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Nutrition and the Covid-19 pandemic: Three factors with high impact on community health

Published:December 07, 2020DOI:https://doi.org/10.1016/j.numecd.2020.12.001

      Abstract

      Aims

      In the course of the COVID-19 pandemic, multiple suggestions have been delivered through websites and social media referring to natural substances and various kinds of supplements with thaumaturgical properties in preventing and/or fighting the coronavirus infection. Indeed, there is no clinical trial evidence that a dietary or pharmacological supplementation of any particular substance will increase the effectiveness of the immune defences. There are however three nutritional issues that deserve special attention under the present circumstances, namely vitamin D deficiency, excess salt intake and inappropriate alcohol consumption. Here is a short review of the current knowledge about the possible role of these factors in the immunity defence system and their potential impact on the modulation of the immune response to SARS-COV2 infection.

      Data synthesis

      For all of these factors there is convincing evidence of an impact on the immune defence structure and function. In the absence of RCT demonstration that increased ingestion of any given substance may confer protection against the new enemy, special attention to correction of these three nutritional criticisms is certainly warranted at the time of COVID pandemic.

      Conclusions

      We propose that the inappropriate intake of salt and alcohol and the risk of inadequate vitamin D status should be object of screening, in particular in subjects at high mortality risk from SARS-COV 2 infection, such as institutionalised elderly subjects and all those affected by predisposing conditions.

      Keywords

      Introduction

      In the course of the COVID-19 pandemic, multiple suggestions have been delivered through websites and social media referring to natural substances and various kinds of supplements which were attributed thaumaturgical properties in preventing and/or fighting the coronavirus infection. For some of these substances such as several minerals and vitamins, it is true that they are functional to the efficiency of the immune system: it does not follow however that a dietary or pharmacological supplementation of these substances above the quantities recommended in the context of a correct diet, will increase the effectiveness of the immune defences. In fact, during the pandemic, the World Health Organization provided very simple indications regarding the cornerstones of a correct and adequate diet, which recall the general Guidelines for healthy nutrition. They reflect a Mediterranean-like dietary model, based on the prevalent consumption of fresh and unprocessed plant foods and on the avoidance of excessive consumption of salt, sugars and saturated fats [
      • WHO EMRO
      Nutrition advice for adults during the COVID-19 outbreak.
      ].
      Review articles have also been published in scientific journals that specifically discuss the role of nutrition in protecting against infectious diseases. An authoritative example of such reviews proposed to double the recommended intake of some vitamins and minerals which have a recognized role in the correct functioning of the immune system, through the supplementation of a multimineral and vitamin preparation [
      • Calder P.C.
      • Carr A.C.
      • Gombart A.F.
      • Eggersdorfer M.
      Optimal nutritional status for a well-functioning immune system is an important factor to protect against viral infections.
      ]. In particular, the article highlighted the possible role of zinc, vitamin C and omega 3 fatty acids in relation to the severity of the inflammatory process aroused by the viral agent. Although the suggestions provided are inspired to caution and moderation, it should be noted that there is no RCT evidence of the concrete benefits attributed to the aforementioned measures. Therefore, the authors' advice must be taken as authoritative expert rather than evidence based recommendation.
      There are however three nutritional issues that, in our view, deserve special attention under the present circumstances: 1) vitamin D deficiency, 2) excess salt intake and 3) inappropriate alcohol consumption. All of these three factors have been object of extensive investigation with regard to their effects on the immune system function, yet this aspect is paid very little if any attention by clinicians. The same three factors are indeed object of major attention by clinicians and epidemiologists but for reasons other than their role in the immune defence.
      Therefore we thought that a short review of the current knowledge about the possible role of these factors in the innate and the acquired immunity defence system and the potential effects of the related nutritional inadequacies would be warranted under the present circumstances [
      • Lee A.H.
      • Dixit V.D.
      Dietary regulation of immunity.
      ,
      • Delcuve G.P.
      • Lakowski T.M.
      • Su R.C.
      • Beacon T.H.
      • Davie J.R.
      SARS-CoV-2 multifaceted interaction with human host. Part I: what we have learn.
      ,
      • Beacon T.H.
      • Su R.C.
      • Lakowski T.M.
      • Delcuve G.P.
      • Davie J.R.
      SARS-CoV-2 multifaceted interaction with the human host. Part II: innate immunity response, immunopathology, and epigenetics.
      ]. Before considering the specific role of each of these factors and referring the reader to other appropriate sources for more extensive and specialist description [
      • Morsink M.A.J.
      • Willemen N.G.A.
      • Leijten J.
      • Bansal R.
      • Shin S.R.
      Immune organs and immune cells on a chip: an overview of biomedical applications.
      ], we recall here that the innate immunity comprises i) the mechanisms of primary defence of our organism against external pathogens (bacteria, viruses, fungi), including the integrity of the skin and of the mucous barriers, and ii) the components of the more advanced defence against the same pathogens, once they should overcome these barriers, based on the activity of circulating monocytes and their transformation into macrophages, the cellular elements that will attack and try to block the invasion. The acquired immunity is instead based on the proliferation and balanced differentiation of lymphocytes into B cells, which are primarily intended for the production of circulating antibodies, and T cells, which differentiate into different subtypes producing different cytokines, molecules involved in the inflammatory response to pathogens, some of which increase the power of the inflammatory response whereas others tend to modulate and possibly attenuate it.

