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1.  Pattern recognition receptor-mediated cytokine response in infants across 4 continents⋆☆ 
Background
Susceptibility to infection as well as response to vaccination varies among populations. To date, the underlying mechanisms responsible for these clinical observations have not been fully delineated. Because innate immunity instructs adaptive immunity, we hypothesized that differences between populations in innate immune responses may represent a mechanistic link to variation in susceptibility to infection or response to vaccination.
Objective
Determine whether differences in innate immune responses exist among infants from different continents of the world.
Methods
We determined the innate cytokine response following pattern recognition receptor (PRR) stimulation of whole blood from 2-year-old infants across 4 continents (Africa, North America, South America, and Europe).
Results
We found that despite the many possible genetic and environmental exposure differences in infants across 4 continents, innate cytokine responses were similar for infants from North America, South America, and Europe. However, cells from South African infants secreted significantly lower levels of cytokines than did cells from infants from the 3 other sites, and did so following stimulation of extracellular and endosomal but not cytosolic PRRs.
Conclusions
Substantial differences in innate cytokine responses to PRR stimulation exist among different populations of infants that could not have been predicted. Delineating the underlying mechanism(s) for these differences will not only aid in improving vaccine-mediated protection but possibly also provide clues for the susceptibility to infection in different regions of the world.
doi:10.1016/j.jaci.2013.09.038
PMCID: PMC3969582  PMID: 24290283
Innate immunity; immune development; infectious disease; global; LPS, Lipopolysaccharide; MDP, Muramyl dipeptide; NOD, Nucleotide-binding oligomerization domain-containing protein; PCA, Principal-component analysis; PGN, Peptidoglycan; Poly I:C, Polyinosinic-polycytidylic acid; PRR, Pattern-recognition receptor; R848, Resiquimod; TLR, Toll-like receptor
2.  Hygiene, atopy and wheeze–eczema–rhinitis symptoms in schoolchildren from urban and rural Ecuador 
Thorax  2013;69(3):232-239.
Background
Rural residence is protective against atopy and wheeze–rhinitis–eczema symptoms in developed countries, an effect attributed to farming and poor hygiene exposures. There are few data from developing countries addressing this question. We compared atopy and wheeze–rhinitis–eczema symptoms between urban and rural Ecuador, and explored the effects of farming and poor hygiene exposures.
Methods
We performed cross sectional studies of schoolchildren living in rural and urban Ecuador. Data on symptoms and farming/hygiene exposures were collected by parental questionnaire, atopy by allergen skin prick test reactivity and geohelminth infections by stool examinations.
Results
Among 2526 urban and 4295 rural schoolchildren, prevalence was: atopy (10.0% vs 12.5%, p=0.06), wheeze (9.4% vs 10.1%, p=0.05), rhinitis (8.1% vs 6.4%, p=0.02) and eczema (5.9% vs 4.7%, p=0.06). A small proportion of symptoms were attributable to atopy (range 3.9–10.7%) with greater attributable fractions for respiratory symptoms observed in urban schoolchildren. Respiratory symptoms were associated with poor hygiene/farming exposures: wheeze with lack of access to potable water; and rhinitis with household pets, no bathroom facilities and contact with large farm animals. Birth order was inversely associated with respiratory symptoms. Area of residence and atopy had few effects on these associations.
Conclusions
Urban schoolchildren living in Ecuador have a similar prevalence of atopy, eczema and wheeze but a higher prevalence of rhinitis compared with rural children. Some farming and poor hygiene exposures were associated with an increase in the prevalence of wheeze or rhinitis while birth order was inversely associated with these symptoms.
doi:10.1136/thoraxjnl-2013-203818
PMCID: PMC3932750  PMID: 24105783
Wheeze-Rhinitis-Eczema; Atopy; Hygiene; Farming; Urban-Rural
3.  Correction: Household Transmission of Rotavirus in a Community with Rotavirus Vaccination in Quininde, Ecuador 
PLoS ONE  2013;8(9):10.1371/annotation/b1efd2d1-cc25-44c8-99e1-4bcdd3b8ccc8.
