key: cord-0889598-so87mup3
authors: Midha, Ish K.; Kumar, Nilesh; Kumar, Amit; Madan, Taruna
title: Mega doses of retinol: A possible immunomodulation in Covid‐19 illness in resource‐limited settings
date: 2020-12-31
journal: Rev Med Virol
DOI: 10.1002/rmv.2204
sha: 3a6779bd2180423ea3dde2fd1c5e252423c64f37
doc_id: 889598
cord_uid: so87mup3

Of all the nutrients, vitamin A has been the most extensively evaluated for its impact on immunity. There are three main forms of vitamin A, retinol, retinal and retinoic acid (RA) with the latter being most biologically active and all‐trans‐RA (ATRA) its main derivative. Vitamin A is a key regulator of the functions of various innate and adaptive immune cells and promotes immune‐homeostasis. Importantly, it augments the interferon‐based innate immune response to RNA viruses decreasing RNA virus replication. Several clinical trials report decreased mortality in measles and Ebola with vitamin A supplementation.During the Covid‐19 pandemic interventions such as convalescent plasma, antivirals, monoclonal antibodies and immunomodulator drugs have been tried but most of them are difficult to implement in resource‐limited settings. The current review explores the possibility of mega dose vitamin A as an affordable adjunct therapy for Covid‐19 illness with minimal reversible side effects. Insight is provided into the effect of vitamin A on ACE‐2 expression in the respiratory tract and its association with the prognosis of Covid‐19 patients. Vitamin A supplementation may aid the generation of protective immune response to Covid‐19 vaccines. An overview of the dosage and safety profile of vitamin A is presented along with recommended doses for prophylactic/therapeutic use in randomised controlled trials in Covid‐19 patients.

Of all the nutrients, vitamin A has been the most extensively evaluated for its impact on immunity. There are three main forms of vitamin A, retinol, retinal and retinoic acid (RA) with the latter being most biologically active and all-trans-RA (ATRA) its main derivative. Vitamin A is a key regulator of the functions of various innate and adaptive immune cells and promotes immune-homeostasis. Importantly, it augments the interferon-based innate immune response to RNA viruses decreasing RNA virus replication. Several clinical trials report decreased mortality in measles and Ebola with vitamin A supplementation.

During the Covid-19 pandemic interventions such as convalescent plasma, antivirals, monoclonal antibodies and immunomodulator drugs have been tried but most of them are difficult to implement in resource-limited settings.

The current review explores the possibility of mega dose vitamin A as an affordable adjunct therapy for Covid-19 illness with minimal reversible side effects. Insight is provided into the effect of vitamin A on ACE-2 expression in the respiratory tract and its association with the prognosis of Covid-19 patients.

Vitamin A supplementation may aid the generation of protective immune response to vaccines. An overview of the dosage and safety profile of vitamin A is presented along with recommended doses for prophylactic/therapeutic use in randomised controlled trials in Covid-19 patients.

