Publications by authors named "Linda J Wammes"

30 Publications

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Establishing a controlled hookworm human infection (CHHI) model for Africa: A report from the stakeholders meeting held in Lambaréné, Gabon, November 10-11, 2019.

Arch Public Health 2021 Jul 5;79(1):120. Epub 2021 Jul 5.

Centre de Recherches Médicales de Lambaréné, BP242, Lambaréné, Gabon.

Background: Hookworm is a major contributor to worldwide disease burden with over 230 million people infected. It has been identified as one of the Neglected Tropical Diseases that can be controlled and even eliminated through mass drug administration and other effective interventions. Mathematical models have shown that hookworm can only be eliminated via a vaccine. Controlled Hookworm Human Infection (CHHI) models can facilitate rapid development of vaccines and drugs.

Methods: As a first step towards the establishment of CHHI in Africa, we held a stakeholders meeting in Lamberene, Gabon from 10 to 11 November 2019.

Results: Discussions revolved around the roles of the different regulatory institutions concerned; the need to strengthen existing regulatory capacity and the role of legislation; creating Gabon-specific ethical guidelines to govern Controlled Human Infection (CHI) studies; development of a study protocol; consideration of cultural and social peculiarities; the need for regular joint review meetings between interested parties throughout the process of protocol implementation; and participant compensation. Moreover, operational considerations concerning the introduction of CHHI in Gabon include the use of the local strain of hookworm for the challenge infections, capacity building for the local production of challenge material, and the establishment of adequate quality assurance procedures.

Conclusion: The workshop addressed several of the anticipated hurdles to the successful implementation of CHHI in Gabon. It is our aim that this report will stimulate interest in the implementation of this model in the sub-Saharan African setting.
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http://dx.doi.org/10.1186/s13690-021-00650-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256403PMC
July 2021

Case series of four secondary mucormycosis infections in COVID-19 patients, the Netherlands, December 2020 to May 2021.

Euro Surveill 2021 06;26(23)

Center for Infectious Disease Research, Diagnostics and Laboratory Surveillance National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands.

We describe four secondary fungal infections caused by Mucorales species in COVID-19 patients. Three COVID-19 associated mucormycosis (CAM) occurred in ICU, one outside ICU. All were men aged > 50 years, three died. Clinical presentations included pulmonary, rhino-orbital cerebral and disseminated infection. Infections occurred in patients with and without diabetes mellitus. CAM is an emerging disease and our observations underscore the need to be aware of invasive mucormycosis, including in COVID-19 patients without (poorly controlled) diabetes mellitus and outside ICU.
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http://dx.doi.org/10.2807/1560-7917.ES.2021.26.23.2100510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193993PMC
June 2021

Early diagnosis and follow-up of acute schistosomiasis in a cluster of infected Belgian travellers by detection of antibodies and circulating anodic antigen (CAA): A diagnostic evaluation study.

Travel Med Infect Dis 2021 May-Jun;41:102053. Epub 2021 Apr 3.

Department of Parasitology, Leiden University Medical Center, Leiden, the Netherlands.

Background: In order to evaluate the diagnostic value of schistosome circulating anodic antigen (CAA) detection, serum and urine CAA-levels were determined in a single cluster of 34 Belgian tourists at three timepoints within a period of 14 weeks following proven Schistosoma exposure in South Africa and compared with two in-house antibody assays.

Methods: Samples were collected 4-5 and 7-8 weeks post-exposure and subsequently 5-6 weeks following praziquantel treatment. Schistosoma antibodies were detected by an adult worm antigen-immunofluorescence assay (AWA-IFA) and a soluble egg antigen-enzyme-linked immunosorbent assay (SEA-ELISA), while CAA concentrations were determined by the Up-Converting reporter Particle labelled Lateral Flow (UCP-LF) test.

Results: Antibodies were detected in 25/34 (73%) travellers pre-treatment and in 27/34 (79%) post-treatment, with the AWA-IFA showing better performance than the SEA-ELISA. Pre-treatment, CAA was detected in 13/34 (38%) and 33/34 (97%) of the travellers in urine and serum, respectively. Post-treatment, all except one traveller became serum CAA negative. This in contrast to the detected antibodies, as well as the previously reported diagnostic results of this cluster.

Conclusions: The UCP-LF CAA serum assay has been demonstrated as the most sensitive method for the diagnosis of early Schistosoma infections and post-treatment monitoring in travellers.
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http://dx.doi.org/10.1016/j.tmaid.2021.102053DOI Listing
September 2021

The Effect of Gut Microbiome Composition on Human Immune Responses: An Exploration of Interference by Helminth Infections.

Front Genet 2019 6;10:1028. Epub 2019 Nov 6.

Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands.

