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Zinc and Diarrheal Disease: Current Status and Future Perspectives

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Zinc plays an important role in modulating host resistance 10 inlcctious agents and reducing the risk, scvcrity, and duration ofdiarrheal diseases. Zinc is important in the developing world and in low-income and middle-income countries where mild-tomoderate zinc deficiency is highly prevalent. The WHOfUNICEF recommendations for zinc supplementation: 20mg zinc/day for10-14 days for children with acute diarrhea and 10 mg/day for infants under 6 months of age. Effective fOnTIS include sulfate,gluconate, or acetate. No similar studies have been conducted on adults. Thus, carefully conducted clinical trials are necessary toascertain the efficacy ofzine in prevention of acute and persistcnt diarrhea in adults. Faced with rising antibiotic resistance and thelack of effective antidiarrheal vaccines, oral zinc provides substantial benefit in the reduction of stool output and disease durationcombined with safety, selectivity of action, and low cost. Thus, oral zinc supplementation is a practical therapeutic intervention forthe treatment of diarrhea in children, and by extension, should be provided to adults.

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Cholera, diarrhea, cntcrotoxigenic Escherichia coli, HIV, shigellosis

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Zinc and diarrheal disease: current status and future perspectivesAngus G. Scrimgeour" and Henry C. Lukaskib

'us Army Rasoa,,;h Institute of EnvoronmcnlalMedIC"''', Military NUlnbon Div,s""" Na~ck.

Massachuscns and bUS Department o! Agriculture,Agricultural Research SeMCC, Grand FOfks HumanNutntion Research Center, Grand Fork., North Dakota.USA

Correspondence to Angus G. Scnmgoour, US ArmyResearch Instltule of E''''''onmental Medicine,Military Nutnllon Divis",", Natick, MA 01760, USATel; +1508 233 5155;c-mail: angus.scrimgcou.@us.army.mi

Current Opinion in Clinical Nutrition andMetabolic Care 2008, 11 :711 -717

Purpose of reviewTo evaluate clinical data indicating the benefits of oral zinc supplementation to prevent

and/or treat diarrhea in children and extend Ihese findings to adults.

Recent findingsZinc plays an important role in modulating host resistance to infectious agents andreducing the risk, severity, and duration of diarrheal diseases. Zinc is important in thedeveloping world and in low-income and middle-income countries where mild-to­

moderate zinc deficiency is highly prevalent.The WHO/UNICEF recommendations for zinc supplementation are based on meta­

analyses of randomized, controlled intervention trials on children: 20mg zinc/day for10-14 days for children with acute diarrhea and 10 mg/day for infants under 6 months

of age. Effective forms include sulfate, gluconate, or acetate, No similar studies havebeen conducted on adults. Thus, carefully conducted clinical trials are necessary to

ascertain the efficacy of zinc in prevention of acute and persistent diarrhea in adults.SummaryFaced with rising antibiotic resistance and the lack of effective antidiarrheal vaccines,oral zinc provides substantial benefit in the reduction of stool output and disease

duration combined with safety, selectivity of action, and low cost. Thus, oral zincsupplementation is a practical therapeutic intervention for the treatment of diarrhea inchildren, and by extension, should be provided to adults.

Keywordscholera, diarrhea, enterotoxigenic Escherichia coli, HIV, shigellosis, zinc

CUlT op'" Clin Nulr Metab Care 11 :711 -717C 2008 Wooers Kluwer Health I Lippin<:ott Williams &. Wilkins1363-1950

IntroductionDiarrhea is a syndrome that is frequently not differen­tiated clinically by specific etiologic agent. Diarrhearemains a major public health problem, especially inchildren in devclopinl; countries, with :tpproximatdy1.5 billion episodes per year. It is estimated that diarrhealdiseases cause 2 million deaths annually in childrcnunder the age of S years and contribute substantially to

malnutrition in the surviving children II J. The usc ofglucose-e1ectrolytc oral rchydration therapy (ORS) hasdramatically reduced mortality from dehydration causedby diarrhea - estimates of global mortality from diarrheadeclined from approximately 4.6 million annual deathsduring the mid-1980s to the current estimate of 2 million.In contrast, rates of morbidity as a result of diarrhearcmain as high as ever [2]. Recently, Roy eJ 01. !3Jreported that the estimated rate of acute l;aStrointcstinalillness (AGl) in the USA alone is 0.65 episodes perperson-year. Fot this estimate, AGI was defined as atleast three loose stools in a 24 h period resulting in animpairment of daily activities or diarrhea duration greater

1363·1950 0 2008 Wolters Kluwer Health I Lippincott Williams & Wilkins

than I day. 'rhus, Jiarrhea represents:I practical publichealth problem.