Abbreviations: 9-cisRA, 9-cis retinoic acid; ACE-2, angiotensin converting enzyme 2; ACE-I, angiotensin converting enzyme inhibitor; AID, activation-induced cytidine deaminase; ALDH1A, aldehyde dehydrogenase 1A; APCs, antigen presenting cells; ARB, angiotensin-receptor blockers; ARDS, acute respiratory distress syndrome; ATRA, all-trans-retinoic acid; Blimp-1, B lymphocyte-induced maturation protein-1; BMP, Bone morphogenic protein; BRSV, bovine respiratory syncytial virus; Covid-19, coronavirus disease 2019; COX-2, cyclooxygenase-2; CSIF, human cytokine synthesis inhibitory factor; CXCL10, C-X-C motif chemokine ligand 10; CXCL9, C-X-C motif chemokine ligand 9; EBF1, early B cell factor 1; FDA, U.S. Food and Drug Administration; FDCs, follicular dendritic cells; GATA3, G-A-T-A binding protein 3; GCs, germinal centers; GM-CSF, granulocyte macrophage colony stimulating factor; IFNγ, interferon gamma; IL-1, interleukin-1; IL-10, interleukin 10; IL-12, interleukin 12; IL-13, interleukin 13; IL-1β, interleukin 1 beta (leukocytic pyrogen); IL-23, Interleukin 23; IL-4, Interleukin 4; IL-6, interleukin 6; IL-6R, interleukin 6 receptor; IL-8, interleukin 8 (or chemokine [C-X-C motif] ligand 8, CXCL8); ILC, innate lymphoid cells; IP-10, interferon gamma inducible protein 10 kD (or CXCL10); IRF-4, interferon regulatory factor 4; LPS, lipopolysaccharide; LTBP, latent TGF-β binding proteins; LTi, lymphoid tissue inducing cells; MCP-1, monocyte chemoattractant protein-1 (CCL2); MERS-CoV, Middle-East respiratory syndrome coronavirus; MHC, major histocompatibility complex; MIP-1α, macrophage inflammatory protein 1α (CCL3); MMP, matrix metalloproteinases; mTOR signaling pathway, mammalian target of rapamycin signaling pathway; NFkB pathway, nuclear factor kappa-light-chain-enhancer of activated B cells; NK cells, natural killer cells; NO, nitric oxide; Pax-5, paired box protein-5; PGE2, prostaglandin E2; PPAR-β, peroxisome proliferator-activating receptor beta; pre-DCs, precursor dendritic cells; RA, retinoic acid; RDA, recommended dietary allowance; RIG-I, retinoic acid inducible gene I; RLRs, RIG-I like receptors; RORγt, retinoic acid receptor-related orphan nuclear receptor gamma (RORγt); RSV, respiratory syncytial virus; RXR, retinoid X receptor; SARS-CoV, severe acute respiratory syndrome associated coronavirus; SARS-CoV-2, severe acute respiratory syndrome associated coronavirus-2 (Cov-2019); STRA6 receptor, signaling receptor and transporter of retinoic acid 6; TGF-β1, transforming growth factor beta 1; Th17 cells, T helper cells type 17; Th1 cells, T helper cells type 1; Th2 cells, T helper cells type 2; TLR, toll-like receptors; TNF-α, tumor necrosis factor-α; Tregs, regulatory T cells. Having faced recent outbreaks of Ebola virus disease, SARS-CoV and MERS-CoV, the scientific community initiated rapid research for potential preventive and curative treatments 6 and clinical trials for the SARS-CoV-2 are emerging at a rate never observed before. 7

A well-coordinated rapid innate immune response with appropriate cytokines is the key defence against an infectious agent but an exaggerated immune dysregulation has potential to produce tissue damage. [8] [9] [10] [11] [12] [13] This dysregulated and excessive immune response is called cytokine storm and is a major cause of acute respiratory distress syndrome (ARDS) and multiple organ failure in Covid-19 patients. [14] [15] [16] The most immediate and important defence mounted by the body against viral infections is IFN-I or IFN-α/β production especially in the early stages. [17] [18] [19] After infection, SARS-CoV-2 generates proteins that effectively inhibit the innate immune response, especially RIG-I-dependent immune response. 20, 21 Thus, post SARS-CoV-2 infection an insignificant IFN response is mounted for 48 h and in severe cases is followed by a hyper-inflammatory state with release of various pro-inflammatory cytokines like Interleukin (IL) 6, Monocyte Chemoattractant Protein-1 (MCP1), C-X-C motif chemokine (CXCL) 1, CXCL5 and CXLC10. 22 Clinical data also suggested that severity of Covid-19 is due to an imbalanced activation of the adaptive immune response promoting virus replication. 14 Animal studies suggested that dysregulated immune response was more prominent in older non-human primates and BALB/c mice irrespective of viral titers. 23, 24 A positive correlation exists between worsening of Covid-19 symptoms and augmented serum levels of proinflammatory cytokines IL-2R, IL-6, granulocyte colony-stimulating factor, IP-10, MCP-1, macrophage inflammatory protein-1A, and TNF-α, with serum levels of IL-2R and IL-6 being directly proportional to the severity of illness. 14, 25 Therefore, treatment of Covid-19 should deal with inflammation and immune-modulatory drugs should be added to the line of treatment for improved prognosis. Dexamethasone decreases inflammation and has now been licensed in Covid-19 patients based on the results of randomised controlled trials. 26 A randomised clinical trial of inhaled interferon-beta also reported clinical benefit in Covid-19 patients. 27 

