Viewpoints Micronutrient Supplementation and Deworming in Children with Geohelminth Infections Selvi Rajagopal1, Peter J. Hotez1,2*, Donald A. P. Bundy3* 102469 1 Departments of Medicine, Pediatrics, and Molecular Virology and Microbiology, National School of Tropical Medicine, Baylor College of Medicine, Houston, Texas, United States of America, 2 Sabin Vaccine Institute and Texas Children’s Hospital Center for Vaccine Development, Houston, Texas, United States of America, 3 Human Development Department, World Bank, Washington, D.C., United States of America Introduction the relative benefits of vitamin A supple- has potentially important consequences for mentation for children with ascariasis global health, especially since ascariasis Soil-transmitted helminth (also known infection and iron supplementation for may be the most common chronic child- as ‘‘geohelminth’’) infections are among children with trichuriasis and hookworm hood infection worldwide [12]. the most common chronic infections infections, with and without deworming, While the exact mechanism of deficien- worldwide. The World Health Organiza- and consider whether there are circum- cy induced by ascariasis remains unclear, tion (WHO) estimates that almost 900 stances in which deworming programs studies have established that children million children require treatment (also should be complemented by micronutrient absorb less vitamin A following oral known as deworming) for geohelminth programs. supplementation when they are infected infection, while the 2010 Global Burden of [13]. Mucosal changes in the gastrointes- Disease Study estimates that more than tinal tract with ascariasis, including blunt- Vitamin A 5.2 million disability-adjusted life years ing of the intestinal villi and morphological (DALYs) are attributable to geohelminth Vitamin A deficiency is defined by changes in the intestinal crypts, may infection [1,2]. In 2001, the World Health WHO as a serum retinol level explain the malabsorption [14]. Similarly, Assembly resolved to treat 75% of children ,0.35 mmol/L [8]. Several studies have the ability of the intestinal tract to absorb at risk for morbidity from these geohel- linked human Ascaris lumbricoides infec- vitamin A, a fat-soluble vitamin, may be minths by 2010. However, WHO reported tion to vitamin A deficiency with robust influenced by the impaired capacity for that by 2010 only approximately one-third evidence for a relationship between high intestinal fat absorption in children with of all children at risk had achieved access intensity ascaris infection and lower levels ascariasis infection [13]. to mass drug administration (MDA). of vitamin A (,0.70 mmol/L) [9]. The Methods of improving vitamin A status Treating the remaining two-thirds by relationships between trichuris and hook- in children have been explored in relation 2020 is the target of the 2012 London worm infections and vitamin A deficiency to supplementation and deworming, alone Declaration for Neglected Tropical Dis- are less well documented; therefore, this and in combination. There is extensive eases [3]. discussion is limited to ascariasis. literature on the benefits of vitamin A The 2012 London Declaration and the Not all children with ascariasis meet supplementation alone on the community global aspirations for universal deworming WHO criteria for vitamin A deficiency, health of preschool-age pediatric popula- arise partly from studies conducted over although serious health consequences have tions, although a recent large-scale trial in the last two decades demonstrating the been observed in the children who still have India and associated meta-analysis of all severe morbidity and poor cognitive, relatively lower vitamin A levels large-scale trials suggests that the effect in intellectual, and physical child develop- (,0.70 mmol/L). Xeropthalmia, a severe terms of mortality prevention may be less ment in populations with endemic geohel- complication of vitamin A deficiency that than sometimes suggested [15]. In com- minth infections, and the resulting eco- sometimes leads to blindness, is found more munities in which vitamin A deficiency nomic losses [4,5]. Nutritional deficiencies, commonly in children with ascariasis [10]. coexists with geohelminth infection, de- including protein malnutrition and micro- As well as having direct effects, severe worming alone and in combination with nutrient losses secondary to geohelminth vitamin A deficiency can have significant vitamin A supplementation has been infection, represent a potentially important indirect consequences, for example, in- explored as a means to correct or reduce mechanism by which geohelminths weak- creasing susceptibility to potentially fatal deficiency in infected children. A popula- en their host, causing ill health and illnesses such as measles and lower respira- tion study in Uttar Pradesh, India, found