Mass deworming for improving health and cognition of children in endemic helminth areas: A systematic review and individual participant data network meta‐analysis

BackgroundSoil transmitted (or intestinal) helminths and schistosomes affect millions of children worldwide.ObjectivesTo use individual participant data network meta‐analysis (NMA) to explore the effects of different types and frequency of deworming drugs on anaemia, cognition and growth across potential effect modifiers.Search MethodsWe developed a search strategy with an information scientist to search MEDLINE, CINAHL, LILACS, Embase, the Cochrane Library, Econlit, Internet Documents in Economics Access Service (IDEAS), Public Affairs Information Service (PAIS), Social Services Abstracts, Global Health CABI and CAB Abstracts up to March 27, 2018. We also searched grey literature, websites, contacted authors and screened references of relevant systematic reviews.Selection CriteriaWe included randomised and quasirandomised deworming trials in children for deworming compared to placebo or other interventions with data on baseline infection.Data Collection and AnalysisWe conducted NMA with individual participant data (IPD), using a frequentist approach for random‐effects NMA. The covariates were: age, sex, weight, height, haemoglobin and infection intensity. The effect estimate chosen was the mean difference for the continuous outcome of interest.ResultsWe received data from 19 randomized controlled trials with 31,945 participants. Overall risk of bias was low. There were no statistically significant subgroup effects across any of the potential effect modifiers. However, analyses showed that there may be greater effects on weight for moderate to heavily infected children (very low certainty evidence).Authors' ConclusionsThis analysis reinforces the case against mass deworming at a population‐level, finding little effect on nutritional status or cognition. However, children with heavier intensity infections may benefit more. We urge the global community to adopt calls to make data available in open repositories to facilitate IPD analyses such as this, which aim to assess effects for the most vulnerable individuals.</div

A possible schematic role of inflammatory cells networks on T2D and CVD.

<p>(A) The situation in animal models of T2D and CVD without the presence of helminths and in humans living in affluent areas not endemic for helminths. (B) The situation in animal models in the presence of helminths and in humans living in areas endemic for helminths. Although it is known that genes and lifestyle factors are involved in the development of insulin resistance and cardiovascular disease, it is becoming increasingly accepted that the immune system and inflammation play an important role as well. Obese people with metabolic syndrome have a higher degree of inflammation, characterized by increased TNF, a cytokine associated with insulin resistance. When the balance of T cell subsets is disturbed, increased frequencies of pro-inflammatory T cells such as T helper (Th) 1 and Th17 can drive classically activated macrophages (CAMs) which release TNF and, when in metabolic organs such as the adipose tissue, can interfere with insulin signaling. There is also evidence that, under inflammatory conditions, mast cells (MCs) contribute to the pathogenesis of metabolic disorders. High-affinity IgE, present on MCs, can lead to degranulation and initiate inflammation when cross-linked (A). However, the immune system is also endowed with cells such as Th2 and Treg that can exert anti-inflammatory activity and counterbalance the effects of TNF. The balance between pro- and anti-inflammatory activities in the immune system would determine insulin sensitivity. The situation seems to be different in rural areas of LMICs where helminth infections are highly prevalent. Helminths need nutrients from their host for their growth and reproduction, and this might use the energy of their host and therefore forestall obesity and insulin resistance. However, helminths can also lead to the expansion of alternatively activated Th2 and Treg. Th2 cytokines result in increased eosinophilia (EO) and, when in adipose tissue, can lead to the alternative activation of macrophages in this metabolically active organ; the AAMs in turn release anti-inflammatory cytokines such as IL-10. The signaling pathways are currently being dissected, but so far there is evidence that this cascade of events involves the activation of PPAR, STAT6, and/or Akt. Moreover, it has been noted that when the immune system is exposed to chronic helminth infections, EO and MCs no longer behave as pro-inflammatory immune cells, and IgE under these conditions appears to be of low affinity showing poor functional activity in terms of inducing MC degranulation. Thus, in the presence of helminth infections, the immune system is in an anti-inflammatory mode that is considered to be disadvantageous to the development of T2D and CVD (B). The solid lines represent associations based on data available, while dotted lines represent theoretical associations that are yet to be tested.</p

Prevalence rates with 95% confidence intervals for STH infections in Mainang village before and after MDA with DEC/albendazole.