Soil-transmitted helminths have been shown to have the immune regulatory capacity, which they use to enhance their long term survival within their host. As these parasites reside in the gastrointestinal tract, they might modulate the immune system through altering the gut bacterial composition. Although the relationships between helminth infections or the microbiome with the immune system have been studied separately, their combined interactions are largely unknown. In this study we aim to analyze the relationship between bacterial communities with cytokine response in the presence or absence of helminth infections. For 66 subjects from a randomized placebo-controlled trial, stool and blood samples were available at both baseline and 21 months after starting three-monthly albendazole treatment. The stool samples were used to identify the helminth infection status and fecal microbiota composition, while whole blood samples were cultured to obtain cytokine responses to innate and adaptive stimuli. When subjects were free of helminth infection (helminth-negative), increasing proportions of was associated with lower levels of IL-10 response to LPS {estimate [95% confidence interval (CI)] -1.96 (-3.05, -0.87)}. This association was significantly diminished when subjects were helminth-infected (helminth positive) (-value for the difference between helminth-negative versus helminth-positive was 0.002). Higher diversity was associated with greater IFN-γ responses to PHA in helminth-negative (0.95 (0.15, 1.75); versus helminth-positive [-0.07 (-0.88, 0.73), -value = 0.056] subjects. Albendazole treatment showed no direct effect in the association between bacterial proportion and cytokine responses, although the ' effect on IL-10 responses to LPS tended downward in the albendazole-treated group [-1.74 (-4.08, 0.59)] versus placebo [-0.11 (-0.84, 0.62); -value = 0.193]. We observed differences in the relationship between gut microbiome composition and immune responses, when comparing individuals infected or uninfected with geohelminths. Although these findings are part of a preliminary exploration, the data support the hypothesis that intestinal helminths may modulate immune responses, in unison with the gut microbiota. ISRCTN, ISRCTN83830814. Registered 27 February 2008 - Retrospectively registered, http://www.isrctn.com/ISRCTN83830814.
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http://dx.doi.org/10.3389/fgene.2019.01028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856646PMC
November 2019

Transforming growth factor-beta profiles correlate with clinical symptoms and parameters of haemostasis and inflammation in a controlled human malaria infection.

Cytokine 2020 01 13;125:154838. Epub 2019 Sep 13.

Department of Medical Microbiology & Infectious Diseases, Erasmus MC University Medical Center, Rotterdam 3015 GD, the Netherlands. Electronic address:

Background: After a controlled human malaria infection (CHMI), presentation of clinical signs and symptoms and host responses is heterogeneous. Transforming growth factor-beta (TGF-β) is the first serum cytokine that changes in malaria-naïve volunteers after CHMI. We studied a possible relation between TGF-β changes, pro-inflammatory cytokines, activation of haemostasis and endothelial cells and clinical symptoms.

Methods: A panel of cytokines including TGF-β, and markers of activation of haemostasis and endothelial cells were measured in blood samples of 15 volunteers at baseline before CHMI and during CHMI at day of treatment. The change of the parameters on the day of treatment was examined for a significant alteration during infection.

Results: Nine of 15 volunteers showed a significant decrease in TGF-β compared to baseline, with concomitant increased concentrations of D-dimer (p = 0.012), Von Willebrand factor (p = 0.017), IL-6 (p = 0.012) and IFN-γ (0.028) and a significantly decreased platelet count (p = 0.011). In contrast, 6 of 15 volunteers showed sustained or increased TGF-β concentrations without change in the aforementioned parameters. The sustained responders presented with less moderate and severe clinical symptoms than the negative responders (p = 0.036) and had a higher baseline lymphocyte count (p = 0.026). TGF-β concentrations did not correlate with the parasitaemia on day of treatment.

Conclusion: Early decreases of serum TGF-β might function a marker for a pro-inflammatory host response and downstream clinical symptoms and pathology during CHMI.
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http://dx.doi.org/10.1016/j.cyto.2019.154838DOI Listing
January 2020

Controlled Human Malaria Infection with Graded Numbers of NF135.C10- or NF166.C8-Infected Mosquitoes.

Am J Trop Med Hyg 2018 09 12;99(3):709-712. Epub 2018 Jul 12.

Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.

Controlled human malaria infections (CHMIs) with () parasites are well established. Exposure to five (NF54)-infected mosquitoes results in 100% infection rates in malaria-naïve volunteers. Recently clones NF135.C10 and NF166.C8 were generated for application in CHMIs. Here, we tested the clinical infection rates of these clones, using graded numbers of -infected mosquitoes. In a double-blind randomized trial, we exposed 24 malaria-naïve volunteers to bites from one, two, or five mosquitoes infected with NF135.C10 or NF166.C8. The primary endpoint was parasitemia by quantitative polymerase chain reaction. For both strains, bites by five infected mosquitoes resulted in parasitemia in 4/4 volunteers; 3/4 volunteers developed parasitemia after exposure to one or two infected mosquitoes infected with either clone. The prepatent period was 7.25 ± 4.0 days (median ± range). There were no serious adverse events and comparable clinical symptoms between all groups. These data confirm the eligibility of NF135.C10 and NF166.C8 for use in CHMI studies.
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http://dx.doi.org/10.4269/ajtmh.18-0194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169176PMC
September 2018

Competing for blood: the ecology of parasite resource competition in human malaria-helminth co-infections.

