Does treatment of intestinal helminth infections influence malaria? Background and methodology of a longitudinal study of clinical, parasitological and immunological parameters in Nangapanda, Flores, Indonesia (ImmunoSPIN Study)

Contains fulltext : 88856.pdf (publisher's version ) (Open Access)BACKGROUND: Given that helminth infections are thought to have strong immunomodulatory activity, the question whether helminth infections might affect responses to malaria antigens needs to be addressed. Different cross-sectional studies using diverse methodologies have reported that helminth infections might either exacerbate or reduce the severity of malaria attacks. The same discrepancies have been reported for parasitemia. METHODS/DESIGN: To determine the effect of geohelminth infections and their treatment on malaria infection and disease outcome, as well as on immunological parameters, the area of Nangapanda on Flores Island, Indonesia, where malaria and helminth parasites are co-endemic was selected for a longitudinal study. Here a Double-blind randomized trial will be performed, incorporating repeated treatment with albendazole (400 mg) or placebo at three monthly intervals. Household characteristic data, anthropometry, the presence of intestinal helminth and Plasmodium spp infections, and the incidence of malaria episodes are recorded. In vitro cultures of whole blood, stimulated with a number of antigens, mitogens and toll like receptor ligands provide relevant immunological parameters at baseline and following 1 and 2 years of treatment rounds. The primary outcome of the study is the prevalence of Plasmodium falciparum and P. vivax infection. The secondary outcome will be incidence and severity of malaria episodes detected via both passive and active follow-up. The tertiary outcome is the inflammatory cytokine profile in response to parasite antigens. The project also facilitates the transfer of state of the art methodologies and technologies, molecular diagnosis of parasitic diseases, immunology and epidemiology from Europe to Indonesia. DISCUSSION: The study will provide data on the effect of helminth infections on malaria. It will also give information on anthelminthic treatment efficacy and effectiveness and could help develop evidence-based policymaking. TRIAL REGISTRATION: This study was approved by The Ethical Committee of Faculty of Medicine, University of Indonesia, ref:194/PT02.FK/Etik/2006 and has been filed by ethics committee of the Leiden University Medical Center. Clinical trial number:ISRCTN83830814. The study is reported in accordance with the CONSORT guidelines for cluster-randomized studies

Community deworming alleviates geohelminth-induced immune hyporesponsiveness

In cross-sectional studies, chronic helminth infections have been associated with immunological hyporesponsiveness that can affect responses to unrelated antigens. To study the immunological effects of deworming, we conducted a cluster-randomized, double-blind, placebo-controlled trial in Indonesia and assigned 954 households to receive albendazole or placebo once every 3 mo for 2 y. Helminth-specific and nonspecific whole-blood cytokine responses were assessed in 1,059 subjects of all ages, whereas phenotyping of regulatory molecules was undertaken in 121 school-aged children. All measurements were performed before and at 9 and 21 mo after initiation of treatment. Anthelmintic treatment resulted in significant increases in proinflammatory cytokine responses to Plasmodium falciparum-infected red blood cells (PfRBCs) and mitogen, with the largest effect on TNF responses to PfRBCs at 9 mo—estimate [95% confidence interval], 0.37 [0.21–0.53], P value over time (Ptime) < 0.0001. Although the frequency of regulatory T cells did not change after treatment, there was a significant decline in the expression of the inhibitory molecule cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) on CD4+ T cells of albendazole-treated individuals, –0.060 [–0.107 to –0.013] and –0.057 [–0.105 to –0.008] at 9 and 21 mo, respectively; Ptime = 0.017. This trial shows the capacity of helminths to up-regulate inhibitory molecules and to suppress proinflammatory immune responses in humans. This could help to explain the inferior immunological responses to vaccines and lower prevalence of inflammatory diseases in low- compared with high-income countries

Infection with Soil-Transmitted Helminths Is Associated with Increased Insulin Sensitivity