      Vitamin D

      Vitamin D is mainly synthesised in the skin under the influence of ultraviolet (UV)-B light. In addition, a small amount is obtained from the diet through a few food sources, such as oily fish, egg yolk and vitamin D fortified dairy products. After its production or ingestion with food, it gives rise to a complex biological system comprising hormone precursors, active metabolites, carriers, enzymes, and receptors involved in genomic and non-genomic effects. This system has been shown to activate multiple molecular mediators and elicit many physiological functions, which are associated with glucose homeostasis, blood pressure regulation, inflammation, and cancer [
      • Pilz S.
      • Zittermann A.
      • Trummer A.
      • Theiler-Schwetz V.
      • Lerchbaum E.
      • Keppel M.H.
      • et al.
      Vitamin D testing and treatment: a narrative review of current evidence.
      ]. In particular, vitamin D has long been known to participate in the activity of the immune system through its active form, 1–25 dihydroxycalciferol (calcitriol). The vitamin D receptor (VDR) is present in both B and T cells and vitamin D was shown to modulate the proliferation, differentiation and inhibition of these same cells [
      • Wu D.
      • Lewis E.D.
      • Pae M.
      • Meydani S.N.
      Nutritional modulation of immune function: analysis of evidence, mechanisms, and clinical relevance.
      ]. While initially vitamin D was considered basically an immunosuppressive agent, more recently it has rather been thought to play a modulating role in tolerance and homeostasis, mainly based on animal experimental and in vitro studies [
      • Peelen E.
      • Knippenberg S.
      • Muris A.H.
      • Thewissen M.
      • Smolders J.
      • Cohen Tervaert J.W.
      • et al.
      Effects of vitamin D on the peripheral adaptive immune system: a review.
      ,
      • Allan G.M.
      • Cranston L.
      • Lindblad A.
      • McCormack J.
      • Kolber M.R.
      • Garrison S.
      • et al.
      Vitamin D: a narrative review examining the evidence for ten beliefs.
      ], but also with some evidence in humans [
      • Prietl B.
      • Treiber G.
      • Pieber T.R.
      • Amrein K.
      Vitamin D and immune function.
      ,
      • Charoenngam N.
      • Holick M.F.
      Immunologic effects of vitamin D on human health and disease.
      ]. Evidence has been produced of favourable actions of vitamin D both in terms of innate and of acquired immunity. Although the role of the vitamin D on neutrophil activity is still poorly understood, there is evidence that these cells have the VDR on their surface and that exogenously administered calcitriol reduces their production of inflammatory mediators and formation of reactive oxygen species [
      • Hirsch D.
      • Archer F.E.
      • Joshi-Kale M.
      • Vetrano A.M.
      • Weinberger B.
      Decreased anti-inflammatory responses to vitamin D in neonatal neutrophils.
      ]. Exposure to 1,25(OH)2D3 enhances the differentiation of macrophages from monocytes and induces autophagy, phagosomal maturation and the production of antimicrobial peptides such as cathelicidins [
      • Liu P.T.
      • Stenger S.
      • Li H.
      • Wenzel L.
      • Tan B.H.
      • Krutzik S.R.
      • et al.
      Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response.
      ] for the intracellular killing of bacteria like Mycobacterium tuberculosis. Furthermore, the vitamin active metabolite can reduce the production of proinflammatory mediators from M1 macrophages, e.g. cytokines IL-1b, IL-6, IL-12p40, tumor necrosis factor [TNF]-a) and chemokines [
      • Vanherwegen A.-S.
      • Gysemans C.
      • Mathieu C.
      Regulation of immune function by vitamin D and its use in diseases of immunity.
      ]. We have learned that one of the elements responsible of an unfavourable outcome in SARS-COV2 infection is an excess of inflammatory response, due to a defect in modulation of the response itself [
      • Felsenstein S.
      • Herbert J.A.
      • McNamara P.S.
      • Hedrich C.M.
      COVID-19: immunology and treatment options.
      ,
      • Melenotte C.
      • Silvin A.
      • Goubet A.G.
      • Lahmar I.
      • Dubuisson A.
      • Zumla A.
      • et al.
      Immune responses during COVID-19 infection.
      ]: vitamin D could exert an important action in this regard, having the ability to direct the immune response toward a reduction in the production of pro-inflammatory cytokines, while favouring the differentiation of T cells towards the production of subtypes that substantially modulate and attenuate the extent of inflammation [
      • Laird E.
      • McNulty H.
      • Ward M.
      • Hoey L.
      • McSorley E.
      • Wallace J.M.
      Vitamin D deficiency is associated with inflammation in older Irish adults.
      ,
      • Sassi F.
      • Tamone C.
      • D'Amelio P.
      Vitamin D: nutrient, hormone, and immunomodulator.
      ]. The benefits of normal vitamin D status against Sars-Cov-2 infection might go actually beyond its immunomodulatory function, involving the preservation of the integrity of the pulmonary epithelial barrier, the stimulation of epithelial repair and an antithrombotic effect which is conceivably related to its anti-inflammatory action [
      • Quesada-Gomez J.M.
      • Entrenas-Castillo M.
      • Bouillon R.
      Vitamin D receptor stimulation to reduce acute respiratory distress syndrome (ARDS) in patients with coronavirus SARS-CoV-2 infections: Revided Ms SBMB 2020_166.
      ].
      More recently, some authors assessed the relationship between Covid-19 disease and vitamin D deficiency. The results of these studies are summarised in Table 1.
      Table 1Main findings of studies which assessed the relationship between Covid-19 and Vitamin D deficiency.
      AuthorMain results
      Maghbooli et al.

      PLOS ONE, 2020 [
      • Maghbooli Z.
      • Sahraian M.A.
      • Ebrahimi M.
      • Pazoki M.
      • Kafan S.
      • Tabriz H.M.
      • et al.
      Vitamin D sufficiency, a serum 25-hydroxyvitamin D at least 30 ng/mL reduced risk for adverse clinical outcomes in patients with COVID-19 infection.
      ]
      In 235 hospitalised patients vitamin D sufficiency was statistically associated with a lower risk of unconsciousness (p = 0.03) and hypoxia (p = 0.004), a lower C-reactive protein blood level (p = 0.01) and a higher blood lymphocyte percentage (p = 0.03). Moreover, in a logistic regression model, vitamin D sufficiency was independently associated with decreased disease severity.
      Entrenas Castillo et al.

      J Steroid Biochem and Mol Biol, 2020 [
      • Entrenas Castillo M.
      • Entrenas Costa L.M.
      • Vaquero Barrios J.M.
      • Alcalá Díaz J.F.
      • López Miranda J.
      • Bouillon R.
      • et al.
      Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: a pilot randomized clinical study.
      ]
      Among 76 hospitalised patients (50 with and 26 without Calcifediol treatment) 98% of the patients on calcifediol did not require Intensive Care Unit versus only 50% of the patients not treated with Calcifediol (p < 0.001).
      Ilie et al.

      Aging Clin. Exp. Res, 2020 [
      • Ilie P.C.
      • Stefanescu S.
      • Smith L.
      The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality.
      ]
      In European countries: a) inverse correlation between average vitamin D level and number of COVID-19 cases per million population r = − 0.44; p = 0.050]; b) inverse correlation between average vitamin D level and number of COVID-19 related deaths per million, r = − 0.43; p = 0.050).
      D'Avolio et al.

