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1.  Risk factors for tuberculosis in older children and adolescents: a matched case–control study in Recife, Brazil 
Background
Tuberculosis is a major disease worldwide and most research focus on risk factors for adults, although there is a marked adolescent peak in incidence. The objective of this study was to identify risk factors for tuberculosis in children aged 7 to 19.
Methods
A case control study matched by age with 169 cases and 477 controls. The study population consisted of adolescents and older children from Recife, Brazil. Cases were individuals diagnosed with tuberculosis in the control programme and controls were selected in the neighborhood of cases. Conditional logistic regression was used to identify risk factors.
Results
Cigarette smoking increased by 50% the risk of tuberculosis but that this was not statistically significant (OR = 1.6). Other risk factors were sleeping in the same house as a case of tuberculosis (OR = 31.6), living in a house with no piped water (OR = 7.7) (probably as a proxy for bad living conditions), illiteracy (OR = 3.7) and male sex (OR = 1.8). The increase in risk with living in houses with no piped water was much more marked in males. The proportion of cases of tuberculosis attributed to contact with someone with TB was 38% and to illiteracy, lack of piped water and smoking, 20%.
Conclusion
Household contact with tuberculosis, social factors and male sex play the biggest role in determining risk of TB disease among children and adolescents in the study. We recommend further research on the relationship of cigarette smoking on tuberculosis in adolescents, and on whether the sex differentials are more marked in bad living conditions. Separate studies should be conducted in older children and in adolescents.
doi:10.1186/s12982-014-0020-5
PMCID: PMC4312596  PMID: 25642275
Tuberculosis; Adolescents; Risk factors; Household contacts; Socio-economic factors; Smoking
2.  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
3.  Empirical treatment for TB in HIV: lessons from a cohort study of people living with HIV treated in Recife, Brazil 
BMC Public Health  2014;14:289.
Background
Tuberculosis (TB) is the leading cause of death related to HIV worldwide. This study analyzes the survival of People Living with HIV (PLHIV) reporting cough without bacteriological confirmation of TB and identify factors associated with death.
Methods
Prospective cohort with a consecutive sample of PLHIV, aged ≥ 18 years. Patient inclusion criteria were complaint of current cough of any duration at the time of the first study interview or during their subsequent routine visits to health services and for whom AFB sputum smear was either negative or not performed during the whole follow-up period. Kaplan-Meier method was used to calculate the probability of survival. We estimated the Hazard Ratio (HR) in bivariate and multivariate Cox regression analyses.
Results
Mortality was 4.6 per 100 py; 73% were receiving HAART at recruitment. Average time from the first recorded date of cough until empirical treatment for tuberculosis was six months. Mortality was higher when the CD4 count was low (HR = 5.3; CI 95%: 3.2-9.0; p = 0.000), in those with anemia (HR = 3.0; CI 95%: 1.6-5.6; p = 0.001) and with abnormal chest X-rays (HR = 2.4; CI 95%: 1.4-4.0; p = 0.001). Mortality was higher in those receiving empirical TB treatment (HR = 2.4; CI 95%: 1.4-4.0; p = 0.002), but only in those with normal X-rays, no history of tuberculosis and no bacteriology requests. Empirical treatment for TB was more frequent in PLHIV with low CD4 counts, anemia, history of opportunistic infections, weight loss, previous tuberculosis, negative bacteriology test (as opposed to not having a test) and abnormal chest X-ray.
Conclusions
Higher mortality in PLHIV reporting a current cough without bacteriological confirmation of tuberculosis was identified for those with a CD4 cell count <200, abnormal chest X-ray, anemia and empirical treatment for tuberculosis. Mortality was not significantly higher in those empirically treated for TB, who had three characteristics suggestive of the disease (abnormal chest X-ray, history of TB treatment, AFB sputum smear or M.tb culture testing). Routine cohorts are not an adequate setting to evaluate the impact of empirical treatment for TB on the mortality of PLHIV.
doi:10.1186/1471-2458-14-289
PMCID: PMC4020612  PMID: 24679187
TB/HIV; Mortality rate; Survival analysis
4.  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
5.  The second study of infectious intestinal disease (IID2): increased rates of recurrent diarrhoea in individuals aged 65 years and above 
BMC Public Health  2013;13:739.
