Published online October 1, 2007
PEDIATRICS Vol. 120 No. 4 October 2007, pp. e846-e855 (doi:10.1542/peds.2006-2187)
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ARTICLE

Effect of Vitamin A and Zinc Supplementation on Gastrointestinal Parasitic Infections Among Mexican Children

Kurt Z. Long, PhDa, Jorge L. Rosado, PhDb, Yura Montoya, MDc, Maria de Lourdes Solano, BSd, Ellen Hertzmark, MAe, Herbert L. DuPont, MDf and Jose Ignacio Santos, MDg

a Departments of Nutrition
e Epidemiology, Harvard School of Public Health, Boston, Massachusetts
b Department of Nutrition, School of Natural Sciences, Universidad Autónoma de Querétaro, Querétaro, Mexico
c Center for Childhood and Adolescent Health, Secretary of Health, Mexico City, Mexico
d Department of Animal Nutrition, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubiran," Mexico City, Mexico
f Center for Infectious Diseases, School of Public Health and University of Texas Medical School, Houston, Texas
g Office of Director General, Hospital Infantil de Mexico "Federico Gomez," Mexico City, Mexico


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. Gastrointestinal parasites continue to be an important cause of morbidity and stunting among children in developing countries. We evaluated the effect of vitamin A and zinc supplementation on infections by Giardia lamblia, Ascaris lumbricoides, and Entamoeba histolytica.

METHODS. A randomized, double-blind, placebo-controlled trial was conducted among 707 children who were 6 to 15 months of age and from periurban areas of Mexico City, Mexico, between January 2000 and May 2002. Children, who were assigned to receive either vitamin A every 2 months, a daily zinc supplement, a combined vitamin A and zinc supplement, or a placebo, were followed for 1 year. The primary end points were the 12-month rates and durations of infection for the 3 parasites and rates of parasite-associated diarrheal disease as determined in stools collected once a month and after diarrheal episodes.

RESULTS. G lamblia infections were reduced and A lumbricoides infections increased among children in the combined vitamin A and zinc group or the zinc alone group, respectively. Durations of Giardia infections were reduced among children in all 3 treatment arms, whereas Ascaris infections were reduced in the vitamin A and zinc group. In contrast, E histolytica infection durations were longer among zinc-supplemented children. Finally, E histolytica–and A lumbricoides–associated diarrheal episodes were reduced among children who received zinc alone or a combined vitamin A and zinc supplement, respectively.

CONCLUSIONS. We found that vitamin A and zinc supplementation was associated with distinct parasite-specific health outcomes. Vitamin A plus zinc reduces G lamblia incidence, whereas zinc supplementation increases A lumbricoides incidence but decreases E histolytica–associated diarrhea.

Key Words: vitamin A • zinc • G lamblia • A lumbricoides • E histolytica • diarrhea

Abbreviations: Th2—T-helper type 2 • Th1—T-helper type 1 • IgA—immunoglobulin A • RR—rate ratio • CI—confidence interval

Intestinal parasitic infections continue to be an important health problem in many developing countries. It is estimated that 1.5 billion people harbor Ascaris lumbricoides, 478 million of whom are children (<15 years of age),1 and that there are ~2.8 million Giardia lamblia infections per year.2 Similarly, amoebiasis is responsible for an estimated 40000 to 100000 deaths.3 Recurrent asymptomatic and symptomatic infections by these and other intestinal parasites among young children can have long-term effects on overall growth4,5 and development.6,7

Mass chemoprophylaxis has proved to be an effective public health intervention that reduces parasite burden and substantially improves the nutritional status of children.8,9 However, treated children are frequently reinfected as a result of their continued exposure to parasites in households and communities where water and sanitation facilities are deficient or lacking. There is a need, then, for the development of more cost-effective measures that not only reduce disease burden but also reduce rates of reinfection. Micronutrient supplementation may be a simple, cost-effective public health intervention that could be used in conjunction with antiparasitic treatment to control these infections more effectively. Micronutrients such as vitamin A and zinc have been shown to have beneficial effects on infant mortality and overall infectious disease morbidity, respectively.10,11 Few studies, however, have addressed the impact that these micronutrients have on the risk for intestinal parasitic infection and disease.12,13