      Nutrients, 2020 [
      • D'Avolio A.
      • Avataneo V.
      • Manca A.
      • Cusato J.
      • De Nicolò A.
      • Lucchini R.
      • et al.
      25-Hydroxyvitamin D concentrations are lower in patients with positive PCR for SARS-CoV-2.
      ]
      By retrospective analysis of 107 patients undergoing a nasopharyngeal swab with PCR analysis for SARS-CoV-2 and concomitant serum 25(OH)D measurement, lower 25(OH)D levels (11.1 ng/mL) were found in patients positive to SARS-CoV-2 compared with negative patients (24.6 ng/mL), p = 0.004).
      Panagiotou, Clinical Endocrinology, 2020 [
      • Panagioto G.
      • Tee S.A.
      • Ihsan Y.
      • Athar W.
      • Marchitelli G.
      • Kelly D.
      • et al.
      Low serum 25-hydroxyvitamin D (25[OH]D) levels in patients hospitalized with COVID-19 are associated with greater disease severity.
      ]
      The analysis of 134 Covid-19 hospitalised patients showed that 66.4% were vitamin D insufficient and 37.3% were vitamin D deficient (21.6% severely deficient). Moreover, patients admitted to Intensive Therapy Unit (ITU) had a lower 25(OH)D level compared with non-ITU patients despite being younger (p = 0.02).
      The issue of vitamin D and immune defence is clinically and epidemiologically relevant given the documented widespread deficiency or insufficiency of vitamin D in the population, particularly among institutionalized elderly people [
      • Lips P.
      • Cashman K.D.
      • Lamberg-Allardt C.
      • Bischoff-Ferrari H.A.
      • Obermayer-Pietsch B.
      • Bianchi M.L.
      • et al.
      Current vitamin D status in European and Middle East countries and strategies to prevent vitamin D deficiency: a position statement of the European Calcified Tissue Society.
      ]. The impact of vitamin D on the regulation of the inflammatory process is of particular importance in older adults, in obese people and in all those with chronic inflammatory conditions who may be susceptible to a heightened immune response. In these population groups, which were the preferred target of the Coronavirus in its 2020 winter and spring outbreak, hypovitaminosis D is often associated with skeletal demineralization and involves a greater risk of falls and bone fractures [
      • Bouillon R.
      • Marcocci C.
      • Carmeliet G.
      • Bikle D.
      • White J.H.
      • Dawson-Hughes B.
      • et al.
      Skeletal and extraskeletal actions of vitamin D: current evidence and outstanding questions.
      ]. It is thus widely recognized that diagnostic screening and correction of hypovitaminosis D is indicated in the elderly population in relation to the health and functionality of the skeletal and muscular system [
      • Amrein K.
      • Scherkl M.
      • Hoffmann M.
      • Neuwersch-Sommeregger S.
      • Köstenberger M.
      • Tmava Berisha A.
      • et al.
      Vitamin D deficiency 2.0: an update on the current status worldwide.
      ]: albeit in the absence of randomized controlled trial evidence, it is conceivable that this type of intervention may also benefit the immune system functionality.

      Sodium

      The harmful effects of excess salt intake on the cardiovascular system [
      • Strazzullo P.
      • D'Elia L.
      • Kandala N.B.
      • Cappuccio F.P.
      Salt intake, stroke, and cardiovascular disease: meta-analysis of prospective studies.
      ] are paid justified attention, but little or no attention has been given so far to its potential effects onto the immune system activity. Indeed, in the last 10 years increasing evidence has accumulated about the role that sodium plays at this level and about the possible consequences of excess salt intake in this respect [
      • Wilck N.
      • Balogh A.
      • Markó L.
      • Bartolomaeus H.
      • Müller D.N.
      The role of sodium in modulating immune cell function.
      ]. It is now known that the skin represents a site of significant sodium accumulation, sodium being linked to glycosaminoglycans in the extracellular matrix, in the absence of an equivalent amount of water, thus in a condition of local hyperosmolarity [
      • Kopp C.
      • Linz P.
      • Dahlmann A.
      • Hammon M.
      • Jantsch J.
      • Muller D.N.
      • et al.
      Na magnetic resonance imaging determined tissue sodium in healthy subjects and hypertensive patients.
      ]. It was also found that a high dietary salt intake induces a greater accumulation of sodium in the skin and also in other sites which are at the “frontier” of our immune defence system, i.e. the gut and the kidney [
      • Titze J.
      • Shakibaei M.
      • Schafflhuber M.
      • Schulze-Tanzil G.
      • Porst M.
      • Schwind K.H.
      • et al.
      Glycosaminoglycan polymerization may enable osmotically inactive Na+ storage in the skin.
      ,
      • Muller S.
      • Quast T.
      • Schroeder S.
      • Klotz L.
      • Jantsch J.
      • Gerzer R.
      • et al.
      Salt- dependent chemotaxis of macrophages.
      ]. It has been shown that inflammatory states favour an increase in salinity, and that hypersalinity, in turn, attracts macrophages and induces their preferential differentiation into “pro-inflammatory” phenotypes [
      • Machnik A.
      • Neuhofer W.
      • Jantsch J.
      • Dahlmann A.
      • Tammela T.
      • Machura K.
      • et al.