Background
Infectious intestinal disease (IID) is a major health and economic burden in high-income countries. In the UK, there are an estimated 17 million IID cases annually, of which 6 million are caused by the 12 most common pathogens. Host factors that influence risk of IID are not well understood.
Methods
We analyzed data from the IID2 Study, a UK cohort that measured IID incidence, to investigate factors associated with recurrent IID. We calculated rates of IID by age group, sex, previous episodes experienced, and socioecomic indicators. We used Cox models to investigate factors associated with recurrent illness.
Results
The rate of IID was five times higher among infants than those aged 65 years and above (hazard ratio, HR = 5.0, 95% CI: 3.1 – 8.0). However, the association between previous IID and a subsequent IID episode was stronger in the elderly. Among those aged 65 years and above, each additional IID episode increased the rate of subsequent IID three-fold (HR = 3.1, 95% CI: 2.5 – 3.7). Among infants, the corresponding increase was 1.7-fold (HR = 1.7, 95% CI: 1.3 – 2.3).
Conclusions
Elderly populations have a high propensity for recurrent IID. More detailed studies are needed to identify vulnerable subgroups and susceptibility factors, and inform adequate control policies among the elderly.
doi:10.1186/1471-2458-13-739
PMCID: PMC3750603  PMID: 24219653
Diarrhoea; Diarrhoeal diseases; Infectious intestinal disease; Enteric pathogens; Elderly populations; Cohort studies
6.  BCG vaccination in England since 2005: a survey of policy and practice 
BMJ Open  2012;2(5):e001303.
Objective
Assess the current BCG vaccination policies and delivery pathways for immunisation in Primary Care Trusts (PCTs) in England since the 2005 change in recommendations.
Design
A survey of key informants across PCTs using a standardised, structured questionnaire.
Setting
152 PCTs in England.
Results
Complete questionnaires were returned from 127 (84%) PCTs. Sixteen (27%) PCTs reported universal infant vaccination and 111 (73%) had selective infant vaccination. Selective vaccination outside infancy was also reported from 94 (74%) PCTs. PCTs with selective infant policy most frequently vaccinated on postnatal wards (51/102, 50%), whereas PCTs with universal infant vaccination most frequently vaccinated in community clinics (9/13, 69%; p=0.011). To identify and flag up eligible infants in PCTs with targeted infant immunisation, those who mostly vaccinate on postnatal wards depend on midwives and maternity records, whereas those who vaccinate primarily in the community rely more often on various healthcare professionals.
Conclusions
Targeted infant vaccination has been implemented in most PCTs across the UK. PCTs with selective infant vaccination provide BCG vaccine via a greater variety of healthcare professionals than those with universal infant vaccination policies. Data on vaccine coverage would help evaluate the effectiveness of delivery. Interruptions of delivery noted here emphasise the importance of not just an agreed, standardised, local pathway, but also a named person in charge.
doi:10.1136/bmjopen-2012-001303
PMCID: PMC3467615  PMID: 22964115
7.  A Community Study of Factors Related to Poorly Controlled Asthma among Brazilian Urban Children 
PLoS ONE  2012;7(5):e37050.
Background
Asthma constitutes a serious public health problem in many regions of the world, including the city of Salvador, State of Bahia – Brazil. The purpose of this study was to analyse the factors associated with poor asthma control.
Methodology/Principal Findings
Two definitions were used for asthma: 1) wheezing in the last 12 months; 2) wheezing in the last 12 months plus other asthma symptoms or asthma diagnosis ever. The definition of poorly controlled asthma was: at least one reported hospitalisation due to asthma and/or high frequency of symptoms, in the last year. Children with poorly controlled asthma (N = 187/374) were compared with wheezing children with controlled asthma regarding age, gender, atopy, parental asthma, rhinitis, eczema, exposure to second hand tobacco smoke, presence of moulds, pets and pests in the house, helminth infections and body mass index. Crude and logistic regression adjusted odds ratios were used as measures of association. There was a higher proportion of poorly controlled asthma among children with eczema (OR = 1.55; 95% CI 1.02; 2.37). The strength of the association was greater among children with eczema and rhinitis (42.6%, 53.4% and 57.7%, respectively, in children who had no rhinitis nor eczema, had only one of those, and had both (p = 0.02 for trend test). The presence of mould in the houses was inversely associated with poorly controlled asthma (OR = 0.54; 95% CI 0.34; 0.87).
