REVIEW ABOUT THERAPEUTIC AND PROPHYLACTIC EFFECTS OF VITAMIN (D AND E) ON SOME RESPIRATORY VIRAL INFECTIONS, AND COVID 19

associated in other inducing immune storm which increase generation of reactive-oxygen species(ROS) that causes damage in small vessels cellular membranes extensively at viral infections durance.Vitamin E considered as one amongmany antioxidants examinedin mice in infections of influenza virus, with a leader position for its ability in blocking oxidative damage by its scavenging activity of free-radical. and some respiratory viruses, like covid 19.Retinoic acid has important role in cell differentiation and growth,where vitamin A partially can regulate viral growth. Retinoidsinfluence many of virus infections in different complex ways i.e., ifvariouslines of cellshave an infectionby the human cytomegalic-virus(hCMV), cells exposure to retinoic acid (RA) encouragesexpression of viral nucleic acid with vulnerability to infection .

Oxidative stress associated with almost all viral infections; in other words, inducing immune storm which increase generation of reactiveoxygen species(ROS) that causes damage in small vessels cellular membranes extensively at viral infections durance.Vitamin E considered as one amongmany antioxidants examinedin mice in infections of influenza virus, with a leader position for its ability in blocking oxidative damage by its scavenging activity of free-radical. The phenomenon of Vitamin D multi-directional activity is probablybecause of the existence of theVit. Dreceptors (VDR)sin most human cells of non-skeletal.Also, vit. D able tochange the immunity (acquired and innate) , therefore able to be utilized as preventive, therapeutic adjuvant vaccine, for many viral infections difficultly to treat like influenza virus, and course modulating therapy for oral herpes virus, Epstein bar virus, hepatitis B virus, and some respiratory viruses, like covid 19.Retinoic acid has important role in cell differentiation and growth,where vitamin A partially can regulate viral growth. Retinoidsinfluence many of virus infections in different complex ways i.e., ifvariouslines of cellshave an infectionby the human cytomegalic-virus(hCMV), cells exposure to retinoic acid (RA) encouragesexpression of viral nucleic acid with vulnerability to infection .

Serum Concentrations Guidance:
Vit. D status of the bodydepends on the serum 25(OH)D levels, sinceit's relatively to DBP hashigh affinity and of 25 days as the half-life . Assessment of 1α,25(OH) 2 D in the bodyto define level of vitamin D is not advisable, as its serum half-life is only a some hours (ca. 7 h) [10,13]. 25(OH)D serum concentration, that indicates vit.Davailable in sufficient level for organism, is (ca. 75-200 nM/L) or 30-80 ng/mL.A strong deficiency of vit. D is whenconcentrations are less than10 ng/mL [13,20,21,22,23,24].

Vit. D anti-infectionagent:
Functions of Vit. D forsystem of immunityisnot easy to identifysince the immunity response is not constant and relies on stage of infection.
VDR detected in cells of immunitypropose that vit. D is one of the organizers of immune system.Activated B and T cells in vitroas wellas the cells of epitheliumthat line the lower and upper tract of respirationable of transforming25(OH)D (inactive metabolite) into 1α,25(OH) 2 D(which is metabolically active). Thelatter metabolite affects cells of immunity inparacrine way or an autocrine,intracrine(for example,via insidepathways of cells) [25][26][27].
Vit. D probable role in diseases of infectionsis illustratedthrough its effect on the adaptive and innate immunity (  [5].