      Macrophages regulate salt- dependent volume and blood pressure by a vascular endothelial growth factor- C-dependent buffering mechanism.
      ], while inhibiting the function of alternatively activated macrophages (M2 macrophages) which exert a modulatory function on the inflammation process [
      • Binger K.J.
      • Gebhardt M.
      • Heinig M.
      • Rintisch C.
      • Schroeder A.
      • Neuhofer W.
      • et al.
      High salt reduces the activation of IL-4- and IL-13-stimulated macrophages.
      ]. Overall, this pattern of response is functional to the elimination of external pathogens [
      • Jantsch J.
      • Schatz V.
      • Friedrich D.
      • Schroeder A.
      • Kopp C.
      • Siegert I.
      • et al.
      Cutaneous Na+ storage strengthens the antimicrobial barrier function of the skin and boosts macrophage- driven host defense.
      ], but also determines a lower representation of cellular phenotypes oriented to the modulation of the inflammatory response with the result, at the skin level, of delaying the healing time of wounds and in general inflammatory lesions [
      • Binger K.J.
      • Gebhardt M.
      • Heinig M.
      • Rintisch C.
      • Schroeder A.
      • Neuhofer W.
      • et al.
      High salt reduces the activation of IL-4- and IL-13-stimulated macrophages.
      ]. In keeping with these findings, it was also shown that a higher sodium environment increased the expression of proinflammatory while inhibiting the expression of anti-inflammatory genes in human monocyte-derived macrophages [
      • Zhang W.C.
      • Zheng X.J.
      • Du L.J.
      • Sun J.Y.
      • Shen Z.X.
      • Shi C.
      • et al.
      High salt primes a specific activation state of macrophages, M(Na).
      ].
      Many studies focused on the effect of salt on T lymphocyte differentiation. Activated T lymphocytes proliferate and differentiate in secondary lymphoid organs into effector cells to enter the circulation and migrate to inflamed tissues, as necessary. Depending on the cytokine microenvironment, they can differentiate into TH1, TH2, TH17 or into regulatory T (Treg) cell subtypes [
      • Kaiko G.E.
      • Horvat J.C.
      • Beagley K.W.
      • Hansbro P.M.
      Immunological decision-making: how does the immune system decide to mount a helper T cell response?.
      ]. Several studies suggested that salt promotes the differentiation of T17 cells and, conversely, that treating TH17 cells with salt increased their pathogenicity in terms of production of inflammatory cytokines [
      • Wu C.
      • Yosef N.
      • Thalhamer T.
      • Zhu C.
      • Xiao S.
      • Kishi Y.
      • et al.
      Induction of pathogenic TH17 cells by inducible salt- sensing kinase SGK1.
      ]. On the other hand, Treg cells are known to limit the inflammatory process mediated by TH17 cells [
      • Crome S.Q.
      • Clive B.
      • Wang A.Y.
      • Kang C.Y.
      • Chow V.
      • Yu J.
      • et al.
      Inflammatory effects of ex vivo human Th17 cells are suppressed by regulatory T cells.
      ], but their function is inhibited by hypersalinity [
      • Hernandez A.L.
      • Kitz A.
      • Wu C.
      • Lowther D.E.
      • Rodriguez D.M.
      • Vudattu N.
      • et al.
      Sodium chloride inhibits the suppressive function of FOXP3+regulatory T cells.
      ].
      A different but related issue is the effect of excess dietary salt consumption on the intestinal microbiota, which has been recognized as an integral part of our immune system [
      • Elijovich F.
      • Laffer C.L.
      • Sahinoz M.
      • Pitzer A.
      • Ferguson J.F.
      • Kirabo A.
      The gut microbiome, inflammation, and salt-sensitive hypertension.
      ]. It was reported that a salt load in healthy volunteers reduced the abundance of various Lactobacillus species in faecal samples, and this was associated with a rise in the concentration of proinflammatory TH17 cells in the blood [
      • Wilck N.
      • Matus M.G.
      • Kearney S.M.
      • Olesen S.W.
      • Forslund K.
      • Bartolomaeus H.
      • et al.
      Salt- responsive gut commensal modulates TH17 axis and disease.
      ]. Another study showed that a high salt diet in mice led to the expansion of TH17 cells in the small intestine and to elevated IL-17 levels in the blood [
      • Faraco G.
      • Brea D.
      • Garcia-Bonilla L.
      • Wang G.
      • Racchiumi G.
      • Chang H.
      • et al.
      Dietary salt promotes neurovascular and cognitive dysfunction through a gut- initiatedTH17 response.
      ]. These findings suggest that, by affecting the intestinal microbiota, dietary salt might indirectly influence immune cell function in various tissues and therefore also modulate the inflammatory process [
      • Smiljanec K.
      • Lennon S.L.
      Sodium, hypertension, and the gut: does the gut microbiota go salty?.
      ].
      What was said previously for vitamin D applies to sodium as well: although there are no randomized controlled trials demonstrating that reducing salt intake increases the protection against viral infections, the correction of excess salt intake, strongly indicated for the known and proven benefits on the cardiovascular system, may conceivably bring about some benefit with regard to the optimal modulation of the inflammatory response in the case of infection, which may be of particular importance in the Covid-19 pandemic.