Anti-inflammatory effects of vitamin A were known since 1928. 28 Dietary vitamin A is absorbed from the gut, transformed into retinyl esters which gets hydrolysed into retinol and gets stored in the hepatic stellate cells of liver. 29 Retinol after binding to retinol binding protein in the liver enters the circulation and its cellular uptake is mediated by receptors such as STRA6 receptor (Signalling receptor and transporter of retinoic acid 6). 30 Retinol gets oxidised into retinal by alcohol dehydrogenase and further to retinoic acid (RA) by retinal dehydrogenase. 29 There are three main forms of RA, the most abundant all-trans-RA (ATRA), 9-cis-RA and 13-cis-RA. 31 RA mediates its immunomodulatory effects by interacting with nuclear receptors such as retinoic acid receptor (RAR), retinoid receptor X (RXR), peroxisome proliferator-activating receptor beta (PPAR-β) and regulates the transcription of several genes including cytokines, chemokines, integrins and genes related to lipid metabolism and glucose homeostasis. 32 RA supplementation has significant impact on functions of various immune cells and mucosal epithelial cells (Figure 1 ).

RA promoted the differentiation of murine precursor dendritic cells (pre-DCs) to pre-mucosal DCs to intestinal tolerogenic CD103 + CD11b + DCs with an inherent ability to synthesise RA and promote generation of Il-10 secreting, FoxP3+ regulatory T cells. 33 RA induced expression of gut trafficking receptors α4β7 and CCR9 on these DCs, enable them to promote gut-homing migration of T and B cells. 34 Prostaglandin E2 (PGE2) may inhibit RA synthesis and suppress generation of tolerogenic DCs. 35 Whereas, GM-CSF, IL-4, IL-13 and ligands of TLR-2 and TLR-5 induced the RA synthesis. [36] [37] [38] During infections, RA induced the production of pro-inflammatory cytokines by DCs, leading to enhanced number of effector T cells and formation of tertiary lymphoid structures. 34 

ATRA suppressed TNF, NO, PGE2, COX-2, IL-12 production in peritoneal macrophages challenged by endotoxin and IFN-γ and human monocytic cell lines. [40] [41] [42] [43] RA synergised with TGF-β, PGE2 and IL-4 to polarise macrophages to M2 type and regulate inflammation in mice. 44 Importantly, vitamin A deficient mice are unable to convert monocyte-derived inflammatory macrophages to M2 type during infection. 45 ATRA through activation of the mTOR signalling pathway enhances neutrophil extracellular traps and cytotoxicity. 46 of gut-homing receptors on ILCs 1and 3. 49 Along with IL-2, RA contributes to secretion of IL-5 and IL-13 by ILC2 and IFN-γ by ILCs 1 and 3 in allergic diseases. 50 RA induced IL-22 secretion by ILC3 promoted intestinal tolerance in mice. 47, 48 RA has both inhibitory and activating effects on natural killer cells (NK cells), a circulating subtype of ILC1. IFN-α induced cytotoxicity of NK cells, IFN-γ and Granzyme B release from NK cells are inhibited by ATRA. 50, 51 A killer inhibitory receptor of NK cells, CD158b is induced by 13-cis RA. 52 On the other hand, there is a positive correlation between number of NK cells and the retinol levels. 53 

Deficiency of vitamin A and zinc lead to decreased IgA and mucosal immunity. 54 RA increased early B-cell factor 1 (EBF1) and paired box protein-5 (Pax-5) and increased the number of B cells in the spleen. 55 Formation of antibody secreting plasma cells and immunoglobulin production (IgG, IgM, IgA) is promoted by RA by upregulation of activation-induced cytidine deaminase (AID), B lymphocyte-induced maturation protein-1 (Blimp-1), CD138, interferon regulatory factor 4 (IRF-4). [56] [57] [58] These evidences support an integral role of RA in the humoral immune response at the mucosal barriers.

