Maritza Vaca

Effect of albendazole treatments on the prevalence of atopy in children living in communities endemic for geohelminth parasites: a cluster-randomised trial

BACKGROUND Epidemiological studies have shown inverse associations between geohelminth (intestinal helminth) infection and atopy, leading to the suggestion that geohelminths might protect against allergy. Periodic deworming of school children with anthelmintics is a widely implemented intervention and has raised concerns that such programmes could increase allergy. We investigated the effect of repeated anthelmintic treatments with albendazole over 12 months on the prevalence of atopy and clinical indices of allergy. METHODS We did a cluster-randomised controlled trial in schoolchildren from 68 rural schools. Children were randomly assigned by school to either albendazole (34 schools, 1164 children) every 2 months for 12 months, or to no intervention (34 schools, 1209 children). The intervention schools received a total of seven albendazole treatments. The primary outcome was atopy at 12 months (allergen skin-test reactivity), and analysis was by intention-to-treat for whole-school analyses and per protocol for children. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN61195515. FINDINGS Data for analysis were available for all schools and from 67.4% (784 of 1164) and 70.1% (848 of 1209) of children in albendazole and no-treatment groups, respectively. Albendazole treatment caused large reductions in geohelminth prevalence over the study period (adjusted odds ratio 0.13, 95% CI 0.09-0.19, p<0.001), but there was no evidence that treatment was associated with an increase in atopy prevalence (0.97, 0.68-1.39, p=0.862), or clinical allergy (wheeze, 1.07, 0.54-2.11, p=0.848) in the albendazole compared with the no-treatment group. INTERPRETATION We saw no increase in the prevalence of atopy or clinical allergy associated with albendazole treatment. Deworming programmes for schoolchildren are unlikely to be accompanied by an increase in allergy.

A Novel, Multi-Parallel, Real-Time Polymerase Chain Reaction Approach for Eight Gastrointestinal Parasites Provides Improved Diagnostic Capabilities to Resource-Limited At-Risk Populations

Diagnosis of gastrointestinal parasites has traditionally relied on stool microscopy, which has low diagnostic sensitivity and specificity. We have developed a novel, rapid, high-throughput quantitative multi-parallel real-time polymerase chain reaction (qPCR) platform. Species-specific primers/probes were used for eight common gastrointestinal parasite pathogens: Ascaris lumbricoides, Necator americanus, Ancylostoma duodenale, Giardia lamblia, Cryptosporidium spp., Entamoeba histolytica, Trichuris trichiura, and Strongyloides stercoralis. Stool samples from 400 13-month-old children in rural Ecuador were analyzed and the qPCR was compared with a standard direct wet mount slide for stool microscopy, as were 125 8-14-year-old children before and after anthelmintic treatment. The qPCR showed higher detection rates for all parasites compared with direct microscopy, Ascaris (7.0% versus 5.5%) and for Giardia (31.5% versus 5.8%). Using an enhanced DNA extraction method, we were able to detect T. trichiura DNA. These assays will be useful to refine treatment options for affected populations, ultimately leading to better health outcomes.

Long-term periodic anthelmintic treatments are associated with increased allergen skin reactivity

Background The low prevalence of allergic disease in the rural tropics has been attributed to the protective effects of chronic helminth infections. There is concern that treatment‐based control programmes for these parasites may lead to an increase in the prevalence of allergic diseases.

Patent human infections with the whipworm, Trichuris trichiura, are not associated with alterations in the faecal microbiota

Background The soil-transmitted helminth (STH), Trichuris trichiura colonises the human large intestine where it may modify inflammatory responses, an effect possibly mediated through alterations in the intestinal microbiota. We hypothesised that patent T. trichiura infections would be associated with altered faecal microbiota and that anthelmintic treatment would induce a microbiota resembling more closely that observed in uninfected individuals. Materials and Methods School children in Ecuador were screened for STH infections and allocated to 3 groups: uninfected, T. trichiura only, and mixed infections with T. trichiura and Ascaris lumbricoides. A sample of uninfected children and those with T. trichiura infections only were given anthelmintic treatment. Bacterial community profiles in faecal samples were studied by 454 pyrosequencing of 16 S rRNA genes. Results Microbiota analyses of faeces were done for 97 children: 30 were uninfected, 17 were infected with T. trichiura, and 50 with T. trichiura and A. lumbricoides. Post-treatment samples were analyzed for 14 children initially infected with T. trichiura alone and for 21 uninfected children. Treatment resulted in 100% cure of STH infections. Comparisons of the microbiota at different taxonomic levels showed no statistically significant differences in composition between uninfected children and those with T. trichiura infections. We observed a decreased proportional abundance of a few bacterial genera from the Clostridia class of Firmicutes and a reduced bacterial diversity among children with mixed infections compared to the other two groups, indicating a possible specific effect of A. lumbricoides infection. Anthelmintic treatment of children with T. trichiura did not alter faecal microbiota composition. Discussion Our data indicate that patent human infections with T. trichiura may have no effect on faecal microbiota but that A. lumbricoides colonisation might be associated with a disturbed microbiota. Our results also catalogue the microbiota of rural Ecuadorians and indicate differences with individuals from more urban industrialised societies.

