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1.  Macrophage-Derived Human Resistin Is Induced in Multiple Helminth Infections and Promotes Inflammatory Monocytes and Increased Parasite Burden 
PLoS Pathogens  2015;11(1):e1004579.
Parasitic helminth infections can be associated with lifelong morbidity such as immune-mediated organ failure. A better understanding of the host immune response to helminths could provide new avenues to promote parasite clearance and/or alleviate infection-associated morbidity. Murine resistin-like molecules (RELM) exhibit pleiotropic functions following helminth infection including modulating the host immune response; however, the relevance of human RELM proteins in helminth infection is unknown. To examine the function of human resistin (hResistin), we utilized transgenic mice expressing the human resistin gene (hRetnTg+). Following infection with the helminth Nippostrongylus brasiliensis (Nb), hResistin expression was significantly upregulated in infected tissue. Compared to control hRetnTg− mice, hRetnTg+ mice suffered from exacerbated Nb-induced inflammation characterized by weight loss and increased infiltration of inflammatory monocytes in the lung, along with elevated Nb egg burdens and delayed parasite expulsion. Genome-wide transcriptional profiling of the infected tissue revealed that hResistin promoted expression of proinflammatory cytokines and genes downstream of toll-like receptor signaling. Moreover, hResistin preferentially bound lung monocytes, and exogenous treatment of mice with recombinant hResistin promoted monocyte recruitment and proinflammatory cytokine expression. In human studies, increased serum resistin was associated with higher parasite load in individuals infected with soil-transmitted helminths or filarial nematode Wuchereria bancrofti, and was positively correlated with proinflammatory cytokines. Together, these studies identify human resistin as a detrimental factor induced by multiple helminth infections, where it promotes proinflammatory cytokines and impedes parasite clearance. Targeting the resistin/proinflammatory cytokine immune axis may provide new diagnostic or treatment strategies for helminth infection and associated immune-mediated pathology.
Author Summary
Parasitic helminths, which infect an estimated two billion people worldwide, represent a significant global public health problem. Infection is associated with life-long morbidity including growth retardation and organ failure. Despite these debilitating conditions, there are currently no successful vaccines against helminths. Further, great variability in the host immune response to helminths exists, with the ability of some individuals to develop immunity, while others are susceptible when re-exposed or maintain life-long chronic infections. Identifying new factors that are differentially expressed in immune versus susceptible individuals could provide new targeting strategies for diagnosis or treatment of helminth infection. Here, we identify an important immunoregulatory function for human resistin in helminth infection. Employing transgenic mice in which the human resistin gene was inserted, we show that human resistin is induced by infection with the helminth Nippostrongylus brasiliensis, where it promotes excessive inflammation and impedes parasite killing. Moreover, analysis of clinical samples from two cohorts of individuals infected with filarial nematodes or soil-transmitted helminths revealed increased resistin and serum proinflammatory cytokines compared to putatively immune individuals. Together, these studies suggest that human resistin is a detrimental cytokine that is expressed in multiple helminth infections, mediates pathogenic inflammation, and delays parasite clearance.
doi:10.1371/journal.ppat.1004579
PMCID: PMC4287580  PMID: 25568944
2.  Asthma in Hispanics. An 8-Year Update 
This review provides an update on asthma in Hispanics, a diverse group tracing their ancestry to countries previously under Spanish rule. A marked variability in the prevalence and morbidity from asthma remains among Hispanic subgroups in the United States and Hispanic America. In the United States, Puerto Ricans and Mexican Americans have high and low burdens of asthma, respectively (the “Hispanic Paradox”). This wide divergence in asthma morbidity among Hispanic subgroups is multifactorial, likely reflecting the effects of known (secondhand tobacco smoke, air pollution, psychosocial stress, obesity, inadequate treatment) and potential (genetic variants, urbanization, vitamin D insufficiency, and eradication of parasitic infections) risk factors. Barriers to adequate asthma management in Hispanics include economic and educational disadvantages, lack of health insurance, and no access to or poor adherence with controller medications such as inhaled corticosteroids. Although considerable progress has been made in our understanding of asthma in Hispanic subgroups, many questions remain. Studies of asthma in Hispanic America should focus on environmental or lifestyle factors that are more relevant to asthma in this region (e.g., urbanization, air pollution, parasitism, and stress). In the United States, research studies should focus on risk factors that are known to or may diverge among Hispanic subgroups, including but not limited to epigenetic variation, prematurity, vitamin D level, diet, and stress. Clinical trials of culturally appropriate interventions that address multiple aspects of asthma management in Hispanic subgroups should be prioritized for funding. Ensuring high-quality healthcare for all remains a pillar of eliminating asthma disparities.
