Search

Background: Immuno-epidemiologists are often faced with multivariate outcomes, measured repeatedly over time. Such data are characterised by complex inter- and intra-outcome relationships which must be accounted for during analysis. Scientific questions of interest might include determining the effect of a treatment on the evolution of all outcomes together, or grouping outcomes that change in the same way. Modelling the different outcomes separately may not be appropriate because it ignores the underlying relationships between outcomes. In such situations, a joint modelling strategy is necessary. This paper describes a pairwise joint modelling approach and discusses its benefits over more simple statistical analysis approaches, with application to data from a study of the response to BCG vaccination in the first year of life, conducted in Entebbe, Uganda. Methods: The study aimed to determine the effect of maternal latent Mycobacterium tuberculosis infection (LTBI) on infant immune response (TNF, IFN-γ, IL-13, IL-10, IL-5, IL-17A and IL-2 responses to PPD), following immunisation with BCG. A simple analysis ignoring the correlation structure of multivariate longitudinal data is first shown. Univariate linear mixed models are then used to describe longitudinal profiles of each outcome, and are then combined into a multivariate mixed model, specifying a joint distribution for the random effects to account for correlations between the multiple outcomes. A pairwise joint modelling approach, where all possible pairs of bivariate mixed models are fitted, is then used to obtain parameter estimates. Results: Univariate and pairwise longitudinal analysis approaches are consistent in finding that LTBI had no impact on the evolution of cytokine responses to PPD. Estimates from the pairwise joint modelling approach were more precise. Major advantages of the pairwise approach include the opportunity to test for the effect of LTBI on the joint evolution of all, or groups of, outcomes and the ability to estimate association structures of the outcomes. Conclusions: The pairwise joint modelling approach reduces the complexity of analysis of high-dimensional multivariate repeated measures, allows for proper accounting for association structures and can improve our understanding and interpretation of longitudinal immuno-epidemiological data. [ABSTRACT FROM AUTHOR]

Introduction Prenatal exposures such as infections and immunisation may influence infant responses. We had an opportunity to undertake an analysis of innate responses in infants within the context of a study investigating the effects of maternal mycobacterial exposures and infection on BCG vaccine-induced responses in Ugandan infants. Material and methods Maternal and cord blood samples from 29 mother-infant pairs were stimulated with innate stimuli for 24 h and cytokines and chemokines in supernatants were measured using the Luminex® assay. The associations between maternal latent Mycobacterium tuberculosis infection (LTBI), maternal BCG scar (adjusted for each other’s effect) and infant responses were examined using linear regression. Principal Component Analysis (PCA) was used to assess patterns of cytokine and chemokine responses. Gene expression profiles for pathways associated with maternal LTBI and with maternal BCG scar were examined using samples collected at one (n = 42) and six (n = 51) weeks after BCG immunisation using microarray. Results Maternal LTBI was positively associated with infant IP-10 responses with an adjusted geometric mean ratio (aGMR) [95% confidence interval (CI)] of 5.10 [1.21, 21.48]. Maternal BCG scar showed strong and consistent associations with IFN-γ (aGMR 2.69 [1.15, 6.17]), IL-12p70 (1.95 [1.10, 3.55]), IL-10 (1.82 [1.07, 3.09]), VEGF (3.55 [1.07, 11.48]) and IP-10 (6.76 [1.17, 38.02]). Further assessment of the associations using PCA showed no differences for maternal LTBI, but maternal BCG scar was associated with higher scores for principal component (PC) 1 (median level of scores: 1.44 in scar-positive versus −0.94 in scar-negative, p = 0.020) in the infants. PC1 represented a controlled proinflammatory response. Interferon and inflammation response pathways were up-regulated in infants of mothers with LTBI at six weeks, and in infants of mothers with a BCG scar at one and six weeks after BCG immunisation. Conclusions Maternal BCG scar had a stronger association with infant responses than maternal LTBI, with an increased proinflammatory immune profile. [ABSTRACT FROM AUTHOR]