Recent work has suggested that vitamin A and zinc supplementation may have distinct effects on the innate and adaptive immune responses that are important in protecting against parasite infections.14 Vitamin A upregulates the T-helper type 2 (Th2) humoral response and downregulates the T-helper type 1 (Th1) cellular response, whereas zinc downregulates the Th2 response and upregulates the Th1 response.15–18 The upregulation of the Th2 response by vitamin A supplementation may lead to greater immunoglobulin E–mediated expulsion of helminths and to stronger mucosal immunoglobulin A (IgA)–mediated protection against onset of infection by Entamoeba histolytica and Giardia.19–21 In contrast, the upregulation of the Th1 response by zinc may lead to the more rapid resolution of chronic infections by Giardia and reduce symptoms that are associated with invasive E histolytica infections.22,23

We conducted a randomized clinical micronutrient trial to address the impacts of vitamin A and zinc supplementation on pathogen-specific diarrheal disease among young children who were 6 to 15 months of age and living in La Magdalena, a periurban community of Mexico City, Mexico. Here, we address the effect that vitamin A and zinc supplementation has on rates of infection by 3 very different parasites: G lamblia, a luminal pathogen; A lumbricoides, a parasite that has an extraintestinal migratory phase that often is associated with eosinophilia; and E histolytica, a parasite that has limited spread from the gut to the liver. We hypothesized that vitamin A and zinc supplementation would produce distinct health outcomes for each of these gastrointestinal parasites: vitamin A supplementation would be associated with reductions in the incidence of noninvasive gastrointestinal pathogens for which a humoral immune response is protective, and zinc supplementation would be associated with reductions in invasive infections for which a cell-mediated response is protective.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Study Design
We conducted a randomized, population-based, placebo-controlled, double-blind trial within La Magdalena Atlicpac, a community located in the state of Mexico on the eastern perimeter of Mexico City. This study site was chosen to address the impact that vitamin A and zinc have on childhood health outcomes in marginalized urban communities. Households with eligible children who were 6 to 15 months of age and identified in a community census were invited to participate in the trial after the project was fully explained to them by field personnel. Children were excluded from the study when they had diseases that cause immunosuppression or any congenital or acquired alteration of the digestive tract that could alter the absorption of micronutrients or when they had received a vitamin A supplement from a source outside the project. On acceptance, the child was randomly assigned to 1 of the 4 groups by the project field coordinator, who was blinded to these groups.

Randomization and Interventions
The randomization sequence was generated using a random-number table by project personnel based at the Center for Childhood and Adolescent Health, a division of the Mexican Ministry of Health. The study used a factorial design in which children were assigned to 1 of 4 groups: a vitamin A group supplemented with 20000 IU of retinol every 2 months for children who were younger than 1 year; 45000 IU for children who were older than 1 year, a group that received a daily dose equivalent to 20 mg of elemental zinc as zinc methionine, a group that received the zinc supplement and the vitamin A supplement as mentioned, and a placebo group. This design would allow the evaluation of the impact of frequent, low doses of vitamin A or zinc given independently or in combination on rates of infection by G lamblia, A lumbricoides, and E histolytica and associated diarrheal disease episodes. Restricting the study to children of this age range would allow this evaluation to be conducted during the period when the children's immune response is developing after weaning. Zinc methionine was used as a zinc supplement because it is better absorbed than other chemical forms of zinc.24

Personnel at the National Institute of Nutrition prepared the supplements to ensure that field personnel and the principal investigator were blinded. Children in all 4 groups received a daily 5-mL solution similar in taste and appearance from identical opaque plastic droplet bottles numbered consecutively and color coded. Field personnel administered the solution orally to the children on the 2 days of the week when they visited each household and left bottles for the remaining days of the week with instructions on how to administer the solution.