      Alcohol

      The harmful effects of inappropriate consumption of alcoholic beverages on the immune system have been well described, both with regard to a single bout and to the consequences of a chronic abuse of the substance. It was reported that upon a single episode of binge alcohol consumption (with mean peak blood alcohol levels above 130 mg/dL) by human volunteers there was within minutes an initial rise in the number of peripheral blood monocytes and in the LPS-induced TNF-α production: this was followed however in a few hours by a rebound fall in circulating monocytes with an increase in the level of the anti-inflammatory IL-10 [
      • Afshar M.
      • Richards S.
      • Mann D.
      • Cross A.
      • Smith G.B.
      • Netzer G.
      • et al.
      Acute immunomodulatory effects of binge alcohol ingestion.
      ]. These results are in keeping with those of experiments in rodent models in which the measurement of serum cytokine levels at 2hr distance from the administration of ethanol at a dosage equivalent to the one resulting in loss of consciousness in humans showed a decreased production of the inflammatory cytokines IL-6 and IL-12 and by contrast an increase in the production of IL-10 [
      • Pruett S.B.
      • Zheng Q.
      • Fan R.P.
      • Matthews K.
      • Schwab C.
      Ethanol suppresses cytokine responses induced through Toll-like receptors as well as innate resistance to Escherichia coli in a mouse model for binge drinking.
      ].
      In contrast to the inhibitory effects of acute alcohol ingestion, prolonged exposure of peripheral blood monocytes from human subjects to ethanol for several days appears to increase TNF-α production without affecting IL-10 production in response to an appropriate cell stimulation [
      • Mandrekar P.
      • Bala S.
      • Catalano D.
      • Kodys K.
      • Szabo G.
      The opposite effects of acute and chronic alcohol on lipopolysaccharide-induced inflammation are linked to IRAK-M in human monocytes.
      ,
      • Pang M.
      • Bala S.
      • Kodys K.
      • Catalano D.
      • Szabo G.
      Inhibition of TLR8- and TLR4-induced Type I IFN induction by alcohol is different from its effects on inflammatory cytokine production in monocytes.
      ]. Also, prolonged ethanol ingestion in male mice up-regulated NFκB activation and increased the circulating levels of IL-6 and TNF-α in response to lipopolysaccharide stimulation [
      • Maraslioglu M.
      • Oppermann E.
      • Blattner C.
      • Weber R.
      • Henrich D.
      • Jobin C.
      • et al.
      Chronic ethanol feeding modulates inflammatory mediators, activation of nuclear factor-kappaB, and responsiveness to endotoxin in murine Kupffer cells and circulating leukocytes.
      ]. Overall, the available evidence suggests that alcohol modulates the function of innate immune cells in a dose and time dependent manner, in such a way that acute high dose exposure inhibits whereas long-term assumption stimulates proinflammatory cytokine production [
      • Barr T.
      • Helms C.
      • Grant K.
      • Messaoudi I.
      Opposing effects of alcohol on the immune system.
      ]. Alcohol consumption also impacts cell-mediated and humoral immunity. Thus, in humans it appears that alcohol consumption can lower lymphocyte number [
      • McFarland W.
      • Libre E.P.
      Abnormal leukocyte response in alcoholism.
      ,
      • Mili F.
      • Flanders W.D.
      • Boring J.R.
      • Annest J.L.
      • DeStefano F.
      The associations of alcohol drinking and drinking cessation to measures of the immune system in middle-aged men.
      ]. In addition, alcohol abuse was associated with shifts in T lymphocyte phenotype pattern, with decreased percentage of CD45RA+ “naïve” CD4 and CD8 T cells and an increased percentage of CD45RO+ “memory” subsets, as observed in men who consumed an average 400 g/day of alcohol for approximately 25 years [
      • Cook R.T.
      • Waldschmidt T.J.
      • Ballas Z.K.
      • Cook B.L.
      • Booth B.M.
      • Stewart B.C.
      • et al.
      Fine T-cell subsets in alcoholics as determined by the expression of L-selectin, leukocyte common antigen, and beta-integrin.
      ,
      • Cook R.T.
      • Ballas Z.K.
      • Waldschmidt T.J.
      • Vandersteen D.
      • LaBrecque D.R.
      • Cook B.L.
      Modulation of T-cell adhesion markers, and the CD45R and CD57 antigens in human alcoholics.
      ]. Similarly in mice, chronic consumption of 20% ethanol in water for up to 6 months decreased the percentage of naïve T cells and increased the percentage of memory T cells [
      • Cho B.K.
      • Rao V.P.
      • Ge Q.
      • Eisen H.N.
      • Chen J.
      Homeostasis-stimulated proliferation drives naive T cells to differentiate directly into memory T cells.
      ,
      • Song K.
      • Coleman R.
      • Zhu X.
      • Alber C.
      • Ballas Z.
      • Waldschmidt T.
      • et al.
      Chronic ethanol consumption by mice results in activated splenic T cells.
      ,
      • Zhang H.
      • Meadows G.G.
      Chronic alcohol consumption in mice increases the proportion of peripheral memory T cells by homeostatic proliferation.
      ]. Accumulation of memory T cells has been associated with increased incidence of chronic inflammatory diseases [
      • Hakim F.T.
      • Gress R.E.
      Immunosenescence: deficits in adaptive immunity in the elderly.
      ,
      • Chou J.P.
      • Effros R.B.
      T cell replicative senescence in human aging.
      ] whereas the loss of naïve T cells is expected to interfere with the development of efficacious responses to infection and vaccination [
      • Appay V.
      • Sauce D.
      Naive T cells: the crux of cellular immune aging?.
      ]. It must be noticed however that these alterations in lymphocyte number and phenotype have been described with massive but not with “moderate” alcohol consumption [
      • Romeo J.
      • Warnberg J.
      • Diaz L.E.
      • Gonzalez-Gross M.
      • Marcos A.
      Effects of moderate beer consumption on first-line immunity of healthy adults.
      ]. Chronic alcohol intake was also found to be associated with alterations in circulating immunoglobulin (Ig) levels and in particular with a trend to dose-dependent higher IgA and IgM production [
      • Mili F.
      • Flanders W.D.
      • Boring J.R.
      • Annest J.L.
      • DeStefano F.
      The associations of alcohol drinking and drinking cessation to measures of the immune system in middle-aged men.
      ,
      • Gonzalez-Quintela A.
      • Alende R.
      • Gude F.
      • Campos J.
      • Rey J.
      • Meijide L.M.
      • et al.
      Serum levels of immunoglobulins (IgG, IgA, IgM) in a general adult population and their relationship with alcohol consumption, smoking and common metabolic abnormalities.
      ]. Several studies have examined the effects of alcohol consumption on the host response to infection. Thus, chronic alcohol abuse was found to lead to increased susceptibility to bacterial and viral infections [
      • Schmidt W.
      • De Lint J.
      Causes of death of alcoholics.
      ] and severity [
      • Saitz R.
      • Ghali W.
      • Moskowitz M.
      The impact of alcohol-related diagnoses on pneumonia outcomes.
      ] compared with control subjects. The incidence of M. tuberculosis infection among alcoholics has been found to be increased [
      • Panic E.
      • Panic I.
      Chronic alcoholics' knowledge regarding tuberculosis.
      ]. Alcohol use has also been shown to drive disease progression in chronic viral infections such as human immunodeficiency virus (HIV) [
      • Baum M.
      • Rafie C.
      • Lai S.
      • Sales S.
      • Bryan Page J.
      • Campa A.
      Alcohol use accelerates HIV disease progression.
      ] and Hepatitis C [
      • Bhattacharya R.
      • Shuhart M.
      Hepatitis C and alcohol: interactions, outcomes, and implications.
      ]. In addition, the magnitude of antibody response following vaccination toward Hepatitis B virus was lower in alcoholics compared to controls [
      • Nalpas B.
      • Thepot V.
      • Driss F.
      • Pol S.
      • Courouce A.
      • Saliou P.
      • et al.
      Secondary immune response to hepatitis B virus vaccine in alcoholics.
      ]. Again, in contrast to the studies above, moderate alcohol consumption was not associated with reduced immune response to infection and vaccination in various studies [
      • Barr T.
      • Helms C.
      • Grant K.
      • Messaoudi I.
      Opposing effects of alcohol on the immune system.
      ].

      Conclusions

      We have analysed vitamin D, salt intake and alcohol consumption, as three nutritional factors playing a role in the proper functioning of the immune system and have discussed their potential impact on the modulation of the immune response to SARS-COV2 infection. Obviously, there is no specific recipe to prevent or contrast the SARS-COV 2 infection on nutritional grounds and there is no RCT demonstration that increased ingestion or supplementation of any given substance will confer protection against the new enemy. It may be convened that the maintenance of an optimal nutritional status through the adherence to the evidence-based nutrition guidelines and the practise of a regular physical activity may help to contrast the disease. In particular, we suggest that special attention to the three nutritional factors we hereby highlighted would be part of a logical approach to a nutritional policy at the time of COVID pandemic. For all of these factors there is a large, yet “circumstantial”, evidence of an impact on the immune defence: this warrants in our view particular efforts by the health authorities to pursue the best possible implementation of the measures useful to correct the related well known nutritional criticisms, i.e. vitamin D deficiency or insufficiency, excess salt intake and inappropriate consumption of alcoholic beverages. The detection of individuals affected or at increased risk of occurrence of these criticisms would enable the preventive application of personalized nutritional guidelines to promote individual health, and, accordingly, to improve population health. We propose that the inappropriate intake of salt and alcohol and the risk of inadequate vitamin D status should be object of screening, in particular in subjects at high mortality risk from SARS-COV 2 infection, such as institutionalised elderly subjects and all those affected by predisposing conditions. Appropriate nutritional and pharmacological strategies must be put in place to help individuals to reach an optimal nutritional state. Any improvement in this regard is expected to translate into great advantages for community health.