disability [5]. There is growing evidence tory infections [11]. As a result, the link that twice-yearly deworming alone on that serum levels of multiple micronutri- between vitamin A deficiency and ascariasis lightly infected children did not result in ents, including vitamin A, iron, copper, selenium, cobalt, and zinc, are reduced by Citation: Rajagopal S, Hotez PJ, Bundy DAP (2014) Micronutrient Supplementation and Deworming in geohelminth infection and some evidence Children with Geohelminth Infections. PLoS Negl Trop Dis 8(8): e2920. doi:10.1371/journal.pntd.0002920 that these effects can be reversed by Editor: Judd L. Walson, University of Washington, United States of America deworming [6,7]. In some cases, micronu- trient supplementation has been added in Published August 7, 2014 order to complement local or regional Copyright: ß 2014 Rajagopal et al. This is an open-access article distributed under the terms of the Creative deworming efforts. Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Here we focus on iron and vitamin A Funding: No direct funding was provided for this article. deficiencies, two major micronutrient def- icits which have been causally linked to Competing Interests: The authors have declared that no competing interests exist. geohelminthiases. We specifically explore * E-mail: hotez@bcm.edu (PJH); dapbundy@gmail.com (DAPB) PLOS Neglected Tropical Diseases | www.plosntds.org 1 August 2014 | Volume 8 | Issue 8 | e2920 either significant weight gain or a reduc- transmission is intense, such as in Zanzi- into account the greater blood loss from A. tion in mortality [16]. Studies of pre- bar, 25% of all anemia, 35% of iron- duodenale compared to N. americanus school-age children in Bangladesh, India, deficiency anemia, and 73% of severe [40] so that the benefits of iron supple- and Indonesia, however, showed that anemia were attributable to hookworm mentation in a given location may reflect combined deworming and supplementa- [26]. In sub-Saharan Africa, hookworm the relative prevalence of these endemic tion with beta-carotene, an inactive form and malaria coinfections are common and hookworm species. of vitamin A, resulted in the greatest rise in are often additive in terms of producing serum retinol levels, as compared to severe anemia [27]. Heavy infections with Conclusions children treated with deworming alone whipworm are also linked to anemia or beta-carotene supplementation exclu- through a combination of blood loss as a More than a thousand million deworm- sively [17,18]. While there is some evi- result of trichuris dysentery syndrome and ing treatments have been delivered for the dence to suggest an added benefit to chronic inflammation (anemia of chronic three common (and coendemic) geohel- combined deworming and vitamin A disease) due to trichuris colitis [28,29]. minths. The evidence presented here supplementation, a number of studies in There is substantial evidence that iron- suggests that adding micronutrient supple- similar settings have either been unable to deficiency anemia from causes in early mentation may provide additional bene- reproduce this positive outcome or have childhood can result in intellectual, cogni- fits, but the case is far from clear. With not specifically tested the combined inter- tive, and behavioral deficits; several differ- vitamin A, there are demonstrable addi- vention [19,20]. Thus, while the WHO ent mechanisms have been proposed, tive effects in some settings, but in others and the United Nations Children’s Fund including altered dopaminergic function there is no clear benefit or no clear (UNICEF) recommend that benzimid- [30]. Moderate-to-heavy hookworm infec- difference from supplementation alone. azole anthelminthics can be safely coad- tions and trichuriasis specifically have in With iron supplementation, in contrast, ministered with vitamin A [21], the some circumstances been shown to lead to there does not appear to be a significant potential synergies of deworming with failure to achieve intellectual potential added benefit over deworming alone vitamin A supplementation are neither [31] and cognitive impairment [32]. except in two cases: first, in pregnant well documented nor consistent. There is a Malaria occurring in combination with women in hookworm endemic areas and, need for additional studies, especially hookworm infection has been identified as second, in those with very intense infection randomized clinical trials, given the fre- a potential risk factor, exacerbating the and existing anemia. Individuals in both quent coexistence of dietary deficiency cognitive deficits [33]. Anemia and a situations could benefit from a combina- and infection in endemic areas. moderate-to-heavy parasite burden of tion of deworming and supplementation. either helminth species were identified as Delivering a bundled package for de- Iron independent risk