(http://www.ugm.ac.id)

BOOK CHAPTER

Nutrition, Immunity, and Infection Caryn Gee Morse and Kevin P. HighMandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 11, 125­133.e2

Although the effects of malnutrition have been recorded for centuries, the mechanistic linksbetween nutrition, immunity, and resistance to infection have only been defined over the pastseveral decades. The relationship between nutrition and immunity is most striking in thedeveloping world, where protein­energy malnutrition (PEM) predominates. In both developedand developing countries, however, specific micronutrient deficiencies are relatively common,even where PEM syndromes are rare. Both PEM and micronutrient deficiencies are associatedwith immune dysfunction and infection risk. Malnutrition not only affects immune function butalso virulence of infectious agents, progression of chronic infections such as tuberculosis andhuman immunodeficiency virus (HIV) infection, and transcriptional regulation of inflammatorygenes that may determine the outcome of infections.

Overnutrition—obesity—has emerged as a major public health threat, particularly exploding in theUnited States in the past 2 decades as noted in a report from the Centers for Disease Control andPrevention (CDC) ( www.cdc.gov/obesity/data/index.html (http://www.cdc.gov/obesity/data/index.html) ).According to the World Health Organization (WHO), obesity and overweight are evolving issueseven in developing countries, where some segments of the population, usually in urban areas, areexperiencing rapidly increasing numbers of overweight people whereas other segments, usually inrural areas, continue to have populations with widespread undernutrition. Obesity, typicallydefined as a body mass index (BMI) of 30 or higher, has a complex association with infection riskand outcome, and recent developments are highlighted in the following sections.

This chapter explores the relationships among nutritional factors, immunity, and virulence ofpathogens and their ties to the management of infectious diseases.

Epidemiology of Malnutrition

The WHO estimates that more than 30% of residents in developing nations are affected by hungerand malnutrition, with PEM cited as the primary cause of immunodeficiency worldwide. Amongchildren younger than 5 years of age, five infectious diseases—acute respiratory infections,diarrhea, malaria, measles, and HIV/acquired immunodeficiency syndrome (AIDS)—account formore than 50% of all deaths, and about half of those deaths are due to malnutrition.

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In developed nations, at­risk populations for malnutrition, primarily micronutrient malnutritionrather than PEM, include children, the elderly, pregnant women, homeless people, alcoholabusers, persons affected by acute and chronic illnesses including HIV/AIDS and end­stage renaldisease, and people with dietary restrictions, such as those with anorexia nervosa or bulimia andconsumers of vegetarian diets.

Malnutrition can be broadly defined as a decrease in nutrient reserve; and under this definitionundernutrition is prevalent even in the United States, affecting up to 15% of ambulatoryoutpatients, 25% to 60% of patients in long­term care, and 35% to 65% of hospitalized patients. A major reason for the wide range of rates cited is that many definitions for malnutrition exist.Several biochemical markers of nutritional status can give a general indication of nutritionalreserve, including visceral proteins (albumin, prealbumin, and transferrin), but low levels ofvisceral protein are not specific and may have other causes, including hepatic disease andincreased capillary permeability. Global indicators of cell­mediated immune function arecommonly used to assess malnutrition and can be estimated by total lymphocyte count (TLC) anddelayed­type hypersensitivity testing with a series of common antigens. Compromise of cell­

mediated immunity due to malnutrition is suggested by a TLC less than 1000/mm 3 or by lack ofskin test induration greater than 5 mm above glycerin control at 48 hours, unless another cause oflymphocyte dysfunction is present. However, these tests should be interpreted cautiously duringan acute illness, because cell­mediated immunity may be depressed in the absence ofmalnutrition.

The Institute of Medicine of the National Academy of Sciences and the Food and Nutrition Boardprovide dietary reference intakes (DRIs), including recommended dietary allowances (RDAs), foroverall protein, calories, and specific nutrients, including age­, gender­, and condition­specificrecommendations.

Malnutrition and Immune Function

PEM describes nutritional macrodeficiency syndromes, including marasmus (deficiency ofcalories), kwashiorkor (deficiency of protein), nutritional dwarfism in children, and wastingsyndromes in adults. Primary PEM, caused by inadequate nutrient intake, typically affectschildren and elderly people, and brief PEM effects are typically reversible with nutritional therapy.However, prolonged primary PEM can result in serious and irreversible changes in organ functionand growth. Secondary PEM results from illnesses, injuries, or treatments that alter appetite,digestion, absorption, or metabolism and have similar effects. Although the nutritional deficits ofpatients with PEM due to gastrointestinal tract dysfunction often can be restored to normal ifadequate nutritional support is provided by dietary supplements, enteral tube feeding, orparenteral nutrition, wasting disorders such as cancer or AIDS are characterized by involuntaryweight loss, often despite increased caloric intake. In wasting diseases, alterations in metabolismresult in greater loss of muscle tissue than would be expected from reductions of caloric intakealone and muscle mass is not restored by nutritional supplementation unless the underlyinginflammatory disease is treated. Weight gain that occurs as a result of nutritional support inpatients with these syndromes usually represents increases in fat mass and body water withoutsignificant change in lean tissue.

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PEM has been associated with a number of impairments in the immune response. Documented abnormalities of innate immunity include reduced production of cytokines, reducedphagocytosis, interruptions in the integrity of physical barriers and diminished quality of mucus,and reductions in complement components (C3 and C5). Alterations in adaptive immunity include

reduced or delayed cutaneous hypersensitivity to recall and new antigens and reductions in CD4 +

and CD8 + T­cell subsets, CD4 + /CD8 + ratio, lymphocyte proliferative capacity, immunoglobulin(Ig) G (IgG), and secretory IgA. In addition, malnourished children and elderly adultsdemonstrate elevated baseline biomarkers of inflammation, such as interleukin (IL)­6.

Specific Nutrients and Their Roles in Immunity

A complete review of nutrients and their roles in immune function is beyond the scope of thischapter. Several outstanding reviews are available, and the reader is referred to these publicationsfor additional information. A very brief review of major micronutrients and theirroles in immunity follows.

Fat­Soluble Vitamins

Vitamin A

Vitamin A is a subclass of the retinoic acids, a family of lipid­soluble compounds that includesretinols, β­carotenes, and other carotenoids. Retinol, or preformed vitamin A, is the most activeform; it is found primarily in animal food sources or can be synthesized from carotenoids. Theimportant role of vitamin A in immune system function is well established. Vitamin Adeficiency can affect host immunity through direct actions on immune cell function and throughindirect effects on epithelial cell differentiation and, consequently, host barrier defenses.