Children were followed prospectively for 12 months once they were enrolled. At the first household visit, trained personnel obtained anthropometric measurements of height and weight from each child using calibrated methods and standardized techniques. The mother was interviewed during the baseline visit regarding the number, ages, and education level of household members; household construction materials; household water source; household sanitation facilities; and household possessions. Information was also collected during the first visit to determine the child's feeding and weaning patterns as well as morbidity experience in the previous 2 weeks. A previously validated questionnaire was used in the collection of these data by project personnel who had received training in its application.

After enrollment, each child was visited twice a week for 12 months. At each visit, mothers or child caregivers were interviewed to determine the presence of the following symptoms between the last field visit and the current visit: diarrhea, the number and consistency of evacuations, the presence of blood and mucus in stools, fever, cough, and respiratory difficulty. A stool sample was collected once a month among healthy children, and up to 3 stools were collected in the week after a diarrheal episode. In addition, height and weight measurements were obtained monthly for each child. No systematic initial and final blood samples were taken from the study children because parents of the study children did not consent for blood to be drawn. The Kato-Katz technique and wet mounts of concentrated stool with trichrome staining of slides were performed to determine the presence or absence of ova and parasite in stool.25,26

Outcomes Measures
The primary end points for the study were the prevalence and durations of infections by G lamblia, A lumbricoides, and E histolytica as well as the incidence of diarrheal episodes associated with these infections during the 1-year follow-up of each child. An infection by G lamblia, A lumbricoides, or E histolytica was defined as a stool that was positive for the given parasite. Infection duration was defined as time from first positive stool-test result until first negative stool-test result among sequentially collected stools. Diarrhea was defined as the passage of 3 or more liquid stools by the child as reported by the child's mother or caregiver with the end of the episode defined as 3 or more symptom-free days. A diarrheal episode was associated with an infection by 1 of these 3 parasites when the episode occurred within 7 days before or after a positive stool-test result. An asymptomatic infection was defined as a stool that was positive for a parasite and was not associated with a diarrheal episode.

Statistical Analysis
Analyses were carried separately for the prevalence and duration of G lamblia, A lumbricoides, and E histolytica infections and the prevalence of parasite-associated diarrhea. Rate ratios for parasite infections among all children who were randomly assigned to the 4 groups were estimated by fitting separate Poisson regression models to overall counts of infections of each parasite. The duration of parasite infections was then compared among the various treatment arms using parametric regression survival-time models with maximum-likelihood procedures. The results are presented as mean durations and, graphically, as cumulative hazards. Poisson regression models were then fit to counts of diarrheal episodes among children with stools that were positive for each parasite.27 All models included breastfeeding status, access to water and sanitation facilities, and nutritional status of children as effect modifiers.

The primary analysis of the main effects of vitamin A and zinc for each outcome was based on the factorial design of the study: comparisons were made between groups that received zinc (zinc and zinc + vitamin A) and groups that did not receive zinc (vitamin A and placebo) and between groups that received vitamin A (vitamin A and vitamin A + zinc) and groups that did not receive vitamin A (zinc and placebo). An additional analysis for each outcome was then carried in which a term for the vitamin A–zinc interaction was included in the model to test whether there is a multiplicative effect of these 2 micronutrients. Only the results from the analysis of the original 4 study arms are presented when a significant interaction was found. Statistical significance was set at a probability level of <.05 and <.1 for interactions. The analysis was by intention to treat. Data were analyzed by using the GENMOD procedure in SAS (SAS Institute, Cary, NC) and the STREG procedure in Stata (Stata Corp, College Station, TX). The guidelines for the reporting of randomized, controlled trials as laid out in the Consolidated Standards of Reporting Trials (CONSORT) statement are used in the reporting of these results.