doi:10.1371/annotation/b1efd2d1-cc25-44c8-99e1-4bcdd3b8ccc8
PMCID: PMC3782570  PMID: 24086218
4.  Helminth infection is associated with decreased basophil responsiveness in humans 
doi:10.1016/j.jaci.2012.04.017
PMCID: PMC3387338  PMID: 22608572
Basophil; histamine; helminth; IgE; anthelmintic therapy; type 2 immune response
5.  Does IFN-γ play a role on the pathogenesis of non-atopic asthma in Latin America children? 
In this work we explore differences in blood cells and cytokine profiles in children according to atopic status and asthma (atopic or non-atopic). The study involved measurement of Th1(IFN-γ) and Th2 (IL-5 and IL-13) cytokines in Dermatophagoides pteronyssinus stimulated peripheral blood leukocytes, blood cell count, skin prick test and specific IgE against common aeroallergens. Atopic status was associated with eosinophilia and production of Th2 type cytokines. Atopic asthma was associated with eosinophilia and non-atopic asthma was associated with IFN-γ and elevated monocytes in blood. IFN-γ and monocytes might play a role in immunopathology of non-atopic asthma in Latin American children.
doi:10.1186/1710-1492-8-18
PMCID: PMC3564733  PMID: 23253516
Non-atopic asthma; Cytokines; IFN-g; Monocytes; Atopic-asthma; IgE; Atopy
6.  Interactions between helminth parasites and allergy 
Purpose of review:
This article will review the findings of recent human studies of the association between helminth parasite infections and allergy and discuss their potential relevance to public health.
Recent findings:
Different helminth parasites may have different effects on allergy that may depend on the timing of the exposure. Infections with T. trichiura in early life are associated with a reduced prevalence of allergen skin test reactivity later in life and infants of helminth-infected mothers have been reported to have a reduced prevalence of eczema. Hookworm infection has been associated with a reduced prevalence of asthma in Ethiopia. Several studies have reported that anti-Ascaris IgE is an important risk factor for asthma, but this could be explained by an enhanced ability of atopics to produce IgE. Toxocara infections may be associated with an increased risk of wheeze in some populations that may be caused by the host response to the parasite or by parasite-enhanced Th2 responses to aeroallergens.
Summary:
Although helminth infections can modulate the host inflammatory response directed against the parasite, a causal association between helminths and atopic diseases remains uncertain.
doi:10.1097/ACI.0b013e32831f44a6
PMCID: PMC2680069  PMID: 19106698
Helminths; Geohelminths; Allergy; Asthma
7.  Upper Airways Microbiota in Antibiotic-Naïve Wheezing and Healthy Infants from the Tropics of Rural Ecuador 
PLoS ONE  2012;7(10):e46803.
Background
Observations that the airway microbiome is disturbed in asthma may be confounded by the widespread use of antibiotics and inhaled steroids. We have therefore examined the oropharyngeal microbiome in early onset wheezing infants from a rural area of tropical Ecuador where antibiotic usage is minimal and glucocorticoid usage is absent.
Materials and Methods
We performed pyrosequencing of amplicons of the polymorphic bacterial 16S rRNA gene from oropharyngeal samples from 24 infants with non-infectious early onset wheezing and 24 healthy controls (average age 10.2 months). We analyzed microbial community structure and differences between cases and controls by QIIME software.
Results
We obtained 76,627 high quality sequences classified into 182 operational taxonomic units (OTUs). Firmicutes was the most common and diverse phylum (71.22% of sequences) with Streptococcus being the most common genus (49.72%). Known pathogens were found significantly more often in cases of infantile wheeze compared to controls, exemplified by Haemophilus spp. (OR = 2.12, 95% Confidence Interval (CI) 1.82–2.47; P = 5.46×10−23) and Staphylococcus spp. (OR = 124.1, 95%CI 59.0–261.2; P = 1.87×10−241). Other OTUs were less common in cases than controls, notably Veillonella spp. (OR = 0.59, 95%CI = 0.56–0.62; P = 8.06×10−86).