Bacille Calmette--Guérin (BCG) immunization provides variable protection against tuberculosis. Prenatal antigen exposure may have lifelong effects on responses to related antigens and pathogens. We therefore hypothesized that maternal latent Mycobacterium tuberculosis infection (LTBI) influences infant responses to BCG immunization at birth. We measured antibody (n = 53) and cellular (n = 31) responses to M. tuberculosis purified protein derivative (PPD) in infants of mothers with and without LTBI, in cord blood and at one and six weeks after BCG. The concentrations of PPD-specific antibodies declined between birth (median [interquartile range (IQR)]) 5600 ng ml-1 [3300-11 050] in cord blood) and sixweeks (0.00 ng ml-1 [0-288]). Frequencies of PPD-specific IFN-γ-expressing CD4+T cells increased at one week and declined between one and six weeks ( p = 0.031). Frequencies of IL-2- and TNF-α-expressing PPD-specific CD4+T cells increased between one and six weeks ( p = 0.019, p = 0.009, respectively). At one week, the frequency of PPD-specific CD4+T cells expressing any of the three cytokines, combined, was lower among infants of mothers with LTBI, in crude analyses ( p = 0.002) and after adjusting for confounders (mean difference, 95% CI -0.041% (-0.082, -0.001)). In conclusion, maternal LTBI was associated with lower infant anti-mycobacterial T-cell responses immediately following BCGimmunization. These findings are being explored further in a larger study. [ABSTRACT FROM AUTHOR]

Background BCG is used widely as the sole licensed vaccine against tuberculosis, but it has variable efficacy and the reasons for this are still unclear. No reliable biomarkers to predict future protection against, or acquisition of, TB infection following immunisation have been identified. Lessons from BCG could be valuable in the development of effective tuberculosis vaccines. Objectives Within the Entebbe Mother and Baby Study birth cohort in Uganda, infants received BCG at birth. We investigated factors associated with latent tuberculosis infection (LTBI) and with cytokine response to mycobacterial antigen at age five years. We also investigated whether cytokine responses at one year were associated with LTBI at five years of age. Methods Blood samples from age one and five years were stimulated using crude culture filtrates of Mycobacterium tuberculosis in a six-day whole blood assay. IFN-γ, IL-5, IL-13 and IL-10 production was measured. LTBI at five years was determined using T-SPOT.TB ® assay. Associations with LTBI at five years were assessed using multivariable logistic regression. Multiple linear regression with bootstrapping was used to determine factors associated with cytokine responses at age five years. Results LTBI prevalence was 9% at age five years. Only urban residence and history of TB contact/disease were positively associated with LTBI. BCG vaccine strain, LTBI, HIV infection, asymptomatic malaria, growth z-scores, childhood anthelminthic treatment and maternal BCG scar were associated with cytokine responses at age five. Cytokine responses at one year were not associated with acquisition of LTBI by five years of age. Conclusion Although multiple factors influenced anti-myocbacterial immune responses at age five, factors likely to be associated with exposure to infectious cases (history of household contact, and urban residence) dominated the risk of LTBI. [ABSTRACT FROM AUTHOR]

The article discusses a study which investigated whether prenatal exposure to and treatment of maternal helminth infections affects development of an infant's immune response to immunisations and unrelated infections. The study enrolled 2507 women in the second or third trimester of pregnancy who were planning to deliver at the Entebbe General Hospital in Uganda. It was shown that neither albendazole nor praziquantel treatments affected infant response to BCG, tetanus or measles immunisation, except in infants of mothers with hookworm infection.

Abstract: Some vaccines show poor efficacy in tropical countries. Within a birth cohort in Uganda, we investigated factors that might influence responses to BCG and tetanus immunisation. Whole blood assay responses to crude culture filtrate proteins of Mycobacterium tuberculosis (cCFP)) and tetanus toxoid (TT) were examined among 1506 and 1433 one-year-olds, respectively. Maternal Mansonella perstans infection was associated with higher interleukin (IL)-10 responses to both immunogens but no reduction in gamma interferon (IFN-γ), IL-5 and IL-13 responses; other maternal helminth infections showed little effect. Tetanus immunisation during pregnancy was associated with higher infant responses to TT; maternal BCG scar (from past immunisation) with lower infant IL-5 and IL-13 responses to cCFP. IFN-γ, IL-5 and IL-13 to TT were reduced in HIV-exposed-uninfected infants; infant malaria and HIV were associated with lower IFN-γ, IL-5 and IL-13 responses to both immunogens. We conclude that maternal helminth infections are unlikely to explain poor vaccine efficacy in the tropics. Effects of maternal immunisation on infant responses to vaccines should be explored. Prevention of infant malaria and HIV could contribute to effectiveness of immunisation programmes. [ABSTRACT FROM AUTHOR]