Polarisation to T-helper cell 2 response is promoted by RA, RXR agonists and 9-cisRA by inducing IL-12 secretion from APCs and IL-4 expression in naive T cells. 29, 59, 60 Repression of RORγt by RA favours differentiation to Th1 over the Th17 cells. 61 ATRA induces TGF-βdependent anti-inflammatory immune responses by increasing T-regulatory cells (Tregs) and inhibits induction of pro-inflammatory cells (Th-17) and this anti-inflammatory phenomenon happens by ATRA induced Foxp3 activation through nuclear RAR. 62 ATRA is not only essential for Treg formation and regulating immunity but also fundamental to provide stability to Tregs in pro-inflammatory environments, where IL-6 and IL-21 induce transformation of already present Tregs into inflammatory Th-17 augmenting inflammation. 62 This phenomenon of T-cell differentiation is dependent on ATRA concentration; if the concentration is above a certain threshold Tregs are formed but at the lower concentrations, ATRA favours Th-17 cell differentiation. 29, 63 RA induced inhibition of IL-23 and IL-6 signalling blocks differentiation of naïve T cells to Th17 cells. 64 To summarise, RA balances the differentiation of T-helper cell subsets to maintain immune homeostasis.

Though the role of oral vitamin A supplementation in asthma is controversial owing to Th2 upregulation, RXR agonist alleviated allergic airway inflammation. 65, 66 Importantly, there is increased asthma incidence in children with deficiency of vitamin A and lower retinoid concentrations correlated with severe asthma. 67, 68 In murine model of ovalbumin-induced pulmonary inflammation, RA administration led to induction of Tregs in the lung besides decreased eosinophilic infiltration. 69 ATRA downregulated Th2 and Th17 cells by inhibiting GATA3 and RORγt in the lung. 70 Akin to tolerised DCs in the gut, lung resident macrophages coexpress TGFβ and retinal dehydrogenases and induce Tregs in airways. 71 Vitamin A regulated IL-6, MCP-1 and IL-10 expression in respiratory epithelial and macrophage cells infected with lipopolysaccharide (LPS) or Sendai virus is suggestive of increased elimination of pulmonary pathogens. 72 The three plausible mechanisms are augmentation of anti-inflammatory cytokine production by antigen presentation cells, increased production of virus-specific IgA, and reduction in the pathogen replication by inducing senescence in epithelial cells. Borderline vitamin A levels cause impairment of epithelial integrity. 73 Reduced numbers of cilia in ciliated cells of the pulmonary tract and the olfactory cells were also associated with deficiency of vitamin A. 74 Therefore, optimal levels of vitamin A are critical to sustain epithelial barrier integrity in order to face off the pathogen challenges.

Vitamin A is a nutrient well studied in relation to immune function with its link to immunity deduced as early as in 1931. 75 Earlier reports showed that the infection outcome of malnourished dogs was improved with butter intake and that the deficiency of vitamin A increased the susceptibility of rats to infections. 28, 76 In the early 1930s, 

The double-stranded RNA formed within cells by viral pathogens is primarily sensed by pattern recognition receptors including retinoic acid inducible gene I (RIG-I) and RIG-I-like receptors (RLRs). 83 These receptors induce NFkB pathway leading to alpha/beta interferon production. Thus, vitamin A directly induces the most immediate innate antiviral immune response within infected cells. Vitamin A derivatives inhibit growth of many RNA viruses including murine norovirus, 84 mumps, 85 Ebola 86,87 and measles. 88 In vitro studies of HIV replication in different model systems found conflicting results with addition of retinoids. 89, 90 Addition of ATRA improved the clinical response in patients suffering from hepatitis C virus infection. 91 The clinical impact of supplementation with mega doses of vitamin A in measles and Ebola are discussed in depth.