Risk factors for atopic and non-atopic asthma in a rural area of Ecuador

Background Asthma has emerged as an important public health problem of urban populations in Latin America. Epidemiological data suggest that a minority of asthma cases in Latin America may be associated with allergic sensitisation and that other mechanisms causing asthma have been overlooked. The aim of the present study was to investigate risk factors for atopic and non-atopic asthma in school-age children. Methods A cross-sectional study was conducted among 3960 children aged 6–16 years living in Afro-Ecuadorian rural communities in Esmeraldas province in Ecuador. Allergic diseases and risk factors were assessed by questionnaire and allergic sensitisation by allergen skin prick reactivity. Results A total of 390 (10.5%) children had wheeze within the previous 12 months, of whom 14.4% had at least one positive skin test. The population-attributable fraction for recent wheeze associated with atopy was 2.4%. Heavy Trichuris trichiura infections were strongly inversely associated with atopic wheeze. Non-atopic wheeze was positively associated with maternal allergic symptoms and sedentarism (watching television (>3 h/day)) but inversely associated with age and birth order. Conclusions The present study showed a predominance of non-atopic compared with atopic wheeze among schoolchildren living in a poor rural region of tropical Latin America. Distinct risk factors were associated with the two wheeze phenotypes and may indicate different causal mechanisms. Future preventive strategies in such populations may need to be targeted at the causes of non-atopic wheeze.

Urbanisation is associated with prevalence of childhood asthma in diverse, small rural communities in Ecuador

Background Studies conducted in transitional communities from Africa and Asia have pointed to the process of urbanisation as being responsible for the increase in asthma prevalence in developing regions. In Latin America, there are few published data available on the potential impact of urbanisation on asthma prevalence. The aim of the present study was to explore how the process of urbanisation may explain differences in asthma prevalence in transitional communities in north-eastern Ecuador. Methodology/principal findings An ecological study was conducted in 59 communities in Esmeraldas Province, Ecuador. Indicators of urbanisation were grouped into three indices representing the processes associated with urbanisation: socioeconomic, lifestyle and urban infrastructure. Categorical principal components analysis was used to generate scores for each index and a fourth index—a summary urbanisation index—was derived from the most representative variables in each of the three indices. The authors analysed the associations between community asthma prevalence and the indices, as well as with each indicator variable of every group. The overall prevalence of asthma was 10.1% (range 0–31.4% between communities). Three of the four indices presented significant associations with community asthma prevalence: socioeconomic (r=0.295, p=0.023), lifestyle (r=0.342, p=0.008) and summary urbanisation index (r=0.355, p=0.006). Variables reflecting better socioeconomic status and a more urban lifestyle were associated with greater asthma prevalence. Conclusions These data provide evidence that the prevalence of asthma increases with increasing levels of urbanisation in transitional communities, and factors associated with greater socioeconomic level and changes towards a more urban lifestyle may be particularly important.

Impact of Long-Term Treatment with Ivermectin on the Prevalence and Intensity of Soil-Transmitted Helminth Infections