Background: Praziquantel treatment of schistosomiasis during pregnancy was only recommended in 2002; hence the effects of treatment during pregnancy are not fully known. We have therefore evaluated the effects on infection intensity and the immunological effects of praziquantel treatment against Schistosoma mansoni during pregnancy, compared with treatment after delivery. Methods: A nested cohort of 387 Schistosoma mansoni infected women was recruited within a larger trial of de-worming during pregnancy. Women were randomised to receive praziquantel or placebo during pregnancy. All women were treated after delivery. Infection intensity after treatment was assessed by a single Kato-Katz examination of stool samples with duplicate slides and categorised as undetected, light (1-99 eggs per gram (epg)), moderate (100-399 epg) or heavy (≥400 epg). Antibodies against S. mansoni worm and egg antigens were measured by ELISA. Results were compared between women first treated during pregnancy and women first treated after delivery. Results: At enrolment, 252 (65.1%) of the women had light infection (median (IQR) epg: 35 (11, 59)), 75 (19.3%) moderate (median (IQR) epg: 179(131, 227)) and 60 (15.5%) had heavy infection (median (IQR) epg: 749 (521, 1169)) with S. mansoni. At six weeks after praziquantel treatment during pregnancy S. mansoni infection was not detectable in 81.9% of the women and prevalence and intensity had decreased to 11.8% light, 4.7% moderate and 1.6% heavy a similar reduction when compared with those first treated after delivery (undetected (88.5%), light (10.6%), moderate (0.9%) and heavy (0%), p = 0.16). Parasite specific antibody levels were lower during pregnancy than after delivery. Praziquantel treatment during pregnancy boosted anti-worm IgG isotypes and to a lesser extent IgE, but these boosts were less pronounced than in women whose treatment was delayed until after delivery. Praziquantel had limited effects on antibodies against egg antigens. Conclusion: S mansoni antigen-specific antibody levels and praziquantel-induced boosts in antibody levels were broadly suppressed during pregnancy, but this was not associated with major reduction in the efficacy of praziquantel. Long-term implications of these findings in relation to resistance to re-infection remain to be explored. Trial registration: International Standard Randomised Controlled Trial Number for the current study: ISRCTN32849447 http://www.controlled-trials.com/ISRCTN32849447/elliott [ABSTRACT FROM AUTHOR]

Background. Praziquantel treatment of schistosomiasis boosts antischistosome responses, with type 2 helper T cell bias that may contribute to immunologically mediated killing and to protection against reinfection. Praziquantel treatment during pregnancy was recommended in 2002, but the immunological effects of the treatment had not been investigated. Methods. A cohort of 387 Schistosoma mansoni-infected women were recruited from a larger trial of deworming during pregnancy. Women were randomized to receive either praziquantel or placebo during pregnancy. Six weeks after delivery, all women received praziquantel. Cytokine responses to S. mansoni worm and egg antigens were measured in whole blood culture before and 6 weeks after each treatment. Results. Schistosome-specific cytokine responses were suppressed during pregnancy. Praziquantel treatment during pregnancy caused significant boosts in interferon-γ (IFN-γ), interleukin (IL)-2, IL-4, IL-5, IL-13, and IL-10 responses to schistosome worm antigen and in IFN-γ, IL-5, and IL-13 responses to schistosome egg antigen, but these boosts were not as substantial as those seen for women treated after delivery. Conclusion. Pregnancy suppresses a potentially beneficial boost in cytokine responses associated with praziquantel treatment. Further studies are needed on the long-term effects that treatment of schistosomiasis during pregnancy have on morbidity and resistance to reinfection among treated women and their offspring. Trial registration. International Standard Randomized Controlled Trial Number for the parent study: ISRCTN32849447. [ABSTRACT FROM AUTHOR]