Ecol Lett 2018 04 8;21(4):536-545. Epub 2018 Feb 8.

Department of Ecology and Evolutionary Biology, Princeton University, Princeton, NJ, USA.

Ecological theory suggests that co-infecting parasite species can interact within hosts directly, via host immunity and/or via resource competition. In mice, competition for red blood cells (RBCs) between malaria and bloodsucking helminths can regulate malaria population dynamics, but the importance of RBC competition in human hosts was unknown. We analysed infection density (i.e. the concentration of parasites in infected hosts), from a 2-year deworming study of over 4000 human subjects. After accounting for resource-use differences among parasites, we find evidence of resource competition, priority effects and a competitive hierarchy within co-infected individuals. For example reducing competition via deworming increased Plasmodium vivax densities 2.8-fold, and this effect is limited to bloodsucking hookworms. Our ecological, resource-based perspective sheds new light into decades of conflicting outcomes of malaria-helminth co-infection studies with significant health and transmission consequences. Beyond blood, investigating within-human resource competition may bring new insights for improving human health.
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http://dx.doi.org/10.1111/ele.12919DOI Listing
April 2018

Changes in total and differential leukocyte counts during the clinically silent liver phase in a controlled human malaria infection in malaria-naïve Dutch volunteers.

Malar J 2017 Nov 10;16(1):457. Epub 2017 Nov 10.

Institute for Tropical Diseases, Harbour Hospital, Rotterdam, The Netherlands.

Background: Both in endemic countries and in imported malaria, changes in total and differential leukocyte count during Plasmodium falciparum infection have been described. To study the exact dynamics of differential leukocyte counts and their ratios, they were monitored in a group of healthy non-immune volunteers in two separate Controlled Human Malaria Infection (CHMI) studies.

Methods: In two CHMI trials, CHMI-a and CHMI-b, 15 and 24 healthy malaria-naïve volunteers, respectively, were exposed to bites of infected mosquitoes, using the P. falciparum research strain NF54 and the novel clones NF135.C10 and NF166.C8. After mosquito bite exposure, twice-daily blood draws were taken to detect parasitaemia and to monitor the total and differential leukocyte counts. All subjects received a course of atovaquone-proguanil when meeting the treatment criteria.

Results: A total of 39 volunteers participated in the two trials. Thirty-five participants, all 15 participants in CHMI-a and 20 of the 24 volunteers in CHMI-b, developed parasitaemia. During liver stage development of the parasite, the median total leukocyte count increased from 5.5 to 6.1 × 10 leukocytes/L (p = 0.005), the median lymphocyte count from 1.9 to 2.2 (p = 0.001) and the monocyte count from 0.50 to 0.54 (p = 0.038). During the subsequent blood stage infection, significant changes in total and differential leukocyte counts lead to a leukocytopenia (nadir median 3.3 × 10 leukocytes/L, p = 0.0001), lymphocytopenia (nadir median 0.7 × 10 lymphocytes/L, p = 0.0001) and a borderline neutropenia (nadir median 1.5 × 10 neutrophils/L, p = 0.0001). The neutrophil to lymphocyte count ratio (NLCR) reached a maximum of 4.0. Significant correlations were found between parasite load and absolute lymphocyte count (p < 0.001, correlation coefficient - 0.46) and between parasite load and NLCR (p < 0.001, correlation coefficient 0.50). All parameters normalized after parasite clearance.

Conclusions: During the clinically silent liver phase of malaria, an increase of peripheral total leukocyte count and differential lymphocytes and monocytes occurs. This finding has not been described previously. This increase is followed by the appearance of parasites in the peripheral blood after 2-3 days, accompanied by a marked decrease in total leukocyte count, lymphocyte count and the neutrophil count and a rise of the NLCR.
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http://dx.doi.org/10.1186/s12936-017-2108-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5681833PMC
November 2017

Longitudinal study of changes in γδ T cells and CD4 T cells upon asymptomatic malaria infection in Indonesian children.

Sci Rep 2017 08 18;7(1):8844. Epub 2017 Aug 18.

Leiden Immunoparasitology Group, Department of Parasitology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.

Both γδ T cells and CD4 T cells have been implicated in immunity to malaria, but their association with natural gain or loss of infection has not been studied before. Therefore, we followed up asymptomatic children living in an area endemic for malaria in Indonesia for 21 months. The percentage of γδ T cells was related to both current and previous infection, with higher percentages in infected than uninfected children and declining after infections resolve. Infected children also had higher levels of Th1 and Th17 cells, lower levels of CD25 FOXP3 regulatory T cells (Tregs), but similar levels of Th2 cells as compared to uninfected children. However, TNF, IFN-γ, and IL-17 cytokine responses to Plasmodium falciparum-infected red blood cells (PfRBCs) were similar, while IL-5 and IL-13 responses were lower in infected children. Furthermore, infected children had more phenotypically exhausted PD-1 CD4 T cells, more Tregs expressing TNF-RII, and higher IL-10 responses to PfRBCs, which persisted following resolution of infection. Altogether, this study demonstrates that asymptomatic malaria infection is associated with some long-lasting changes in the frequencies and immunoregulation of circulating innate and adaptive T cells, which might in part explain how pre-exposure to malaria affects responses to subsequent immunological challenges.
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http://dx.doi.org/10.1038/s41598-017-09099-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5562820PMC
August 2017

Infectivity of sporozoites determines emerging parasitemia in infected volunteers.