      Declaration of competing interest

      The authors have nothing to disclose.

      References

        • WHO EMRO
        Nutrition advice for adults during the COVID-19 outbreak.
        • Calder P.C.
        • Carr A.C.
        • Gombart A.F.
        • Eggersdorfer M.
        Optimal nutritional status for a well-functioning immune system is an important factor to protect against viral infections.
        Nutrients. 2020; 12: 1181https://doi.org/10.3390/nu12041181
        • Lee A.H.
        • Dixit V.D.
        Dietary regulation of immunity.
        Immunity. 2020; 53: 510-523https://doi.org/10.1016/j.immuni.2020.08.013
        • Delcuve G.P.
        • Lakowski T.M.
        • Su R.C.
        • Beacon T.H.
        • Davie J.R.
        SARS-CoV-2 multifaceted interaction with human host. Part I: what we have learn.
        IUBMB Life. 2020; : 1-18https://doi.org/10.1002/iub.2380
        • Beacon T.H.
        • Su R.C.
        • Lakowski T.M.
        • Delcuve G.P.
        • Davie J.R.
        SARS-CoV-2 multifaceted interaction with the human host. Part II: innate immunity response, immunopathology, and epigenetics.
        IUBMB Life. 2020; : 1-24https://doi.org/10.1002/iub.2379
        • Morsink M.A.J.
        • Willemen N.G.A.
        • Leijten J.
        • Bansal R.
        • Shin S.R.
        Immune organs and immune cells on a chip: an overview of biomedical applications.
        Micromachines. 2020; 11: E849https://doi.org/10.3390/mi11090849
        • Pilz S.
        • Zittermann A.
        • Trummer A.
        • Theiler-Schwetz V.
        • Lerchbaum E.
        • Keppel M.H.
        • et al.
        Vitamin D testing and treatment: a narrative review of current evidence.
        Endocr Connect. 2019; 8: R27-R43https://doi.org/10.1530/EC-18-0432
        • Wu D.
        • Lewis E.D.
        • Pae M.
        • Meydani S.N.
        Nutritional modulation of immune function: analysis of evidence, mechanisms, and clinical relevance.
        Front Immunol. 2019; 9: 3160https://doi.org/10.3389/fimmu.2018.03160
        • Peelen E.
        • Knippenberg S.
        • Muris A.H.
        • Thewissen M.
        • Smolders J.
        • Cohen Tervaert J.W.
        • et al.
        Effects of vitamin D on the peripheral adaptive immune system: a review.
        Autoimmun Rev. 2011; 10: 733-743
        • Allan G.M.
        • Cranston L.
        • Lindblad A.
        • McCormack J.
        • Kolber M.R.
        • Garrison S.
        • et al.
        Vitamin D: a narrative review examining the evidence for ten beliefs.
        J Gen Intern Med. 2016; 31: 780-791
        • Prietl B.
        • Treiber G.
        • Pieber T.R.
        • Amrein K.
        Vitamin D and immune function.
        Nutrients. 2013; 5: 2502-2521https://doi.org/10.3390/nu5072502
        • Charoenngam N.
        • Holick M.F.
        Immunologic effects of vitamin D on human health and disease.
        Nutrients. 2020; 12: 2097https://doi.org/10.3390/nu12072097
        • Hirsch D.
        • Archer F.E.
        • Joshi-Kale M.
        • Vetrano A.M.
        • Weinberger B.
        Decreased anti-inflammatory responses to vitamin D in neonatal neutrophils.
        Mediators Inflamm. 2011; : 598345https://doi.org/10.1155/2011/598345
        • Liu P.T.
        • Stenger S.
        • Li H.
        • Wenzel L.
        • Tan B.H.
        • Krutzik S.R.
        • et al.
        Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response.
        Science. 2006; 311: 1770-1773
        • Vanherwegen A.-S.
        • Gysemans C.
        • Mathieu C.
        Regulation of immune function by vitamin D and its use in diseases of immunity.
        Endocrinol Metab Clin N Am. 2017; 46: 1061-1094
        • Felsenstein S.
        • Herbert J.A.
        • McNamara P.S.
        • Hedrich C.M.
        COVID-19: immunology and treatment options.
        Clin Immunol. 2020; 215: 108448https://doi.org/10.1016/j.clim.2020.108448
        • Melenotte C.
        • Silvin A.
        • Goubet A.G.
        • Lahmar I.
        • Dubuisson A.
        • Zumla A.
        • et al.
        Immune responses during COVID-19 infection.
        Oncoimmunology. 2020; 9: 1807836https://doi.org/10.1080/2162402X.2020.1807836
        • Laird E.
        • McNulty H.
        • Ward M.
        • Hoey L.
        • McSorley E.
        • Wallace J.M.
        Vitamin D deficiency is associated with inflammation in older Irish adults.
        J Clin Endocrinol Metab. 2014; 99: 1807-1815
        • Sassi F.
        • Tamone C.
        • D'Amelio P.
        Vitamin D: nutrient, hormone, and immunomodulator.
        Nutrients. 2018; 10: 1656https://doi.org/10.3390/nu10111656
        • Quesada-Gomez J.M.
        • Entrenas-Castillo M.
        • Bouillon R.
        Vitamin D receptor stimulation to reduce acute respiratory distress syndrome (ARDS) in patients with coronavirus SARS-CoV-2 infections: Revided Ms SBMB 2020_166.
        J Steroid Biochem Mol Biol. 2020; 202: 105719https://doi.org/10.1016/j.jsbmb.2020.105719
        • Maghbooli Z.
        • Sahraian M.A.
        • Ebrahimi M.
        • Pazoki M.
        • Kafan S.
        • Tabriz H.M.
        • et al.
        Vitamin D sufficiency, a serum 25-hydroxyvitamin D at least 30 ng/mL reduced risk for adverse clinical outcomes in patients with COVID-19 infection.
        PloS One. 2020; 15e0239799https://doi.org/10.1371/journal.pone.0239799
        • Entrenas Castillo M.
        • Entrenas Costa L.M.
        • Vaquero Barrios J.M.
        • Alcalá Díaz J.F.
        • López Miranda J.
        • Bouillon R.
        • et al.
        Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: a pilot randomized clinical study.
        J Steroid Biochem Mol Biol. 2020; 203: 105751https://doi.org/10.1016/j.jsbmb.2020.105751
        • Ilie P.C.
        • Stefanescu S.
        • Smith L.
        The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality.
        Aging Clin Exp Res. 2020; 32: 1195-1198https://doi.org/10.1007/s40520-020-01570-8