Vitamin A deficiency results in reduced mitogen­stimulated T­cell proliferation and antigen­

specific IgA and IgG production, impairs the ability of CD4 + T lymphocytes to stimulate Th2responses (B­cell antigen­specific IgG 1 responses), and limits the ability of neutrophils to

phagocytose bacterial pathogens.

Vitamin A supplementation has been examined in a number of randomized, double­blind,placebo­controlled trials of undernourished and malnourished children in developing nations.Antibody­mediated responses are impaired in individuals with vitamin A deficiency; and in somestudies (but not all), supplementation has improved antibody titer responses to measles vaccine,sustained gut integrity, and lowered the incidence of respiratory tract infections.

A Cochrane Review on the subject found that oral vitamin A supplementation in children reducedoverall mortality (relative risk [RR], 0.76; 95% confidence interval [CI], 0.69 to 0.83) anddiarrheal­associated mortality (RR, 0.72; CI, 0.57 to 0.91). Further, supplementation reduced theincidence of diarrhea (RR, 0.85; CI, 0.82 to 0.87) and measles (RR, 0.50; CI, 0.37 to 0.67) andreduced the prevalence of vision problems in children aged 6 months to 5 years.

In light of these trials and others demonstrating beneficial effects of vitamin A supplementationon immune function and its efficacy in preventing infection, the WHO recommends that vitamin Asupplementation be provided to young children and mothers residing in developing nations, even

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in the absence of signs or symptoms of deficiency. Implementation of this program has been oneof the great WHO success stories.

Although studies suggest an association between vitamin A deficiency and increased mortality,disease progression, and vertical transmission of HIV, vitamin A supplementation has not beenshown to improve outcomes in HIV­infected populations. Similarly, vitamin A supplementationdoes not improve outcomes in persons with active tuberculosis. Therefore, caution should beexercised in applying recommendations to other populations, especially those at much lower riskfor vitamin A deficiency. Excessive intake of vitamin A can produce acute toxic manifestations(headache, vomiting, stupor, and papilledema). Chronic toxicity is associated with weight loss,nausea, and vomiting; dryness of the mucosa of the lips; bone and joint pain; hyperostosis; andhepatomegaly with parenchymal damage and fibrosis. In the 1990s, two large trials evaluating therole of β­carotene in lung cancer prevention observed an increased risk for lung cancer in subjects(male smokers) receiving β­carotene. The reasons for this finding of increased risk remainunclear, emphasizing the need for further study on the role of retinoids in human health andimmunity before widespread supplementation with retinoid precursors can be recommended inwell­nourished populations.

Vitamin D

Vitamin D deficiency is remarkably common even in developed nations, particularly in those withreduced exposure to sunlight or reduced dairy intake or both. However, as with other vitamins,the prevalence depends on which metabolite is measured (25­hydroxyvitamin D or 1,25­dihydroxyvitamin D) and the cutoff value used for “deficiency.” Because it is easy to measure andwidely available, most population surveys use serum 25­hydroxyvitamin D levels, but thedefinition of “deficiency” depends on the outcome measured, and no standard has been declared.Regardless of the standard used, women more than men, older adults more than young adults

and children, and races other than white are more likely to be deficient. Older, institutionalizedadults and those with comorbidities that reduce their sunlight exposure or oral intake of fortifieddairy products are also at greatly increased risk.

The role of vitamin D (1,25­dihydroxycholecalciferol) in immune response has been recognized fordecades but recently has received more attention as the importance and ubiquity of vitamin Dreceptor expression has been shown and its role in host defenses against mycobacterial diseasehas been better defined. Vitamin D actually suppresses many adaptive immune responses (T­cellproliferation, antibody production) and some innate immune responses (dendritic cell co­stimulation and cytokine secretion). However, vitamin D is essential for proper function of otheraspects of the innate immune system, particularly in macrophage­mediated defenses. Thisappears to be principally important in Toll­like receptor–mediated defenses against intracellularpathogens such as Mycobacterium tuberculosis.

Persons with low 25­hydroxyvitamin D levels appear to be more susceptible to tuberculosis and athigher risk for progression from infection to disease. However, vitamin D supplementationtrials have failed to demonstrate an improvement in tuberculosis­related mortality or sputumsmear conversion rates. Additional data suggest that vitamin D deficiency is associatedwith impaired wound healing and predisposes to periodontal disease and upper respiratory

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tract infection, although no trials to date document benefits of supplementation. Ongoingstudies of vitamin D supplementation for the reduction of infection, cancer, and cardiovasculardisease–related morbidity and mortality should provide additional insight into the complex role ofvitamin D in human disease.

Vitamin E

A group of eight closely related fat­soluble compounds (four tocopherols and four tocotrienols) allexhibit vitamin E biologic activity, but α­tocopherol is the most active form, is abundant in manyfoods, and is most widely available as a supplement. Vitamin E is one of a group of antioxidantsthat scavenge free radicals formed in redox reactions throughout the body. Vitamin E activity iscomplemented by that of selenium, which, as a constituent of glutathione peroxidase, alsometabolizes peroxides before they cause membrane damage.

Hypovitaminosis E resulting from a deficient diet is uncommon in the developed world and occursalmost exclusively in association with severe fat malabsorption, in low­birth­weight infants, and inpatients with rare genetic disorders such as abetalipoproteinemia. Vitamin E supplementation hasmultiple immunologic effects, including enhanced T­cell proliferation, perhaps mediated bysuppressed production of prostaglandin E 2 (PGE 2 ), a T­cell–suppressive compound, and

enhanced delayed­type hypersensitivity responses. Clinical effects of vitamin Esupplementation have been studied mainly in the elderly (see “ Older Adults ”). Extensive researchon the biology of immune senescence and the effects of vitamin E on age­related immunedysfunction has been reviewed. Although beneficial effects of vitamin E supplementation havebeen suggested in a variety of noninfectious diseases, such as macular degeneration and hepaticsteatosis, the recent findings of increased risk for prostate cancer in healthy men receiving vitaminE supplementation will impact future intervention trials with vitamin E.

Water­Soluble Vitamins

Vitamin C

Vitamin C (ascorbic acid) can augment a number of biochemical reduction reactions involvingiron and copper and acts as an enzymatic cofactor and antioxidant in physiologically importantprocesses, including fatty acid transport, collagen synthesis, and neurotransmitter formation.