doi:10.1164/rccm.201401-0186PP
PMCID: PMC4098086  PMID: 24881937
asthma; Hispanics; genetics; risk factors
3.  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
4.  Risk factors for non-atopic asthma/wheeze in children and adolescents: a systematic review 
Background
The study of non-atopic asthma/wheeze in children separately from atopic asthma is relatively recent. Studies have focused on single risk factors and had inconsistent findings.
Objective
To review evidence on factors associated with non-atopic asthma/wheeze in children and adolescents.
Methods
A review of studies of risk factors for non-atopic asthma/wheeze which had a non-asthmatic comparison group, and assessed atopy by skin-prick test or allergen-specific IgE.
Results
Studies of non-atopic asthma/wheeze used a wide diversity of definitions of asthma/wheeze, comparison groups and methods to assess atopy. Among 30 risk factors evaluated in the 43 studies only 3 (family history of asthma/rhinitis/eczema, dampness/mold in the household, and lower respiratory tract infections in childhood) showed consistent associations with non-atopic asthma/wheeze. No or limited period of breastfeeding was less consistently associated with non-atopic asthma/wheeze. The few studies examining the effects of overweight/obesity and psychological/social factors showed consistent associations. We used a novel graphical presentation of different risk factors for non-atopic asthma/wheeze, allowing a more complete perception of the complex pattern of effects.
Conclusions
More research using standardized methodology is needed on the causes of non-atopic asthma.
doi:10.1186/1742-7622-11-5
PMCID: PMC4068161  PMID: 24963333
Non-atopic asthma; Non-atopic wheeze; Risk factors; Mould; Respiratory infections
5.  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.
doi:10.4269/ajtmh.12-0726
PMCID: PMC3752800  PMID: 23509117
6.  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
7.  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
8.  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
9.  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
11.  Household Transmission of Rotavirus in a Community with Rotavirus Vaccination in Quininde, Ecuador 
PLoS ONE  2013;8(7):e67763.
Background
We studied the transmission of rotavirus infection in households in peri-urban Ecuador in the vaccination era.
Methods
Stool samples were collected from household contacts of child rotavirus cases, diarrhea controls and healthy controls following presentation of the index child to health facilities. Rotavirus infection status of contacts was determined by RT-qPCR. We examined factors associated with transmissibility (index-case characteristics) and susceptibility (household-contact characteristics).
Results
Amongst cases, diarrhea controls and healthy control household contacts, infection attack rates (iAR) were 55%, 8% and 2%, (n = 137, 130, 137) respectively. iARs were higher from index cases with vomiting, and amongst siblings. Disease ARs were higher when the index child was <18 months and had vomiting, with household contact <10 years and those sharing a room with the index case being more susceptible. We found no evidence of asymptomatic infections leading to disease transmission.
Conclusion
Transmission rates of rotavirus are high in households with an infected child, while background infections are rare. We have identified factors associated with transmission (vomiting/young age of index case) and susceptibility (young age/sharing a room/being a sibling of the index case). Vaccination may lead to indirect benefits by averting episodes or reducing symptoms in vaccinees.
doi:10.1371/journal.pone.0067763
PMCID: PMC3706538  PMID: 23874443
12.  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
13.  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
14.  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
15.  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
16.  Maternal Geohelminth Infections Are Associated with an Increased Susceptibility to Geohelminth Infection in Children: A Case-Control Study 
Background
Children of mothers infected with soil-transmitted helminths (STH) may have an increased susceptibility to STH infection.