In the past, measles has been a disease with not only a high secondary attack rate but also with high case fatality rate. 92 With improvement of vaccination coverage cases of measles have progressively decreased but are not infrequent even at places with high vaccine coverage. 93 Measles is associated with depressed serum retinol levels and retinol supplementation results in augmentation of these levels. [94] [95] [96] [97] The plausible reasons for the low levels of retinol in patients could be lack of mobilization of hepatic stores and/or enhanced consumption.

Interestingly, the seriousness of measles is directly related to the level of hyporetinemia. 98 Markowitz et al., emphasized that children under 2 years with hyporetinemia are at a higher risk of mortality. 96 A meta-analysis of eight trials (n = 2574 participants) analysed the impact of vitamin A supplementation on morbidity and mortality in patients suffering from measles 99 (Tables 1 and 2) . 77, 94, [100] [101] [102] [103] [104] [105] These trials not only varied in their durations but also had a difference in the age groups of participants, dosages, formulations used (oil-or water-based) and were done in communities with dissimilar measles-related fatality rates.

The cumulative analysis of the data derived from all the high quality studies suggested no significant effect of retinol supplementation on risk of dying due to measles-related complications (RR 0.83; 95% CI 0.51 to 1.34). Importantly, when the data belonging exclusively to patients requiring hospitalization due to measles was analysed, those who received 2 megadoses of vitamin A showed a statistically significant (64%) decrease in their risk of mortality (RR 0.40; 95% CI 0.19 to 0.87). This impact was most evident in children less than 2 years of age where an 83% reduction in risk of mortality (RR 0.21; 95% CI 0.07 to 0.66) was observed. Need of hospitalization being a measure of severity, it was concluded that the impact of retinol supplementation was most significant in sick children. 99 Impact of solitary dose of retinol was assessed in populations with lower measles-related fatality rate (<6%) but influence of the two dose regimen was assessed on populations having higher measles-related deaths (>10%). Areas with higher measles-related mortality have greater potential to show a positive impact of retinol supplementation, therefore, it cannot be concluded whether two-dose retinol supplementation has greater impact on measles mortality compared to single dose. In mild cases of measles, solitary dose supplementation of oil based retinol preparation resulted in 70% augmentation in serum retinol levels. 103 Since aqueous formulations or retinol are more rapidly absorbed they result in higher serum retinol levels. However, oil-based preparations are economical, easily accessible and more stable. When the data of studies that were based on supplementation of two doses of retinol was stratified for preparations used, it was found that aqueous preparations resulted in 81% decrease in the risk of mortality (RR 0.23; 95% CI 0.06 to 0.89). 99 During assessment of effect of retinol supplementation on anti-measles antibody titres, it was concluded that there was a dose-dependent increase in titres. 81, 106, 107 In an immunocompetent person where measles is a novel virus, like an unimmunised adult, it can cause severe pneumonia and ARDS.

There are case reports of adult patients having severe measles and timely mega dose vitamin A supplementation has been used as an adjunct therapy with favourable results in many cases. 108 Thus, it was concluded that lack of immunity was associated with severe infection. 112 As per WHO recommendation, paediatric populations residing in areas of high prevalence of vitamin A deficiency and suffering from measles, should receive oral retinol supplementation (100,000 IU in infancy and 200,000 IU after infancy) for two consecutive days. 99 

Aluisio et al., studied the impact of mega doses of retinol to adults suffering from Ebola virus disease during the West African epidemic. 113 Supplementation with 200,000 IU of retinol on day 1 and/ or 2 within the first 48 h of admission resulted in 16.9% decrease in mortality. Authors inferred that early mega dose retinol supplementation has potential to reduce mortality due to Ebola virus disease. 113 