Innate Immunity and Vit. D: Pathogen Recognizing Receptors (PRR)s:
Generally, innate immune response or nonspecific, was proved to be the first defense line against agents of infection and initiates presentation of antigen [28,29].
Production ofCYP27B1 byTLR ligation is probably occurs if alternate PRRs or TLRs encourageenzyme (extrarenal) activation, permitting calcitriol to causeeffects more extensively on the immunity response [7]. In case of infection by virus, pathogen-associated molecular patterns(PAMPs) mightidentified by different PRRs, e.g. nucleotide binding-oligomerizationreceptors domain (NOD)-like ligand (NLRs) and retinoic-acid-inducible receptors of gene-I (RIG-I)-like ligand. In epithelial cells and myeloid, 1α, 25(OH) 2 D encouraged the receptor of NOD2through2 VDREs in NOD2gene. Products of lysosomal breakdown (peptidoglycan of bacteria), if associated with calcitriol, it would induce NOD2 to enhance signaling of AMP and expression of beta defensin 2 [7,30]. Interleukins (IL) IL-1β, TNFα and -6, and -12 and other inflammatory cytokines are yielded at an innate immune response early phase. Among others, cytokines encourageproteins of acute phase synthesis and contribute to the cells activation and recruitment of the response of adaptive immunity. Signaling of PRR also contribute to the chemokine ligands (CXCLs) production of e.g. IL-15 and CXCL8-CXCL10 thatstimulate production ofnatural killer cells (NK) and neutrophils which have role, particularly in immunity (innate) versusbacteria [7].
Pathogens destruction is aresponse ofmany of antibacterial innate immunityvia autophagy [27]. Chun et al. [30], suggestedsuch process which is significant for the antimicrobial response that triggered by vit. D against infection ofMycobacterium tuberculum .
AMPs released by TLRhave wide-spectrumantiviral and microbial effect, and proved to inactivate viral influenza [25]. The AMPs antiviral effect is resulting fromenvelope proteins destruction performed via cathelicidins. As for antibacterial impacts, AMPs, cause disruption of microbialmembrane. Cathelicidin 37-residue in humans, as active antimicrobial along withLL-37helical peptide, amphipathic, is cleaved from the pro-peptide , human cathelicidin (hCAP18). The cathelicidin majority is kept in vesicles of neutrophil as well as other kinds of immunity cells, as B lymphocytes and NK and monocytes that are able to express hCAP18 [3]. In vitro, 1α, 25(OH) 2 D and vitamin D active metabolite stimulatecathelicidins production in human macrophages throughelevated VDR expression [26]. Sundaram and Coleman [26], mentioned that VDRE up-regulation via TLRs causecathelicidin transcription that destroys intracellular Mycobacterium tuberculosis. Szymczak and Pawliczak [27], revealed that hCAP18 has activity against viruses and bacteria. In case of infection by virus, the cells of lung epithelium are able to convertecalcidiol into the calcitriol as active metabolite, causing an increase inproduction of hCAP18. Beard et al. [3] showed thatexpression of cathelicidin in keratinocytes and macrophages is encouraged by CYP27B1, and when there is no VDR, CYP27B1, or 25(OH)D, the capacity of cells to yieldcathelicidins is highly disrupted. Report of Pawliczak and Szymczak [27]showed that not only signaling of TLR is contributing, yet cytokines also do so, e.g. IL-4 and IFNγ might affect CYP27B1production. IFNγexistence encouragesCYP27B1 of macrophage. 1α,25(OH) 2 D has role in the down feedback strategy which inhibits TLRs hyper-activation [27].

Anti-Microbe -Proteins or Peptides (AMP)s:
AMPs are organized byVitamin D, e.g. defensins. 1α,25(OH) 2 D stimulates modestly human beta defensin 2 and the effect of the latter as antiviral comes from its ability as chemo-attractive for monocytes and neutrophils [3,26]. Nevertheless, concentration of 25(OH)D serum was not associated with AMPs serum levels in pneumonia of community-acquired origin [26].