        • D'Avolio A.
        • Avataneo V.
        • Manca A.
        • Cusato J.
        • De Nicolò A.
        • Lucchini R.
        • et al.
        25-Hydroxyvitamin D concentrations are lower in patients with positive PCR for SARS-CoV-2.
        Nutrients. 2020; 12: 1359https://doi.org/10.3390/nu12051359
        • Panagioto G.
        • Tee S.A.
        • Ihsan Y.
        • Athar W.
        • Marchitelli G.
        • Kelly D.
        • et al.
        Low serum 25-hydroxyvitamin D (25[OH]D) levels in patients hospitalized with COVID-19 are associated with greater disease severity.
        Clin Endocrinol. 2020; 93: 508-514https://doi.org/10.1111/cen.14276
        • Lips P.
        • Cashman K.D.
        • Lamberg-Allardt C.
        • Bischoff-Ferrari H.A.
        • Obermayer-Pietsch B.
        • Bianchi M.L.
        • et al.
        Current vitamin D status in European and Middle East countries and strategies to prevent vitamin D deficiency: a position statement of the European Calcified Tissue Society.
        Eur J Endocrinol. 2019; 180: P23-P54https://doi.org/10.1530/EJE-18-0736
        • Bouillon R.
        • Marcocci C.
        • Carmeliet G.
        • Bikle D.
        • White J.H.
        • Dawson-Hughes B.
        • et al.
        Skeletal and extraskeletal actions of vitamin D: current evidence and outstanding questions.
        Endocr Rev. 2019; 40: 1109-1151https://doi.org/10.1210/er.2018-00126
        • Amrein K.
        • Scherkl M.
        • Hoffmann M.
        • Neuwersch-Sommeregger S.
        • Köstenberger M.
        • Tmava Berisha A.
        • et al.
        Vitamin D deficiency 2.0: an update on the current status worldwide.
        Eur J Clin Nutr. 2020 Jan 20; : 1-16https://doi.org/10.1038/s41430-020-0558-y
        • Strazzullo P.
        • D'Elia L.
        • Kandala N.B.
        • Cappuccio F.P.
        Salt intake, stroke, and cardiovascular disease: meta-analysis of prospective studies.
        BMJ. 2009; 339: b4567
        • Wilck N.
        • Balogh A.
        • Markó L.
        • Bartolomaeus H.
        • Müller D.N.
        The role of sodium in modulating immune cell function.
        Nat Rev Nephrol. 2019; 15: 546-558
        • Kopp C.
        • Linz P.
        • Dahlmann A.
        • Hammon M.
        • Jantsch J.
        • Muller D.N.
        • et al.
        Na magnetic resonance imaging determined tissue sodium in healthy subjects and hypertensive patients.
        Hypertension. 2013; 61: 635-640
        • Titze J.
        • Shakibaei M.
        • Schafflhuber M.
        • Schulze-Tanzil G.
        • Porst M.
        • Schwind K.H.
        • et al.
        Glycosaminoglycan polymerization may enable osmotically inactive Na+ storage in the skin.
        Am J Physiol Heart Circ Physiol. 2004; 287: H203-H208
        • Muller S.
        • Quast T.
        • Schroeder S.
        • Klotz L.
        • Jantsch J.
        • Gerzer R.
        • et al.
        Salt- dependent chemotaxis of macrophages.
        PloS One. 2013; 8e73439
        • Machnik A.
        • Neuhofer W.
        • Jantsch J.
        • Dahlmann A.
        • Tammela T.
        • Machura K.
        • et al.
        Macrophages regulate salt- dependent volume and blood pressure by a vascular endothelial growth factor- C-dependent buffering mechanism.
        Nat Med. 2009; 15: 545-552
        • Binger K.J.
        • Gebhardt M.
        • Heinig M.
        • Rintisch C.
        • Schroeder A.
        • Neuhofer W.
        • et al.
        High salt reduces the activation of IL-4- and IL-13-stimulated macrophages.
        J Clin Invest. 2015; 125: 4223-4238
        • Jantsch J.
        • Schatz V.
        • Friedrich D.
        • Schroeder A.
        • Kopp C.
        • Siegert I.
        • et al.
        Cutaneous Na+ storage strengthens the antimicrobial barrier function of the skin and boosts macrophage- driven host defense.
        Cell Metabol. 2015; 21: 493-501
        • Zhang W.C.
        • Zheng X.J.
        • Du L.J.
        • Sun J.Y.
        • Shen Z.X.
        • Shi C.
        • et al.
        High salt primes a specific activation state of macrophages, M(Na).
        Cell Res. 2015; 25: 893-910
        • Kaiko G.E.
        • Horvat J.C.
        • Beagley K.W.
        • Hansbro P.M.
        Immunological decision-making: how does the immune system decide to mount a helper T cell response?.
        Immunology. 2008; 123: 326-338
        • Wu C.
        • Yosef N.
        • Thalhamer T.
        • Zhu C.
        • Xiao S.
        • Kishi Y.
        • et al.
        Induction of pathogenic TH17 cells by inducible salt- sensing kinase SGK1.
        Nature. 2013; 496: 513-517
        • Crome S.Q.
        • Clive B.
        • Wang A.Y.
        • Kang C.Y.
        • Chow V.
        • Yu J.
        • et al.
        Inflammatory effects of ex vivo human Th17 cells are suppressed by regulatory T cells.
        J Immunol. 2010; 185: 3199-3208
        • Hernandez A.L.
        • Kitz A.
        • Wu C.
        • Lowther D.E.
        • Rodriguez D.M.
        • Vudattu N.
        • et al.
        Sodium chloride inhibits the suppressive function of FOXP3+regulatory T cells.
        J Clin Invest. 2015; 125: 4212-4222
        • Elijovich F.
        • Laffer C.L.
        • Sahinoz M.
        • Pitzer A.
        • Ferguson J.F.
        • Kirabo A.
        The gut microbiome, inflammation, and salt-sensitive hypertension.
        Curr Hypertens Rep. 2020; 22: 79https://doi.org/10.1007/s11906-020-01091-9
        • Wilck N.
        • Matus M.G.
        • Kearney S.M.
        • Olesen S.W.
        • Forslund K.
        • Bartolomaeus H.
        • et al.
        Salt- responsive gut commensal modulates TH17 axis and disease.
        Nature. 2017; 551: 585-589
        • Faraco G.
        • Brea D.
        • Garcia-Bonilla L.
        • Wang G.
        • Racchiumi G.
        • Chang H.
        • et al.
        Dietary salt promotes neurovascular and cognitive dysfunction through a gut- initiatedTH17 response.
        Nat Neurosci. 2018; 21: 240-249