Physiologically, ACE-2 degenerates vasoconstrictive angiotensin II to vasodilator angiotensin (1-7). 114 SARS-CoV-2 attaches to ACE-2 enzyme to enter host cells with an affinity around 10-to 20-fold higher than SARS-CoV, and is a plausible reason for higher transmission rates in COVID-19. 115, 116 It was hypothesised that increased cellular ACE-2 levels may increase chances of severe SARS-CoV-2 infection in the host. 117 Since, ATRA supplementation upregulated ACE-2 enzyme, American Nutrition Association issued a caution against the use of vitamin A and its derivatives in amounts that exceed the recommended dietary allowance (RDA). [118] [119] [120] On the other hand, downregulated ACE-2/angiotensin (1-7) may play an integral role in inflammatory mechanisms leading to tissue injury MIDHA ET AL. In the beginning of pandemic, it was observed that many Covid-19

patients with cardiac comorbidities on ACE-1/ARB (angiotensin-receptor blockers) drugs, had adverse outcomes. 126 Since, use of ACE inhibitors or ARB is also associated with upregulation of ACE-2 expression, concerns were raised for their continuation during SARS-CoV-2 infection. [127] [128] [129] However, an earlier systematic review and meta-analysis had inferred an association of use of ACE inhibitors with a significant reduction in risk of pneumonia and pneumonia-related mortality. 130 Hospitalised hypertensive patients suffering from SARS-CoV-2 infection, taking ACE-I or ARB showed lesser mortality (3.7%) compared to others (9.8%) who were on different drugs. 131 The older people on ACE inhibitors were at almost 40% lower risk for Covid-19

hospitalization. However, the younger patients or the group with ARBs did not show any such alteration in risk for hospitalisation. 132 BRACE CORONA trial on patients on chronic ACE I/ARB therapy showed no significant difference in hospital stay and day 30 mortality outcomes with discontinuation versus continuation of therapy. 117 Therefore, many regulatory bodies and professional societies advised for continuation of treatment with ACE-1 and ARB medications in patients suffering from Covid-19. [133] [134] [135] With these evidences in the support of benefits extended by upregulated ACE-2, it is likely that vitamin A induced upregulation of ACE-2 may benefit Covid-19 patients.

Animal studies evaluating serum retinol levels suggest that despite higher levels in the liver, serum levels decline with age. 136 Studies in older individuals and diabetics suggest vitamin A deficiency. [137] [138] [139] T A B L E 2 Summary of clinical trials suggesting impact of Vitamin A supplementation on morbidity of measles patients In aged mice and in humans over the age of 65, activation of the aged innate immune system leads to dysregulated inflammation.

There is aggravated basal inflammation associated with lack of effective innate and adaptive immune responses to the newly encountered pathogens or vaccine antigens. 10 All three viral illnesses measles, Ebola and Covid-19 are suspected to have jumped species from other animals to humans, [140] [141] [142] have multisystem involvement and severe courses in naïve geriatric population compared to young adults. 143, 144 (Figure 2 ).

Despite adequate retinol stores, hyporetinemia may occur during an infection, probably due to slower speed of mobilization of stores than required to keep the levels in normal range. 168, 148 Use of mega dose, therefore, has been proven to be useful in hospitalized patients with measles and Ebola.

When large amounts of vitamin A are ingested, this overwhelms the absorptive capacity of intestines leading to formation of large amounts of retinoic acid. 148, 149 This may be the reason for its dosedependent protective immunomodulatory and antiviral effects, which in turn may influence disease severity. Combination of retinoic acid with simvastatin (an oral antilipemic agent) supplementation in animal models of ARDS exerted anti-inflammatory and pro-repair effects on respiratory tracts. 149, 150 This anti-inflammatory and prorepairing effect might be of help in ARDS related to Covid-19. randomized controlled trials to assess their efficacy. Its use may be explored in following ways:

Moderate to severe cases: Since adults are known to tolerate higher doses, larger doses 300,000-500,000 IU may be used for supplementation during acute and critical phase of illness in attempt to achieve the desired immunomodulatory effect.

