Protection against Diarrhea Associated with Giardia intestinalis Is Lost with Multi-Nutrient Supplementation: A Study in Tanzanian Children

Abstract

BackgroundAsymptomatic carriage of Giardia intestinalis is highly prevalent among children in developing countries, and evidence regarding its role as a diarrhea-causing agent in these settings is controversial. Impaired linear growth and cognition have been associated with giardiasis, presumably mediated by malabsorption of nutrients. In a prospective cohort study, we aim to compare diarrhea rates in pre-school children with and without Giardia infection. Because the study was conducted in the context of an intervention trial assessing the effects of multi-nutrients on morbidity, we also assessed how supplementation influenced the relationship between Giardia and diarrhoea rates, and to what extent Giardia modifies the intervention effect on nutritional status.Methods and FindingsData were collected in the context of a randomized placebo-controlled efficacy trial with 2×2 factorial design assessing the effects of zinc and/or multi-micronutrients on morbidity (n = 612; height-for-age z-score <−1.5 SD). Outcomes measures were episodes of diarrhea (any reported, or with ≥3 stools in the last 24 h) and fever without localizing signs, as detected with health-facility based surveillance. Giardia was detected in stool by enzyme-linked immunosorbent assay. Among children who did not receive multi-nutrients, asymptomatic Giardia infection at baseline was associated with a substantial reduction in the rate of diarrhea (HR 0.32; 0.15–0.66) and fever without localizing signs (HR 0.56; 0.36–0.87), whereas no such effect was observed among children who received multi-nutrients (p-values for interaction 0.03 for both outcomes). This interaction was independent of age, HAZ-scores and distance to the research dispensary. There was no evidence that Giardia modified the intervention effect on nutritional status.ConclusionAlthough causality of the Giardia-associated reduction in morbidity cannot be established, multi-nutrient supplementation results in a loss of this protection and thus seems to influence the proliferation or virulence of Giardia or associated intestinal pathogens.

Persistent G. lamblia impairs growth in a murine malnutrition model

“…Delineating how the host mucosal immune response affects epithelial cell proliferation will thus be critical for understanding disease pathogenesis subsequent to Giardia, mechanisms which may account for the variability seen in the subset of children who have associated growth failure subsequent to infection. humans, to profound wasting and developmental delay (1,13,14), to even potential antidiarrheal effects (18). In what we believe to be a novel murine model of persistent infection that utilizes the previously untested G. lamblia H3 (assemblage B) isolate, we replicated many aspects of chronic human giardiasis that herein are associated with growth failure -an outcome that is profoundly influenced by host nutritional status.…”

“…In other investigations, G. lamblia infection was not sufficient to explain long-term growth faltering (16). With regard to "asymptomatic" giardiasis, there are also conflicting reports of positive (17) or no correlation with longitudinal stunting (18,19). Active G. lamblia infection has also been associated with vitamin A (20) and zinc deficiency (21,22) and malnutrition in general (23).…”

“…demonstrated a relationship between G. lamblia during early childhood and gut dysfunction (24), suggesting the potential for intestinal pathology concomitant with infection. Conversely, the presence of G. lamblia in children has been associated with an increased time to the first episode of any diarrheal event, an effect that was eliminated after multinutrient supplementation (18). A recent systematic review and meta-analysis of endemic pediatric giardiasis concluded that there is an apparently paradoxical association with protection from acute diarrhea, yet an increased risk of persistent diarrhea (25).…”

Giardia duodenalis Cathepsin B Proteases Degrade Intestinal Epithelial Interleukin-8 and Attenuate Interleukin-8-Induced Neutrophil Chemotaxis

“…Microarray analysis of jejunal tissues collected from assemblage E Giardia-infected calves revealed decreased mRNA expression of several proinflammatory mediators and increased expression of anti-inflammatory transcription factors (26). Several human studies have suggested that Giardia infections in children may reduce the incidence or severity of diarrheal disease (17,27,28). One study demonstrated that Tanzanian children infected with Giardia had a reduced likelihood of developing fever and had lower levels of serum C-reactive protein, a classic marker of inflammation, than did their noninfected counterparts (27).…”

“…Several human studies have suggested that Giardia infections in children may reduce the incidence or severity of diarrheal disease (17,27,28). One study demonstrated that Tanzanian children infected with Giardia had a reduced likelihood of developing fever and had lower levels of serum C-reactive protein, a classic marker of inflammation, than did their noninfected counterparts (27). A separate study suggested that children coinfected with rotavirus and Giardia displayed a marked reduction in the severity of diarrheal disease compared to children infected with only rotavirus (17).…”