Diarrhca is c;H1sed hy many pathogens. EnterotoxigenicEsdm7rhin coli (ETEC), C(J/llp),loh{}r!er, and Shif!.d/aaccount for approximately 60% of bacterial pathogenscausing travelers' diarrhea [4J. Additionally, limitedvaccines to prevent diarrheal illness arc availablc.and antibiotic-resistant diarrhea cannot be effectivelytreated with common antibiotics. In the absence of anti­diarrheal vaccines, development of altcrnative treat­ments that minimize incidence of and morbidity dueto diarrhea in adults is necessary. An association betweendiarrhea-associated morbidity and zinc intake was firstnoted in early observational studies that documentedincreased fecal zinc loss, a negative zinc balance, andlow tissue zinc concentrations among children with diar­rhea. Conservative estimates suggest that at least 2.')% ofthe world's population is at risk of zinc deficiency [SJ.Zinc deficiency is highly prevalent in developingcountrres because of inadequate dIetary intake, lack of

DOI:1 0.1 097/MCO.Ob013c32831 09092

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712 Micronutrlents

intake of :.Illimal foods, ami/or reduced bioavailability ofzinc because of J high phytatc:zinc ratio in the diet [2J.The adverse effects of zine deficiency on the immuneresponse arc likely to inere<lse the susceptibility ofchildren to infectious diarrhea, and ehronil: or persistentdiarrheJ may furthcr compromise the zinc status becJuseof increased fecal losses of zinc during diarrheJl episodes[6J. A recent estimate of diseJse-specific and all-causemortality attributable to zinc deficiency indicates thatzinc deficiency was responsible for 453 207 deaths (4.4%of childhood deaths) and 1.2% of the burdl.:n of dIsease(3.8% among children between 6 months and 5 ye~ltS) inAfric:l, Asia, and Latin America 12J. Similar dJta for adultsarc not ~lVailable.

Zinc supplementation of children with acute and persis­tent diJrrheJ increases serum zmc concentration andhelps them to maintain an improved zinc StalUS duringthe convalescent period [7J. The rccent WHO/UNICEFrecommendations for zinc supplementation in childrenarc based on a summary of scientific evidence [81: 20 mgzinc supplements/day for 10-14 days for children withacute diarrhea and IOmg/day for infants less thJn6 months old. Each individual dose of zinc should contJin10 or 20mg of elemental zinc. The zinc salt should besoluble in water - only zinc sulphate, zinc acetate, or zincgluconate should be used. The most recent meta-analysisof randomized, controlled trials (Ref's) compared zincsuppleml.:ntation with placebo in 22 studies involvingchildren and the authors concur with the WHO/UNICEFrecommendations: zinc sllpp1cml.:ntation reduces theduration and severity of both acute and persistentdiarrhea [9·J. Dcspite the strong evidence showing thatzim: supplementation reduces diarrhea in children, theimpact of supplemental zinc on diarrheal morbidity inadults is unknown. 'rhe following review examinesthe effects of zinc on the immune response to variousdiarrheal pathogens.