Sci Transl Med 2017 06;9(395)

Department of Medical Microbiology, Radboud University Medical Centre, Nijmegen, Netherlands.

Malaria sporozoites must first undergo intrahepatic development before a pathogenic blood-stage infection is established. The success of infection depends on host and parasite factors. In healthy human volunteers undergoing controlled human malaria infection (CHMI), we directly compared three clinical isolates for their ability to infect primary human hepatocytes in vitro and to drive the production of blood-stage parasites in vivo. Our data show a correlation between the efficiency of strain-specific sporozoite invasion of human hepatocytes and the dynamics of patent parasitemia in study subjects, highlighting intrinsic differences in infectivity among isolates from distinct geographical locales. The observed heterogeneity in infectivity among strains underscores the value of assessing the protective efficacy of candidate malaria vaccines against heterologous strains in the CHMI model.
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http://dx.doi.org/10.1126/scitranslmed.aag2490DOI Listing
June 2017

Molecular diagnostics and lack of clinical allergy in helminth-endemic areas in Indonesia.

J Allergy Clin Immunol 2017 10 24;140(4):1196-1199.e6. Epub 2017 May 24.

Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2017.04.040DOI Listing
October 2017

Human to human transmission of arthropod-borne pathogens.

Curr Opin Virol 2017 02 2;22:13-21. Epub 2016 Dec 2.

Department of Microbiology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece. Electronic address:

Human-to-human (H2H) transmitted arthropod-borne pathogens are a growing burden worldwide, with malaria and dengue being the most common mosquito-borne H2H transmitted diseases. The ability of vectors to get infected by humans during a blood meal to further propel an epidemic depends on complex interactions between pathogens, vectors and humans, in which human interventions and demographic and environmental conditions play a significant role. Herein, we discuss the distal and proximal drivers affecting H2H vector-borne pathogen transmission and identify knowledge gaps and future perspectives.
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http://dx.doi.org/10.1016/j.coviro.2016.11.005DOI Listing
February 2017

Community deworming alleviates geohelminth-induced immune hyporesponsiveness.

Proc Natl Acad Sci U S A 2016 11 17;113(44):12526-12531. Epub 2016 Oct 17.

Department of Parasitology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands;

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 (P) < 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; P = 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.
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http://dx.doi.org/10.1073/pnas.1604570113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5098677PMC
November 2016

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

PLoS One 2015 10;10(6):e0127746. Epub 2015 Jun 10.

Department of Endocrinology & General Internal Medicine, Leiden University Medical Center, 2333ZA, Leiden, The Netherlands; Department of General Internal Medicine, Radboud University Medical Center, 6525GA, Nijmegen, The Netherlands.

Objective: 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.

Design: We performed a cross-sectional study on Flores island, Indonesia, an area with high prevalence of STH infections.

Methods: From 646 adults, stool samples were screened for Trichuris trichiura by microscopy and for Ascaris lumbricoides, Necator americanus, Ancylostoma duodenale, and Strongyloides stercoralis 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.

Results: 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).

Conclusion: STH infections are associated with a modest improvement of insulin sensitivity, which is not accounted for by STH effects on BMI alone.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0127746PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4464734PMC
June 2016

Helminth therapy or elimination: epidemiological, immunological, and clinical considerations.

Lancet Infect Dis 2014 Nov 26;14(11):1150-1162. Epub 2014 Jun 26.

Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands. Electronic address:

Deworming is rightly advocated to prevent helminth-induced morbidity. Nevertheless, in affluent countries, the deliberate infection of patients with worms is being explored as a possible treatment for inflammatory diseases. Several clinical trials are currently registered, for example, to assess the safety or efficacy of Trichuris suis ova in allergies, inflammatory bowel diseases, multiple sclerosis, rheumatoid arthritis, psoriasis, and autism, and the Necator americanus larvae for allergic rhinitis, asthma, coeliac disease, and multiple sclerosis. Studies in animals provide strong evidence that helminths can not only downregulate parasite-specific immune responses, but also modulate autoimmune and allergic inflammatory responses and improve metabolic homoeostasis. This finding suggests that deworming could lead to the emergence of inflammatory and metabolic conditions in countries that are not prepared for these new epidemics. Further studies in endemic countries are needed to assess this risk and to enhance understanding of how helminths modulate inflammatory and metabolic pathways. Studies are similarly needed in non-endemic countries to move helminth-related interventions that show promise in animals, and in phase 1 and 2 studies in human beings, into the therapeutic development pipeline.
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http://dx.doi.org/10.1016/S1473-3099(14)70771-6DOI Listing
November 2014

Risk Factors Associated with the Development of Atopic Sensitization in Indonesia.