Background. Studies showing that helminths stimulate type 2 cytokine responses and influence responses to unrelated antigens suggest that helminths may accelerate human immunodeficiency virus type 1 (HIV-1) disease progression in coinfected individuals and that antihelminthic therapy may be beneficial. By the same logic, however, the increase in type 2 cytokines occurring immediately after antischistosomal treatment might increase viral replication and be detrimental. Methods. To assess the effect of antischistosomal therapy on immune responses and HIV-1 replication, a cohort of 163 Ugandans coinfected with Schistosoma mansoni and HIV-1 was treated with praziquantel. CD4+ T lymphocyte counts, eosinophil counts, and plasma HIV-1 RNA concentrations were measured before treatment and 1 month and 5 months after treatment. Schistosoma mansoni- and Mycobacterium tuberculosis-specific cytokine responses and serum interleukin (IL)-10 concentrations were analyzed. Results. Transient increases in viral load and sustained decreases in CD4+ T lymphocyte count were observed, especially in subjects with higher-intensity infections. Despite enhanced posttreatment S. mansoni-specific type 2 responses, no increase in eosinophils or in M. tuberculosis-specific type 2 responses nor any decline in M. tuberculosis-specific interferon (IFN)-γ responses were seen. A significant decline in circulating IL-10 concentrations was observed. Conclusion. Although the mechanisms underlying the increase in viral load after treatment with praziquantel are unclear, these results do not support the hypothesis that treating schistosomiasis is beneficial in the management of HIV-1 disease in Africa. [ABSTRACT FROM AUTHOR]

Background: Environmental enteric dysfunction (EED) is an acquired subclinical condition of the small intestine with lasting health implications for nutritional status, linear growth and development among children. EED is characterised by structural and functional changes to the gut barrier. There are no standardised diagnostic criteria, however, a number of biomarkers have been evaluated to capture EED domains. While the causes of EED are not fully understood, risk factors include poor water, sanitation and hygiene conditions and exposure to enteric pathogens. Very few studies have evaluated the impact of schistosomiasis on EED despite repeated intestinal damage from parasite eggs passing across the gut barrier. Methods: In a cohort of 354 preschool‐aged children aged 12–47 months with Schistosoma mansoni infection recruited from the Lake Albert region of Uganda, we assessed exposure to water, sanitation and hygiene conditions and measured markers from each EED domain: intestinal inflammation (faecal calprotectin), epithelial damage (serum intestinal fatty‐acid binding‐protein), increased permeability (urine lactulose to mannitol ratio and faecal alpha‐1 antitrypsin) and microbial translocation (serum endotoxin core antibody). Results: In multivariable linear regression models, we found that children whose drinking water was sourced from Lake Albert had higher concentrations of intestinal fatty‐acid binding‐protein (β = 0.48, 95% CI 0.20–0.76, p < 0.001), and lack of toilet/latrine access was associated with higher concentrations of calprotectin (β = 0.48, 95% CI 0.18–0.78, p < 0.01). Higher schistosomiasis intensity (eggs per gram of stool) was associated with higher calprotectin (β = 0.10, 95% CI 0.02–0.17, p = 0.01), but not with other EED markers. Conclusions: Few studies have investigated schistosomiasis‐related morbidities in very young children infected with schistosomiasis. Our findings from Uganda show that poor water, sanitation and hygiene conditions and heavier schistosomiasis burden are associated with intestinal inflammation and damage, contributing to EED. Improved treatment coverage for preschool‐aged children infected with schistosomiasis may reduce the burden from EED and associated long‐term morbidities. [ABSTRACT FROM AUTHOR]