Epidemiologic surveillance reports from the Mexican Ministry of Health led us to assume that the study population would have a Giardia prevalence of ~30%. Sample size calculations were initially made to detect a 20% change in G lamblia infection with zinc or vitamin A at the 5% level of significance with a power of 80% and an expected loss to follow-up of 20%. Our calculated sample size was 800 children on the basis of these criteria. The study was approved by the ethical review committee from the National Center for the Health of Infants and Adolescences of Mexico.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
The recruitment of children was from January 2000 to January 2001 with follow-up completed in May 2002. In all, 800 children were recruited for the study after consent was obtained from the mothers (Fig 1). Fourteen children were not randomly assigned to a treatment arm, and 35 children were lost to follow-up; the remaining 751 children were followed for 12 months. The duration of follow-up did not differ significantly by the 3 treatment arms and the placebo group (P = .62). Children received 88% of all scheduled supplements overall with no significant differences in compliance found between children in the various groups (P = .48). An additional 44 children were excluded from the analysis phase because of an insufficient number of stool samples, leaving 707 children: 170 in the vitamin A group, 181 in the vitamin A–zinc group, 183 in the zinc group, and 173 in the placebo group. No adverse effects were reported among children in the 3 treatment arms.


Figure 1
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  		FIGURE 1 Trial profile.

 
The distribution of sociodemographic characteristics of study children and households in the 4 groups has been reported previously.28 Briefly, the average age of children at recruitment was 9.8 ± 4.7 months. The proportion of households with access to piped water within each group ranged from 73% to 78%; between ~46% and 56% of the mothers in the study had >6 years of schooling; only 7% to 13% of the children had stunted growth. The initial vitamin A and zinc status of this population was not assayed. However, the National Nutrition Survey conducted in Mexico in 1998 reported that children from this region of Mexico City were not deficient but that 37% had low serum retinol levels (10–20 µg/dL retinol) and 36% of these children were zinc deficient (<65 µg/dL).29 At the end of the study, approximately 7.5% of children overall had stunted growth with 8.38%, 4.52%, 3.93%, and 9.19% in the placebo, vitamin A, zinc, and vitamin A–zinc groups, respectively, being stunted. We reported previously that vitamin A was associated with a significant 27% increased prevalence of diarrhea and a significant increase in the prevalence of persistent diarrhea in this same study.28 Zinc had no effect on these outcomes.

In all, 5144 samples were collected from the 707 children. G lamblia had the highest 1-year prevalence in this population, with ~42% of all study children infected at least once, followed by A lumbricoides, (28%); E histolytica had the lowest 1-year prevalence (11%). A significant reduction in the prevalence of G lamblia was associated with vitamin A supplementation in the factorial analysis (rate ratio [RR]: 0.83; 95% confidence interval [CI]: 0.70–1.00; Table 1). There were significant interactions between vitamin A and zinc in the factorial analysis of the prevalence of E histolytica and A lumbricoides infections (P = .06 and .04, respectively), indicating that the effects of these 2 micronutrients are not multiplicative. In the 4-group analysis of these 2 parasites, zinc alone was associated with a significantly increased prevalence of A lumbricoides infections and a marginally significant increase in E histolytica infections as reported in Table 1 (RR: 1.51 [95% CI: 0.98–2.31], P = .05, and RR: 1.65 [95% CI: 0.92–2.96], P = .08).


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  		TABLE 1 Effect of Vitamin A and Zinc Supplementation on Incidence of Parasite Infections

 
The effect of vitamin A supplementation on the duration of pathogen infections was determined by fitting parametric regression models to these durations. Significant interactions were found between vitamin A and zinc in the factorial analysis of durations for all 3 parasites (E histolytica: P = .01; A lumbricoides: P = <.01; and G lamblia: P = .05; Table 2). In the 4-group analysis, the mean durations of Ascaris infections among children in the vitamin A–zinc group and mean durations of Giardia infections among children in all 3 treatment arms were significantly reduced compared with mean durations of parasite infections among children in the placebo group (Table 2, Fig 2). Mean durations of E histolytica infections were significantly longer among children in the zinc group. Shorter or longer infections/episodes are associated with higher or lower cumulative hazards in Fig 2, respectively.


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  		TABLE 2 Effect of Vitamin A and Zinc Supplementation on Durations of Parasite Infections

 

Figure 2
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  		FIGURE 2 Duration of parasite infections according to treatment arms. A, E histolytica infections; B, A lumbricoides infections; C, G lamblia infections. Shorter or longer infections/episodes are associated with higher or lower cumulative hazards, respectively. Coinfections by other parasites are included in each analysis.