Adaptive Immunity and Vitamin D: T-Lymphocytes:
Response of adaptive basis is: presentation of antigen to cells of T and B type, where antigen-stimulated production of antibodies, cytokines, chemokines, hormones, and enzymes of a wide spectrum will occur. The existence of VDR in the activated lymphocytes was first to be noticed to correlatevit. D role with system of immunity [30]. Subgroups of T cells are few kinds of cells:cells of CD8 + T showvitamin D-activating 1α-hydroxylase and VDR at high levels relatively; cells of CD4 + T; cells of memory; and cells of NK. Activated cells of CD8 + T able todifferentiate to cytotoxic (CTLs), importantagainst cancer and intracellular pathogens. Activated cells of CD4 + T able to differentiate to cells of Th cells, cellsof regulatory (T-reg) (cells of suppressor)type, Th17, and γδT cells, Th2, Th1, and Th9cells thatyieldvariouscytokines profiles. Thus interferon γ, IL-2, and TNFα produced from Th1 cells, whileIL-3, -4, -5, -10, and -13 secreted from Th2. cytokines induced-CD+4 T cells give enforcement to other cells of immunity, e.g. CTLs, and to the response of antibody in circulation, by CD40:CD40 bond of antigenspecific B cells co-stimulatory sites [6,26,27,28,30,32]. Th cells role involve: immunoglobulin production enhancement, activation of macrophage, and mastocytes(Th2) and eosinophilsgeneration [28]. Response of stimulated Th1-is the main factor for variousviral and bacterial infections whereaswhen thisprocess becomes not controlled, it causes autoimmunity [29].
Regardingvit. D role in response of immunity, itbehaves likeTh cell generation modulator and changingproduction of cytokine type , as well asbyT-reg cells promotion, that are related to anti-inflammatory reply , immune suppression, and for limitation processes of inflammation [29]. One report concentrated on25(OH)D ability for stimulatingT-regcells viathe cells for antigen presentation (dendritic cell (DC))induction to synthesizeCYP27B1 and VDR [33]. Jeffrey et al. [33] reported the vitamin D significant form forcells T-reggeneration was non-25(OH)D DBP-bound. Areport by Bruce et al. [29] showed that 1α,25(OH) 2 D able to regulate cells of invariant NK T (iNKT), that are able tobehaveasorganizer cells and associate in the relation between adaptive immunity and innate. Induction of iNKThadproven protection against autoimmunitydiseases. A report of Sigmundsdottir et al. [34] mention that chemokine expression of receptor 10 (CCR10) by1α,25(OH) 2 D-on cells of T-lymphocyte eases associationwithcells of competent immunity, e.g.detecting keratinocytes CCL27 . In vitro,1α,25(OH) 2 D,blocks Th1 cytokines expression and stimulates cytokines of Th2. Cells of Thsubgroups;forexample,cellsof Th17, secrete IL-17, have important role in autoimmunity [6,30].
Inverse relationships between activity of disease and concentrations of vitamin D in patients with T1DM, disease of inflammatory bowel, autoimmune thyroiditis, arthritis (rheumatoid), or multiple sclerosis had been noticed [35].
According tostudies of animals, it was proposed that Th2 cells progression might have exacerbating effects on diseases of allergye.g.dermatitis, asthma atopiabyinflammatory processes induction [6]. The increased Th2 cytokines production (IL-4, -5, -13)noticed in the atopic dermatitis acute period, leads to cathelicidin suppression and infection vulnerabilityincrement. In the disease chronic phase, Th1 cells were ofpredominance [6].
T cell responses regulation is viaDC existence and vitamin D inactive metabolite such as 25(OH)D. Jeffery et al. [33], described upon maturation,CYP27B1 is produced by DC if come in contact with LPS or T cell resulting in the 1α,25(OH) 2 D release and synthesis that affects responses of T cell.

B-Lymphocyte s:
1α,25(OH) 2 D considered to be generation inhibitor and actsin vitro as anagent of pro-apoptosis in B cells (activated). Despite it does not generate thesecells;yet it act as differentiation inhibiter [26]. Fang et al. stated that in mice having virus of influenza (primary infection),and inducing immune protection, meaning a significantdependance on existence oflymphocytes B [40].

Vitamin D Anti-Inflammatory Action:
Vitamin D behaves byfeedback loop promotion to blockinflammatory events and antibacterial processes over activity through TLR4 and TLR2 down regulation in monocytes [26,30]. 1α,25(OH) 2 D was stated to reduceproinflammatory chemokine production in cells of epithelium of human respiratory system and down regulate cytokines such asTNFα, IL-6, and IL-8, in vitro within various cells [26].In respect tolymphocytes of human, vitamin D anti-inflammatory effect occurs through inhibition of NFκB. This factor of transcription regulates genes expression encoding for proteins of immunity yieldedin infection, e.g.proteins of acute phase, chemokines, and cytokines or enzymes of inducible effectors [6,26].
Proliferation of T-cell considered as Vitamin D-modulated wherethe mechanisms partially lead to responses of antiinflammatory throughelevation ofT cells subgroup proliferation, CD8α. Cells of T type, unlike cells of CD8 + T, considered of no cytotoxicity, rathermighthave a role in gastro-inflammation suppressing [30].

Time-Dependencey of Vitamin D Immuno-modulatory Effects:
Vitamin D immune-modulatory effects areassociated to infection (late or early periods). The association levels in circulationfor 25(OH)D and α 1 -antichymotrypsin , in tuberculosis, protein of an acute-phase was illness-correlated, and not with the response of early acute-phase of infection [46]. Also, 1α,25(OH) 2 D interacted differently with various mechanisms stated to account on time in human cells leukemia.Report ofTse et al. [47] stated dependency of time forNFκB in HL-60 cells biphasic regulation. After HL-60 cells exposure to 1α,25(OH) 2 D, suppression in first 4h ca. with a late(8-72h)prolonged -NFκBtranscription factor reactivation.With this stimulation, there weregenes of anti-apoptotic and inflammatory up-regulation e.g.IL-1β, Bcl-xLand TNFα [47]. This effect has indirect impact on the regulation of immunityillustratedvia vitamin D since the processes of inflammation are related highly to the cells immune response to pathogens. Sundaram and Coleman [26],proposed that in vivo study, the response of immunityin mice to allergens suggested that supplementation of (1α,25(OH) 2 D by injection of 100 ng) appliedfollowingprimary sensitization period blockedlocal inflammatory response and eosinophils at high levels in lung tissues and bronchoalveolar lavage fluid. But this effect couldn'tbe seeninevery day-supplementation throughout that study.