PLoS One 2013 19;8(6):e67064. Epub 2013 Jun 19.

Department of Microbiology, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia ; Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands.

Background: The prevalence of allergic diseases has increased not only in high income but also in low-to-middle income countries. However, risk factors for their development are still not well established, particularly in the latter.

Objective: To assess prevalence and identify risk factors for sensitization to two major inhalant allergens among children from semi-urban and rural areas in Indonesia.

Method: A cross-sectional survey was performed among 1,674 school children aged 5-15 years old. Information on potential risk factors and reported allergic symptoms were obtained by questionnaire. Helminth infections were assessed. Skin prick tests (SPT) were performed, total IgE as well as allergen-specific IgE for house dust mite (HDM) and cockroach were measured.

Result: The prevalence of allergic skin sensitization to both aeroallergens was significantly higher in the semi-urban than in the rural area. However, serum IgE against HDM and cockroach as well as total IgE were significantly lower in semi-urban than in rural children. In the semi-urban area, there was a significant positive association between SPT to HDM and higher paternal education but a negative one with hookworm infection. The risk factors linked to cockroach sensitization were different: being of a farmer offspring and lacking access to piped water were associated with an increased risk for a positive SPT to cockroach. No significant associations between measured risk factors and having a positive SPT were found in the rural area.

Conclusion: Sensitization to HDM and cockroach is common in Indonesia, more often translating into a positive SPT in the semi-urban than in the rural setting. Whereas high paternal education and low hookworm infection were associated with increased risk of SPT to HDM, we were surprised to find parameters of lower SES were identified as risk factor for cockroach SPT.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0067064PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3686782PMC
October 2017

Epidemiology of Plasmodium infections in Flores Island, Indonesia using real-time PCR.

Malar J 2013 May 24;12:169. Epub 2013 May 24.

Background: DNA-based diagnostic methods have been shown to be highly sensitive and specific for the detection of malaria. An 18S-rRNA-based, real-time polymerase chain reaction (PCR) was used to determine the prevalence and intensity of Plasmodium infections on Flores Island, Indonesia.

Methods: Microscopy and real-time multiplex PCR for the detection of Plasmodium species was performed on blood samples collected in a population-based study in Nangapanda Flores Island, Indonesia.

Results: A total 1,509 blood samples were analysed. Real-time PCR revealed prevalence for Plasmodium falciparum, Plasmodium vivax, and Plasmodium malariae to be 14.5%, 13.2%, and 1.9% respectively. Sub-microscopic parasitaemia were found in more than 80% of all positive cases. The prevalence of P. falciparum and P. vivax was significantly higher in subjects younger than 20 years (p ≤ 0.01). In the present study, among non-symptomatic healthy individuals, anaemia was strongly correlated with the prevalence and load of P. falciparum infections (p ≤ 0.01; p = 0.02) and with the load of P. vivax infections (p = 0.01) as detected with real-time PCR. Subjects with AB blood group tend to have a higher risk of being infected with P. falciparum and P. vivax when compared to other blood groups.

Conclusion: The present study has shown that real-time PCR provides more insight in the epidemiology of Plasmodium infections and can be used as a monitoring tool in the battle against malaria. The unsurpassed sensitivity of real-time PCR reveals that sub microscopic infections are common in this area, which are likely to play an important role in transmission and control.

Trial Registration: Trials number ISRCTN83830814.
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http://dx.doi.org/10.1186/1475-2875-12-169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3679745PMC
May 2013

The effect of three-monthly albendazole treatment on malarial parasitemia and allergy: a household-based cluster-randomized, double-blind, placebo-controlled trial.

PLoS One 2013 19;8(3):e57899. Epub 2013 Mar 19.

Department of Parasitology, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia.

Background: Helminth infections are proposed to have immunomodulatory activities affecting health outcomes either detrimentally or beneficially. We evaluated the effects of albendazole treatment, every three months for 21 months, on STH, malarial parasitemia and allergy.

Methods And Findings: A household-based cluster-randomized, double-blind, placebo-controlled trial was conducted in an area in Indonesia endemic for STH. Using computer-aided block randomization, 481 households (2022 subjects) and 473 households (1982 subjects) were assigned to receive placebo and albendazole, respectively, every three months. The treatment code was concealed from trial investigators and participants. Malarial parasitemia and malaria-like symptoms were assessed in participants older than four years of age while skin prick test (SPT) to allergens as well as reported symptoms of allergy in children aged 5-15 years. The general impact of treatment on STH prevalence and body mass index (BMI) was evaluated. Primary outcomes were prevalence of malarial parasitemia and SPT to any allergen. Analysis was by intention to treat. At 9 and 21 months post-treatment 80.8% and 80.1% of the study subjects were retained, respectively. The intensive treatment regiment resulted in a reduction in the prevalence of STH by 48% in albendazole and 9% in placebo group. Albendazole treatment led to a transient increase in malarial parasitemia at 6 months post treatment (OR 4.16(1.35-12.80)) and no statistically significant increase in SPT reactivity (OR 1.18(0.74-1.86) at 9 months or 1.37 (0.93-2.01) 21 months). No effect of anthelminthic treatment was found on BMI, reported malaria-like- and allergy symptoms. No adverse effects were reported.