In humans, vitamin C deficiency is manifested as scurvy, the principal feature of which is impairedcollagen synthesis, with signs including capillary fragility, bleeding gums, delayed wound healing,and impaired bone formation. Animal studies and a limited number of human studies havesuggested an immunomodulatory role for ascorbic acid, with increased resistance to viral illnessand some anticarcinogenic effects, perhaps via reduced T­cell apoptosis.

Many trials have been performed to determine whether vitamin C might be useful to prevent ortreat the common cold. A comprehensive review concluded that vitamin C supplementation didnot reduce the incidence of common colds but did produce a consistent reduction in the duration

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of cold symptoms. A range from 0.07% to 39% reduction in symptom days was seen in differentstudies, and larger doses demonstrated a trend toward greater benefit. In contrast to mostother dietary antioxidants, vitamin C appears to be safe even at high levels of consumption.

Vitamin B

Vitamin B 6 (pyridoxine) plays an essential role in nucleic acid and protein synthetic pathways.

Not surprisingly, it appears to be essential for optimal lymphocyte function, maturation andgrowth, antibody production, cytokine production, and natural killer (NK)­cell activity. Increased consumption of vitamin B 6 enhanced lymphocyte proliferation and cytokine

production.

Folate

Folate deficiency is associated with reduced numbers of circulating lymphocytes, poor lymphocyteproliferation, impaired Th1 immunity, including delayed­type hypersensitivity responses, and NK­cell activity. Supplementation studies with immune response end points are few, butsupplementation has improved age­related declines in NK­cell function.

Vitamin B

Like folate, vitamin B 12 is essential to cell reproduction, including lymphocyte proliferation.

Vitamin B 12 deficiency is associated with reduced production of antibody to pneumococcal

polysaccharide; however, no study has been done to assess whether repletion of vitamin B 12reverses this defect, and a causal relationship has not been established.

Trace Metals

Zinc

Zinc (Zn 2+ ) is a dietary trace mineral that plays a critical role in the structure of cell membranesand in the function of cells of the immune system. Zinc is required for the activity of hundreds ofenzymes associated with carbohydrate and energy metabolism, protein synthesis and degradation,nucleic acid synthesis, heme biosynthesis, and carbon dioxide transport.

Zinc deficiency occurs most commonly in association with starvation, PEM, and malabsorptionsyndromes. In the developed world, zinc deficiency is seen primarily in children and the elderly,although it is estimated that a larger proportion of North Americans may be at risk. Zincdeficiency has been documented in association with numerous conditions of relativeimmunocompromise, including pregnancy, alcoholism, kidney disease, burns, inflammatorybowel disease, and HIV infection.

Clinical manifestations of zinc deficiency include growth impairment, delayed sexual maturation,hypogonadism, impotence, oligospermia, alopecia, dysgeusia, night blindness, impaired woundhealing, skin abnormalities, and impaired immunity.

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Clinical trials have examined the role of zinc in immune system modulation during infection andother illnesses. For children living in developing nations, zinc supplementation limited growthstunting and reduced the duration and intensity of diarrheal illness, acute lower respiratory tract

infections, and pneumonia. Children receiving zinc supplements had higher CD3 + and CD4 +

lymphocyte counts and higher CD4 + /CD8 + ratios in peripheral blood and improved cell­mediated immunity when compared with control subjects. Zinc supplementation also reduced theincidence of clinical disease caused by Plasmodium falciparum. In patients with sickle celldisease, zinc supplementation increased IL­2 production and decreased microbiologicallyconfirmed infections and hospitalizations.

A number of studies have evaluated the role of zinc in protecting against the common cold.Postulated mechanisms include zinc­mediated interference with rhinoviral protein cleavage andassembly of viral particles and protection of plasma membranes against lysis by cytotoxic agentssuch as microbial toxins and complement; some of these effects may be due to correction ofsubclinical zinc deficiency. It has also been suggested that common cold symptoms—sneezing andnasal discharge—may be reduced in intensity by elevations in intranasal zinc salts throughproduction of a “chemical clamp” on trigeminal and facial nerve endings. However, other trialshave cast doubt on the validity of these findings. The antirhinoviral effect of zinc is weak, andserum zinc concentrations are well below those required for a direct antiviral effect. A meta­analysis of eight published randomized trials found no clear benefit for the use of zinc lozenges inthe treatment of the common cold, and there are mixed/inconclusive data on the efficacy ofzinc to prevent otitis media or as adjunctive treatment for pneumonia in children.

Selenium

Selenium is essential for the function of selenium­dependent proteins, which play critical roles inthe redox regulation of key enzymes, transcription factors, and receptors. Beyond its role as anantioxidant, selenium may have additional immune properties that contribute to the maintenanceof normal immune function. Selenium is ubiquitous in the soil and enters the diet through bothplant and animal sources. Dietary intake varies depending on geographic region. Overt seleniumdeficiency is rare and is limited to certain regions of China. However, the effects of relativeselenium deficiency on disease susceptibility and disease progression remain only partiallycharacterized and are a subject of intense ongoing studies of both hosts and pathogen (see “ HostNutritional Status and Pathogen Virulence ”).

Selenium deficiency has been shown to decrease the production of free radicals and killing byneutrophils, IL­2 receptor affinity and expression on T cells, T­cell proliferation anddifferentiation, and lymphocyte cytotoxicity. In vitro, selenium deficiency results in enhancedneutrophil adherence to endothelial cells, an early event in the inflammatory response. In bothmice and humans, supplementation with selenium has been shown to increase lymphocyteproliferative responses, IL­2 receptor expression, and macrophage and cytolytic T­lymphocyte–dependent tumor cytotoxicity. Even at plasma selenium levels associated with normal dietaryintake in the United States, supplementation with 200 µg selenium per day has considerableimmunoenhancing effects, although an upper limit is likely, because “megadose” therapy may beassociated with reduced immunity.

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Iron

Iron deficiency is the most common trace element deficiency worldwide. It is estimated to affect20% to 50% of the world's population, including infants, children, and women of childbearing agein tropical regions. The effects of iron deficiency are seen in multiple systems of the humanbody, including the immune system. In animal and human studies, iron deficiency has beenassociated with impairments in cell­mediated immunity, reductions in neutrophil activity withdecreased myeloperoxidase activity and bactericidal activity, and diminished NK­cell activity. Iron deficiency has been shown to impair lymphocyte and neutrophil functions in children,

although no resultant increase in susceptibility to infection has been described. Whereas irondeficiency and infection often coexist in developing nations, no cause­and­effect relationship hasbeen established, except for the well­documented association between gastrointestinal blood lossand heavy infestations of hookworms.