RetinoidsRole in Influenza Symptoms and Pathogenesis:
Influenza A epidemiologic observations and seasonality are due to wide population-impairing immunity ofinnate typeattributed to a reductionin sunlight exposure atwinter months and a consequent vitamin D deficiency [48][49][50]. Theory of Cannell proposed that epidemics of influenza are consequent of disease dormancy which is activatedresponding to deficiency of vit. D.

VitaminsD and A have intermingling roles in influenza and retinoids have indirect role in pathogenesis of influenza infection. For example, radiation of sun has differentimpact on vit.D and A;
i.e. reduces Vit. A,yetelevates vit. D.Vitamin A and D can inhibit one the other. Retinoids can regulate growth ofepithelial cell of airways, gene expression, andprogression.Influenzasymptoms are identical to toxicity of retinoid. pharmacological and/or supplementary levels induce symptoms of influenza-like.They also partially organize the activity of virus. Theyaffect block or stimulation ofpathogenesis of influenza.
Sunlight reduction, and/or deficiency of vit. D elevatessimultaneously accumulation, expression, and endogenous retinoidstoxicity potentials (such asreductionin the vit. D-to-vit. A ratio), thatagitate activation of virus or elevatesusceptibility of host to influenza virus (novel strains). Moreover, during normal retinoid physiological concentrations seem to functionalong wiothvitamin D to blockpathogenesis of influenza, higher concentrations with (very low vit.D: A ratios) make it wors and mightencouragefatal disease or severe complications. Influenza infections outcome mightpartially relies onbalance ofthe ratio amongvitamins concentrations.Vit.A and Vit. D roles in influenza may extend to genetic variability in their metabolism and their levels [51].