Zinc and the immune systemThe immune-related functions of zinc have beenreviewed recently [10,11 [. BrieAy, sub-clinical zincdeficienc), Impairs cellular mediators of innate immunitysuch as phagocytosis by macrophages and neutrophils,natural killer cell activity, generation of the oxidativcburst, and complement activity [6J. These alterationscontribute to increased susceptibility to infection [12J.Two phenotypically distinct T-Iymphocyte populationshave been identified that are zinc-sensitive: the Th Iresponse, importanr in protecting agJinst intracellularinfections and the Th2 response, important in protectingagainst noninvasive infections such as helminths.Adequate zinc and energy intake leads to a dominant'rh 1 response and a downregulated Th2 response,whcreas inadequate intake of zinc and energy activates

the Th2 response and downregulates the Th I response[13, 14-J. An upregulaled 'l'h 1 response is more protectiveagainst many of the invasive di:Jrrheal pathogens such asShigella spp. [15). In contrast. adequate vitamin A intakeactiv:Jtes Th2 response and downregu[ates the Th Iresponse, whereJs vitamin A deficiency reverses thesepatterns [16J. This differential immune regulation ofmicronutrient intake has distinct effects on specific stagesof the natural history of infection by various pathogens,with distinct protective roles of the Th I-Th2 responses.

In-vitro studies and studies on zine-deficienr patients[10, II, 17J have demonstrated that zinc plays an essentialrole in both cell-mediated and humoral immunity.Consistent findings In zinc deficiency are a decrease III

lymph(X;yte numbers (lymphopenia). imp:Jired lympho­cyte development, reduced proliferation, increased apop­tosis, and thymic atrophy [ISJ. Zinc deficiency in ex­perimental animals is associated with low thymic weight,a progressive loss of T-Iymphocytes and macrophagcs,delayed hypersensitivity and cytotoxic activity, impairedB and T-cell function, and reduced antibody recallresponses. Zinc is an essential cofactor for the thymichormone thymulin, which induces several T-cell markersand promotes T-cell function, including allogenic cyto­toxicity, suppressor functiuns, and IL·2 production. Italso modltlates cytokinc release by pcripheral bloodnuclear cells and induces the proliferation of CDST-cells, which function as cytotoxic cells able to re­cognize and kill pathogens [10]. In experimentallyinduced zinc deficiency, patients had low serum thymu­lin activity, impaired T-cell :Jnd natural killer cell activi­ties, and decreased IL-2 and interferon production 119J.

Zinc and mucosal cell functionZinc 31so plays a key role in maintenance of gur mucosalcells. Zinc blocks basolateral potassium (K+) channelsand thus inhibits cAMP-induced chloride-dependentAuid secretion, a major control point for Auid secretionsin the large intestine [20J. The mech:Jnism(s) by whichzinc may act as an enteroprotective have not yetbeen determined. Treatment with ORS would have itsgreatest effect on reducing Auid loss by increasing smallintestine absorption. Zinc inhibits cAMP-inducedchloride secretion by specifically inhibiting basolateralK+ channels with no blockage of calcium-mediated K+channels in in-vitro studies witl1 rJt ileum [20J. Zinc alsoinhibits cholerJ toxin-induced, but not E. roN heal-stableenterotoxin-induced, ion secretion in cultured Caco-2cells. One stlldy 121J showed that cA1\IP acted as theintracellular effector of heat-labile enterotoxin-induccdAuid secretion. Guanosine 3'.5'-cyclic monophosphate(cGMP) mediates heat-stable-induced Auid secretion.If substantiated, then the effectiveness of zinc wouldbe limited to heat-labile-induced diarrhea or to diarrhea

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Zinc and diarrheal disease Scrimgeour and Lukaski 713

Figure 1 Model for OiIntidiarrheal action of zinc In Intestinal cells

,.

* •• : T'. -----..~')

11,0 CI,,'".**:

tcAMP

'"'ZIP4

,.,

(a) Normal zinc uptake by ZIP4 transporters on the luminal surface of enterocytes. ZIP·transporters arc involved in zinc uptake and localize mainly to theluminal surface; ZnT-transporters are mostly vesicular and responsible for zinc eHlux and intracellular sequestration, With an adequate zinc supply,enterocyles have a greater expression of metallothioneins MTt and MT2, and ZIP5 is localized to the basolateral membrane, (b) Movement duringsecretory/watery diarrhea: increased mucosallevcls of cAMP induce water movement across the cell. In inflammatory diarrhea (e.g. following Shigellainfection) thore is alse extensive histological damage to the luminal surface (not shown here). (c) Zinc action includes induction 01 cation absorptionand/or inhibition of anion secretion; inhibition of cAMP·mediated CI secretion on luminal surface, and cAMP·activated K+ channels on basolateralmembrane, reducing water loss/transit across the cell.