Conclusions: The study indicates that intensive community treatment of 3 monthly albendazole administration for 21 months over two years leads to a reduction in STH. This degree of reduction appears safe without any increased risk of malaria or allergies.

Trial Registration: Controlled-Trials.com ISRCTN83830814.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057899PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3602425PMC
September 2013

Asymptomatic plasmodial infection is associated with increased tumor necrosis factor receptor II-expressing regulatory T cells and suppressed type 2 immune responses.

J Infect Dis 2013 May 13;207(10):1590-9. Epub 2013 Feb 13.

Department of Parasitology, Leiden University Medical Center, the Netherlands.

Background: In malaria-endemic areas, a proportion of individuals becomes chronic carriers of parasites with few or no clinical signs. There is little information on cellular immune responses in asymptomatic parasite carriers.

Methods: In 80 schoolchildren residing in a malaria-endemic area of Flores Island, Indonesia, T-helper subsets, regulatory T-cell (Treg) frequencies, tumor necrosis factor receptor type II (TNFRII) expression on Tregs, and cytokine responses induced by Plasmodium falciparum-infected red blood cells (RBCs) were measured, and values for asymptomatic infected subjects were compared to those for uninfected controls. To ascertain that alterations found were due to the presence of malaria parasites, the immune responses were analyzed in 16 children before and 1 month after antimalarial treatment.

Results: TNFRII expression, a marker of activation on Tregs, was higher during infection but decreased upon treatment. GATA3-positive cells and the level of interleukin 13 secretion in response to P. falciparum-infected RBCs appeared to be suppressed by plasmodial infection, as both increased after antimalarial treatment. TNFRII expression on Tregs correlated positively with TNF in response to P. falciparum-infected RBCs, but this association disappeared following treatment.

Conclusions: Malaria parasites associated with asymptomatic infections seem to result in increased TNFRII expression on Tregs, as well as suppressed Th2 cytokine responses, features that might be important for survival of the parasites in asymptomatic carriers.
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http://dx.doi.org/10.1093/infdis/jit058DOI Listing
May 2013

Relationship between carotid intima media thickness and helminth infections on Flores Island, Indonesia.

PLoS One 2013 24;8(1):e54855. Epub 2013 Jan 24.

Department of Parasitology, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia.

Objective: To examine the association between helminth infections and atherosclerosis.

Background: Chronic helminth infection, which can lead to poor nutritional status and anti-inflammatory response, might protect against the development of atherosclerosis.

Methods: A cross-sectional study was performed in Flores, Indonesia, an area highly endemic for soil-transmitted helminths (STH). Stool samples from 675 participants aged 18-80 years were collected and screened for Trichuris trichiura by microscopy and for Ascaris lumbricoides, Necator americanus, Ancylostoma duodenale, and Strongyloides stercoralis by qPCR. We collected data on body mass index (BMI), waist to hip ratio (WHR), blood pressure, fasting blood glucose (FBG), lipid, high sensitive C-reactive protein (hs-CRP), total immunoglobulin-E (TIgE) and Escherichia coli lipopolysaccharide stimulated cytokines (tumor necrosis factor and interleukin-10). In a subset of 301 elderly adults (≥40 years of age) carotid intima media thickness (cIMT) was measured.

Results: Participants with any STH infection had lower BMI (kg/m2) (mean difference -0.66, 95%CI [-1.26, -0.06]), WHR (-0.01, [-0.02, -0.00]), total cholesterol (mmol/L) (-0.22, [-0.43, -0.01]) and LDL-cholesterol (mmol/L) (-0.20, [-0.39, -0.00]) than uninfected participants. After additional adjustment for BMI the association between helminth infection and total cholesterol (mean difference -0.17, 95%CI [-0.37, 0.03]) as well as LDL-cholesterol (-0.15, [-0.33, 0.04]) was less pronounced. BMI, WHR, and total cholesterol were negatively associated with number species of helminth co-infections. Participants with high TIgE, an indicator of exposure to helminths, had lower FBG, TC, and HDL. The association between TIgE and TC and HDL remained significant after adjustment with BMI. No clear association was found between STH infection or TIgE and mean cIMT.

Conclusions: This cross-sectional study presents evidence that helminth infections were negatively associated with risk factors for cardiovascular disease, an association at least partially mediated by an effect on BMI. The significance of this finding needs to be determined.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0054855PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3554693PMC
July 2013

T-helper 17 cells are associated with pathology in human schistosomiasis.

J Infect Dis 2013 Jan 19;207(1):186-95. Epub 2012 Oct 19.

Immunology Unit, Laboratory of Bacteriology and Virology, Aristide Le Dantec Teaching Hospital, Dakar, Senegal.