<div><p>Objective</p><p>Given that helminth infections have been shown to improve insulin sensitivity in animal studies, which may be explained by beneficial effects on energy balance or by a shift in the immune system to an anti-inflammatory profile, we investigated whether soil-transmitted helminth (STH)-infected subjects are more insulin sensitive than STH-uninfected subjects.</p><p>Design</p><p>We performed a cross-sectional study on Flores island, Indonesia, an area with high prevalence of STH infections.</p><p>Methods</p><p>From 646 adults, stool samples were screened for <i>Trichuris trichiura</i> by microscopy and for <i>Ascaris lumbricoides</i>, <i>Necator americanus</i>, <i>Ancylostoma duodenale</i>, <i>and Strongyloides stercoralis</i> by qPCR. No other helminth was found. We collected data on body mass index (BMI, kg/m²), waist-to-hip ratio (WHR), fasting blood glucose (FBG, mmol/L), insulin (pmol/L), high sensitive C-reactive protein (ng/ml) and Immunoglobulin E (IU/ml). The homeostatic model assessment for insulin resistance (HOMAIR) was calculated and regression models were used to assess the association between STH infection status and insulin resistance.</p><p>Results</p><p>424 (66%) participants had at least one STH infection. STH infected participants had lower BMI (23.2 vs 22.5 kg/m², p value = 0.03) and lower HOMAIR (0.97 vs 0.81, p value = 0.05). In an age-, sex- and BMI-adjusted model a significant association was seen between the number of infections and HOMAIR: for every additional infection with STH species, the HOMAIR decreased by 0.10 (p for linear trend 0.01). This effect was mainly accounted for by a decrease in insulin of 4.9 pmol/L for every infection (p for trend = 0.07).</p><p>Conclusion</p><p>STH infections are associated with a modest improvement of insulin sensitivity, which is not accounted for by STH effects on BMI alone.</p></div

Immune parameters in soil-transmitted helminth uninfected and infected participants.

<p>Abbreviations: HsCRP = High sensitive C reactive protein, TNF = tumor necrosis factor, IL10 = interleukin 10, IgE = Immunoglobulin E. HsCRP, TNF, IL10 and IgE are log-transformed.</p><p># The difference is expressed as increase or decrease in the parameter per increasing number of infections per patient (maximum = 3).</p><p>Immune parameters in soil-transmitted helminth uninfected and infected participants.</p

Parameters of glucose metabolism parameters in soil-transmitted helminth uninfected and infected participants.

<p>Abbreviations: BMI = body mass index, WHR = waist to hip ratio, FBG = fasting blood glucose, HOMAIR = Homeostasis model assessment for insulin resistance.</p><p>* WHR is calculated by waist circumference (cm) / hip circumference (cm)</p><p>** HOMAIR index is calculated with HOMAIR formula = fasting serum insulin x fasting glucose / 22.5, using HOMA2 calculator (<a href="https://www.dtu.ox.ac.uk/homacalculator/" target="_blank">https://www.dtu.ox.ac.uk/homacalculator/</a>)</p><p># The difference is expressed as increase or decrease in the parameter per increasing number of helminth species per patient (maximum = 3). Insulin and HOMAIR were log-transformed.</p><p>Parameters of glucose metabolism parameters in soil-transmitted helminth uninfected and infected participants.</p

The association of number of soil-transmitted helminth species per subject and Homeostasis Model Assessment for insulin Resistance (HOMAIR).

<p>The association of number of helminth species infections with HOMAIR (mean, 95%CI) with correction for age, sex, and BMI. The numbers of participants with none, one, two or at least three species were respectively 161, 189, 98 and 29. The p for linear trend is 0.01. *Adjusted mean for HOMAIR were derived from linear regression. White circle = no soil-transmitted helminth infection; black circle = infected with one soil-transmitted helminth species; white square = infected with two soil-transmitted helminth species; black square = infected with at least three soil-transmitted helminth species.</p

Characteristics of the study population.

<p>Abbreviations: BMI = body mass index, WHR = waist to hip ratio, FBG = fasting blood glucose, HOMAIR = Homeostasis model assessment for insulin resistance, HsCRP = High sensitive C reactive protein, TNF = tumor necrosis factor, IL10 = interleukin 10, IgE = Immunoglobulin E.</p><p>^*after logarithmic transformation</p><p>Characteristics of the study population.</p

Characteristic of the group with intima media thickness measurement (population 40+).

<p>1. positive by microscopy.</p><p>2. positive by PCR.</p><p>Abbreviations: BMI = body mass index, WHR = waist to hips ratio, FBG = fasting blood glucose, TC = total cholesterol, TG = triglyceride, HDL-c = high density lipoprotein cholesterol, LDL-c = low density lipoprotein cholesterol, TIgE = total immunoglobulin E, hs-CRP = high sensitive C reactive protein, TNF = tumor necrosis factor, IL-10 = interleukin 10. *Adjusted mean difference for TIgE, hs-CRP and cytokines were anti-log transformed and represent ratio.</p