Conclusions/Significance
Our results indicate an association between eczema and poor asthma control in this environment, but emphasize the role of various other individual and environmental factors as determinants of poor control.
doi:10.1371/journal.pone.0037050
PMCID: PMC3365022  PMID: 22693565
8.  Risk factors for default from tuberculosis treatment in HIV-infected individuals in the state of Pernambuco, Brazil: a prospective cohort study 
BMC Infectious Diseases  2011;11:351.
Background
Concomitant treatment of Human Immunodeficiency Virus (HIV) infection and tuberculosis (TB) presents a series of challenges for treatment compliance for both providers and patients. We carried out this study to identify risk factors for default from TB treatment in people living with HIV.
Methods
We conducted a cohort study to monitor HIV/TB co-infected subjects in Pernambuco, Brazil, on a monthly basis, until completion or default of treatment for TB. Logistic regression was used to calculate crude and adjusted odds ratios, 95% confidence intervals and P-values.
Results
From a cohort of 2310 HIV subjects, 390 individuals (16.9%) who had started treatment after a diagnosis of TB were selected, and data on 273 individuals who completed or defaulted on treatment for TB were analyzed. The default rate was 21.7% and the following risk factors were identified: male gender, smoking and CD4 T-cell count less than 200 cells/mm3. Age over 29 years, complete or incomplete secondary or university education and the use of highly active antiretroviral therapy (HAART) were identified as protective factors for the outcome.
Conclusion
The results point to the need for more specific actions, aiming to reduce the default from TB treatment in males, younger adults with low education, smokers and people with CD4 T-cell counts < 200 cells/mm3. Default was less likely to occur in patients under HAART, reinforcing the strategy of early initiation of HAART in individuals with TB.
doi:10.1186/1471-2334-11-351
PMCID: PMC3297544  PMID: 22176628
9.  Behavior problems and prevalence of asthma symptoms among Brazilian children 
Journal of Psychosomatic Research  2011;71(3):160-165.
Objective
Asthma is the most common chronic disease in childhood and has been designated a public health problem due to the increase in its prevalence in recent decades, the amount of health service expenditure it absorbs and an absence of consensus about its etiology. The relationships among psychosocial factors and the occurrence, symptomatology, and severity of asthma have recently been considered. There is still controversy about the association between asthma and a child's mental health, since the pathways through which this relationship is established are complex and not well researched. This study aims to investigate whether behavior problems are associated with the prevalence of asthma symptoms in a large urban center in Latin America.
Methods
It is a cross-section study of 869 children between 6 and 12 years old, residents of Salvador, Brazil. The International Study of Allergy and Asthma in Childhood (ISAAC) instrument was used to evaluate prevalence of asthma symptoms. The Child Behavior Checklist (CBCL) was employed to evaluate behavioral problems.
Results
19.26% (n = 212) of the children presented symptoms of asthma. 35% were classified as having clinical behavioral problems. Poisson's robust regression model demonstrated a statistically significant association between the presence of behavioral problems and asthma symptoms occurrence (PR: 1.43; 95% CI: 1.10–1.85).
Conclusion
These results suggest an association between behavioral problems and pediatric asthma, and support the inclusion of mental health care in the provision of services for asthma morbidity.
doi:10.1016/j.jpsychores.2011.02.004
PMCID: PMC3160547  PMID: 21843751
SCAALA, Social Changes, Asthma and Allergy in Latin America; ISAAC, International Study of Asthma and Allergies in Childhood; CBCL, Child Behavior Checklist; ICC, Intraclass correlation coefficient; Childhood asthma; Behavior problems; SCAALA Programme
10.  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
11.  Pattern of asthma medication use among children from a large urban center in Brazil 
Purpose
Despite the advances in asthma therapeutics, there are few data on the use and determinants of anti-asthmatic drugs in the general population of children. This study describes the use of asthma medications among children in the general population and in children with current asthma, living in a large urban center in Brazil.
Methods
A population-based cross-sectional survey, aimed at analyzing asthma determinants, was conducted with 1,382 children aged 4–11 years, between February and May 2006, in Salvador, Brazil. At baseline, an extensive questionnaire was applied, including questions about the use of asthma medications in the last 12 months.