Discussion
The airway microbiota appeared to contain many more Streptococci than found in Western Europe and the USA. Comparisons between healthy and wheezing infants revealed a significant difference in several bacterial phylotypes that were not confounded by antibiotics or use of inhaled steroids. The increased prevalence of pathogens such as Haemophilus and Staphylococcus spp. in cases may contribute to wheezing illnesses in this age group.
doi:10.1371/journal.pone.0046803
PMCID: PMC3465279  PMID: 23071640
8.  Galactose-α-1,3-Galactose–Specific IgE Is Associated with Anaphylaxis but Not Asthma 
Rationale: IgE antibodies to the mammalian oligosaccharide galactose-α-1,3-galactose (α-gal) are common in the southeastern United States. These antibodies, which are induced by ectoparasitic ticks, can give rise to positive skin tests or serum assays with cat extract.
Objectives: To evaluate the relationship between IgE antibodies to α-gal and asthma, and compare this with the relationship between asthma and IgE antibodies to Fel d 1 and other protein allergens.
Methods: Patients being investigated for recurrent anaphylaxis, angioedema, or acute urticaria underwent spirometry, exhaled nitric oxide, questionnaires, and serum IgE antibody assays. The results were compared with control subjects and cohorts from the emergency department in Virginia (n = 130), northern Sweden (n = 963), and rural Kenya (n = 131).
Measurements and Main Results: Patients in Virginia with high-titer IgE antibodies to α-gal had normal lung function, low levels of exhaled nitric oxide, and low prevalence of asthma symptoms. Among patients in the emergency department and children in Kenya, there was no association between IgE antibodies to α-gal and asthma (odds ratios, 1.04 and 0.75, respectively). In Sweden, IgE antibodies to cat were closely correlated with IgE antibodies to Fel d 1 (r = 0.83) and to asthma (P < 0.001).
Conclusions: These results provide a model of an ectoparasite-induced specific IgE response that can increase total serum IgE without creating a risk for asthma, and further evidence that the main allergens that are causally related to asthma are those that are inhaled.
doi:10.1164/rccm.201111-2017OC
PMCID: PMC3326422  PMID: 22281828
α-gal; red meat allergy; ticks; total serum IgE; ectoparasite
9.  A Single Dose of Oral BCG Moreau Fails to Boost Systemic IFN-γ Responses to Tuberculin in Children in the Rural Tropics: Evidence for a Barrier to Mucosal Immunization 
Journal of Tropical Medicine  2012;2012:132583.
Immune responses to oral vaccines are impaired in populations living in conditions of poverty in developing countries, and there is evidence that concurrent geohelminth infections may contribute to this effect. We vaccinated 48 children living in rural communities in Ecuador with a single oral dose of 100 mg of BCG Moreau RDJ and measured the frequencies of tuberculin-stimulated peripheral blood mononuclear cells expressing IFN-γ before and after vaccination. Vaccinated children had active ascariasis (n = 20) or had been infected but received short- (n = 13) or long-term (n = 15) repeated treatments with albendazole prior to vaccination to treat ascariasis. All children had a BCG scar from neonatal vaccination. There was no evidence of a boosting of postvaccination IFN-γ responses in any of the 3 study groups. Our data provide support for the presence of a barrier to oral vaccination among children from the rural tropics that appeared to be independent of concurrent ascariasis.
doi:10.1155/2012/132583
PMCID: PMC3263634  PMID: 22287972
10.  Risk Factors for Soil-Transmitted Helminth Infections during the First 3 Years of Life in the Tropics; Findings from a Birth Cohort 
Background
Soil-transmitted helminths (STH) infect more than 2 billion humans worldwide, causing significant morbidity in children. There are few data on the epidemiology and risk factors for infection in pre-school children. To investigate risk factors for infection in early childhood, we analysed data prospectively collected in the ECUAVIDA birth cohort in Ecuador.
Methods and Findings
Children were recruited at birth and followed up to 3 years of age with periodic collection of stool samples that were examined microscopically for STH parasites. Data on social, demographic, and environmental risk factors were collected from the mother at time of enrolment. Associations between exposures and detection of STH infections were analysed by multivariable logistic regression. Data were analysed from 1,697 children for whom a stool sample was obtained at 3 years. 42.3% had at least one STH infection in the first 3 years of life and the most common infections were caused by A. lumbricoides (33.2% of children) and T. trichiura (21.2%). Hookworm infection was detected in 0.9% of children. Risk of STH infection was associated with factors indicative of poverty in our study population such as Afro-Ecuadorian ethnicity and low maternal educational level. Maternal STH infections during pregnancy were strong risk factors for any childhood STH infection, infections with either A. lumbricoides or T. trichiura, and early age of first STH infection. Children of mothers with moderate to high infections intensities with A. lumbricoides were most at risk.