<p>The first round of MDA was performed just after this the 2002 survey. The 2007 STH data were from a survey that was performed just prior to the last (6^th) round of MDA. <b>A </b><i>Ascaris lumbricoides</i>. <b>B</b> Hookworm (mainly <i>Necator americanus</i>) and <b>C </b><i>Trichiuris trichiura</i>.</p

Prevalence rates with 95% confidence intervals for anti-filarial antibodies based on the Brugia Rapid test in children aged between 3 and 10 years of age prior to MDA (2001) and after one or more rounds of MDA.

<p>The last round of MDA was performed in 2007. Since only selective treatment of MF carriers was performed in 2001, no Brugia Rapid tests were performed on the samples collected in 2002.</p

Schematic overview of the study design.

<p>In 2001 microfilaria and anti-filarial IgG4 baseline surveys were performed and MF positive and lymphoedema patients were selectively treated. Baseline data on STH infections was collected in 2002, and the village was re-examined for filarial infections at that time just prior the first round of MDA with diethylcarbamazine plus albendazole. Subsequent post-MDA surveys were performed 9 to 11 months after each round of MDA. MDA was continued until 2007, when the last (6^th) round of MDA was provided and annual follow-up surveys were continued until 2010.</p

A Prevalence rates with 95% confidence intervals for <i>Brugia timori</i> microfilaraemia in Mainang village before and after MDA with DEC/albendazole.

<p>Selective treatment of microfilaraemics and lymphedema patients was performed after the baseline survey in 2001. The first round of MDA was distributed following the survey in 2002, and the last (6^th) round of MDA was distributed after the 2007 survey was performed. MDA coverage rates ranged between 75 and 85%. <b>B</b> Prevalence rates with 95% confidence intervals for anti-filarial antibodies as assessed by the Brugia Rapid test. Since only selective treatment was performed in 2001, no Brugia Rapid tests were performed on the samples collected in 2002.</p

Geometric mean egg counts per gram of stool (as assessed by a single Kato-Katz smear) for individuals with STH infections in Mainang village in 2002 (before the 1^st round of MDA, black bars) and in 2009 (22 months after the 6^th and final round of DEC/albendazole MDA, gray bars).

<p>The data are shown by age group. Error bars indicate the 75 percentiles, and the broken lines represent thresholds for light and moderate infection intensities according to WHO guidelines. The number on top of each column represents the number of positive individuals tested per age group. <b>A </b><i>Ascaris lumbricoides</i>. <b>B</b> Hookworm (mainly <i>Necator americanus</i>).</p

Prevalence rates with 95% confidence intervals for antifilarial antibodies by age group as assessed by the Brugia Rapid test.

<p>Baseline data for 2001 (prior to MDA) are shown with black bars should be compared with data from 2010 (black bars) (about 34 months after the 6th and final round of MDA).</p

Prevalence of <i>A</i>. <i>lumbricoides</i>, hookworm and <i>T</i>. <i>trichiura</i> infections based on stool examination and serological examination for <i>A</i>. <i>lumbricoides</i> infections during and after mass drug administration with DEC + albendazole in a subset of the treated population that was studied from 2002 to 2009 on Alor Island, Indonesia.

<p>Prevalence of <i>A</i>. <i>lumbricoides</i>, hookworm and <i>T</i>. <i>trichiura</i> infections based on stool examination and serological examination for <i>A</i>. <i>lumbricoides</i> infections during and after mass drug administration with DEC + albendazole in a subset of the treated population that was studied from 2002 to 2009 on Alor Island, Indonesia.</p

Changes in age-specific <i>Ascaris</i> infection rates, AsHb antibody rates, and average egg output per age group for different times before and after MDA.

<p>Prevalence based on eggs in the stool (A) or serology (B) shows a notable reduction over all age categories between the year 2002 and 2004. While the prevalence goes back up in all age categories based on the presence of eggs in the stool in subsequent years, the percentage seropositive individuals remains low. (C) The average group egg output (sum of EPG divided by the number of people analyzed per group) is also reduced between 2002 and 2009 over all age categories. Too few subjects (less than 5) younger than 10 years of age were tested in 2007 and 2009 to produce meaningful data for this age category.</p