Results
In all studied children (n = 1,382) aged 4–11 years, oral beta2-agonists were the drugs most frequently used (9.8%), followed by short-acting inhaled beta2-agonists (4.3%) and systemic corticosteroids (1.6%). Anti-asthmatic drug use was higher among males than females, and it significantly decreased with age in both genders. A total of 312 children (22.6%) reported current asthma, and 62% of them were not being treated with any anti-asthmatic drugs. Of all those who reported following a certain type of treatment, 20% used oral beta2-agonists alone; 6.1%, short-acting inhaled beta2-agonists alone; and 4.8%, a combination of both drugs. Anti-asthmatic drug use did not differ according to socioeconomic status, except for the use of inhaled beta2-agonists and systemic corticosteroids.
Conclusions
An overwhelming majority of asthmatic children were not using long-term medications for asthma, in particular inhaled corticosteroids, regardless of the severity of their disease. This result points to the deficiencies of the Brazilian public health system in recognizing this important pharmacological need for child care and thereby limiting the access of these children to a group of efficacious, available, and low risk therapeutic medications.
doi:10.1007/s00228-011-1092-6
PMCID: PMC3414696  PMID: 21717145
Asthma; Pharmacoepidemiology; Asthma; Therapy; Children; Prevalence; Cross-sectional studies; Brazil
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.  Longitudinal study of infectious intestinal disease in the UK (IID2 study): incidence in the community and presenting to general practice 
Gut  2011;61(1):69-77.
Objectives
To estimate, overall and by organism, the incidence of infectious intestinal disease (IID) in the community, presenting to general practice (GP) and reported to national surveillance.
Design
Prospective, community cohort study and prospective study of GP presentation conducted between April 2008 and August 2009.
Setting
Eighty-eight GPs across the UK recruited from the Medical Research Council General Practice Research Framework and the Primary Care Research Networks.
Participants
6836 participants registered with the 88 participating practices in the community study; 991 patients with UK-acquired IID presenting to one of 37 practices taking part in the GP presentation study.
Main outcome measures
IID rates in the community, presenting to GP and reported to national surveillance, overall and by organism; annual IID cases and GP consultations by organism.
Results
The overall rate of IID in the community was 274 cases per 1000 person-years (95% CI 254 to 296); the rate of GP consultations was 17.7 per 1000 person-years (95% CI 14.4 to 21.8). There were 147 community cases and 10 GP consultations for every case reported to national surveillance. Norovirus was the most common organism, with incidence rates of 47 community cases per 1000 person-years and 2.1 GP consultations per 1000 person-years. Campylobacter was the most common bacterial pathogen, with a rate of 9.3 cases per 1000 person-years in the community, and 1.3 GP consultations per 1000 person-years. We estimate that there are up to 17 million sporadic, community cases of IID and 1 million GP consultations annually in the UK. Of these, norovirus accounts for 3 million cases and 130 000 GP consultations, and Campylobacter is responsible for 500 000 cases and 80 000 GP consultations.
Conclusions
IID poses a substantial community and healthcare burden in the UK. Control efforts must focus particularly on reducing the burden due to Campylobacter and enteric viruses.
doi:10.1136/gut.2011.238386
PMCID: PMC3230829  PMID: 21708822
Campylobacter; diarrhoeal disease; epidemiology; infectious diarrhoea; salmonella
14.  A Controlled Trial of the Knowledge Impact of Tuberculosis Information Leaflets among Staff Supporting Substance Misusers: Pilot Study 
PLoS ONE  2011;6(6):e20875.
Background
Information leaflets are widely used to increase awareness and knowledge of disease. Limited research has, to date, been undertaken to evaluate the efficacy of these information resources. This pilot study sought to determine whether information leaflets developed specifically for staff working with substance mis-users improved knowledge of tuberculosis (TB).
Method
Staffs working with individuals affected by substance mis-use were recruited between January and May 2008. All participants were subjectively allocated by their line manager either to receive the TB-specific leaflet or a control leaflet providing information on mental health. Level of knowledge of TB was assessed using questionnaires before and after the intervention and data analysed using McNemar's exact test for matched pairs.