Background: Schistosome infections are often clinically silent, but some individuals develop severe pathological reactions. In several disease processes, T-helper 17 (Th17) cells have been linked to tissue injuries, while regulatory T cells (Tregs) are thought to downmodulate inflammatory reactions. We assessed whether bladder pathology in human Schistosoma haematobium infection is related to the balance of Th17 cells and Tregs. We used a murine model of Schistosoma mansoni infection to further investigate whether the peripheral profiles reflected ongoing events in tissues.

Methods: We characterized T-helper cell subsets in the peripheral blood of children residing in a S. haematobium-endemic area and in the peripheral blood, spleen, and hepatic granulomas of S. mansoni-infected high-pathology CBA mice and low-pathology C57BL/6 mice.

Results: S. haematobium-infected children with bladder pathology had a significantly higher percentage of Th17 cells than those without pathology. Moreover, the Th17/Treg ratios were significantly higher in infected children with pathology, compared with infected children without pathology. Percentages of interleukin 17-producing cells were significantly higher in spleen and granulomas of CBA mice, compared with C57BL/6 mice. This difference was also reflected in the peripheral blood.

Conclusions: This is the first study to indicate that Th17 cells may be involved in the pathogenesis of human schistosomiasis.
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http://dx.doi.org/10.1093/infdis/jis654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3571236PMC
January 2013

Regulatory T cells in human lymphatic filariasis: stronger functional activity in microfilaremics.

PLoS Negl Trop Dis 2012 29;6(5):e1655. Epub 2012 May 29.

Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands.

Infection with filarial parasites is associated with T cell hyporesponsiveness, which is thought to be partly mediated by their ability to induce regulatory T cells (Tregs) during human infections. This study investigates the functional capacity of Tregs from different groups of filarial patients to suppress filaria-specific immune responses during human filariasis. Microfilaremic (MF), chronic pathology (CP) and uninfected endemic normal (EN) individuals were selected in an area endemic for Brugia timori in Flores island, Indonesia. PBMC were isolated, CD4CD25(hi) cells were magnetically depleted and in vitro cytokine production and proliferation in response to B. malayi adult worm antigen (BmA) were determined in total and Treg-depleted PBMC. In MF subjects BmA-specific T and B lymphocyte proliferation as well as IFN-gamma, IL-13 and IL-17 responses were lower compared to EN and CP groups. Depletion of Tregs restored T cell as well as B cell proliferation in MF-positives, while proliferative responses in the other groups were not enhanced. BmA-induced IL-13 production was increased after Treg removal in MF-positives only. Thus, filaria-associated Tregs were demonstrated to be functional in suppressing proliferation and possibly Th2 cytokine responses to BmA. These suppressive effects were only observed in the MF group and not in EN or CP. These findings may be important when considering strategies for filarial treatment and the targeted prevention of filaria-induced lymphedema.
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http://dx.doi.org/10.1371/journal.pntd.0001655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3362610PMC
August 2012

Blood pressure class and carotid artery intima-media thickness in a population at the secondary epidemiological transition.

J Hypertens 2011 Nov;29(11):2194-200

Section of Vascular Medicine, Department of General Internal Medicine & Endocrinology, Leiden University Medical Centre, Leiden, The Netherlands.

Objectives: Data relating blood pressure (BP) class to subclinical organ damage are infrequently reported in populations with a traditional 'nonwestern' lifestyle. As the relevance of BP stratification to cardiovascular prognosis has not been elucidated in these low-income countries at the second epidemiological transition, we aimed to study the effect of BP class on carotid artery intima-media thickness (IMT) in Flores Island, Indonesia.

Methods: A cross-sectional study was performed in 476 inhabitants (men/women) of Flores. BP was classified using the European Society of Hypertension/European Society of Cardiology classification. The primary endpoint was mean carotid-IMT measured by ultrasonography in classes of BP. Covariate analysis was performed adjusting for conventional cardiovascular risk factors.

Results: BP ranged from 94 to 250 mmHg systolic and 50 to 125 mmHg diastolic, 35% of the population had 'grade-I hypertension' or higher, 1.7% of the population was short-term treated with antihypertensive therapy. IMT significantly differed for BP classes (P < 0.001). Mean (± SEM) IMT was 587.8 (± 9.3) μm, 621.5 (± 7.6) μm, 653.6 (± 10.5) μm, 717.9 (± 14.0) μm, and 750.1 (± 21.8) μm for 'optimal', '(high) normal', 'grade-I, grade-II, and grade-III hypertension' classes, respectively. After adjustment for cardiovascular risk factors, similar results were obtained.

Conclusion: A strong association was found between BP class and carotid artery IMT in treatment-naive participants of a population with a traditional lifestyle, at the second epidemiological transition. Intriguingly, the increase of IMT was already observed at the 'high normal' BP class. This study may help to prioritize preventive and therapeutic measures to lower BP in countries at the second epidemiological transition.
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http://dx.doi.org/10.1097/HJH.0b013e32834bbba8DOI Listing
November 2011

Immunological footprint: the development of a child's immune system in environments rich in microorganisms and parasites.

Parasitology 2011 Oct 18;138(12):1508-18. Epub 2011 Jul 18.