Objectives: Schistosomiasis is persistent in Lake Albert, Uganda, but local data are limited. This study aims to describe the local burden of moderate‐to‐heavy infection and associated morbidity in all ages and identify factors associated with these outcomes to guide further research. Methods: This cross‐sectional pilot study was conducted in July–August, 2022 in four village sites (Walukuba, Rwentale, Kyabarangwa and Runga) of the Praziquantel in Preschoolers (PIP) trial. Residents (approximately four per household) of any age of households of PIP participants were eligible, but individuals <10 years were only enrolled if no older individuals were available. Socio‐demographic information, household location, single stool Kato‐Katz and hepatic ultrasound results were obtained for a convenience sampled subset of trial households. The primary outcome, moderate‐to‐heavy infection (≥100 eggs per gram of faeces), was analysed using mixed‐effects logistic regression, with a household random effect. Univariate analyses were used for the secondary outcome, periportal fibrosis (Niamey protocol ultrasound image pattern C–F). Results: Of 243 participants with a median age of 22 (interquartile range 12–33) years from 66 households, 49.8% (103/207 with a Kato‐Katz result) had moderate‐to‐heavy infection and 11.2% (25/224 with ultrasound data) had periportal fibrosis. Moderate‐to‐heavy infection clustered by household (intraclass correlation coefficient = 0.11) and, in multivariable analysis, varied by village (Walukuba vs. Kyabarangwa adjusted odds ratio [aOR] 0.11, 95% CI 0.02–0.71), was highest in participants aged 10–15 years (vs. 5–9 years aOR 6.14, 95% CI 1.61–23.38) and lower in those reporting praziquantel treatment in the past year (aOR 0.39, 95% CI 0.18–0.88). Conclusions: In this setting, schistosome infection and morbidity are pervasive in all age groups. More intensive interventions are needed, for example more frequent praziquantel treatment, under investigation in the PIP trial and improved water and sanitation. More research is needed to understand local treatment barriers and optimal control strategies. [ABSTRACT FROM AUTHOR]

In a cross-sectional analysis of 354 Ugandan children (age 12–48 months) infected with Schistosoma mansoni , we assessed relationships between infection intensity and nutritional morbidities. Higher intensity was associated with an increased risk for anemia (RR = 1.05, 95% confidence interval [CI] 1.01–1.10) yet not associated with risk for underweight, stunting, or wasting. [ABSTRACT FROM AUTHOR]

Introduction: Offspring of Schistosoma mansoni-infected women in schistosomiasis-endemic areas may be sensitised in-utero. This may influence their immune responsiveness to schistosome infection and schistosomiasis-associated morbidity. Effects of praziquantel treatment of S. mansoni during pregnancy on risk of S. mansoni infection among offspring, and on their immune responsiveness when they become exposed to S. mansoni, are unknown. Here we examined effects of praziquantel treatment of S. mansoni during pregnancy on prevalence of S. mansoni and immune responsiveness among offspring at age five years. Methods: In a trial in Uganda (ISRCTN32849447, http://www.controlled-trials.com/ISRCTN32849447/elliott), offspring of women treated with praziquantel or placebo during pregnancy were examined for S. mansoni infection and for cytokine and antibody responses to SWA and SEA, as well as for T cell expression of FoxP3, at age five years. Results: Of the 1343 children examined, 32 (2.4%) had S. mansoni infection at age five years based on a single stool sample. Infection prevalence did not differ between children of treated or untreated mothers. Cytokine (IFNγ, IL-5, IL-10 and IL-13) and antibody (IgG1, Ig4 and IgE) responses to SWA and SEA, and FoxP3 expression, were higher among infected than uninfected children. Praziquantel treatment of S. mansoni during pregnancy had no effect on immune responses, with the exception of IL-10 responses to SWA, which was higher in offspring of women that received praziquantel during pregnancy than those who did not. Conclusion: We found no evidence that maternal S. mansoni infection and its treatment during pregnancy influence prevalence and intensity of S. mansoni infection or effector immune response to S. mansoni infection among offspring at age five years, but the observed effects on IL-10 responses to SWA suggest that maternal S. mansoni and its treatment during pregnancy may affect immunoregulatory responsiveness in childhood schistosomiasis. This might have implications for pathogenesis of the disease. Author Summary: Infections with the blood fluke Schistosoma mansoni that cause schistosomiasis (also called Bilharzia) were not usually treated during pregnancy until 2002, but in 2002 a World Health Organization (WHO) team of experts recommended that praziquantel treatment of S. mansoni during pregnancy should be done. However, there was limited information on the effects of maternal S. mansoni infection and treatment during pregnancy on the outcomes in the offspring. We conducted a study in the Entebbe peninsula within Lake Victoria in Uganda to examine whether maternal S. mansoni infection or its treatment during pregnancy may have effects on the children's susceptibility to the infection. The children were examined at age five years old for the level of S. mansoni infection and for immune responses to schistosomes. At five years old few of the children in our study cohort were infected with S. mansoni. Our findings suggest that maternal infection with, or praziquantel treatment of S. mansoni during pregnancy did not influence the level of S. mansoni infection among the offspring. However our findings suggest an influence on regulation of the body's immune responses to schistosomes, which may have some effect on the progress of disease manifestations. This is an issue that needs further investigation. [ABSTRACT FROM AUTHOR]