Many of the immune abnormalities associated with iron deficiency appear to be reversible withiron replacement, but this has been difficult to demonstrate in human studies. Studies inlaboratory animals have demonstrated reversible, deleterious effects of iron deficiency onmeasures of functional immunity, even in mildly iron­deficient animals.

Most clinicians routinely replace iron in documented iron deficiency to avoid anemia andassociated morbidities. However, controversy exists regarding possible deleterious effects of ironsupplementation in some settings. Many microorganisms require trace elements such as iron andzinc for survival and replication in the host and may increase in pathogenicity withsupplementation. Iron deficiency appears to protect against severe malaria, and oral ironsupplementation has been associated with increased infection rates. Further, parenteral ironsupplementation has been shown in human and animal studies to be harmful when administeredduring infection. Therefore, administration of iron, particularly intravenous iron, or iron­chelating agents such as deferoxamine should be delayed in subjects with active infection.

Fatty Acids

Three major groups of dietary fatty acids—oleic acid, linoleic acid, and linolenic acid—serve asprecursors for the biosynthesis of polyunsaturated fatty acids (PUFAs). Metabolic competitionexists among these groups of fatty acids, and modification of dietary fatty acid intake can lead toalterations in the fatty acid composition of tissue lipids and, in turn, changes in cellular responses.

PUFAs, including arachidonic acid and eicosapentaenoic acid (EPA), can be enzymaticallyconverted to eicosanoids. Extensive data suggest a strong modulatory role for fatty acids in variouscellular responses, including inflammation and immune function, and there is growingevidence that they also act as second messengers or regulators of signal­transducing molecules. Among the fatty acids, it is the omega­3 (ω­3) PUFAs that possess the most potentimmunomodulatory activities; and among them, those found concentrated in fish oil, EPA, anddocosahexaenoic acid (DHA) are more biologically potent than α­linolenic acid (ALA).

A number of clinical trials have assessed the benefits of dietary supplementation with fish oils inseveral inflammatory and autoimmune diseases in humans, including rheumatoid arthritis,Crohn's disease, ulcerative colitis, psoriasis, lupus erythematosus, and multiple sclerosis. Animal

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and clinical studies of acute respiratory distress syndrome (ARDS) and sepsis suggest that a high­fat diet containing EPA (fish oil), γ­linolenic acid (GLA; borage oil), and antioxidants can improvelung microvascular permeability, oxygenation, and cardiopulmonary function, reduceproinflammatory eicosanoid synthesis and lung inflammation, and improve survival (see “Surgical and Critically Ill Patients ”).

Overnutrition: Obesity and Infectious Diseases

Obesity, defined as a BMI greater than 30, is epidemic in the United States and rapidly increasingglobally ( www.who.int/mediacentre/factsheets/fs311/en/index.html(http://www.who.int/mediacentre/factsheets/fs311/en/index.html) ). The association of obesity withdiabetes, cardiovascular disease, osteoarthritis, and many other chronic illnesses is well known,but the impact of obesity on infection and immunity is a relatively new field. Infection risk andoutcomes for many syndromes are influenced by obesity but not in a uniform direction ( Table 11­1(t0010) ). For example, it has been well documented that obesity was a major risk factor for adverseoutcomes in hospitalized subjects during the 2009 pandemic H1N1 influenza outbreak.Additionally, obesity is a risk factor for surgical site infection, prosthetic joint infection, andhospital­acquired infections. However, and perhaps surprisingly, there is a strong and consistentassociation with better clinical outcomes in obese patients with community­acquired pneumoniawhen compared with their nonobese counterparts. Several excellent, recent reviews have outlinedthe impact of obesity on infectious disease acquisition and outcome as well as postulated immunechanges that may contribute to these clinical findings.

TABLE 11­1

Risk for Infection Acquisition and/or Adverse Outcome in Obese vs. Nonobese Patients

INFECTION/SYNDROME RISK FORACQUISITION* (hl0000173)

RISK FORADVERSEOUTCOME* (hl0000173)

COMMENT REFERENCES

Respiratory Viruses

Influenza (H1N1 2009pandemic)

± ≫ Obesity clearly increases riskfor morbidity and mortality inhospitalized patients withH1N1 2009 strain, but smallamount of data regardingacquisition does not suggest abig increase in risk. Elevatedleptin, impaired CD4 and CD8T cell responses, and poorTLR­based responses inobese subjects may play apathogenic role.

Multiple;reviewed in

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Influenza (non­H1N1) ± > Weaker database than forH1N1, but some data tosuggest hospitalization due toinfluenza more likely in obesepatients, but not more likely toacquire influenza. Adequacy ofvaccine response depends onoutcome measured(seroprotection/seroconversion[which is not impaired] vs.duration of antibody rise,memory cell production [whichis impaired]).

Respiratory syncytialvirus

NR > (pediatricdata only)

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Community­AcquiredBacterial Pneumonia

± ≪ Risk for acquisition datagreatly confounded byassociated comorbidities; oncethese are adequatelycontrolled, there is little/noassociation of obesity withacquisition of pneumonia.However, there is a surprisingand consistent reduction inmortality in obese patients vs.nonobese patients.

Risk: 113

(reviewed in ) Outcomes:

Bacteremia and Sepsis > >(bacteremia) < (sepsis)

Bacteremia without sepsis onpresentation is associated withincreased mortality in obesepatients in small studies. Incontrast, although obesesubjects have a greater risk forsepsis, when presenting with sepsis, severe sepsis, andseptic shock they fare better than nonobese subjects.

Surgical Site Infections ≫ NR Consistent across general,colorectal, spinal, jointreplacement, cesareansection, and other surgeries

Multiple;recentlyreviewed in

Bone and Joint

Infection

Osteomyelitis NR NR Clearly associated with DM,but no data of obesity riskalone when appropriatelycontrolling other comorbidities

Septic arthritis NR NR

Prosthetic joint infection ≫ NR May be due to increasedsurgical time, underdosing ofprophylactic antibiotics, etc.