mediated by cAMP, but nor by either cGMP or intra­cellular calcium. II has also been reported that the zinctransporter ZnT-I modulates the permeation of cationsthrough the L-type calcium channel (LTCC), therebyregulating; cation homeostasis 122J. ZnT-l m:.ly thus playa role in cellular ion homeostasis by conferring protcctionagainst pathophysiological events linked to cellularcalcium or zinc permeation. A micromolar concentrationof cxtracellular zinc could set off a massive release ofcaklum from intracellular pools in colonocytcs. Asustained increase in intracellular calcium level may also;lugment K+ efflux and a hyperpolarization of cellmembrane potemial, leading to an advantageous clectri­cal gradient for chloride secretion. A model depicting theantidiarrheal action of oral zinc in intestinal cells is shownin Fig. I.

Zinc nutriture and infectious diseasesZinc has been demonstrated to modulate host resistanceto infectious agents. A mild-to-moderate deficiency ofzinc may result in profound effects on overall immunefunction, with increased susceptibility to diarrhcal­causing pathogens (including parasites, bacteria, andviruses). Zinc deficiency in developed countries isuncommon, but groups at risk for zinc undernutritionwcre identified in the National Health and NutritionExamination Survey (NHANES) III study. The groupsat greatest risk of inadequ:Hc zinc intakc were clllidren(1-3 years), adolescent women (12-19 yC~HS). and elderlypeople aged more than 71 years [23l. In developingcountries. infections often coexist with multiple nutri­tional deficiencies that may result from general malnu­trition, especially in children and thc elderly.

Results arc jvailjble from a large number of RCTs ofzinc supplementat ion in prevention of dia rrhea in devel­oping countries. The WHO/UNICEF Zinc Task ForcerepoTted a pooled anjlysis of 12 trials on chil(lren havingacute diarrhea and four trials on children havingpersistcnt diarrhea [8J. Zinc had a positive therapeuticeffect in the treatment of both acute and persistentdiarrhea, that is, it is estimated that zinc supplement­ation reduces duration of the acute diarrhea episodes byup to 25% (comparcd with 24% for persistent diarrhea);zinc supplementation decreases the proportion of ~IClHe

episodes lasting more than 7 days by about 25%, there­fore significantly reducing the proportion of diarrheaepisodes becoming persistent; and it reduces stoolvolume by about 30%. Subsequent trials in llangladesh124.25], India [26,27]. and Brazil [28] corroborated thesefindings. A more recent mcta-analysis [9°1 included16 studies that examincd the efficacy and safety ofsupplementary oral zinc on acute diarrhea (11= 15231)and six studies that examined persistent diarrhea(!I =2968). Mean duration of acute diarrhea and persist~

Cnt diarrhc;l was significantly lower for ~.inc comparedwith placebo. At day 3, presence of diarrhea was signifi­cantly lower in zinc-supplemented compared withphJcebo-treated volunteers in persistent diarrhea trials.but not in acute diarrhea tri:lls. Overall, children whoreceived zinc reported a 19 and 13% reduction in aver­age stool frequency, 15 and 16% shortening of diarrheaduration, and :l 17.9 and 18.0% prob:loility of reducingdiarrhea over placebo in acute and persistent trials,respectively. Similar to the earlier pooled Zinc TaskForce analysis, the authors conclude that zinc supple­mentation reduces the duration and severity of acuteand persistent diarrhea in children.