Results
The control group showed no evidence of a change in knowledge of TB, whereas the TB questionnaire group demonstrated a significant increase in knowledge including TB being curable (81% correct before to 100% correct after), length of treatment required (42% before to 73% after), need to support direct observation (18% to 62%) and persistent fever being a symptom (56% to 87%). Among key workers, who have a central role in implementing a care plan, 88% reported never receiving any TB awareness-raising intervention prior to this study, despite 11% of all respondents having TB diagnosed among their clients.
Conclusion
Further randomized controlled trials are required to confirm the observed increase in short-term gain in knowledge and to investigate whether knowledge gain leads to change in health status.
doi:10.1371/journal.pone.0020875
PMCID: PMC3117836  PMID: 21698103
15.  Chronic virus infections supress atopy but not asthma in a set of children from a large latin american city: a cross-section study 
Background
The prevalence of allergic diseases has increased over recent decades in affluent countries, but remains low in rural populations and some non-affluent countries. An explanation for these trends is that increased exposure to infections may provide protection against the development of allergy. In this work we investigated the association between exposure to viral infections in children living in urban Brazil and the prevalence of atopy and asthma.
Methods
School age children living in poor neighborhoods in the city of Salvador were studied. Data on asthma symptoms and relevant risk factors were obtained by questionnaire. Skin prick tests (SPTs) were performed to seven aeroallergens, and specific IgE was measured to four of these. Viral infections were determined by the presence of specific IgG in serum to Herpes simplex (HSV), Herpes zoster (HZV), Epstein-Barr (EBV), and Hepatitis A (HAV) viruses.
Results
A total of 644 (49.7%) children had at least one allergen-specific IgE> 0.35 kU/L and 489 (37.7%) had specific IgE> 0.70 kU/L. A total of 391 (30.2%) children were skin test positive (SPT+), and 295 (22.8%) children were asthmatic. The seroprevalence of viral infections was 88.9% for EBV, 55.4% for HSV, 45.5% for VZV and 17.5% for HAV. Negative associations were observed between SPT+ and HSV (OR = 0.64, CI = 0.51, 0.82) and EBV (OR = 0.63, CI = 0.44, 0.89) infections, but no associations were seen between viral infections and the presence of allergen-specific IgE or asthma.
Conclusion
These data do not support previous data showing a protective effect of HAV against atopy, but did show inverse associations between SPT+ (but not specific IgE+) and infections with HSV and EBV. These findings suggest that different viral infections may protect against SPT+ in different settings and may indicate an immunoregulatory role of such infections on immediate hypersensitivity responses. The data provide no support for a protective effect of viral infections against asthma in this population.
doi:10.1186/1471-2466-11-24
PMCID: PMC3125392  PMID: 21569568
16.  Selection and quantification of infection endpoints for trials of vaccines against intestinal helminths 
Vaccine  2011;29(20):3686-3694.
Vaccines against human helminths are being developed but the choice of optimal parasitological endpoints and effect measures to assess their efficacy has received little attention. Assuming negative binomial distributions for the parasite counts, we rank the statistical power of three measures of efficacy: ratio of mean parasite intensity at the end of the trial, the odds ratio of infection at the end of the trial, and the rate ratio of incidence of infection during the trial. We also use a modelling approach to estimate the likely impact of trial interventions on the force of infection, and hence statistical power. We conclude that (1) final mean parasite intensity is a suitable endpoint for later phase vaccine trials, and (2) mass effects of trial interventions are unlikely to appreciably reduce the force of infection in the community – and hence statistical power – unless there is a combination of high vaccine efficacy and a large proportion of the population enrolled.
doi:10.1016/j.vaccine.2011.03.026
PMCID: PMC3093614  PMID: 21435404
Helminth vaccines; Parasitological endpoints; Mathematical model
17.  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
18.  Effect of reminders on mitigating participation bias in a case-control study 
Background
Researchers commonly employ strategies to increase participation in health studies. These include use of incentives and intensive reminders. There is, however, little evidence regarding the quantitative effect that such strategies have on study results. We present an analysis of data from a case-control study of Campylobacter enteritis in England to assess the usefulness of a two-reminder strategy for control recruitment.
Methods
We compared sociodemographic characteristics of participants and non-participants, and calculated odds ratio estimates for a wide range of risk factors by mailing wave.