Introduction: Offspring of Schistosoma mansoni-infected women in schistosomiasis-endemic areas may be sensitised in-utero. This may influence their immune responsiveness to schistosome infection and schistosomiasis-associated morbidity. Effects of praziquantel treatment of S. mansoni during pregnancy on risk of S. mansoni infection among offspring, and on their immune responsiveness when they become exposed to S. mansoni, are unknown. Here we examined effects of praziquantel treatment of S. mansoni during pregnancy on prevalence of S. mansoni and immune responsiveness among offspring at age five years. Methods: In a trial in Uganda (ISRCTN32849447, http://www.controlled-trials.com/ISRCTN32849447/elliott), offspring of women treated with praziquantel or placebo during pregnancy were examined for S. mansoni infection and for cytokine and antibody responses to SWA and SEA, as well as for T cell expression of FoxP3, at age five years. Results: Of the 1343 children examined, 32 (2.4%) had S. mansoni infection at age five years based on a single stool sample. Infection prevalence did not differ between children of treated or untreated mothers. Cytokine (IFNγ, IL-5, IL-10 and IL-13) and antibody (IgG1, Ig4 and IgE) responses to SWA and SEA, and FoxP3 expression, were higher among infected than uninfected children. Praziquantel treatment of S. mansoni during pregnancy had no effect on immune responses, with the exception of IL-10 responses to SWA, which was higher in offspring of women that received praziquantel during pregnancy than those who did not. Conclusion: We found no evidence that maternal S. mansoni infection and its treatment during pregnancy influence prevalence and intensity of S. mansoni infection or effector immune response to S. mansoni infection among offspring at age five years, but the observed effects on IL-10 responses to SWA suggest that maternal S. mansoni and its treatment during pregnancy may affect immunoregulatory responsiveness in childhood schistosomiasis. This might have implications for pathogenesis of the disease. [ABSTRACT FROM AUTHOR]

Abstract: Background: Globally, BCG vaccination varies in efficacy and has some non-specific protective effects. Previous studies comparing BCG strains have been small-scale, with few or no immunological outcomes and have compared TB-specific responses only. We aimed to evaluate both specific and non-specific immune responses to different strains of BCG within a large infant cohort and to evaluate further the relationship between BCG strain, scarring and cytokine responses. Methods: Infants from the Entebbe Mother and Baby Study (ISRCTN32849447) who received BCG-Russia, BCG-Bulgaria or BCG-Denmark at birth, were analysed by BCG strain group. At one year, interferon-gamma (IFN-γ), interleukin (IL)-5, IL-13 and IL-10 responses to mycobacteria-specific antigens (crude culture filtrate proteins and antigen 85) and non-mycobacterial stimuli (tetanus toxoid and phytohaemagglutinin) were measured using ELISA. Cytokine responses, scar frequency, BCG associated adverse event frequency and mortality rates were compared across groups, with adjustments for potential confounders. Results: Both specific and non-specific IFN-γ, IL-13 and IL-10 responses in 1341 infants differed between BCG strain groups including in response to stimulation with tetanus toxoid. BCG-Denmark immunised infants showed the highest cytokine responses. The proportion of infants who scarred differed significantly, with BCG scars occurring in 52.2%, 64.1% and 92.6% of infants immunised with BCG Russia, BCG-Bulgaria and BCG-Denmark, respectively (p <0.001). Scarred infants had higher IFN-γ and IL-13 responses to mycobacterial antigens only than infants without a scar. The BCG-Denmark group had the highest frequency of adverse events (p =0.025). Mortality differences were not significant. Conclusions: Both specific and non-specific immune responses to the BCG vaccine differ by strain. Scarring after BCG vaccination is also strain-dependent and is associated with higher IFN-γ and IL-13 responses to mycobacterial antigens. The choice of BCG strain may be an important factor and should be evaluated when testing novel vaccine strategies that employ BCG in prime–boost sequences, or as a vector for other vaccine antigens. [Copyright &y& Elsevier]