factors for stunting [34]. worming and micronutrient supplementa- Both stunting and cognitive delay have tion would have financial implications. In contrast to its relationship with been shown to have lifelong consequences These implications are potentially much less vitamin A, a strong association has not for the productive potential of children. for vitamin A supplements than for iron been identified between ascariasis infection In their systematic review of interven- since the delivery regime for the former is and anemia. Most of the pediatric studies of tions to reduce hookworm anemia follow- similar in frequency to deworming—once or geohelminth infection and the level of ing deworming, Brooker and Smith deter- twice a year. Thus, in theory they could be anemia have examined the relationship mined that, for children and adults, delivered together using the same delivery with either whipworms (Trichuris trichiura) albendazole had demonstrated benefit (a platform. However, current evidence does or hookworms (Necator americanus or mean increase of 1.89 g/l), whereas the not provide clear guidance that this would Ancylostoma duodenale). Most of these benefits from mebendazole did not reach be beneficial under most circumstances. studies have examined subjects aged 2–15 statistical significance [35], findings that It would not appear practical to inte- years, in which anemia is defined as a appear consistent with previous observa- grate deworming with iron supplementa- hemoglobin concentration of ,11.5 g/dL tions of higher hookworm cure rates from tion since the latter requires an extended [22]. Moderate-to-heavy hookworm infec- albendazole versus mebendazole [36]. regime of daily or weekly supplementation tion in children (and light hookworm Whether including iron supplementation over several weeks. Such an approach is infection in both pregnant and nonpreg- with deworming adds substantially to the currently adopted as part of clinical case nant adults) and heavy pediatric trichuriasis overall benefit is unclear. Brooker and management and is appropriate to the can result in anemia, although the precise Smith’s systematic review found no added setting of antenatal care or the manage- burden of infection that serves as a benefit of combining deworming with iron ment of severe anemia. Thus, in popula- threshold for clinical anemia varies de- supplementation [35]. However, a study tions in which hookworm is a significant pending on the host’s existing iron stores. from Sierra Leone demonstrated additive hazard and MDA for deworming is In the case of hookworm infection, iron benefit of deworming and iron-folate offered, it would be useful to ensure that deficiency anemia occurs when adult supplementation in pregnant women with those responsible for case management in hookworms attach to the mucosa and hookworm [37], while both in Sri Lanka the community were aware of the partic- submucosa, where they cause intestinal and India there was added benefit from ular synergies with iron supplementation, blood loss [23]. In a systematic review, adding mebendazole to iron supplementa- especially for pregnant women. Smith and Brooker showed that moderate- tion [38,39]. This seems to suggest that the It is perhaps worth emphasizing that our to-heavy-intensity hookworm infections effectiveness of MDA might be increased hesitancy in recommending cointervention were typically associated with low hemo- by routine iron supplementation of preg- is because of practical and cost-efficiency globin levels in school-age children [24]. nant women, but further studies are issues and not because of the lack of Among adults, even light infections can required to determine whether iron evidence of a causal link between worm produce anemia, especially in pregnant supplementation is relevant to other infection and micronutrient deficiency. women [25]. In areas where hookworm populations. Such studies should also take Even if helminth infection is merely PLOS Neglected Tropical Diseases | www.plosntds.org 2 August 2014 | Volume 8 | Issue 8 | e2920 associated with risk of micronutrient defi- Further operational studies are needed to current state of evidence appears insuffi- ciency, with no proven causation, then explore how best to take advantage of this cient to justify the potentially significant linking micronutrient supplementation to huge opportunity to target children at high additional costs and complexity. A firmer deworming programs would still be justified risk for both conditions. recommendation would require further on the grounds that poor children would Adding supplementation to deworming randomized clinical trials across different likely benefit from both interventions. programs might offer benefits, but the epidemiologic settings. References 1. World Health Organization (2012) Integrated 14. 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