Retinoids:
Retinoid as synthetic and natural congeners,are basicallysignaling molecules of fat-soluble dietary-derived principally liver stored and are necessary for development of embryo, normal homeostasis of cell, differentiation of tissue,secretion of mucus, and growth [52,53]. Vitamin A active form (Retinoic acid) in most systems' cellulardifferentiationconnected to and activates receptors(retinoid X receptors (RXRs)), (retinoic acid receptors (RARs); that regulate many target genestranscription [54][55][56].
RXRs and RARs are lipophilic thyroid / steroid super-family members of factors of ligand-dependent nuclear transcription agentswhich composed ofretinoids, steroids, vitamin D 3 and thyroid hormones. Since they are able todiffuse readily from the source and permeatingthe target, hormones of lipophilic property are of organization potentials for development, cell differentiation, and organ functions [68,69]. The RXRs and RARs present in3products of identifiable gene-β, γ, and α. Atactivation of ligand, the function of receptors as factors of heterodimeric transcription and control the target genes expression viaconnecting to specific sequences of DNA, termed of RA -elements respond (RAREs) [57,58].
Free retinol yield retinoic acid viaretinyl esters hydrolysis,liver stored, and retinol release into circulation and transport to tissues of the target, then bound toretinol-binding peptide (RBP). First, through an alcohol dehydrogenase, to retinaldehyderetinol is oxidized and then synthesis of primarily RA from retinaldehyde within the cell microsomes by the dehydrogenase of retinaldehyde occurs. A level of retinol in circulation stays fixed because of a carefull transport system of regulation and ensures target tissues to receive retinol essentialquantity in spite oflarge fluctuations in intake of diet [59]. Many factors of transcription action are influenced by retinoic acid e.g. AP-1 activation repressing viablocking the c-fos and c-Jun induction [60]. Other nuclear receptors are regulated e.g. receptor of vitamin D, peroxisome proliferation-activereceptors (PPARs), receptor X of farnesoid, and receptor X of liver that hetero-dimerizesalong RXR and regulates the transcription factors activation e.g.STAT-1, NF-κB, and AP-1 [56]. RA shows negative effects on growth of cell byRARs alternative activation versus PPARβδ [61].
Retinoic acids at low concentrations arenecessaryfactors of growth for specifickinds of cells, whereasconcentrations of higher level blockgrowth of cell and are teratogenic, cytotoxic, and mutagenic. Toxicity of exogenous vit. A may take placebecause of excessive consumption of diet or from retinoidstreatments. Even though toxicity of vit. A from pro-vitamin A,but carotenoid of plant as sources has never mentioned.Storage in liver, absorption from fortified foods, supplements, and animal foods inretinyl esters form may causehypervitaminosis A. Retinoid intoxication endogenouslymightnaturally take place at cholestasis, ifmetabolites of vit. A are refluxingto bloodfrom liver [62].
Throughout life, retinoic acid is needed for lung alveoli maintenance and a deficiency resulting inalveoli loss and to emphysema features. Alveolar regeneration is induced by exogenous retinoic acid has been stated in emphysema experiment of rat model.Alveologenesis disruption occurs by action of (disulfiram), a retinoic acid synthesis inhibitor. [63].
Circulating retinol= (1-3 μmol/L as normal) doesn'tgive an idea about liverconcentrations forvit. A , because the RBP secreted is controlledhomeostaticly. Hence,concentrations of retinol in plasmadiffer a bitin spite of major intake alterations in vit. A. Hypervitaminosis A may be seeneven if serum retinol within limits of normality, mentioning that plasma retinol at toxicity conditionsis not anaccurateevaluation of status of vit.A [64,65].
Vit. A is one of the antioxidant vitamins and its supplements are available as measures for protecting human from disease widely. A review in Cochrane,mentioned the antioxidant effectson mortality (including vit. A), according totrials of randomization, Bjelakovicet al. [66] also went over all trials of randomization where adults consuming singly or combined Se, beta-carotene, and vit. A, C, E.Sixty eight trials randomlystudied with 232,606 cases. When antioxidant trials of supplements were analyzed, no significant effectsfor mortality were noticed (RR: 1.02; 95% CI: 0.98-1.06). Nevertheless, analyzingmulti-variate regression illustrated that, in -low bias‖ trials as better designed, βcarotene was correlated of significant risk 7% increasing, vit. A 16% risk increasing, and vit. E 4% mortality risk increasing.Vit. C and Se are of no significant effect. Reaserchers arrived to a conclusion that vit. A, vitamin E, and β-carotene treatments mightelevate mortality.
Below are a summary for many evidence lines supporting the model proposed: 1. Vit. A is ofphoto-oxidation sensitivity. Generally, activity of virus is ofretinoidsregulation.
Retinoidshave an influence to mechanisms and elements which both contribute and blockpathogenesis of influenza. [66]

Influenza virus infection and Vitamin E:
Oxidative stress in organism infected with virus of influenza producesaturated lipid chains oxidation of cytoplasmic membrane (lipid peroxidation), thatminimizes membranes permeability. Atdeficiency of antioxidant,ifmembranes damaged and/or exposed, influenza infection proceeds atstrong pathology and lead tobody serious damage at all levels.
Throughoutinfection of influenza in mice, antioxidant enzymes activity catalase and SOD were modified, besides a reductionon the endogenous antioxidants quantity of low-molecular-weight e.g. ascorbate, α-tocopherol (Table 1) and glutathione. Vit. E endogenic levels were decreased significantly in lung, blood plasma and liver. Moreover,cytochromes modifications were noticed alonga reduction in activities of hepaticcytochrome P-450dependent mono-oxygenases. Along with the abovementioned, in the disease course, the organism's antioxidant protection buffering capacity is diminished [67]. The aboveinformationshows that, during influenza infection virus, a reduction in antioxidant of natural vit. E was observed along with anelevation ofproducts of endogenous lipid peroxidation significantly.
In humans factor of nuclear (erythroid-derived 2)-like 2 (NRF2) encoded viagene NSF2, is regulating protein forantioxidant proteins expression whichhave a role against triggered oxidative damage throughinflammation and injury. NRF2 can control the induced and basal response of antioxidant element-dependent expression of genes for regulatingpatho-physiological and physiological outcomes of exposure to oxidant. NRF2 is ofa significant impact on toxicity and oxidative stress, organizingthe defense byantioxidant [67].
NRF2 can controlpathway of antioxidant andconsidered as pivotal for lungs protection against influenza virus development, injury and inflammation of infection-induced pulmonary under oxidative stress conditions. The antioxidant system of NRF2-mediated is necessary to save the lungs from oxidative storm and injury induced viaviralinfluenza. [67].
Since there is animportantoxidative stress role in viralinfluenza pathogenesis, enormous work had employed to examine the antioxidants influence on influenza course. Pathway of NRF2 stimulated by drugs isexamined for diseases treatment of oxidative stress andinfective influenza virus. In vivo models experiments, in mice predominantly, have animportant place in such studies.
α-tocopherol (vitamin E) is an antioxidants examined against infections of influenza virus in mice,it is alsoof leading position since its impact in blocking damage of oxidation via its scavenging activity of ROS [67].
NRF2 protein expression is noticed to beelevated in vit. E-supplemented rabbits and cholesterol-fed byNRF2activation pathway, leading to induction of manygenes of antioxidant. Vit.Eseemed to stimulate the NRF2protection effect. Furthermore, it was observed that vit. E blocks suppression of NRF2 via allergens in macrophages of alveoli, showed in vivo for asthmatic cases [67].
Clearly the above informationproves the antioxidants role e.g.vit. E, thatable to be shown in differentmethods: 1. Capturing free radicals in multiplemechanism(s) (non-enzymatic or enzymatic).