Conclusions
Our data show high rates of infection with STH parasites during the first 3 years of life in an Ecuadorian birth cohort, an observation that was strongly associated with maternal STH infections during pregnancy. The targeted treatment of women of childbearing age, in particular before pregnancy, with anthelmintic drugs could offer a novel approach to the prevention of STH infections in pre-school children.
Author Summary
Soil-transmitted helminths (STH) are intestinal worms that cause significant morbidity in school age and pre-school children in developing countries. Infections are associated with poverty, particularly through lack of access to sanitation and clean drinking water. Current control strategies rely on periodic anthelmintic treatment of schoolchildren but new strategies are required for STH control in young children. There are few data on modifiable risk factors in pre-school children. We investigated environmental and socioeconomic risk factors for STH infection in the first 3 years of life in a birth cohort from an STH-endemic region of Latin America. Our data provide evidence that maternal STH infections documented during pregnancy are an important risk factor for infection in young children, raising the possibility of a novel intervention for the prevention of STH-associated morbidity in early childhood through the deworming of women of childbearing age, in particular before pregnancy.
doi:10.1371/journal.pntd.0002718
PMCID: PMC3937274  PMID: 24587469
11.  Urbanisation is associated with prevalence of childhood asthma in diverse, small rural communities in Ecuador 
Thorax  2011;66(12):1043-1050.
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.
doi:10.1136/thoraxjnl-2011-200225
PMCID: PMC3221322  PMID: 21825085
Asthma; urbanisation; transitional communities; childhood; urban lifestyle; asthma epidemiology; asthma in primary care; bacterial infection; cytokine biology; eosinophil biology; exercise; immunodeficiency; lymphocyte biology; neutrophil biology; allergic lung disease; respiratory infection; tuberculosis; asthma guidelines; cystic fibrosis; exhaled airway markers; lung physiology; paediatric asthma; paediatric lung disease
12.  Impact of early life exposures to geohelminth infections on the development of vaccine immunity, allergic sensitization, and allergic inflammatory diseases in children living in tropical Ecuador: the ECUAVIDA birth cohort study 
BMC Infectious Diseases  2011;11:184.
Background
Geohelminth infections are highly prevalent infectious diseases of childhood in many regions of the Tropics, and are associated with significant morbidity especially among pre-school and school-age children. There is growing concern that geohelminth infections, particularly exposures occurring during early life in utero through maternal infections or during infancy, may affect vaccine immunogenicity in populations among whom these infections are endemic. Further, the low prevalence of allergic disease in the rural Tropics has been attributed to the immune modulatory effects of these infections and there is concern that widespread use of anthelmintic treatment in high-risk groups may be associated with an increase in the prevalence of allergic diseases. Because the most widely used vaccines are administered during the first year of life and the antecedents of allergic disease are considered to occur in early childhood, the present study has been designed to investigate the impact of early exposures to geohelminths on the development of protective immunity to vaccines, allergic sensitization, and allergic disease.
Methods/Design
A cohort of 2,403 neonates followed up to 8 years of age. Primary exposures are infections with geohelminth parasites during the last trimester of pregnancy and the first 2 years of life. Primary study outcomes are the development of protective immunity to common childhood vaccines (i.e. rotavirus, Haemophilus influenzae type B, Hepatitis B, tetanus toxoid, and oral poliovirus type 3) during the first 5 years of life, the development of eczema by 3 years of age, the development of allergen skin test reactivity at 5 years of age, and the development of asthma at 5 and 8 years of age. Potential immunological mechanisms by which geohelminth infections may affect the study outcomes will be investigated also.
Discussion
The study will provide information on the potential effects of early exposures to geohelminths (during pregnancy and the first 2 years of life) on the development of vaccine immunity and allergy. The data will inform an ongoing debate of potential effects of geohelminths on child health and will contribute to policy decisions on new interventions designed to improve vaccine immunogenicity and protect against the development of allergic diseases.