Background: Maternal schistosomiasis and filariasis have been shown to influence infant responses to neonatal bacille Calmette-Guérin (BCG) immunisation but the effects of maternal hookworm, and of de-worming in pregnancy, are unknown. Methods: In Entebbe, Uganda, we conducted a randomised, double-blind, placebo-controlled trial of a single dose of 400 mg of albendazole in the second trimester of pregnancy. Neonates received BCG. Interferon-gamma (IFN-γ) and interleukin (IL)-5 responses to a mycobacterial antigen (crude culture filtrate proteins (CFP) of Mycobacterium tuberculosis) were measured in a whole blood assay. We analysed results for binary variables using χ2 tests and logistic regression. We analysed continuous variables using Wilcoxon's tests. Results: Maternal hookworm was associated with reduced maternal IFNγ. responses to CFP (adjusted odds ratio for IFNγ. > median response: 0.14 (95% confidence interval 0.02 —0.83, p = 0.021). Conversely, maternal hookworm was associated with subsequent increased IFNγ responses in their one-year-old infants (adjusted OR 17.65 (1.20—258.66; p = 0.013)). Maternal albendazole tended to reduce these effects. Conclusion: Untreated hookworm infection in pregnancy was associated with reduced maternal IFNγ responses to mycobacterial antigens, but increased responses in their infants one year after BCG immunisation. The mechanisms of these effects, and their implications for protective immunity remain, to be determined. [ABSTRACT FROM AUTHOR]

Background: Over 200 million individuals worldwide are infected with Schistosoma species, with over half of infections occurring in children. Many children experience first infections early in life and this impacts their growth and development; however praziquantel (PZQ), the drug used worldwide for the treatment of schistosomiasis, only has regulatory approval among adults and children over the age of four, although it is frequently used "off label" in endemic settings. Furthermore, pharmacokinetic/pharmacodynamics (PK/PD) evidence suggests the standard PZQ dose of 40 mg/kg is insufficient in preschool-aged children (PSAC). Our goal is to understand the best approaches to optimising the treatment of PSAC with intestinal schistosomiasis.Methods: We will conduct a randomised, controlled phase II trial in a Schistosoma mansoni endemic region of Uganda and a Schistosoma japonicum endemic region of the Philippines. Six hundred children, 300 in each setting, aged 12-47 months with Schistosoma infection will be randomised in a 1:1:1:1 ratio to receive either (1) 40 mg/kg PZQ at baseline and placebo at 6 months, (2) 40 mg/kg PZQ at baseline and 40 mg/kg PZQ at 6 months, (3) 80 mg/kg PZQ at baseline and placebo at 6 months, or (4) 80 mg/kg PZQ at baseline and 80 mg/kg PZQ at 6 months. Following baseline treatment, children will be followed up for 12 months. The co-primary outcomes will be cure rate and egg reduction rate at 4 weeks. Secondary outcomes include drug efficacy assessed by novel antigenic endpoints at 4 weeks, actively collected adverse events and toxicity for 12 h post-treatment, morbidity and nutritional outcomes at 6 and 12 months, biomarkers of inflammation and environmental enteropathy and PZQ PK/PD parameters.Discussion: The trial will provide valuable information on the safety and efficacy of the 80 mg/kg PZQ dose in PSAC, and on the impact of six-monthly versus annual treatment, in this vulnerable age group.Trial Registration: ClinicalTrials.gov NCT03640377 . Registered on 21 Aug 2018. [ABSTRACT FROM AUTHOR]