Results
Non-participants were more often male, younger and from more deprived areas. Among participants, early responders were more likely to be female, older and live in less deprived areas, but despite these differences, we found little evidence of a systematic bias in the results when using data from early reponders only.
Conclusions
We conclude that the main benefit of using reminders in our study was the gain in statistical power from a larger sample size.
doi:10.1186/1471-2288-11-33
PMCID: PMC3079699  PMID: 21453477
bias; case-control studies; epidemiologic methods; survey methods; data collection; nonrespondents; respondents; community surveys
19.  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
20.  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
21.  Validation of epidemiological tools for eczema diagnosis in brazilian children: the isaac's and uk working party's criteria 
BMC Dermatology  2010;10:11.
Background
Instruments for field diagnosis of eczema are increasingly used, and it is essential to understand specific limitations to make best use of their strengths. Our objective was to assess the validity of ISAAC and UK Working Party criteria for field diagnosis of eczema in children.
Methods
We performed a cohort study in urban Brazil. Parents/guardians of 1,419 children answered ISAAC phase II questionnaire. Children were examined for skin lesions (UKWP protocol). Two dermatologists examined most cases of eczema (according to ISAAC or UKWP), and a sample without eczema.
Results
Agreement between repeat questionnaires on the filter question was poor (kappa = 0.4). Agreement between the 2 dermatologists was fair (kappa = 0.6). False positive reports included scabies in 39% of ISAAC cases and 33% of UKWP cases. Sensitivity and PPV were low (ISAAC: 37.1% and 16.1%; UKWP: 28.6% and 23.8%). Specificity and NPV were high (ISAAC: 90.0% and 96.6%; UKWP: 95.3% and 96.2%). One-year prevalence of eczema was 11.3% (ISAAC), 5.9% (UKWP) and 4.9% (adjusted dermatologist diagnosis). Point prevalence of scabies (alone or not) was 43%, 33% and 18%, in eczemas according to ISAAC, to UKWP and to dermatologists. The reasons why children with eczema were not identified by ISAAC or UKWP were wrongly denying dry skin, itchy rash or personal history of atopic diseases. A limitation is that questionnaire was already validated in Brazil, but not field tested in this specific setting.
Conclusions
Studies using UKWP or ISAAC criteria should include a validation arm, to contribute to the understanding of potential limitations of their use in different contexts and to explore solutions. We list specific recommendations.
doi:10.1186/1471-5945-10-11
PMCID: PMC2992474  PMID: 21062476
22.  Is it better to be rich in a poor area or poor in a rich area? A multilevel analysis of a case–control study of social determinants of tuberculosis 
Background Tuberculosis is known to have socio-economic determinants at individual and at area levels, but it is not known whether they are independent, whether they interact and their relative contributions to the burden of tuberculosis.
Methods A case–control study was conducted in Recife, Brazil, to investigate individual and area social determinants of tuberculosis, to explore the relationship between determinants at the two levels and to calculate their relative contribution to the burden of tuberculosis. It included 1452 cases of tuberculosis diagnosed by the tuberculosis services and 5808 controls selected at random from questionnaires completed for the demographic census. Exhaustive information on social factors was collected from cases, using the questionnaire used in the census. Socio-economic information for areas was downloaded from the census. Multilevel logistic regression investigated individual and area effects.
Results There was a marked and independent influence of social variables on the risk of tuberculosis, both at individual and area levels. At individual level, being aged ≥20, being male, being illiterate, not working in the previous 7 days and possessing few goods, all increased the risk of tuberculosis. At area level, living in an area with many illiterate people and where few households own a computer also increased this risk; individual and area levels did not appear to interact. Twice as many cases were attributable to social variables at individual level than at area level.
Conclusions Although individual characteristics are the main contributor to the risk of tuberculosis, contextual characteristics make a substantial independent contribution.
doi:10.1093/ije/dyp224
PMCID: PMC2755128  PMID: 19656772
Tuberculosis; social determinants; multilevel; Brazil; poverty
23.  Allergies and Diabetes as Risk Factors for Dengue Hemorrhagic Fever: Results of a Case Control Study 
Background
The physiopathology of dengue hemorrhagic fever (DHF), a severe form of Dengue Fever, is poorly understood. We are unable to identify patients likely to progress to DHF for closer monitoring and early intervention during epidemics, so most cases are sent home. This study explored whether patients with selected co-morbidities are at higher risk of developing DHF.