Trial registration
Current Controlled Trials ISRCTN41239086.
doi:10.1186/1471-2334-11-184
PMCID: PMC3141416  PMID: 21714922
13.  The relevance of tick bites to the production of IgE antibodies to the mammalian oligosaccharide galactose-α-1,3-galactose 
Background
In 2009, we reported a novel form of delayed anaphylaxis to red meat, which is related to serum IgE antibodies to the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal). Most of these patients had tolerated meat for many years previously. The implication is that some exposure in adult life had stimulated the production of these IgE antibodies.
Objectives
To investigate possible causes of this IgE antibody response, focusing on evidence related to tick bites, which are common in the region where these reactions occur.
Methods
Serum assays were carried out using biotinylated proteins and extracts bound to a streptavidin ImmunoCAP.
Results
Prospective studies on IgE antibodies in three subjects following tick bites showed an increase in IgE to alpha-gal of twenty-fold or greater. Other evidence included i) a strong correlation between histories of tick bites and IgE to alpha-gal (χ2=26.8, p<0.001), ii) evidence that these IgE antibodies are common in areas where the tick Amblyomma americanum is common, and iii) a significant correlation between IgE antibodies to alpha-gal and IgE antibodies to proteins derived from A. americanum (rs=0.75, p<0.001).
Conclusion
The results presented here provide evidence that tick bites are a cause, or possibly the only cause, of IgE specific for alpha-gal in this area of the United States. Both the number of subjects becoming sensitized and the titer of IgE antibodies to alpha-gal are striking. Here we report the first example of a response to an ectoparasite giving rise to an important form of food allergy.
doi:10.1016/j.jaci.2011.02.019
PMCID: PMC3085643  PMID: 21453959
ticks; anaphylaxis; oligosaccharide; alpha-gal; IgE antibody to CCD
14.  Evidence for a modulatory effect of IL-10 on both Th1 and Th2 cytokine production: The role of the environment 
Clinical Immunology (Orlando, Fla.)  2011;139(1-3):57-64.
Allergic and other immune-mediated diseases are complex disease states determined by interplay between host genetics and environmental factors. Environmental changes such as fewer infections and reduced exposure to microbial products have been suggested to have led to insufficient regulation of Th1 and Th2 immune responses, causing an increased incidence of inflammatory diseases. The objective of the present study was to investigate the effect of poor living environmental conditions on mitogen-induced production of cytokines (Th1 and Th2) by peripheral blood leukocytes in children living in urban Brazil and investigate the role of IL-10 in modifying this effect. Our data showed that the proportion of children producing Th1 and Th2 cytokines was lower among those with poor living conditions and that this finding was stronger in children producing IL-10. These results provide a possible biologic explanation for the temporal trends of increasing risk of inflammatory diseases observed in populations living in affluent countries.
doi:10.1016/j.clim.2010.12.019
PMCID: PMC3070800  PMID: 21285005
BMI, Body mass index; CpG-DNA, bacterial DNA; DC, dendritic cell; IFN, Interferon; LB, B lymphocyte; LPS, lipopolysaccharide; MΦ, macrophage; MHC, major histocompatibility complex; Neu, neutrophil; NO, nitric oxide; OR, odds ratio; PBLs, peripheral blood leukocytes; SCAALA, Social Changes Asthma and Allergy in Latin America; TGF-β, transforming growth factor β; Th1, T helper 1; Th17, T helper 17; Th2, T helper 2; TLR, toll like receptors; Treg, T regulatory; WBC, whole blood cells culture; IL-10; Th1/Th2; Environment; Sewage system; Street paving; Immune regulation
15.  Evidence for in utero sensitization to Ascaris lumbricoides in newborns of mothers with ascariasis 
The Journal of infectious diseases  2009;199(12):1846-1850.
Human infections with Ascaris lumbricoides may have important effects on allergy and susceptibility to infectious diseases that start in early life. To investigate if sensitization to Ascaris occurs in utero, we measured IFN-γ and IL-4 responses in Ascaris antigen-stimulated cord blood of newborns of infected and non-infected mothers using flow cytometry. There was evidence of elevated frequencies of IFN-γ and IL-4-expressing CD4+ T cells in newborns of infected mothers compared to those of non-infected mothers. Our data provide evidence of in utero sensitization to A. lumbricoides, and raise the possibility that the immunological effects of infection start in the fetus.
doi:10.1086/599214
PMCID: PMC2869024  PMID: 19426111
Ascaris lumbricoides; in utero; sensitization; newborn
16.  Risk factors for atopic and non-atopic asthma in a rural area of Ecuador 
Thorax  2010;65(5):409-416.