Methods and Findings
We did a case-control study nested in a birth cohort in Ecuador. Data from 1,004 children aged 7 months to 3 years were analyzed. Cases were defined as children with Ascaris lumbricoides and/or Trichuris trichiura, controls without. Exposure was defined as maternal infection with A. lumbricoides and/or T. trichiura, detected during the third trimester of pregnancy. The analysis was restricted to households with a documented infection to control for infection risk. Children of mothers with STH infections had a greater risk of infection compared to children of uninfected mothers (adjusted OR 2.61, 95% CI: 1.88–3.63, p<0.001). This effect was particularly strong in children of mothers with both STH infections (adjusted OR: 5.91, 95% CI: 3.55–9.81, p<0.001). Newborns of infected mothers had greater levels of plasma IL-10 than those of uninfected mothers (p = 0.033), and there was evidence that cord blood IL-10 was increased among newborns who became infected later in childhood (p = 0.060).
Conclusion
Our data suggest that maternal STH infections increase susceptibility to infection during early childhood, an effect that was associated with elevated IL-10 in cord plasma.
Author Summary
Soil-transmitted helminths (intestinal worms) are among the most common childhood infections worldwide and are a significant cause of morbidity particularly among poor populations living in developing countries. The potent immune modulatory effects of these parasites have been suggested to be a determinant of the epidemiological distributions of other infectious diseases (e.g., HIV and tuberculosis) and allergy. There is strong epidemiological evidence that some individuals have an increased susceptibility to re-infection after treatment and the mechanisms underlying this are not well understood. A possible explanation is that in utero exposure to maternal STH infections may increase the risk of infection during childhood, but, as far as we are aware, no published study has addressed this hypothesis for STH infections in humans. In this study, we evaluated whether children of mothers infected with STH infections have a greater risk of infection when compared to children of uninfected mothers. We also examined whether this increased susceptibility to infection might occur through the tolerogenic effects of increased levels in the systemic circulation of the immune regulatory cytokine IL-10, in early life. Our data provide evidence that maternal STH infections predispose children to infections with STH parasites, and this effect was associated with elevated levels of IL-10 in newborn blood.
doi:10.1371/journal.pntd.0001753
PMCID: PMC3404107  PMID: 22848773
17.  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
18.  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
19.  Effects of Chronic Ascariasis and Trichuriasis on Cytokine Production and Gene Expression in Human Blood: A Cross-Sectional Study 
Background
Chronic soil-transmitted helminth (STH) infections are associated with effects on systemic immune responses that could be caused by alterations in immune homeostasis. To investigate this, we measured the impact in children of STH infections on cytokine responses and gene expression in unstimulated blood.
Methodology/Principal Findings
Sixty children were classified as having chronic, light, or no STH infections. Peripheral blood mononuclear cells were cultured in medium for 5 days to measure cytokine accumulation. RNA was isolated from peripheral blood and gene expression analysed using microarrays. Different infection groups were compared for the purpose of analysis: STH infection (combined chronic and light vs. uninfected groups) and chronic STH infection (chronic vs. combined light and uninfected groups). The chronic STH infection effect was associated with elevated production of GM-CSF (P = 0.007), IL-2 (P = 0.03), IL-5 (P = 0.01), and IL-10 (P = 0.01). Data reduction suggested that chronic infections were primarily associated with an immune phenotype characterized by elevated IL-5 and IL-10, typical of a modified Th2-like response. Chronic STH infections were associated with the up-regulation of genes associated with immune homeostasis (IDO, P = 0.03; CCL23, P = 0.008, HRK, P = 0.005), down-regulation of microRNA hsa-let-7d (P = 0.01) and differential regulation of several genes associated with granulocyte-mediated inflammation (IL-8, down-regulated, P = 0.0002; RNASE2, up-regulated, P = 0.009; RNASE3, up-regulated, p = 0.03).