Urinary Tract Infection > NR More prominent effect ofobesity in males than infemales

Hospital­AcquiredInfections † (hl0000176)

≫ > Worse outcomes in obesepatients include longer lengthof stay and ventilator durationin addition to adverse clinicaloutcomes (e.g., mortality)

Helicobacter pyloriInfection

≫ > Multiple studies demonstrateincreased prevalence in obeseindividuals perhaps due to lackof H. pylori altering ghrelinexpression and predisposingto obesity rather than obesitypredisposing to H. pylori infection

HIV Infection NR > Greatly increasing obesityprevalence, particularly amongwomen with HIV; weight gainis substantial after initiatingHAART; obesity associatedwith ↑ risk for DM,cardiovascular disease, frailty,and multimorbidity

Modified from data from [object Object].

DM, diabetes mellitus; HAART, highly active antiretroviral therapy; HIV, humanimmunodeficiency virus; TLR, Toll­like receptor.

* ≫, substantially greater risk; >, greater risk; ±, little difference; <, less risk; ≪, substantially lessrisk; NR, not reported.

† Consists of hospital­acquired bacteremia, catheter­related infection, pneumonia, urinary tractinfection, and Clostridium difficile colitis.

The immune mechanisms affected by obesity are broad, involve all aspects of the immuneresponse, and, in general, upregulate inflammatory responses while diminishing most cellularresponses, but there are notable exceptions. In humans, obesity has been associated withan increased inflammatory milieu that has been hypothesized to increase the production of short­term memory T­cell and B­cell responses but impaired memory responses ( Fig. 11­1 (f0010) ). Thisis consistent with the finding that obesity does not impair initial vaccine responses to influenzaand other antigens but shortens the duration of protective immunity.

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FIGURE 11­1

Hypothesized alterations in immune responses to influenza in obese hosts.A, Influenza infection andresponse processes modified by obesity are shown in red. B, Net result of obesity is elevated levels of short­lived effector cells (SLEC) but impaired long­lived memory cells. AICD, activation­induced cell death; APC,

antigen­presenting cell; DC, dendritic cell; IFN, interferon; IL, interleukin; MCP, monocyte chemotactic protein;

MPEC, memory precursor effector cells; NK, natural killer; RANTES, regulated on activation, normal T cell

expressed and secreted; TNF, tumor necrosis factor.

(From Karlsson EA, Beck MA. The burden of obesity on infectious diseases. Exp Biol Med (Maywood).

2010;235:1412­1424.)

At least in the case of 2009 H1N1 influenza, overexuberant inflammatory responses may be amajor driving factor in adverse outcomes and are likely mediated by high leptin levels in obesity.Increased mortality in obese mice, similar to that seen in obese humans, is markedly attenuatedby administration of antileptin antibodies.

Special Populations: Clinical Trials of Nutritional Supplementation to Reduce InfectionRisk

To illustrate the general issues discussed to this point, three clinical populations of specificinterest are highlighted: surgical and critically ill patients, HIV­infected persons, and older adults.These populations are frequently encountered by infectious disease specialists, and research inthese three groups has been of particularly high quality, with well­designed epidemiologic andinterventional studies.

Surgical and Critically Ill Patients

Enteral and parenteral nutrition have been compared in a number of conditions in critically illpatients by randomized, controlled trials, confirming the utility of this approach. Further, a recentreview of enteral versus parenteral nutrition for acute pancreatitis demonstrated reduced risks fordeath, multiple organ failure, systemic infection, and local septic complications, as well as reducedlength of stay when using enteral rather than parenteral nutrition. For severe pancreatitis, thereduction in mortality for enteral versus parenteral nutrition was over 80% (RR, 0.18; 95% CI,0.06 to 0.58). Thus, the adage of “if the gut works, use it” appears applicable across the breadthof critical care patient populations, and enteral nutrition should be used whenever possible. Ofcourse, total parenteral nutrition can play a role in those for whom enteral nutrition cannot beapplied. Data from an international survey of nearly 3000 critically ill patients suggested a strong,inverse relationship between 60­day mortality and ventilator­free days with total daily calorieintake, particularly in those patients with a BMI less than 25 or greater than 35, and this was trueeven in the 25% of patients who received total parenteral nutrition alone or in combination withenteral nutrition to achieve caloric goals.

* An outstanding reference with exhaustive and well­organized topical reviews of the concepts discussed in

this section can be found at .

Immunonutrition

Although the mechanism(s) through which nutritional supplementation exerts positive effects oncritically ill patients is uncertain, the reduced infection risk with enteral feeding is hypothesized tobe related to the promotion of intestinal mucosal integrity, blunting of proinflammatoryresponses, and enhanced wound healing. This hypothesis has given rise to the concept of“immunonutrition”—specific formulations to replace micronutrients that frequently becomedeficient in acute inflammatory states and to provide anti­inflammatory nutrients that reduceinfection risk. Supplement studies using glutamine, arginine, N ­acetylcysteine, branched­chainamino acids, nucleotides, ω­3 PUFAs, antioxidant vitamins and trace elements, taurine, andvarious mixtures of these compounds have been investigated. Although some controversy exists,

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guidelines from multiple societies have been published recently and the relative agreement anddisagreement of these guidelines has been well summarized. In general, however, theguidelines agree that:

1. Arginine supplementation should be provided to surgery and trauma patients and reducesinfection rates. However, it should be avoided in patients with severe sepsis because it may beharmful, perhaps owing to overproduction of nitric oxide. The role of arginine inmild/moderate sepsis has yet to be defined.

2. Glutamine supplementation is recommended for all critically ill patients on total parenteralnutrition and is likely of benefit in burn and trauma patients on enteral nutrition.

3. The ω­3 fatty acids (with or without ω­6 γ­linoleic acid) are beneficial and should be used inpatients with acute lung injury/ARDS and probably are of value in those with sepsis, majorsurgery, and trauma.

4. Antioxidants may be of benefit in multiple populations and unlikely to be of harm.

Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome

Recognition of malnutrition and principles of nutritional management are important aspects ofthe primary care of HIV­infected patients. Severe malnutrition was one of the firstrecognized manifestations of advanced disease in HIV­infected persons, initially described as“slim disease” in early reports from Africa. The “wasting syndrome” was later defined by theCDC as a body weight loss equal to or greater than 10% with associated fatigue, fever, and diarrheaunexplained by another cause; however, any weight loss of more than 5% is associated withaccelerated disease progression, impaired functional status, and increased mortality. Early inthe HIV epidemic, studies reported wasting in up to 20% of patients at the time of AIDS diagnosisin the United States. Despite advances in the management and treatment of HIV infection, thewasting syndrome and other forms of malnutrition remain highly prevalent in the HIV­infectedpopulation. Wasting is associated with increased mortality and remains a significant prognosticfactor in advanced HIV disease.