Background Control of soil-transmitted helminth (STH) infections relies on the periodic and long-term administration of anthelmintic drugs to high-risk groups, particularly school-age children living in endemic areas. There is limited data on the effectiveness of long-term periodic anthelmintic treatment on the prevalence of STHs, particularly from operational programmes. The current study investigated the impact of 15 to 17 years of treatment with the broad-spectrum anthelmintic ivermectin, used for the control of onchocerciasis, on STH prevalence and intensity in school-age and pre-school children. Methods and Findings A cross-sectional study was conducted in communities that had received annual or twice-annual ivermectin treatments and geographically adjacent communities that had not received treatment in two districts of Esmeraldas Province in Ecuador. Stool samples were collected from school-age children and examined for STH infection using the Kato-Katz and formol-ether concentration methods. Samples were collected also from pre-school children and examined by the formol-ether concentration method. Data on risk factors for STH infection were collected by parental questionnaire. We sampled a total of 3,705 school-age children (6–16 years) from 31 treated and 27 non-treated communities, and 1,701 pre-school children aged 0–5 years from 18 treated and 18 non-treated communities. Among school-age children, ivermectin treatment had significant effects on the prevalence (adjusted OR =  0.06, 95% CI 0.03–0.14) and intensity of Trichuris trichiura infection (adjusted RR = 0.28, 95% CI 0.11–0.70), but appeared to have no impact on Ascaris lumbricoides or hookworm infection. Reduced prevalence and intensities of T. trichiura infection were observed among children not eligible to receive ivermectina, providing some evidence of reduced transmission of T. trichiura infection in communities receiving mass ivermectin treatments. Conclusion Annual and twice-annual treatments with ivermectin over a period of up to 17 years may have had a significant impact on T. trichiura infection. The present data indicate that the long-term control of onchocerciasis with ivermectin may provide additional health benefits by reducing infections with trichuriasis. The addition of a second anthelmintic drug such as albendazole may be useful for a long-term effect on A. lumbricoides infection.

Immune system development during early childhood in tropical Latin America: Evidence for the age-dependent down regulation of the innate immune response

The immune response that develops in early childhood underlies the development of inflammatory diseases such as asthma and there are few data from tropical Latin America (LA). This study investigated the effects of age on the development of immunity during the first 5 years of life by comparing innate and adaptive immune responses in Ecuadorian children aged 6–9 months, 22–26 months, and 48–60 months. Percentages of naïve CD4+ T cells declined with age while those of memory CD4+ and CD8+ T cells increased indicating active development of the immune system throughout the first five years. Young infants had greater innate immune responses to TLR agonists compared to older children while regulatory responses including SEB-induced IL-10 and percentages of FoxP3+ T-regulatory cells decreased with age. Enhanced innate immunity in early life may be important for host defense against pathogens but may increase the risk of immunopathology.

Effects of geohelminth infection and age on the associations between allergen-specific IgE, skin test reactivity and wheeze: a case-control study

Most childhood asthma in poor populations in Latin America is not associated with aeroallergen sensitization, an observation that could be explained by the attenuation of atopy by chronic helminth infections or effects of age.

Environmental determinants of total IgE among school children living in the rural Tropics: importance of geohelminth infections and effect of anthelmintic treatment

BackgroundThe environmental factors that determine the elevated levels of polyclonal IgE observed in populations living in the Tropics are poorly understood but may include geohelminth infections. We investigated the association between geohelminth infections and total IgE levels in school children in rural tropical Ecuador, and assessed the effect on IgE of repeated anthelmintic treatments over a period of 12 months. The study was nested within a cluster-randomized study that randomized 68 schools to receive either 400 mg of albendazole every 2 months over a year or no treatment. We studied random samples of children completing follow-up and representing four groups stratified by the presence of geohelminth infection at baseline and treatment allocation. We measured levels of total IgE and anti-A. lumbricoides IgG (used as a measure of past and current geohelminth infectious exposure) in blood samples collected at the start of the study and after 12 months.ResultsWe observed elevated levels of total IgE (compared to standard reference values) at the start of the study in this population of school children (geometric mean, 1,004 IU/mL, range 12 to 22,608 IU/mL)) and baseline IgE levels were strongly associated with parameters of geohelminth infection but not with age, nutritional and socioeconomic status. After 12 months, levels of IgE fell significantly in the treatment (by 35.1%) and no treatment (by 10.4%) groups, respectively, but the fall was significantly greater in the treatment group. Falls in IgE were independently associated with albendazole treatment, having a baseline geohelminth infection and with high baseline levels of anti-A. lumbricoides IgG. Increases in IgE at 12 months were associated with the presence of geohelminth infections and increasing levels of anti-A. lumbricoides IgG at 12 months independent of treatment allocation.ConclusionThe data provide evidence that geohelminth infections are an important determinant of total IgE in school children in the rural Tropics and that periodic anthelmintic treatments over 12 months are associated with reductions in IgE. The failure of anthelmintic treatment to reduce IgE levels to that considered normal in industrialized countries may be attributed to continued exposure of children to geohelminths or to the effects of infections in early life in programming a long-lasting Th2-biassed immunity.