Methods
A matched case-control study was conducted in a dengue sero-positive population in two Brazilian cities. For each case of DHF, 7 sero-positive controls were selected. Cases and controls were interviewed and information collected on demographic and socio-economic status, reported co-morbidities (diabetes, hypertension, allergy) and use of medication. Conditional logistic regression was used to calculate the strength of the association between the co-morbidities and occurrence of DHF.
Results
170 cases of DHF and 1,175 controls were included. Significant associations were found between DHF and white ethnicity (OR = 4.70; 2.17–10.20), high income (OR = 6.84; 4.09–11.43), high education (OR = 4.67; 2.35–9.27), reported diabetes (OR = 2.75; 1.12–6.73) and reported allergy treated with steroids (OR = 2.94; 1.01–8.54). Black individuals who reported being treated for hypertension had 13 times higher risk of DHF then black individuals reporting no hypertension.
Conclusions
This is the first study to find an association between DHF and diabetes, allergy and hypertension. Given the high case fatality rate of DHF (1–5%), we believe that the evidence produced in this study, when confirmed in other studies, suggests that screening criteria might be used to identify adult patients at a greater risk of developing DHF with a recommendation that they remain under observation and monitoring in hospital.
Author Summary
Dengue is an arboviral disease that affects large areas of countries in tropical and subtropical regions of the world. Around 500,000 cases and 22,000 deaths of dengue hemorrhagic fever (DHF)/Dengue Shock Syndrome (DSS), the most severe presentations of this disease, occur annually. It is unclear why some cases of dengue fever (0.5% to 4%) progress to DHF/DSS. There is weak evidence that some diseases could have a role in this process, such as diabetes, hypertension, and allergies. In epidemics most dengue fever cases are sent home as there are too many to be kept in observation, but if it were possible to identify those with a higher risk of progression to DHF, they could be kept for observation, for early detection of signs, symptoms and alterations in laboratory tests suggestive of DHF, to enable timely and effective clinical management and early intervention. We study this issue and we believe that the evidence produced in this study, when confirmed in other studies, suggests that screening criteria might be used to identify adult patients at a greater risk of developing DHF with a recommendation that they remain under observation and monitoring in a hospital.
doi:10.1371/journal.pntd.0000699
PMCID: PMC2879373  PMID: 20532230
24.  Methods for determining disease burden and calibrating national surveillance data in the United Kingdom: the second study of infectious intestinal disease in the community (IID2 study) 
Background
Infectious intestinal disease (IID), usually presenting as diarrhoea and vomiting, is frequently preventable. Though often mild and self-limiting, its commonness makes IID an important public health problem. In the mid 1990s around 1 in 5 people in England suffered from IID a year, costing around £0.75 billion. No routine information source describes the UK's current community burden of IID. We present here the methods for a study to determine rates and aetiology of IID in the community, presenting to primary care and recorded in national surveillance statistics. We will also outline methods to determine whether or not incidence has declined since the mid-1990s.
Methods/design
The Second Study of Infectious Intestinal Disease in the Community (IID2 Study) comprises several separate but related studies. We use two methods to describe IID burden in the community - a retrospective telephone survey of self-reported illness and a prospective, all-age, population-based cohort study with weekly follow-up over a calendar year. Results from the two methods will be compared. To determine IID burden presenting to primary care we perform a prospective study of people presenting to their General Practitioner with symptoms of IID, in which we intervene in clinical and laboratory practice, and an audit of routine clinical and laboratory practice in primary care. We determine aetiology of IID using molecular methods for a wide range of gastrointestinal pathogens, in addition to conventional diagnostic microbiological techniques, and characterise isolates further through reference typing. Finally, we combine all our results to calibrate national surveillance data.
Discussion
Researchers disagree about the best method(s) to ascertain disease burden. Our study will allow an evaluation of methods to determine the community burden of IID by comparing the different approaches to estimate IID incidence in its linked components.
doi:10.1186/1471-2288-10-39
PMCID: PMC2886083  PMID: 20444246
25.  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

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