The cause of AIDS­associated wasting is multifactorial. Wasting has been associated withdecreased oral intake, malabsorption syndromes, endocrine dysfunction, and increased cytokineproduction. Reductions in food intake may be caused by disease­ or drug­associated anorexia,central nervous system dysfunction, dysphagia, and odynophagia. Absorption may be impaired byinfectious or drug­associated intestinal inflammation, dysfunction, and diarrhea. Endocrineabnormalities include alterations in thyroid and adrenal function and fluctuations in growthhormone levels. Production of proinflammatory cytokines leads to accelerated metabolicdegradation of essential micronutrients, further compromising the HIV­infected host. The use ofnutritional therapy throughout the course of HIV infection, and with increased intensity duringsymptomatic infection, can slow and perhaps reverse the compounding effects of nutrition­associated immunodeficiency.

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PEM is the most common form of malnutrition seen in HIV disease worldwide, but alterations inthe stores of fat­ and water­soluble vitamins and trace elements are also seen. Vitamin Adeficiency has been associated with the progression of HIV disease, development of secondaryinfections, increased HIV­associated mortality, and increased maternal­fetal transmission. Deficiencies of water­soluble vitamins appear to occur less frequently than those of fat­soluble

vitamins, and only cobalamin (B 12 ) deficiency is associated with HIV disease progression. Of

the trace elements, deficiencies in iron, zinc, and selenium have been described. Zinc levels declineas HIV disease progresses, and zinc supplementation in HIV infection has been shown to improveimmune responses.

Selenium deficiency occurs more commonly in HIV­infected persons, as documented by lowplasma and red blood cell levels of selenium, diminished activity of glutathione peroxidase, andlow selenium levels in cardiac muscle of AIDS patients. Plasma selenium concentrations may bereduced by up to 50% in AIDS patients, with lesser reductions seen in persons receivingantiretroviral therapy. The mechanism of selenium depletion in HIV­infected individuals ispoorly understood and is probably multifactorial. Declines in selenium levels have beendocumented even in the earliest stages of HIV infection, and accelerated progression of HIVdisease has been described in patients with selenium deficiency.

Selenium supplementation trials in HIV­infected individuals improved markers of oxidative

stress, improved CD4 + T­cell counts, and, in pregnant women in Tanzania, reduced mortalityassociated with diarrheal illness.

Strategies to Combat Weight Loss and Wasting Associated with HumanImmunodeficiency Virus

Appetite stimulants, hormone replacement therapy, and anticytokine therapies—all with orwithout exercise—have been used in small clinical trials to combat wasting syndrome in HIV­infected patients with variable success. Treatment with anabolic steroids, particularlyintramuscular testosterone in testosterone­deficient men, may offer sustainable gains in musclemass and improvements in mood and quality of life. A full examination of these strategies isbeyond the scope of this review, but specific nutritional approaches are evaluated in the followingparagraphs.

Macronutrient Supplementation

Macronutrient (calorie and protein) supplementation was recently evaluated in a CochraneCollaboration Review by Grober and colleagues. Fourteen trials with a total of 1996 HIV­positive participants, including 245 children, met the stringent criteria for inclusion; excludedwere studies of more than one nutritional intervention, those involving pregnant women, andthose examining total parenteral nutrition versus enteral nutrition. Total caloric and total proteinintakes were enhanced by supplementation of 600 to 960 kcal/day, but, not surprisingly, bodyweight, fat mass, fat­free mass, CD4 count, and HIV viral load were unchanged.

As pointed out in the Cochrane Review, most studies were small and combining studies is difficultgiven the varying formulations used. Very little data exist in older age groups or in HIV­infectedpatients with lipodystrophy or obesity, in whom nutritional supplementation could result in

70 7172

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increased rates of diabetes or cardiovascular illness.

Micronutrient Supplementation

Micronutrient deficiency is even more common than macronutrient deficiency in the developingworld, and there is strong epidemiologic evidence linking micronutrient deficiencies to adverseoutcomes in many infectious diseases, including HIV infection. A Cochrane Systematic Reviewevaluating micronutrient supplementation in HIV­infected children and adults was published in2005 and updated in 2010. An important feature of this meta­analysis is that most of thestudies were conducted in resource­poor countries where malnutrition is very common. Thirtystudies involving 22,120 HIV­positive participants were included in the analysis. Vitamin Astudies predominated, including five studies of vitamin A supplementation in children and sixstudies of vitamin A/β­carotene supplementation in adults. The other studies were typicallymultivitamin/mineral interventions, with antioxidants playing a prominent role.

Essentially, vitamin A and/or β­carotene supplementation had very little effect on morbidity,mortality, or surrogate markers of immune function in adults. Although the findings wereinconsistent, there was a general trend toward benefit of vitamin A supplementation for HIV­infected children, with reductions in diarrheal disease mortality and overall mortality. In studiesof other micronutrients, usually given as a multivitamin/mineral supplement and sometimes atvery high doses (e.g., 20 times the RDA), some improvements in morbidity (e.g., opportunisticinfections, hospitalizations) or in surrogate markers of immunity such as CD4 count were noted insome studies, but not others. Given the very different formulations used, it is difficult to drawspecific conclusions or to make specific recommendations.

An important subgroup was that of pregnant women. Nutritional indicators of adverse outcomesin pregnancy for HIV­infected women in Africa include a BMI of less than 21.8, a hemoglobinconcentration of less than 8.5 g/dL, and weight loss or excessive weight gain during pregnancy. One relatively large ( N > 1000), randomized trial of multivitamin/mineral supplementation inpregnant or lactating Tanzanian women demonstrated benefit for both mothers and infants. Women experienced less AIDS­related progression of disease and mortality, fewer adverse

pregnancy outcomes, and less diarrheal morbidity. Infants of mothers with impaired immunologicand nutritional parameters suffered less early childhood mortality if they were born to women inthe multivitamin­supplemented group.