Mild cases: Supplementing the usual mega dose of 200,000 IU of vitamin A for 2 days is expected to mediate augmentation in specific IgG1 levels. This may not only decrease their chances of complications, but may also increase the efficacy of their plasma for convalescent plasma therapy. Loss of IgG response over the period of convalescence is also a cause of concern 161 and vitamin A supplementation may be useful during this period.

Health care providers should be offered either monthly mega dose or advised daily supplementation of RDA. This is in view of the reports of children with normal serum retinol levels undergoing milder courses with measles compared to children with vitamin A deficiency.

Adult asymptomatic contacts should be offered 1-2 mega doses to augment their innate immune response to viral antigens.

Vitamin A enhanced IgA production by the stimulated B cells, with support from respiratory epithelial cells as well as mucosal dendritic cells synthesising RA. 162 Measles vaccination at 9 months of age is routinely accompanied by mega dose of vitamin A supplementation (100,000 IU). This has been shown to increase the protective immune response induced by the vaccine. 163 Dietary vitamin A supplemented calves (3300 U/kg of dry matter of diet) showed higher serum retinol concentration, more robust IgG1 response to intramuscular inoculations of bovine coronavirus vaccine. 164 Interestingly, these immunised and vitamin A supplemented calves showed an enhanced ratio of IgG1 to IgG2.

Immune response to mucosal BRSV vaccine was impaired in vitamin A deficient calves and was not protected against bovine RSV challenge. 165 IgA response to influenza vaccine in vitamin A deficient mice was strengthened by oral supplementation with RA. 166 Role of RA as an adjuvant was emphasised in both adult and neonatal mice. 167, 168 Owing to this adjuvant-like ability, vitamin A, may be worthy for consideration of co-administration along with vaccine trials in future.

The commonalities in the mechanisms of pathogenesis in Measles, Ebola and SARS-CoV-2 viral infections and the possible advantages vitamin A can offer at each step of immune response. 8, [145] [146] [147] MIDHA ET AL. 

All the authors declare that there is no conflict of interest. 

Data sharing is not applicable to this article as no new data were created or analysed in this study. Daily dose used in acne (in IU) (for 12 weeks) 153 Men 600

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Severe measles pneumonia in adults with respiratory failure: role of ribavirin and high-dose vitamin A

Fatal measles presenting as acute respiratory distress syndrome in an immunocompetent adult

Case report: ribavirin and vitamin A in a severe case of measles

Clinical report of serious complications associated with measles pneumonia in children hospitalized at Shengjing hospital

Vitamin A supplementation was associated with reduced mortality in patients with Ebola virus disease during the West African outbreak

Angiotensin-converting enzyme 2 (ACE 2) is a key modulator of the renin angiotensin system in health and disease

SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor

Rare driver mutations in head and neck squamous cell carcinomas converge on NOTCH signaling

Continuing versus suspending angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: impact on adverse outcomes in hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)--The BRACE CORONA Trial

Upregulation of angiotensinconverting enzyme 2 by all-trans retinoic acid in spontaneously hypertensive rats

Effect of all-trans retinoic acid treatment on prohibitin and renin-angiotensin-aldosterone system expression in hypoxia-induced renal tubular epithelial cell injury

Personalized Nutrition and the COVID-19 Era: Prepared by the Personalized Nutrition &COVID-19 Task Force of the American Nutrition Association

Angiotensin-converting enzyme 2: SARS-CoV-2 receptor and regulator of the reninangiotensin system: celebrating the 20th anniversary of the discovery of ACE 2

COVID-19, diabetes mellitus and ACE 2: the conundrum

Hypokalemia and Clinical Implications in Patients with Coronavirus Disease

The discovery of angiotensin-converting enzyme 2 and its role in acute lung injury in mice

Pulmonary angiotensin-converting enzyme 2 (ACE2) and inflammatory lung disease

COVID-19 and the Use of Angiotensin-Converting Enzyme Inhibitors and Receptor Blockers

Hypothesis: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the risk of severe COVID-19

Good ACE, bad ACE do battle in lung injury, SARS

COVID-19 and angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: what is the evidence?