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714 Micronutrients

Although there arc many causes of chronic diarrhea, thesemay be different for children and adults. Causes ofchronic diarrhea arc typically ~ro\lped Into two gencralcate~ories; that which is caused by an infection anddiarrhea that is not caused by an infection. Pathogen­negative diarrhea is the most likely cause of traveler'sdiarrhea withom a definable cause [29J. Adult 'travelers'with acute diarrhea, treated with the antibiotic rifa.\iminjXifaxan (Salix Pharmaceuticals, inc.. l'vlorrisville, Nord]Carolina, USA) 200m/!; three times a day for 3 daysl,were assessed in two double-blind, placebo-controlledRCTs. Among pathogen-negative patients, rifaximinwas more effecrive than placebo for median time-to­last-stool (33 vs. 68 h), mean number of unformed stoolspassed (6.5 vs. 8.6), and clinical well ness (77 vs. 61%).Thus, for patho/!;en-negative di;urhea, rifaximin appearsto he an effectivc treatment with no concurrent sideeffects. Converscly, infectious-diarrheal disease may hecaused by a variety of parasites, hacteria, and/or viruses,with a distinct paucity of available antidiarrhcal vacci nes.Currently, non typhoid Sfi/mont/Ia, r-;. coli Ols7:H7, andCII/!lpylobflrler arc amon~ the most prevalent causes offood-borne illness in the USA 130).

Zinc and parasitic diarrheaThe following is a review of RCrs involving zinc supple­mentation in various populations. This review focuses onspecific diarrheal pathogens to provide stron~ evidenccfor a causal relationship between zinc supplement;.ltionand a signific<lntly rcduccd incidence of pathu/!;en­spccifk: diarrhea.

Intestinal protozoan infections by Ciorrlifl and CryPIOS­po,iiliflm arc common in humans worldwide. Especiallyimportant arc infections in children. durin):; pregnancy,and among individuals with HIV/AIDS. Associatedmorbidity and murtality are high, with more than58 million cases of childhood protozoal diarrhea eachyear. Direct costs of management alone arc estimatcdat approximately US$150 million [31 J. It is estimated that1.5 billion people harbor Ascaris Ili/!/bricoiiles, 478 millionof whom arc children « 15 years of age). Also, there arcapproximately 2.8 million Giardia Imnbliil infections peryear. Recurrent asymptomatic and symptom~llic infec­tions by these and other intestinallKlrasites amon/!; youngchildrcn can have long-term effects on overall growth anddevelopment. A recem study conducted on childrenresiding in Mexico Ciry 114·J reponed that vitamin Aand zinc (20mg of elcmental llllC as .-:inc methionine,daily for 1 year) reduced G.lilmblio incidence, whereasZJnC supplementation alone decreased EnlaHlvebahistolylim-associated diarrhea. With no comparable stu­dies on adult populations, it remains to be determinedwhich of these diarrheal pathogens might respond to zincsupplementation and whether age-related differences in

response to dietary zinc may minimize success in adultpopulations.

Zinc and bacterial diarrheaEnteric patho/!;ens constitute a major pediatric threat inthe developing world through their impact on morbidityand mortality and impairment of physical and co):!;nitivedevelopment. It appears likely that a c:luse-and-effectrclationship cxists with malnutrition. Although manybacterial pathogens can cause diarrheal diseases, a groupof fewcr than 10 (including Shigella spp., f'7F.C, Vibn'orholemr, and possibly Cmnpylo!JIIrterjejtllli) account for <lsignificant percentage of these diseases in developingcountries. Vaccines a/!;ainst these agents offer a poten­tially effective control measurc against these diseases,but safe, practical, and effective vaccines for many ofthese agents have yet to he realized. Zinc supplement­ation has been shown to reduce the duration and severityof watery diarrhea in studies worldwidc, bur its mode ofaction is nOI known. Initially, it was believed that zinc wasacting to correct or ameliorate .-:inc deficiency, but thisappears not to be the only means of protection becausechildren and animals that arc not zinc deficient stillbenefited from zinc in studies of diarrhea. Recently,Crane et 01. 132·J repofted (hat zinc decreased adherenceof enteropathogenic E. wli (EPEC) bacteria to rabbitintestinal epithelium. They also demonstrated that zincinhibited a key enzyme, ecto-S' -n llclcotidase, involvcd inthe conversion of s'-ArvlP to adenosine in the lumcn ofthe intestine. Adenosine triggers fluid secretion fromhost intestinal cells and also has growtb-promotingeffccts on EPEC bacleria. The zinc inhibition reducedthe secretory response that trig/!;ers EPEC-activatcdwaleT)' diarrhea. The authors concluded that these effect.~

shuuld be considered pharmacologic effects of zinc, notzinc· replacement therapy, as they also occur in theabsence of zinc deficiency.