Background: Helminth infections may modulate immune responses to unrelated pathogens and allergens; these effects may commence prenatally. We addressed the hypothesis that anthelminthic treatment in pregnancy and early childhood would improve responses to immunisation and modulate disease incidence in early childhood with both beneficial and detrimental effects. Methods and Findings: A randomised, double-blind, placebo-controlled trial was conducted in Entebbe, Uganda [ISRCTN32849447]. In three independent randomisations, 2507 pregnant women were allocated to receive single-dose albendazole or placebo, and praziquantel or placebo; 2016 of their offspring were randomised to receive quarterly singledose albendazole or placebo from age 15 months to 5 years. Primary outcomes were post-immunisation recall responses to BCG and tetanus antigens, and incidence of malaria, diarrhoea, and pneumonia; incidence of eczema was an important secondary outcome. Analysis was by intention-to-treat. Of 2345 live births, 1622 (69%) children remained in follow-up at age 5 years. 68% of mothers at enrolment, and 11% of five-year-olds, had helminth infections. Maternal hookworm and Schistosoma mansoni were effectively treated by albendazole and praziquantel, respectively; and childhood hookworm and Ascaris by quarterly albendazole. Incidence rates of malaria, diarrhoea, pneumonia, and eczema were 34, 65, 10 and 5 per 100 py, respectively. Albendazole during pregnancy caused an increased rate of eczema in the children (HR 1.58 (95% CI 1.15-2.17), p = 0.005). Quarterly albendazole during childhood was associated with reduced incidence of clinical malaria (HR 0.85 (95% CI 0.73-0.98), p = 0.03). There were no consistent effects of the interventions on any other outcome. Conclusions: Routine use of albendazole in pregnancy may not always be beneficial, even in tropical developing countries. By contrast, regular albendazole treatment in preschool children may have an additional benefit for malaria control where helminths and malaria are co-endemic. Given the low helminth prevalence in our children, the effect of albendazole on malaria is likely to be direct. [ABSTRACT FROM AUTHOR]

In 1994 and 2002, respectively, the World Health Organisation proposed that treatment for hookworm and schistosomiasis could be provided during pregnancy. It was hoped that this might have benefits for maternal anaemia, fetal growth and perinatal mortality; a beneficial effect on the infant response to immunisation was also hypothesised. Three trials have now been conducted. Two have examined the effects of benzimidazoles; one (the Entebbe Mother and Baby Study) the effects of albendazole and praziquantel. All three were conducted in settings of high prevalence but low intensity helminth infection. Results suggest that, in such settings and given adequate provision of haematinics, the benefit of routine anthelminthics during pregnancy for maternal anaemia may be small; none of the other expected benefits has yet been demonstrated. The Entebbe Mother and Baby Study found a significant adverse effect of albendazole on the incidence of infantile eczema in the whole study population, and of praziquantel on the incidence of eczema among infants of mothers with Schistosoma mansoni. Further studies are required in settings that differ in helminth species and infection intensities. Further research is required to determine whether increased rates of infantile eczema translate to long-term susceptibility to allergy, and to explore the underlying mechanisms of these effects. The risks and benefits of routine anthelminthic treatment in antenatal clinics may need to be reconsidered. [ABSTRACT FROM PUBLISHER]

We show that Ugandan adults coinfected with Schistosoma mansoni and human immunodeficiency virus type 1 (HIV-1) are able to mount S. mansoni-specific immune responses but that few such responses increase after treatment with praziquantel (PZQ). Levels of soluble worm antigen (SWA)-specific immunoglobulin (Ig) G1, IgG2, IgG3, IgG4, interleukin (IL)-4, and IL-5 increased significantly in HIV-negative participants after treatment with PZQ, whereas most soluble egg antigen-specific antibody responses and levels of interferon- gamma were unaltered. Only levels of SWA-specific IL-5 increased in HIV-1-coinfected participants after treatment. These deficiencies in immune responses may account for the previously reported increased susceptibility to infection and reinfection with S. mansoni in individuals coinfected with HIV-1. [ABSTRACT FROM AUTHOR]