CoV-2: A computational approach.
      ,
      • Chackalamannil S.
      • Rotella D.
      • Ward S.
      Comprehensive medicinal chemistry III.
      ]. Antiviral activity of E, C, and A vitamins have been proved against respiratory viruses, passing through immunomodulatory mechanisms [
      • Toledano J.M.
      • Moreno-Fernandez J.
      • Puche-Juarez M.
      • Ochoa J.J.
      • Diaz-Castro J.
      Implications of Vitamins in COVID-19 Prevention and Treatment through Immunomodulatory and Anti-Oxidative Mechanisms.
      ].
      Trace elements are another noteworthy nutritional factor with antiviral properties. The major function responsible for this property is their immunomodulatory properties. Some trace elements exert a fundamental role in induction of long-term consequences SARS-CoV-2 infection [
      • Srivastava A.
      • Gupta R.C.
      • Doss R.B.
      • Lall R.
      Trace minerals, vitamins and nutraceuticals in prevention and treatment of COVID-19.
      ]. Survivors of SARS-CoV-2 might develop lung fibrosis. Release of TGF-β is reduced by Mg supplementation which consequently result in collagen deposition and the development of lung fibrosis [
      • Wang Y.
      • Dong C.
      • Hu Y.
      • Li C.
      • Ren Q.
      • Zhang X.
      • et al.
      Temporal changes of CT findings in 90 patients with COVID-19 pneumonia: a longitudinal study.
      ]. Several lines of evidence suggest significant suppression of systemic inflammatory responses against SARS-CoV-2 infection using selenium supplementation which could diminish the risk of formation of blood clot in covid-19 cases [
      • Kieliszek M.
      • Lipinski B.
      Selenium supplementation in the prevention of coronavirus infections (COVID-19).
      ]. Zn is another trace element which prohibit SARS-CoV-2 through reduction of viral entry following prevention of virus into the host cell membrane. In other word, RNA dependent RNA polymerase (RdRp) is inhibited by Zn [
      • Srivastava A.
      • Gupta R.C.
      • Doss R.B.
      • Lall R.
      Trace minerals, vitamins and nutraceuticals in prevention and treatment of COVID-19.
      ].
      Fatty acids exert potent immunomodulatory that could be beneficial for covid-19 infection. Omega-3 fatty acid, a natural product, is recognized by their anti-inflammatory effects. Sufficient levels of omega-3 reduction of CRP as well as inflammatory markers. Anti-inflammatory effects related to omega-3 are able to prevent pro-inflammatory cytokine storm of covid-19 [
      • Taha A.M.
      • Shaarawy A.S.
      • Omar M.M.
      • Abouelmagd K.
      • Shalma N.M.
      • Alhashemi M.
      • et al.
      Effect of Omega-3 fatty acids supplementation on serum level of C-reactive protein in patients with COVID-19: a systematic review and meta-analysis of randomized controlled trials.
      ]. Omega-3 and -6 polyunsaturated fatty acids are supposed to not only mount immune responses but also prohibit the development of inhibition and subsequent tissue damage [
      • Sun Y.
      • Chatterjee R.
      • Ronanki A.
      • Ye K.
      Circulating polyunsaturated fatty acids and COVID-19: a prospective cohort study and Mendelian randomization analysis.
      ].
      Coenzyme Q10 (CoQ10) represents anti-platelet and antioxidant properties which makes it a potential candidate for the treatment of covid-19. Wang et al. observed enhanced in vitro ROS level and platelet aggregation by SARS-CoV-2 spike proteins. CoQ10 was able to reduce ROS level and aggregation of platelets induced by viral spike protein [
      • Wang R.
      • Chen Y.
      • Tian Z.
      • Zhu M.
      • Zhang B.
      • Du S.
      • et al.
      Coenzyme Q10 Attenuates Human Platelet Aggregation Induced by SARS-CoV-2 Spike Protein via Reducing Oxidative Stress In Vitro.
      ]. TNF-α, CRP, IL-6, and other inflammatory cytokines are modulated by this potent anti-inflammatory compound. It is also able to pass through Brain Blood Barrier (BBB) and might attenuate BBB damage and CNS inflammation. Indeed, long-term consequences of covid-19 infection could be prevented using Coenzyme Q10 supplementation [
      • Fakhrolmobasheri M.
      • Hosseini M.-S.
      • Shahrokh S.-G.
      • Mohammadi Z.
      • Kahlani M.-J.
      • Majidi S.-E.
      • et al.
      Coenzyme Q10 and its therapeutic potencies against COVID-19 and other similar infections: A molecular review.
      ]. Diverse natural and nutritional compounds could mount host immune responses and prevent COVID-19 infection in different steps. They are also able to prevent the development of comorbidities and deleterious consequences induced by COVID-19.
      Different natural and nutritional compounds may prevent covid-19 through two ways. First, they can demonstrate antiviral activity with mounting host immune response and inhibition of covid-19 in various steps (entrance, replication, and etc.). They also may prevent the COVID19-induced morbidities with a protective activity against the deleterious consequences of the disease.

      Limitations

      It was obligatory to limit the scope of our study to the most important nutritional elements. Indeed, this is incomplete, and the role of gut microbiota is another relevant area of interest. Shortage of sufficient cohort studies is another important issue. Estimated attributable risks could potentially change during time with the prevailing SARS-CoV-2 infection rate. Besides, it was not possible for us to thoroughly cover all factors with the ability to impact the relationship between nutritional state and disease progression. Interpretation of eligible literature is obligatory limited to the context of the original studies. In addition, a wide range of factors preclude extrapolation to the wider population. Thus, factors such as genetic polymorphisms, their frequency and their impact in different populations, age, gender, environment, access to health care, hemoglobinopathies, and other underlying political and economic factors which determine nutritional vulnerability should be considered. The last but not least, most chosen studies were at a high risk for bias due to the selection of hospital-based samples in their conducted studies and taking data related to patients records from secondary recordings. Presence of confounding factors such as gender, age and underlying comorbidities which were not applied in most of the studies, is also of great importance. These factors are determinant of the severity of COVID-19.

      Conclusion

      This article provides comprehensive focal point of evidence on nutritional recommendations to defeat COVID-19. We highlighted fundamental facts in this field from our perspectives in this scoping review. There is considerable information regarding food and nutrition reducing risk of COVID-19 which also helps patient recovery. Moreover, evidence derived from most of these recommendations should be evaluated in detail. Indeed, health care professionals should be cautious when advising this information to the public. It is highly unlikely that an individual nutrient or food had immune boosting capability or being able to prevent COVID-19 infection. The best strategy during COVID-19 era, is healthy eating habits based on the principles of moderation, balance and variety.

      Conflict of interest

      The authors had no conflicts of interest.

      Funding

      No funding was received.

      Authors' contributions

      Amir Hossein Mohammadi, Masoumeh Karami, Ali Sobhani-Nasab, Hamed Amini Rourani, Ebrahim Hazrati, and Alireza Milajerdi designed the study. Amir Hossein Mohammadi, Afrouzossadat Hosseini Abari Sayid Mahdi Mirghazanfari, Vahid Hadi, and Saeid Hadi collected data. Amir Hossein Mohammadi, and Mohaddeseh Behjati, wrote the manuscript. All authors read and approved the final manuscript.

      Consent for publication

      Not applicable.

      Availability of data and materials

      Not applicable.

      Statement of ethics

      Not applicable.

      Acknowledgements

      We thank everyone who consulted in the article.

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