Risk of pneumonia associated with use of angiotensin converting enzyme inhibitors and angiotensin receptor blockers: systematic review and metaanalysis

Association of inpatient use of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19

ACE inhibitors protective against severe COVID-19?

Position Statement of the ESC Council on Hypertension on ACE-Inhibitors and Angiotensin Receptor Blockers

News/position-statement-of-the-esc-council-on-hypertension-on-aceinhibitors-and-ang

Heart or Kidney Disease during COVID-19 Pandemic". European Medicines Agency (EMA)

HFSA/ACC/AHA Statement Addresses Concerns Re: Using RAAS Antagonists in COVID-19. American College of Cardiology (ACC)

Age-related changes of vitamin A status

Prevalence of anemia in elderly subjects living at home: role of micronutrient deficiency and inflammation

Serum vitamin A and retinol-binding protein in patients with insulin-dependent diabetes mellitus

Vitamin A, retinol binding protein and lipids in type 1 diabetes mellitus

Origin of measles virus: divergence from rinderpest virus between the 11th and 12th centuries

The proximal origin of SARS-CoV-2

Balancing the efficacy and safety of vaccines in the elderly

Hemorrhagic fevers caused by filoviruses: Ebola and Marburg

Vitamin A deficiency decreases natural killer cell activity and interferon production in rats

The immune response in measles: virus control, clearance and protective immunity

The role of cytokines and chemokines in filovirus infection

Effects of acute inflammation on plasma retinol, retinol-binding protein, and its mRNA in the liver and kidneys of vitamin A-sufficient rats

Porcine intestinal metabolism of excess vitamin A differs following vitamin A supplementation and liver consumption

Retinoic acid promotes the endogenous repair of lung stem/progenitor cells in combined with simvastatin after acute lung injury: a stereological analysis

/ dam/jcr:651fb6ae-d530-4162-be1a-8bf38c3743c7/Note_Dietary_ Allowance_27_02_2019.pdf. Updated

Nutritional disorders in Cornea

Oral vitamin A in acne vulgaris Preliminary report

The acute and chronic toxic effects of vitamin A

Using national immunization days to deliver vitamin A. EPI Update

Present knowledge in nutrition

Vitamin A Supplementation in Infants and Children 6-59 Months of Age

Assessment the Activity Value of 13-cis-Retinoic Acid (Isotretinoin) in the Treatment of COVID-19

The Vitamin A Story -Lifting the Shadow of the Death

Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections

Respiratory tract epithelial cells express retinaldehyde dehydrogenase ALDH1A and enhance IgA production by stimulated B cells in the presence of vitamin A

Combining vitamin A and vaccines: convenience or conflict?

Effects of dietary vitamin A content on antibody responses of feedlot calves inoculated intramuscularly with an inactivated bovine coronavirus vaccine

Vitamin A deficiency impairs the immune response to intranasal vaccination and RSV infection in neonatal calves

Oral retinyl palmitate or retinoic acid corrects mucosal IgA responses toward an intranasal influenza virus vaccine in vitamin A deficient mice

Retinoic acid and polyriboinosinic: polyribocytidylic acid stimulate robust anti-tetanus antibody production while differentially regulating type 1/type 2 cytokines and lymphocyte populations

The anti-tetanus immune response of neonatal mice is augmented by retinoic acid combined with polyriboinosinic: polyribocytidylic acid

Mega doses of retinol: A possible immunomodulation in Covid-19 illness in resource-limited settings