Conclusions/Significance
Chronic STH infections were associated with a cytokine response indicative of a modified Th2 response. There was evidence that STH infections were associated with a pattern of gene expression suggestive of the induction of homeostatic mechanisms, the differential expression of several inflammatory genes and the down-regulation of microRNA has-let-7d. Effects on immune homeostasis and the development of a modified Th2 immune response during chronic STH infections could explain the systemic immunologic effects that have been associated with these infections such as impaired immune responses to vaccines and the suppression of inflammatory diseases.
Author Summary
Soil-transmitted helminth (STH or intestinal worm) infections are extremely common infectious diseases of childhood in developing countries. Infections tend be chronic and may last for many years. Chronic STH infections are associated with modulation of the immune response, a consequence of which may be a reduced prevalence of allergic inflammatory diseases such as asthma. The mechanisms by which STH infections suppress inflammatory responses are poorly understood. In this study, we hypothesized that STH infections may affect immune responses through alterations of immune homeostasis (or the steady-state adjustments of the immune system that maintain equilibrium). We investigated the capacity of blood from children classified as having no, light, or chronic STH infections to produce cytokines at rest (i.e. no immunologic stimulation) and the expression of genes in blood samples. Our data show that blood cells of children with chronic STH infections have an altered immune response that is likely to be associated with less allergic inflammation (the modified Th2 response) and that the expression of some inflammatory genes are reduced. Our findings provide insights into the mechanisms by which STH infections suppress immune responses in children to ensure the survival of the parasite and reduce inflammation.
doi:10.1371/journal.pntd.0001157
PMCID: PMC3110165  PMID: 21666788
20.  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
21.  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
22.  Immune system development during early childhood in tropical Latin America: Evidence for the age-dependent down regulation of the innate immune response 
Clinical Immunology (Orlando, Fla.)  2011;138(3):299-310.
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.
doi:10.1016/j.clim.2010.12.011
PMCID: PMC3043252  PMID: 21247809
SEB, Staphylococcus enterotoxin B; LA, Latin America; T Regs, regulatory T cells; Innate immunity; Adaptive immunity; Childhood; Tropics
23.  Poverty, dirt, infections and non-atopic wheezing in children from a Brazilian urban center 
Respiratory Research  2010;11(1):167.
Background
The causation of asthma is poorly understood. Risk factors for atopic and non-atopic asthma may be different. This study aimed to analyze the associations between markers of poverty, dirt and infections and wheezing in atopic and non-atopic children.
Methods
1445 children were recruited from a population-based cohort in Salvador, Brazil. Wheezing was assessed using the ISAAC questionnaire and atopy defined as allergen-specific IgE ≥0.70 kU/L. Relevant social factors, environmental exposures and serological markers for childhood infections were investigated as risk factors using multivariate multinomial logistic regression.
Results
Common risk factors for wheezing in atopic and non-atopic children, respectively, were parental asthma and respiratory infection in early childhood. No other factor was associated with wheezing in atopic children. Factors associated with wheezing in non-atopics were low maternal educational level (OR 1.49, 95% CI 0.98-2.38), low frequency of room cleaning (OR 2.49, 95% CI 1.27-4.90), presence of rodents in the house (OR 1.48, 95% CI 1.06-2.09), and day care attendance (OR 1.52, 95% CI 1.01-2.29).
Conclusions
Non-atopic wheezing was associated with risk factors indicative of poverty, dirt and infections. Further research is required to more precisely define the mediating exposures and the mechanisms by which they may cause non-atopic wheeze.
doi:10.1186/1465-9921-11-167
PMCID: PMC3002921  PMID: 21122116
24.  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
25.  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

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