Cholera is a common disease in many countries of theworld. About 230000 cases in more than 50 countries arereponcd globally, but the WHO cstimates that officialnotifications make up only approximately 5% of the realburden ofcholcra [.)]J. This means that as many as threemillion cascs and more than 100000 deaths occur eachyear. Abollt 85% of cpisodes arc mild-to-modnate inseveriry. In animal swdies, lhe nct w;ltcr and sodiurnsecretion induced by cholera toxin was four times grcaterin zinc-deficient compared witl1 zinc-adequate animals.Flltthermore, zinc repletion of the zinc-deficient animalselicited;l 40% reduction in secretion within 48 h of zincrepletion [341. Recently, Roy rt III. 13s·J investigated theimpact of zinc on severe diarrhea in children caused bycholera. Children, aged 3-14 years with watery diarrheathat was confirmed positive by stool culture for V.rholemr,reccived either 30 m):!; elemental zinc per day as ZIllC

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acet:lte, or placebo until rccovcry. All children receivederythromycin suspension orally in <l dose of 12.5 mg/kgevery 6 h for 3 d:lYs. More p:ltients in the zinc group thanin the control group recovered within 2 (49 vs. 32%) or 3(81 vs. 68%) days. Zinc-supplemented children had 12%shorter duration of diarrhea than comrol patients (64 vs.73 h) and 11% less stool output. Thc authors concludedth<lt zinc supplementation was beneficial in reducing theduration of diarrhea and stool O\JtPll[ in childn.:n withcholera.

Shigella is a major cause of childhood morhidity andmortality globally, causing bacillary dysentery in humans,and an acute rectocolitis that reAect.s the capacity of themicroorg3nism to disrupt. invade. and trigger the inflam­matory desuur.:tion of the intestinal epithelium. Shigel­losis typically manifests as bloody-mucoid stools :lnd/orfebrile diarrhC<l. Shigdla SOlmei persists in developed (andtransitional) countrics, causing sporadic diarrhea andot:casional outbreaks in epidemioloj;!;ical niches (such asday-care centers) where personal hygiene can besuboptimal. Travelers from developed to dcvelopingregions, who mainly acquire S. sonllfi :1Od S. fle:(1wiinfeccions, represent a t<lrge! population for Shigelltlvaccines. Levine e/ til. [36J reviewed the most adv<lneedstr:ltegies for Shigella vat:cine developmcnt and thcfactors that have impeded ShigellfJ vaccine development.I'vlcanwhllc, Roy e/ (II. [37-J reported on a RCT using zinc(20 mg/day elemental zinc given as zinc acet<lte. daily for2 weeks) to manage shigellosis in malnourished children.Additionally, all children received pivmecillinam (IS mg/kgevery 6 h for 5 days). The authors rcport that childrenrcceiving zinc recovered from :lcute illness sij;!;nificantlyfastcr than the control children (P < 0.05). The mediantime (in days) to recovery and disappearances ofblood and mucous was significantly shortcr in the zine­supplemented group (50%) compared with the controlgroup. The mean body weight of zinc-supplementedchildrcn increased significantly from 8.8 kg on admissionto 9.2 kg at rccovery (P< 0.01), which was not observcd inthe control childrcn. During thc 6-month follow-uppcriod. zinc-supplcmcnted childrcn had significantlyfcwer mean episodes of diarrhea compared with thecontrol children (2.2 vs. 3.3; P=0.(3). They concludcdthat zinc supplementation significantly shortens theduration of acute sh igcllosis, promotes bctter weight gainduring rccovery, and reduces diarrheal morbidity duringthe subsequent 6 months.