Older Adults

The elderly represent a population at significant risk for malnutrition and its related healthproblems. Malnutrition and decreased oral intake in older adults is often multifactorial. In theinpatient setting, “nothing by mouth” orders, inability to feed oneself, and increased caloric needshead the list. In the outpatient setting, depression, medications, dental or swallowing problems,and social issues (e.g., choices between food and medicine) are paramount. Studies usinganthropometric measures and laboratory values estimate 40% to 60% of hospitalized seniors aremalnourished. A prospective study of non–terminally ill elderly patients discharged from an

acute care hospital found a BMI less than or equal to 20 kg/m 2 to be associated with a markedlyincreased risk for death within 1 year. Among long­term and subacute care residents, the

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prevalence of malnutrition is 15% to 66% and even prevalent in community­dwelling seniors (Table 11­2 (t0015) ). Micronutrient deficiencies are also prevalent among older adults, with 10% to30% having subnormal levels of some vitamins or minerals (see Table 11­2 (t0015) ).

TABLE 11­2

Prevalence of Nutritional Deficiencies in Older Adults Residing in Various Settings [object Object]

NUTRIENT LONG­TERM CARE OR HOSPITALIZED(% DEFICIENT)

COMMUNITY­DWELLING (%DEFICIENT)

Protein/calories 17­85 10­25

Vitamin A 2­20 2­8

Vitamin B 12 ND 7­15

Vitamin D 50­85 8­40

Vitamin E 5­15 ND

Zinc ND 15­25

ND, no data.

* Data are pooled from multiple studies.

Nutritional Supplements in Older Adults: Effects on Immunity and Clinical Outcomes

Although malnutrition in the elderly is clearly associated with impaired immunity and poorclinical outcomes, nutritional supplementation has not definitively been shown to reverse thistrend. Many studies examined only immune response variables rather than clinical end points,and these have been recently reviewed. Studies specifically addressing clinical end pointsare emphasized in the following paragraphs for the most well­studied entities:multivitamin/mineral supplements, vitamin E, and zinc.

Multivitamin and Trace Mineral Supplements

Studies of multivitamin/mineral supplementation for the prevention of infection have beenperformed in both outpatient healthy elderly and long­term care residents and are summarized inTable 11­3 (t0020) .

TABLE 11­3

Randomized, Placebo­Controlled Multivitamin/Mineral Supplementation Trials in Older Adults

REFERENCE(yr)

NO. ANDPOPULATIONSTUDIED

STUDYDURATION(mo)

RANDOMIZEDGROUPS

OUTCOMEMEASURED

COMMENT

Girodon et al 81 NH 24 1. Daily MVI MD­confirmed No mortality

87

12 88 89

90 91 92 93 94 95

90 (1997) residents 2. Daily Zn 2+ , Se 3. Daily

MVI, Zn 2+ , Se 4. Placebo

respiratory orurogenitalinfection–related mortality

difference;lower infectionwith TM or TM+ MVI, but notwith MVI alone

Girodon et al 91 (1999)

725 NHresidents

24 1. Daily MVI

2. Daily Zn 2+ , Se 3. Daily

MVI, Zn 2+ , Se 4. Placebo

MD­confirmedrespiratory orurogenitalinfection–related mortality

No mortalitydifference;borderlinereduction ininfection ( P =.06) andimprovedinfluenzavaccineresponses withTM but not withMVI alone

Graat et al 92

(2002)

652Community­dwelling olderadults

15 1. Daily MVI,

Zn 2+ , Se 2. Daily MVI, Zn

2+ , Se,vitamin E 3. Vitamin E 4. Placebo

Self­reportedrespiratory tractinfection

No difference inincidence ofinfection;significantlyworse symptomseverity invitamin Erecipients

Barringeret al 93 (2003)

130Community­dwelling olderadults (33were >65 yr;others DMpatients)

12 1. Daily MVI,

Zn 2+ , Se 2. Placebo

Self­reportedinfectionconfirmed byMD

Lowerincidence ofinfection overall( P < .001) andin subset withtype 2 DM ( P <.001), but not inelderly subset ( P > .2)

Avenell et al 94 (2005)

910Community­dwelling olderadults

12 1. Daily MVI,

Fe, I, Zn 2+ ,Mn 2. Placebo

No primary caredoctor visits forinfection, self­reportedinfection,quality of life

No significantdifference inany parametermeasured

Liu et al 95

(2007)

763 NHresidents

18 1. Daily MVI,Ca, Mg, Fe, I,

Cu, Zn 2+ , Se 2. Placebo

Infection controlpractitionersurveillance forall infections,hospitalizations,and antibioticuse

No significantdifferenceexcept in posthoc analysis:after excludingsubjects withdementia,infection riskwas reduced inremaining NHresidents (RR,0.81; 95% CI,0.66­0.99).

Ca, calcium; CI, confidence interval; Cu, copper; DM, diabetes mellitus; Fe, iron; I, iodine; MD,medical doctor; Mg, magnesium; Mn, manganese; MVI, multivitamin; NH, nursing home; RR,

relative risk; Se, selenium; TM, trace minerals; Zn 2+, zinc.

Overall, it has been difficult to show any clear benefit from multivitamin/mineralsupplementation in community­dwelling older adults. In long­term care residents, a series ofstudies hints that trace mineral (zinc and selenium) supplementation may be more effective thanmultivitamins for reducing the incidence of respiratory tract infection, but there is little effect onurinary tract infection or pressure ulcers. Further, those patients without dementia maybenefit most from supplementation, based on a post hoc analysis of one study.

Vitamin E

Vitamin E has been shown to enhance both humoral and cell­mediated immune responses inelderly individuals. Supplementation with vitamin E at 200 or 800 mg/day in healthy older adultsimproved delayed­type hypersensitivity responses and immunization responses to hepatitis B butnot to pneumococcal polysaccharide or tetanus. However, in another study, the severity ofsymptoms due to infection was significantly worse in the vitamin E–supplemented group, withgreater total illness duration and number of symptoms and more frequent fever and activityrestriction (compared with those receiving placebo), although it is possible that these findingsrepresent enhanced immune responses in the vitamin E recipients. One additional study in long­term care residents showed varied benefit from vitamin E supplementation, depending on theoutcome measured. There was no difference in the number of overall days of respiratory tractinfection, the primary end point of the study, but a lower proportion of subjects in the vitamin Egroup experienced one or more respiratory tract infections (RR, 0.88; 95% CI, 0.76 to 1.0), andthe effect appeared to be most prominent for upper (vs. lower) respiratory tract infections. Therewas no effect on antibiotic use. A subanalysis of this study implicated low serum zinc levels as arisk factor for pneumonia in these subjects, suggesting that trace minerals should be a focus ofsubsequent studies. Further, there may be interactions between genotypes at specific loci (e.g., IL­10), gender, and vitamin E on risk for respiratory tract infection. That same study suggestedthat specific single nucleotide polymorphisms of IL­1, IL­10, and interferon­γ have lower risk for

90 91 95

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92

96

97

98

respiratory infection regardless of vitamin E supplementation. There are also complex interactionsof vitamin E supplementation in male smokers and risk for upper respiratory tract infections,pneumonia, or tuberculosis depending on duration/severity of prior smoking, activity level, andother vitamin supplementation. Obviously much work remains to determine thosewho may benefit from vitamin E supplementation for reducing infection risk.