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.
doi:10.1136/thx.2009.126490
PMCID: PMC2988616  PMID: 20435862
Asthma; asthma epidemiology; atopy; children; Ecuador; risk factors
17.  Chronic Intestinal Helminth Infections Are Associated with Immune Hyporesponsiveness and Induction of a Regulatory Network▿ † ‡  
Infection and Immunity  2010;78(7):3160-3167.
Helminth infections have been associated with protection against allergy and autoimmune diseases. We investigated the effects of chronic infections with Ascaris lumbricoides and Trichuris trichiura (measured twice over a 5-year period) on cytokine and antibody responses. We collected blood from 1,060 children aged 4 to 11 years living in a poor urban area of Brazil and measured Th1 (gamma interferon [IFN-γ]) and Th2 (interleukin-5 [IL-5] and IL-13) cytokines and the regulatory cytokine IL-10 in unstimulated and stimulated (with mitogen or A. lumbricoides antigens) cultures of peripheral blood leukocytes and levels of total IgE and anti-A. lumbricoides IgG4 and IgE in serum. Intestinal helminth infections were associated with an increased proportion of children producing IL-5 in response to A. lumbricoides and producing IL-10 spontaneously, especially among coinfected and chronically infected children. Helminth infections were associated with a generalized suppression of cytokine responses to mitogen. Levels of total IgE and anti-A. lumbricoides IgG4 and IgE were especially elevated in chronically infected children. In conclusion, intestinal helminth infections were associated with a typical Th2 immune response profile and with the induction of immune hyporesponsiveness that was associated with greater frequencies of the production of spontaneous IL-10.
doi:10.1128/IAI.01228-09
PMCID: PMC2897394  PMID: 20404082
18.  Spontaneous Cytokine Production in Children According to Biological Characteristics and Environmental Exposures 
Environmental Health Perspectives  2009;117(5):845-849.
Background
Environmental factors are likely to have profound effects on the development of host immune responses, with serious implications for infectious diseases and inflammatory disorders such as asthma.
Objective
This study was designed to investigate the effects of environmental exposures on the cytokine profile of children.
Methods
The study involved measurement of T helper (Th) 1 (interferon-gamma), 2 [interleukin (IL)-5 and IL-13], and the regulatory cytokine IL-10 in unstimulated peripheral blood leukocytes from 1,376 children 4–11 years of age living in a poor urban area of the tropics. We also assessed the impact of environmental exposures in addition to biological characteristics recorded at the time of blood collection and earlier in childhood (0–3 years before blood collection).
Results
The proportion of children producing IL-10 was greater among those without access to drinking water [p < 0.05, chi-square test, odds ratio (OR) = 1.67]. The proportion of children producing IL-5 and IL-10 (OR = 10.76) was significantly greater in households that had never had a sewage system (p < 0.05, trend test).
Conclusions
These data provide evidence for the profound effects of environmental exposures in early life as well as immune homeostasis in later childhood. Decreased hygiene (lack of access to clean drinking water and sanitation) in the first 3 years of life is associated with higher spontaneous IL-10 production up to 8 years later in life.
doi:10.1289/ehp.0800366
PMCID: PMC2685851  PMID: 19478971
age; breast-feeding; cytokine profile; IL-10; SCAALA; sewage; sex; tap water
19.  Repeated albendazole treatments enhance Th2 responses to Ascaris lumbricoides but not aeroallergens in children from rural communities in the Tropics 
The Journal of infectious diseases  2008;198(8):1237-1242.