Zinc and viral diarrheaRotavirus infection is the most common cause of severediarrhea disease in children less than 5 years worldwideand continues to have a major global impact on childhoodmorbidity and mortality. In 2006, two new (live, oral.attenuated) vaccines against rotavirus werc licensed,

Zinc and diarrheal disease Scrimgeour <Il1d Lukaski 715

RotaTeq (Merck, Whitehouse Station, New Jersey,USA) and Rotarix (GSK, Rcscarch Triangle Park, NorthCarolina, US:\). Both v;lccines demonstT:lted very goodsafety and efficacy profiles in large ReI's in wcsrernindustrialized countries and in Latin America [38J. 'fhesenew rota virus vaccines offer thc best hope of reducingthe toll of acute rotavirus gastroenteritis in both developedand dcvc10ping countries. With the developmcnt of suchvaccines, the need for micronutrient interventions, specifi­cally "ine-supplemt:nt:nion studics, is not requircd.

Vaccines aj;!;ainst other viral-diarrheal pathogens offer apotentially effcetive control measurc against thcscdi.scases, but safc, practical, and effective vaccines formany viral-diarrhca pathogens have yct to be realized.Although the usc of highly active antiretroviral therapies(ART) has dramatically decreased the morbidity andmortality of I-IIV-1 infections, the major gO:l1 of HIV/AIDS rese;.lrch still eludes us: the dcvelopment of a safeand effct:tive vaccine [39).IVle:lnwhilc, thc side effects ofHIV therapy arc common and include diarrhe3 caused byprotease inhibitors [40J. Several studies in industrializedcountrics have found an association between HIV diseaseproj;!;ression and low blood conccntrations of zinc [41].There is concern that in:ldequate intake of nutrients maycompound the susceptibility to secondary infection andthcreby causc a further worsening of immune function inHIV-poSHivc persons. Reccnr -swdics reporr no bCllefici:11effects of 'line supplementation for persistcll[ diarrhca inchildren [42J or adults [41) with HIV infections. In thestudy of I-IIV-infectcd children [42), neither zinc [Wmgzinc as gluconate d:lily for 18 months] combined withvitamin A nor zinc and vitamin A combined with othermicronutrients reduccd diarrhea morbidity. Two kcyissues with thc design of this stlldy may explain thereponed outcome: thc study did not include a placebogroup (vitamin A alone) and shortly aftcr .study enroll­ment be~an, the host-country government implcmenredregulations requiring thc fonific<ltion of maize meal andwheat flour, including flour used by bakeries. with zinc~ll1d other micronutrients. The amount of fortification (upto .,Orng zinc/kg of m:lizc meal) in the staple foods mayhave improved micronutrient staws in childrcn withaccess to commercially produced mcal or bread [43J. Inthc study of HIV~infcctedadults 141]. zinc supplcrncnt­ation ISO mg of clcmental zinc as zinc sulphate, twicedaily for 14 daysJ reportedly h;.ld no significant effecton the duration or remission of diarrhea. Sevcral studydesign limitations may explain thesc outcomes: 83%of patients had CD4 values less than 200celtshd(rangc 0-9(9) - patients with CD4 v:llues less than200ccllshd may benefit substantially bctter from aggres­sive AR'f until their CD4 valucs arc grc:lter than250t:c1ls/fJ.l; the zinc-supplementation trial was too short(14 days) and thc dosc provided was excessive as 100mgelemental zinc/d:1Y W;.lS provided, dcspitc the llpper limit

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716 Micronutrients

for elemental zinc set at 40mgjday for adults [44]; andthe supplement was provided :is zinc sulph:He heptahy­dmte - the Material Safety Data Sheet (MSDS)for ZnS04.7H zO states that 'if ingested, it will causediarrhea',