 
Approximately 21%, 22%, and 28% of children who were infected with E histolytica, A lumbricoides, and G lamblia, respectively, had at least 1 diarrheal episode associated with these infections. Very few episodes were bloody. There was a significant interaction between vitamin A and zinc in the factorial analysis of E histolytica–and A lumbricoides–associated diarrhea (Table 3). Zinc supplementation and combined vitamin A–zinc supplementation were associated with significant decreases in the prevalence of E histolytica–and A lumbricoides–associated diarrhea infections in the 4-group analysis (RR: 0.24 [95% CI: 0.06–1.01], P = .05, and RR: 0.27 [95% CI: 0.19–0.90], P = .02, respectively). Neither supplement had an effect on diarrheal episodes that were associated with G lamblia infections.


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  		TABLE 3 Effect of Vitamin A and Zinc Supplementation on Incidence of Parasite-Associated Diarrhea

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
This study provides evidence that vitamin A and zinc supplementations have quite distinct effects on G lamblia, A lumbricoides, and E histolytica infection prevalence and duration and, given infection, on the onset of associated diarrheal disease symptoms. Children who were in the group that received a combined vitamin A and zinc supplement had a reduced prevalence and duration of G lamblia infections, whereas children who were supplemented with zinc had an increased prevalence of A lumbricoides infections and longer durations of E histolytica infections. Zinc supplementation was associated with decreased diarrhea among children who were infected with E histolytica, whereas a combined vitamin A–zinc supplement was associated with a decrease in diarrhea among children who were infected with A lumbricoides. These results are in agreement with our findings that the impact of the 3 treatment arms on the growth of parasite-infected children is parasite specific.30 They suggest that the effectiveness of vitamin A and zinc supplementation in prevention of gastrointestinal parasitic infections may be improved by designing community-specific interventions that take into account the prevalence of these different parasites.

Few community trials that are comparable to ours have reported the impact of vitamin A or zinc supplementation on parasite infections. One study reported that multimicronutrient supplements that were given to Kenyan children after antiparasitic chemotherapy had no significant effects on reinfection rates by hookworm, A lumbricoides, or Trichuris trichiura compared with children in the placebo group.13 Kenyan adults who were given elemental iron weekly were also reported to have significantly lower rates of infection by A lumbricoides, T trichiura, and Schistosoma mansoni compared with a placebo group but had significantly higher rates of hookworm.31 This parasite-specific effect of iron supplementation reported in the Kenyan study is similar to our findings of the parasite-specific effect of vitamin A and zinc supplementation. We reported previously that the effect of vitamin A supplementation on clinical outcomes that are associated with gastrointestinal bacterial agents may also be pathogen dependent.32 These distinct pathogen-specific effects may underlie the findings that vitamin A supplementation reduces severity of diarrheal disease episodes and diarrheal disease incidence in some geographic settings while having either an inconsistent or a negative effect in other regions.33,34 Routine zinc supplementation, in contrast, consistently reduces the incidence of acute diarrhea as well as diarrheal episode duration and severity.11,35,36

The regulation of the 2 phenotypically distinct, polarized forms of the heterogeneous T helper response by vitamin A and zinc may be a mechanism that mediates the effects that supplementation with these micronutrients has on parasite-specific outcomes. These responses play separate roles in controlling onset of infection versus the onset of symptomatic diarrhea for other intestinal pathogens.37 The marginally significant increase of E histolytica infections and longer duration of infections among children who were supplemented with zinc in our study may be attributable to the downregulation of the Th2 response, which is important in regulating IgA levels.38 The downregulation of IgA levels may lead to an increased attachment of trophozoites and increased risk for intestinal amebiasis.19,39 The reduced risk for E histolytica–associated diarrhea among zinc-supplemented children may reflect the importance of high levels of the Th1 cytokine interferon-{gamma} in providing resistance against invasive forms of illness by E histolytica.22