Geohelminth infections are associated with a modulation of immunity to parasite antigens and aeroallergens that may be affected by anthelmintic treatment. To investigate this, we compared cytokine responses between children that had received repeated doses of albendazole over a year or no treatment. Whole blood was cultured with Ascaris antigen and house dust mite and cockroach allergens and IL-5, IL-13, IFN-γ, and IL-10 were measured. Anthelmintic treatment was associated with enhanced production of Th2 cytokines to parasite antigen, but did not affect responses to aeroallergens. The data indicate that long-term treatment may be associated with increased antiparasite Th2 immunity.
doi:10.1086/591945
PMCID: PMC2635537  PMID: 18729781
geohelminths; Ascaris lumbricoides; allergy; atopy; aeroallergens; Th2 cytokines; immune modulation
20.  Ascaris lumbricoides-induced interleukin-10 is not associated with atopy in school children in a rural area of the tropics 
The Journal of infectious diseases  2008;197(9):1333-1340.
Background:
Intestinal helminth infections may protect against allergen skin test reactivity in endemic areas and it has been suggested that IL-10 may mediate this effect. We investigated if IL-10 and populations of IL-10+ T cells may modulate atopy in children living in an endemic area for intestinal helminth parasites.
Methods:
Ecuadorian school children from rural communities were assessed for allergen skin test reactivity to Periplaneta americana and Dermatophagoides pteronyssinus. Skin test positive (n=39) and skin test negative (n=41) children were bled and peripheral blood leukocytes were cultured in the presence of Ascaris lumbricoides antigen to measure IL-10 protein and the frequencies of T cell populations expressing intracellular IL-10. We investigated also if these immunological factors affected the association between specific IgE and skin test reactivity to aeroallergens.
Results:
There was no evidence of associations between levels of A. lumbricoides-induced IL-10 protein or IL-10+ T cells and allergen skin test reactivity. The association between allergen-specific IgE and skin test reactivity was not affected by levels of IL-10 protein or the frequencies of IL-10+ T cells.
Conclusions:
Our data do not support a role for IL-10 in modulating atopy in children living in an intestinal helminth-endemic area of the tropics.
doi:10.1086/586904
PMCID: PMC2358946  PMID: 18422446
atopy; IgE; allergen skin test reactivity; Ascaris lumbricoides; intestinal helminths; IL-10; regulatory T cells
21.  Environmental determinants of total IgE among school children living in the rural Tropics: importance of geohelminth infections and effect of anthelmintic treatment 
BMC Immunology  2008;9:33.
Background
The 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.
Results
We 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.
Conclusion
The 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.
doi:10.1186/1471-2172-9-33
PMCID: PMC2459155  PMID: 18588694
22.  A guide to modern statistical analysis of immunological data 
BMC Immunology  2007;8:27.
Background
The number of subjects that can be recruited in immunological studies and the number of immunological parameters that can be measured has increased rapidly over the past decade and is likely to continue to expand. Large and complex immunological datasets can now be used to investigate complex scientific questions, but to make the most of the potential in such data and to get the right answers sophisticated statistical approaches are necessary. Such approaches are used in many other scientific disciplines, but immunological studies on the whole still use simple statistical techniques for data analysis.
Results
The paper provides an overview of the range of statistical methods that can be used to answer different immunological study questions. We discuss specific aspects of immunological studies and give examples of typical scientific questions related to immunological data. We review classical bivariate and multivariate statistical techniques (factor analysis, cluster analysis, discriminant analysis) and more advanced methods aimed to explore causal relationships (path analysis/structural equation modelling) and illustrate their application to immunological data. We show the main features of each method, the type of study question they can answer, the type of data they can be applied to, the assumptions required for each method and the software that can be used.
Conclusion
This paper will help the immunologist to choose the correct statistical approach for a particular research question.
doi:10.1186/1471-2172-8-27
PMCID: PMC2234437  PMID: 17963513
23.  Impact of long-term treatment of onchocerciasis with ivermectin in Ecuador: potential for elimination of infection 
BMC Medicine  2007;5:9.
Background
Onchocerciasis is a leading cause of blindness worldwide, hence elimination of the infection is an important health priority. Community-based treatment programs with ivermectin form the basis of control programs for the disease in Latin America. The long-term administration of ivermectin could eliminate Onchocerca volvulus infection from endemic areas in Latin America.
Methods
A strategy of annual to twice-annual treatments with ivermectin has been used for onchocerciasis in endemic communities in Ecuador for up to 14 years. The impact of ivermectin treatment on ocular morbidity, and O. volvulus infection and transmission was monitored in seven sentinel communities.