Despite those studies indicating that diarrhea is non­responsive to zinc supplemenration III individlmlswith HIV-l, reeenr in-vitro evidence supports a 'zincapproach' for treating diarrhea in HIV-infened paticnts.C:!nani (f tI/. [45"1 repurt that the transactivating peptide'fat (produced by HIV·I) is involved in the pathogenesisof diarrhea in AIDS patients and that zinc preventcdTat~indlJced Ruid seerction, directly limiting a specificmechanism of HIV-rebted diarrhea. Differences inreported responses to supplemental zinc between chil­dren with diarrhea and adults with HIV-infeetion anddiarrhea could also reflect age-dependent differences inzinc homeostasis, host immune response, inclusioncriteria, or supplemenration regimen. Alternatively, theycould reflect the po.ssibility that low plasm:i concen­tr:itions of ,,-inc in persons with HIV-infection do notreRect true zinc deficiency. Supplementation of HIV­infected patients with diet:iry refercnec intake levels ofzinc is prudent, but high doses should be discouraged.Although indIviduals with HIV infection arc expected tobenefit from zinc supplementation, the virologic:!1 andimmunologic:il conseq uenccs of zinc for replication of thevirus need careful assessment, Both the viral nucleo­capsid and inregrase proteins, essential for assembly ofinfectious virions, cont:lin zinc fingers that requirezinc for normal structure and function. In :lddition,zinc activates lymphocytes [46], and activated CD4T-Iymphocytes arc major tarl!:et cells for HIV-I replica­tion and an increase could potentially enhance H IV-1replication. If mass supplementation with zinc is to berecummended in areas with a high prevalence of HIV­infection, the safety of this intervention needs to beestablished. A recent trial of zinc supplementation inHIV-infected children was conducted to assess the effecton plasma HIV-l viral load and infectious disease mor­bidiTy [47]. Zinc supplementation (10m/.!; of elementalzinc dally for 6 months) did not increase plasma J-1IV-1viral load and thus could red lice morbidity causedby diarrhea. The olltcomes of these studies suggcst thatprograms to enh:lnce zinc inrake in deficient popuhl­lions with a high prevaknce of HIV-infection can beimplemented withoUT concern for adverse effects onJ-1IV.! replication.

Thus, the combination of ART, a healthy diet, and a low·dose multivitamin/mineral supplement may be especiallyeffective in the treatment of J-1IV-infected patients 148J.Future research on HIV-associated diarrhea in adultsshould assess more pOTentially effective antimicrobialinterventions, in combinaTion WIth zmc supplementation.

Information from these addition:!1 studies will helpfacilitate guidelines for empiric antimicrobial treatmentalgorithms.

ConclusionOral zinc can correcT a common micronutrient deficiencyin children with diarrhea [II, Large intervention RCTswith daily intakes of 10-30 mg of ,,-inc have shown thatzinc supplementaTion could be an import:.mt adjuvanttherapy for treating diarrhea in children in developingcountries, and by inference, these trials should beextended to include adults. This review would he incom­plete if we did not acknowledge the lack of success inzinc-supplementation STudies condUCTed in countrieswhere the diarrheal pathogens arc noT zinc-responsive,which may in pan be due to distinct parasite-specifichealTh outcomes. A recent study in Mexico City [14"1demonstrated that vitamin A and zinc reduced C.lnmblinincidence, whereas zmc supplementation increasedA. lum/;,.icoides incidence but decreased E. his/oly/ien­associated diarrhea.

Future studies must, thcrcforc, bc designed to allow fordiarrheal-pathogen identification, which could lead to

elucidation of potential zinc-specific benefits and diver­sity in the study population groups to include the elderly,immunocompromised patients, and other communitysettings. Further, carefully conducted RCTs arc necess­ary to confirm (or refute) the efficacy of ,,-ine against bothaeutc and persistent diarrhea in adults, and such trialsmay be of hIgh economic value.

AcknowledgementsThe opiilions or assertions contained hemin are the private views of theauthor(sl aild are not to be construed as official or as reflecting theviews of the Army or Department of Defense. Any citation of commercialorganizations and lrade names does not constitute an officialDepartment of lhe Army endorsemenl of approval of lhe producls orservices of these organizations.

Mention of a trademark or proprietary product does not const~llte aguarantee of the prOdllct by the United States Department ofAgriclliture (USDA) and does not imply its approval to the exclusionof olher prodllCts that may also be suitable.

USDA, Agricllitural Research, Northern P1ains Area is an equalopportun~ylaffirmalive action employer and all agency services areavailable without discrimination.

References and recommended readingPapers of partioular interest, publisood wrth;n too annual period of r""iew, haV<lbeen highlightod as:

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