Department of Parasitology, Faculty of Medicine University of Indonesia, Jakarta 10430, Indonesia.

The shaping of a child's immune system starts in utero, with possible long-term consequences in later life. This review highlights the studies conducted on the development of the immune system in early childhood up to school-age, discussing the impact that environmental factors may have. Emphasis has been put on studies conducted in geographical regions where exposure to micro-organisms and parasites are particularly high, and the effect that maternal exposures to these may have on an infant's immune responses to third-party antigens. In this respect we discuss the effect on responses to vaccines, co-infections and on the development of allergic disorders. In addition, studies of the impact that such environmental factors may have on slightly older (school) children are highlighted emphasizing the need for large studies in low to middle income countries, that are sufficiently powered and have longitudinal follow-up components to understand the immunological footprint of a child and the consequences throughout life.
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http://dx.doi.org/10.1017/S0031182011000588DOI Listing
October 2011

A longitudinal study of allergy and intestinal helminth infections in semi urban and rural areas of Flores, Indonesia (ImmunoSPIN Study).

BMC Infect Dis 2011 Apr 1;11:83. Epub 2011 Apr 1.

Department of Microbiology, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia.

Background: The prevalence of asthma and atopic disease has been reported to be low in low income countries, however helminth infections are likely to be high among these communities. The question of whether helminth infections play a role in allergic diseases can best be addressed by intervention studies. None of the studies so far have been based on a large scale placebo-controlled trial.

Method/design: This study was designed to assess how intestinal helminth infections can influence the immune response and atopic and allergic disorders in children in Indonesia. The relations between allergic outcomes and infection and lifestyle factors will be addressed. This study was set up among school-age children in semi urban and rural areas, located in Ende District of Flores Island, Indonesia. A randomized placebo-controlled anthelmintic treatment trial to elucidate the impact of helminth infections on the prevalence of skin prick test (SPT) reactivity and symptoms of allergic diseases will be performed. The children living in these semi-urban and rural areas will be assessed for SPT to allergens before and after 1 and 2 years of treatment as the primary outcome of the study; the secondary outcome is symptoms (asthma and atopic dermatitis); while the tertiary outcome is immune responses (both antibody levels to allergens and cellular immune responses).

Discussion: The study will provide information on the influence of helminth infections and anthelmintic treatment on immune response, atopy and allergic disorders.

Trial Registration: Current Controlled Trials ISRCTN: ISRCTN83830814.
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http://dx.doi.org/10.1186/1471-2334-11-83DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3090332PMC
April 2011

Polyparasitism and its impact on the immune system.

Int J Parasitol 2010 Aug 23;40(10):1171-6. Epub 2010 May 23.

Department of Parasitology, University of Indonesia, Faculty of Medicine, Salemba Raya, Jakarta, Indonesia.

Parasitic infections are common in many tropical and sub-tropical regions of the world and concomitant infection, polyparasitism, is the rule rather than the exception in such areas. At the immunological level, different parasites induce quite different responses characterised, for example, by protozoa that polarise responses towards Th1, whilst helminths are strong Th2 and regulatory T cell inducers. The question of how the co-existence of such parasites within the same host might influence the immunological responses to each species and, more importantly, whether such interactions affect resistance, susceptibility or clinical outcome, needs to be addressed in well-designed studies of sufficient power. The current paper discusses what we know as well as the gaps in our knowledge of polyparasitism.
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http://dx.doi.org/10.1016/j.ijpara.2010.05.003DOI Listing
August 2010

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).

BMC Infect Dis 2010 Mar 25;10:77. Epub 2010 Mar 25.

Department of Parasitology, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia.

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.
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http://dx.doi.org/10.1186/1471-2334-10-77DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2859773PMC
March 2010

Regulatory T cells in human geohelminth infection suppress immune responses to BCG and Plasmodium falciparum.

Eur J Immunol 2010 Feb;40(2):437-42

Department of Parasitology, Leiden University Medical Center, Leiden, the Netherlands.

Chronic helminth infections induce T-cell hyporesponsiveness, which may affect immune responses to other pathogens or to vaccines. This study investigates the influence of Treg activity on proliferation and cytokine responses to BCG and Plasmodium falciparum-parasitized RBC in Indonesian schoolchildren. Geohelminth-infected children's in vitro T-cell proliferation to either BCG or pRBC was reduced compared to that of uninfected children. Although the frequency of CD4(+)CD25(hi)FOXP3(+) T cells was similar regardless of infection status, the suppressive activity differed between geohelminth-infected and geohelminth-uninfected groups: Ag-specific proliferative responses increased upon CD4(+)CD25(hi) T-cell depletion in geohelminth-infected subjects only. In addition, IFN-gamma production in response to both BCG and parasitized RBC was increased after removal of CD4(+)CD25(hi) T cells. These data demonstrate that geohelminth-associated Treg influence immune responses to bystander Ag of mycobacteria and plasmodia. Geohelminth-induced immune modulation may have important consequences for co-endemic infections and vaccine trials.
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http://dx.doi.org/10.1002/eji.200939699DOI Listing
February 2010
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