Results
Over the period 1990–2003, high rates of treatment coverage of the eligible population were maintained in endemic communities (mean 85.2% per treatment round). Ivermectin reduced the prevalence of anterior segment disease of the eye to 0% in sentinel communities and had a major impact on the prevalence and transmission of infection, with possible elimination of infection in some foci.
Conclusion
The distribution of ivermectin in endemic communities in Ecuador might have eliminated ocular morbidity and significant progress has been made towards elimination of the infection. A strategy of more frequent treatments with ivermectin may be required in communities where the infection persists to achieve the objective of elimination of the infection from Ecuador. The elimination of the infection from an endemic country in Latin America would be a major public health achievement and could stimulate the implementation of elimination strategies in other endemic countries.
doi:10.1186/1741-7015-5-9
PMCID: PMC1890547  PMID: 17521449
24.  Risk factors for asthma and allergy associated with urban migration: background and methodology of a cross-sectional study in Afro-Ecuadorian school children in Northeastern Ecuador (Esmeraldas-SCAALA Study) 
Background
Asthma and allergic diseases are becoming increasingly frequent in children in urban centres of Latin America although the prevalence of allergic disease is still low in rural areas. Understanding better why the prevalence of asthma is greater in urban migrant populations and the role of risk factors such as life style and environmental exposures, may be key to understand what is behind this trend.
Methods/design
The Esmeraldas-SCAALA (Social Changes, Asthma and Allergy in Latin America) study consists of cross-sectional and nested case-control studies of school children in rural and urban areas of Esmeraldas Province in Ecuador. The cross-sectional study will investigate risk factors for atopy and allergic disease in rural and migrant urban Afro-Ecuadorian school children and the nested case-control study will examine environmental, biologic and social risk factors for asthma among asthma cases and non-asthmatic controls from the cross-sectional study. Data will be collected through standardised questionnaires, skin prick testing to relevant aeroallergen extracts, stool examinations for parasites, blood sampling (for measurement of IgE, interleukins and other immunological parameters), anthropometric measurements for assessment of nutritional status, exercise testing for assessment of exercise-induced bronchospasm and dust sampling for measurement of household endotoxin and allergen levels.
Discussion
The information will be used to identify the factors associated with an increased risk of asthma and allergies in migrant and urbanizing populations, to improve the understanding of the causes of the increase in asthma prevalence and to identify potentially modifiable factors to inform the design of prevention programmes to reduce the risk of allergy in urban populations in Latin America.
doi:10.1186/1471-2466-6-24
PMCID: PMC1578586  PMID: 16970809
25.  Human Infection with Ascaris lumbricoides Is Associated with Suppression of the Interleukin-2 Response to Recombinant Cholera Toxin B Subunit following Vaccination with the Live Oral Cholera Vaccine CVD 103-HgR 
Infection and Immunity  2001;69(3):1574-1580.
To investigate the potential immunomodulatory effects of concurrent ascariasis on the cytokine response to a live oral vaccine, we measured cytokine responses to cholera toxin B subunit (CT-B) following vaccination with the live oral cholera vaccine CVD 103-HgR in Ascaris lumbricoides-infected subjects randomized in a double-blind study to receive two doses of either albendazole or placebo prior to vaccination and in a group of healthy U.S. controls. Postvaccination cytokine responses to CT-B were characterized by transient increases in the production of interleukin-2 (IL-2; P = 0.02) and gamma interferon (IFN-γ; P = 0.001) in the three study groups combined; however, postvaccination increases in IFN-γ were significant only in the albendazole-treated A. lumbricoides infection group (P = 0.008). Postvaccination levels of IL-2 were significantly greater in the albendazole-treated group compared with the placebo group (P = 0.03). No changes in levels of Th1 and Th2 cytokines in response to control ascaris antigens were observed over the same period. These findings indicate that vaccination with CVD 103-HgR is associated with a Th1 cytokine response (IL-2 and IFN-γ) to CT-B, that infection with A. lumbricoides diminishes the magnitude of this response, and that albendazole treatment prior to vaccination was able to partially reverse the deficit in IL-2. The potential modulation of the immune response to oral vaccines by geohelminth parasites has important implications for the design of vaccination campaigns in geohelminth-endemic areas.
doi:10.1128/IAI.69.3.1574-1580.2001
PMCID: PMC98058  PMID: 11179329

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