ROS Generation suppression.
3. Indirectly affecting the above processes i.e. by viral replication inhibition.
Sincevit. E is a substance soluble inlipid withhydrophobic terminus; it accumulation within the membranes interior lipid where it behaves as the mainsignificantseries-breaker, as it reacts with lipid radicals (peroxyl)almost4 times faster compared to theirreaction with adjacent side chains of fatty acids. It is famous that vit. E canblock oxidative damage, since its lipophilic property contributes to easy diffusion passively via the membranes of cell, permittingreticulum ( single-plated) and mitochondrial arrival.Vit. E saves them against damage and lipid peroxidation ( Figure 3). Particularlysignificant is its chain -freeradicals reaction termination thatsaves fatty (multiunsaturated) acids of the membrane against oxidation ROS [67]. Vit. E action is steered to the core of tempest. [67].
Vit. E affect immuneresponses in various tissues e.g. respiratory system, throughoxidative stress quenching directly, andbyeicosanoid oxidative modulation pathways and synthesis of prostaglandin , inflammatory mediators inhibition, and apoptotic signaling control of lipid. Vit. E stabilizes phospholipids of membranes [67] (Figure 3).
Manyfunctions (non-antioxidant) of vit.E might be necessary for the cell integrity functions and maintenance, e.g. its anti-phospholipase A2 agent function as lipid bi-layer stabilizer of membranes against oxidized and hydrolyzed lipids [67].
The receptor binding ishost expressed cells which considered as firstinfection step of viral thenfusion followed with the membrane of cell. It is reasoned that the cells of lung epithelia are the viralprimary target. Thus, it has been reported that SARS-CoVhuman-to-human transmissions occurs by the binding between the receptor-binding domain of virus spikes and the cellular receptor which has been identified as receptor of angiotensin-converting enzyme 2 (ACE2) [73,74]. Importantly, sequence of the receptor-binding domain of COVID-19 spikes is identicalto SARS-CoV. This data effectively suggests that entry into the host cells is most likely via the ACE2 receptor [73].

Conclusion:-
Because of the above mentioned great and vast effects of vitamin D on immune system in many diseases , and vitamin E effects on immune system specially on respiratory system during infections, it is better to boost immunity of patients with those 2 vitamins, and ameliorate the over stimulation of inflammatory response with its dramatic derangement on patient's life and health.
As the Globe nowadays is passing through the most vicious pandemic of covid 19, causing paralysis of economy worldwide, taking lives of thousands of humans, spreading horror within nations, burdens financial efforts to overcome this tragedy; so it's recommended to 1. give a high single bolus dose of vitamin D (600 000 IU), (this because vitamin D act as hormone in the body and its receptors number would decline if exposed to this hormone for long period( if given as daily maintenance therapy), so it's better to give it as high single bolus dose, every few months to allow for its receptor to get up-regulated), and give maintenance dose of vitamin E and C, with trace amount of Iron and Zinc (because of being the metallic portion of many cytochromes), and used as usual regimen in all health centers worldwide to be given for all populations at the beginning of each cold seasons, as a preventive measure. 2. As for therapeutic measures for covid 19, give high single dose of Vitamin D3 (600 000 IU), as immunemodulator, with high daily dose of vitamin E and C (as antioxidants, because ROS can act as strong chemoattractants leading to exaggerated immune response, which was observed in patients with COVID -19) with Iron and Zinc maintenance dose.