        • Smiljanec K.
        • Lennon S.L.
        Sodium, hypertension, and the gut: does the gut microbiota go salty?.
        Am J Physiol Heart Circ Physiol. 2019; 317: H1173-H1182https://doi.org/10.1152/ajpheart.00312.2019
        • Afshar M.
        • Richards S.
        • Mann D.
        • Cross A.
        • Smith G.B.
        • Netzer G.
        • et al.
        Acute immunomodulatory effects of binge alcohol ingestion.
        Alcohol. 2015; 49: 57-64https://doi.org/10.1016/j.alcohol.2014.10.002
        • Pruett S.B.
        • Zheng Q.
        • Fan R.P.
        • Matthews K.
        • Schwab C.
        Ethanol suppresses cytokine responses induced through Toll-like receptors as well as innate resistance to Escherichia coli in a mouse model for binge drinking.
        Alcohol. 2004; 33: 147-155https://doi.org/10.1016/j.alcohol.2004.08.001
        • Mandrekar P.
        • Bala S.
        • Catalano D.
        • Kodys K.
        • Szabo G.
        The opposite effects of acute and chronic alcohol on lipopolysaccharide-induced inflammation are linked to IRAK-M in human monocytes.
        J Immunol. 2009; 183: 1320-1327
        • Pang M.
        • Bala S.
        • Kodys K.
        • Catalano D.
        • Szabo G.
        Inhibition of TLR8- and TLR4-induced Type I IFN induction by alcohol is different from its effects on inflammatory cytokine production in monocytes.
        BMC Immunol. 2011; 12: 55
        • Maraslioglu M.
        • Oppermann E.
        • Blattner C.
        • Weber R.
        • Henrich D.
        • Jobin C.
        • et al.
        Chronic ethanol feeding modulates inflammatory mediators, activation of nuclear factor-kappaB, and responsiveness to endotoxin in murine Kupffer cells and circulating leukocytes.
        Mediators Inflamm. 2014; 2014: 808695
        • Barr T.
        • Helms C.
        • Grant K.
        • Messaoudi I.
        Opposing effects of alcohol on the immune system.
        Prog Neuro-Psychopharmacol Biol Psychiatry. 2016; 65: 242-251
        • McFarland W.
        • Libre E.P.
        Abnormal leukocyte response in alcoholism.
        Ann Intern Med. 1963; 59: 865-877
        • Mili F.
        • Flanders W.D.
        • Boring J.R.
        • Annest J.L.
        • DeStefano F.
        The associations of alcohol drinking and drinking cessation to measures of the immune system in middle-aged men.
        Alcohol Clin Exp Res. 1992; 16: 688-694
        • Cook R.T.
        • Waldschmidt T.J.
        • Ballas Z.K.
        • Cook B.L.
        • Booth B.M.
        • Stewart B.C.
        • et al.
        Fine T-cell subsets in alcoholics as determined by the expression of L-selectin, leukocyte common antigen, and beta-integrin.
        Alcohol Clin Exp Res. 1994; 18: 71-80
        • Cook R.T.
        • Ballas Z.K.
        • Waldschmidt T.J.
        • Vandersteen D.
        • LaBrecque D.R.
        • Cook B.L.
        Modulation of T-cell adhesion markers, and the CD45R and CD57 antigens in human alcoholics.
        Alcohol Clin Exp Res. 1995; 19: 555-563
        • Cho B.K.
        • Rao V.P.
        • Ge Q.
        • Eisen H.N.
        • Chen J.
        Homeostasis-stimulated proliferation drives naive T cells to differentiate directly into memory T cells.
        J Exp Med. 2000; 192: 549-556
        • Song K.
        • Coleman R.
        • Zhu X.
        • Alber C.
        • Ballas Z.
        • Waldschmidt T.
        • et al.
        Chronic ethanol consumption by mice results in activated splenic T cells.
        J Leukoc Biol. 2002; 72: 1109-1125
        • Zhang H.
        • Meadows G.G.
        Chronic alcohol consumption in mice increases the proportion of peripheral memory T cells by homeostatic proliferation.
        J Leukoc Biol. 2005; 78: 1070-1080
        • Hakim F.T.
        • Gress R.E.
        Immunosenescence: deficits in adaptive immunity in the elderly.
        Tissue Antigens. 2007; 70: 179-189
        • Chou J.P.
        • Effros R.B.
        T cell replicative senescence in human aging.
        Curr Pharm Des. 2013; 19: 1680-1698
        • Appay V.
        • Sauce D.
        Naive T cells: the crux of cellular immune aging?.
        Exp Gerontol. 2014; 54: 90-93
        • Romeo J.
        • Warnberg J.
        • Diaz L.E.
        • Gonzalez-Gross M.
        • Marcos A.
        Effects of moderate beer consumption on first-line immunity of healthy adults.
        J Physiol Biochem. 2007; 63: 153-159
        • Gonzalez-Quintela A.
        • Alende R.
        • Gude F.
        • Campos J.
        • Rey J.
        • Meijide L.M.
        • et al.
        Serum levels of immunoglobulins (IgG, IgA, IgM) in a general adult population and their relationship with alcohol consumption, smoking and common metabolic abnormalities.
        Clin Exp Immunol. 2008; 151: 42-50
        • Schmidt W.
        • De Lint J.
        Causes of death of alcoholics.
        Q J Stud Alcohol. 1972; 33: 171-185
        • Saitz R.
        • Ghali W.
        • Moskowitz M.
        The impact of alcohol-related diagnoses on pneumonia outcomes.
        Arch Intern Med. 1997; 157: 1446-1498
        • Panic E.
        • Panic I.
        Chronic alcoholics' knowledge regarding tuberculosis.
        Pneumologia. 2001; 50 (1): 232-235
        • Baum M.
        • Rafie C.
        • Lai S.
        • Sales S.
        • Bryan Page J.
        • Campa A.
        Alcohol use accelerates HIV disease progression.
        AIDS Res Hum Retroviruses. 2010 May; 26: 511-518https://doi.org/10.1089/aid.2009.0211
        • Bhattacharya R.
        • Shuhart M.
        Hepatitis C and alcohol: interactions, outcomes, and implications.
        J Clin Gastroenterol. 2003; 36: 242-252https://doi.org/10.1097/00004836-200303000-00012
        • Nalpas B.
        • Thepot V.
        • Driss F.
        • Pol S.
        • Courouce A.
        • Saliou P.
        • et al.
        Secondary immune response to hepatitis B virus vaccine in alcoholics.
        Alcohol Clin Exp Res. 1993; 17: 295-303