It is clear, however, that high doses of vitamin E should be avoided for most seniors. A meta­analysis of vitamin E supplementation trials demonstrated increased mortality for those receivingdaily doses of 400 IU or greater.

Zinc

A wealth of evidence links low levels of zinc to impaired immune function and risk for infection.Zinc supplementation was included in all the clinical trials of vitamin E and/or multivitamin

supplementation to prevent infection in older adults cited previously. Zinc supplementation wasstudied as the primary micronutrient provided to institutionalized seniors in an additional study,

and trends found were lower risk for overall infection, fever, and upper respiratory tractinfections. An important insight regarding zinc and infection risk was noted in a reanalysis of aprior trial based on end­of­trial serum zinc level. In that study, the incidence of pneumonia,duration of pneumonia, and use of antibiotics for pneumonia were all dramatically reduced inthose with an end­of­trial serum zinc level of more than 70 µg/dL, whereas baseline serum zinclevel was not associated with any of these outcomes. This indicates that the ability to increaseserum zinc levels—perhaps due to other unmeasured factors such as absorptive capacity,comorbidity, zinc excretion, etc.—is a strong indicator of pneumonia risk, but the role of the zincreplacement itself remains to be defined.

Host Nutritional Status and Pathogen Virulence

An important link of infection and malnutrition may not lie within the host's impaired responsebut within the pathogen itself that may be altered by specific conditions present in thenutritionally impaired host. In selenium­deficient mice, infection with either coxsackievirus B orinfluenza virus led to the rapid development of mutations in the viral genome; in the case ofinfluenza, mutations occurred specifically in the matrix (M) proteins M1 and M2. These mutationsaltered the virulence of influenza, increasing the severity of illness in subsequent hosts even ifthose hosts were adequately nourished ( Fig. 11­2 (f0015) ). It appears that the redox statusof the host is the key factor governing this process. In follow­up studies, Gay and colleaguesdemonstrated that advanced age, characterized by a limited capacity to buffer oxidative stress(similar to selenium deficiency), could also induce the accelerated mutation rate and virulencechange in coxsackievirus.

99 100 101 102

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106 107

108

FIGURE 11­2

Effect of malnutrition on virulence of a viral pathogen.Replication of relatively nonvirulent strains of a virus

within a malnourished host (e.g., mouse with selenium [Se] deficiency) leads to hypermutation within the viral

genome, resulting in the emergence of more virulent strains. Once the hypervirulent quasi­species emerge,

they cause more serious illness even in nutritionally replete hosts. VitE, vitamin E.

(From Beck MA, Handy J, Levander OA. Host nutritional status: the neglected virulence factor. Trends

Microbiol. 2004;12:417­423.)

Although animal data support the model of enhanced mutation rates and augmented virulenceshown in Figure 11­2 (f0015) , there are sparse data in humans. There have been limitedinvestigations of the mutation rate in subjects with marginal selenium status. Seleniumsupplementation was provided to a small group of human subjects before, during, and after theadministration of live poliovirus (OPV) vaccine, and stool samples were collected to determine themutation rate in the selenium­supplemented and control groups. The mutation rate of the OPVvaccine strain was significantly higher in the group that did not receive selenium supplementation,supporting the animal findings previously outlined. This led to the theory that hosts who arenutritionally deficient (e.g., selenium deficient) or who are oxidatively stressed (e.g., aged adults

) may provide an ideal environment to induce a high mutation rate in infecting pathogens,leading to enhanced virulence (see Fig. 11­2 (f0015) ).

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2. Katona P, and Katona­Apte J: The interaction between nutrition and infection. Clin Infect Dis2008; 46: pp. 1582­1588

7. Omran ML, and Morley JE: Assessment of protein energy malnutrition in older persons, part II:Laboratory evaluation. Nutrition 2000; 16: pp. 131­140

8. Food and Nutrition Information Center, National Agricultural Library, United StatesDepartment of Agriculture : DRI Tables.

9. Strohle A, Wolters M, and Hahn A: Micronutrients at the interface between inflammation andinfection—ascorbic acid and calciferol, part 1: General overview with a focus on ascorbic acid.Inflamm Allergy Drug Targets 2011; 10: pp. 54­63

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10. Strohle A, Wolters M, and Hahn A: Micronutrients at the interface between inflammation andinfection—ascorbic acid and calciferol, part 2: Calciferol and the significance of nutrientsupplements. Inflamm Allergy Drug Targets 2011; 10: pp. 64­74

11. Wintergerst ES, Maggini S, and Hornig DH: Contribution of selected vitamins and traceelements to immune function. Ann Nutr Metab 2007; 51: pp. 301­323

12. Webb AL, and Villamor E: Update: effects of antioxidant and non­antioxidant vitaminsupplementation on immune function. Nutr Rev 2007; 65: pp. 181­217

13. Bikle DD: Vitamin D and the immune system: role in protection against bacterial infection.Curr Opin Nephrol Hypertens 2008; 17: pp. 348­352

14. Stephensen CB: Vitamin A, infection and immune function. Annu Rev Nutr 2001; 21: pp. 167­192

17. Mayo­Wilson E, Imdad A, Herzer K, et al: Vitamin A supplements for preventing mortality,illness, and blindness in children aged under 5: systematic review and meta­analysis. BMJ 2011;343: pp. d5094

18. Wiysonge CS, Shey MS, Sterne JA, et al: Vitamin A supplementation for reducing the risk ofmother­to­child transmission of HIV infection. Cochrane Database Syst Rev 2005;

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39. Haider BA, Lassi ZS, Ahmed A, et al: Zinc supplementation as an adjunct to antibiotics in thetreatment of pneumonia in children 2 to 59 months of age. Cochrane Database Syst Rev 2011;

46. Calder PC, and Grimble RF: Polyunsaturated fatty acids, inflammation and immunity. Eur JClin Nutr 2002; 56: pp. S14­S19

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