The increase of A lumbricoides infections among zinc-supplemented children may result from the downregulation of the Th2 response by zinc. A polarized Th2 response is induced in A lumbricoides infections and is greatly magnified among A lumbricoides–infected children who are supplemented with vitamin A.40–42 Increased Th2 cytokine production correlates with the age-dependent reduction of intestinal helminth infection in communities where the parasite is endemic.21 Th2 cytokines induce immunoglobulin E production by B cells and activating eosinophils, both of which mediate A lumbricoides destruction and expulsion.43 The decrease in A lumbricoides–associated diarrhea among vitamin A–and zinc-supplemented children is unexpected because Ascaris does not typically cause diarrhea. However, helminths can alter susceptibility to tuberculosis or AIDS by shifting the host's response from a protective Th1 response to a more detrimental Th2 response.44 Geohelminth infections may also shift the host's immune response to other gastrointestinal pathogens that cause severe inflammatory diarrhea.45 In our study, the combined vitamin A–zinc supplementation may be countering a similar Ascaris-induced shift in the immune response to coinfections by other intracellular pathogens.

The reduced risk and duration of G lamblia infections among children in the vitamin A–zinc group may reflect the simultaneous induction of both Th1 and Th2 responses in Giardia infections. A number of studies have reported that IgA antibodies and Th2 cytokines are important in eradicating G muris or G lamblia infection.20 However, it is not clear whether a Th2 response is more protective against Giardia, because a strong Th1 response is also important in reducing G lamblia intestinal trophozoites and fecal cyst counts.23 The upregulation of both the Th1 and Th2 responses among children who are supplemented simultaneously with zinc and vitamin A may lead to both increased IgA-mediated protection against initial onset of Giardia infection and increased reduction of Giardia trophozoites and fecal cyst counts once infection is established.

A number of methodologic limitations of our study need to be addressed. First, surveillance that consists of collecting only 1 stool per month is likely to miss enteric infections, because the shedding of parasites is variable over time. However, it is not possible to identify all enteric infections even with stool samples that are collected on 3 consecutive days during a diarrheal episode. It is not clear that increasing the numbers of patients who have infection through additional stool collection would increase the power to find a relationship between specific parasite infection and the immunologic impact of vitamin A and zinc administration. Another limitation of our study was that we had no biochemical indicators of initial vitamin A and zinc status of children. As a result, it was not possible to determine whether children who had deficiency may have benefited more and children who had no or marginal deficiency may have benefited less. We also did not distinguish between E histolytica, a pathogen, and the nonpathogenic E dispar. The presence of E dispar may be confounding the findings regarding the impact of vitamin A and zinc on E histolytica–associated diarrhea. However, the clear effect of zinc on diarrheal disease in our study suggests that the potential for misclassification of Entamoeba to affect the analysis is minimal.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
We found that vitamin A and zinc have distinct effects on parasite prevalence and parasite-associated diarrheal disease. We have argued that these effects are attributable to the role that zinc and vitamin A supplementations play in cross-regulating the Th1 and Th2 arms of the adaptive immune responses and the distinct role that these arms play in protecting against specific parasite infections. Additional work needs to confirm whether vitamin A and zinc supplementations produce these same parasite-specific effects in other community settings. If confirmed, then the implications are that micronutrient supplementation programs should be more closely coordinated with antiparasite public health interventions. The specific micronutrient used and the timing of supplementation relative to the delivery of antiparasitic agents should be designed taking into account which specific parasites are present in specific communities and clinical settings. Such efforts could more effectively reduce parasite reinfection and enhance growth in children and so improve their overall health and development in a more cost-effective manner.


   ACKNOWLEDGMENTS
 
Financial support was received from the Instituto de Nutricion Danone, CONACYT (National Council of Science and Technology of Mexico), and National Institutes of Health grant K01 DK06142-02.

We thank Cristina Barrgan and Matilde Juarez (Clinical Microbiologic Laboratory, Hospital La Perla, Cda Netzahuaycoytl, Mexico) for assistance in the laboratory.


   FOOTNOTES
 
Accepted Feb 6, 2007.

Address correspondence to Kurt Z. Long, PhD, Division of International and Indigenous Health, School of Population Health, University of Queensland, Herston Road, Herston, Brisbane, Queensland 4006, Australia. E-mail: k.long{at}uq.edu.au

The authors have indicated they have no financial relationships relevant to this article to disclose.


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 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics




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