Daniel Pilger

Evidence of an effect of BCG revaccination on incidence of tuberculosis in school-aged children in Brazil: second report of the BCG-REVAC cluster-randomised trial.

BCG revaccination is still used in some tuberculosis endemic countries. Until now, the little evidence available suggested that BCG revaccination confers very limited additional protection, although there was no information on whether protection depends on the setting and age of revaccination, or if protection increases with time since vaccination. Here we report on an extended follow up of the BCG-REVAC trial, a cluster randomised trial conducted in the Brazilian cities Salvador and Manaus including over 200,000 children aged 7-14 years aimed to evaluate the efficacy of BCG revaccination in children who had received neonatal BCG vaccination. With the extended follow-up (9 years) and the additional cases accrued we now have enough power to report vaccine efficacy separately for the two cities (with different distances from Equator and presumably different prevalence of non-tuberculosis mycobacteria), and by age at vaccination and clinical form. The overall vaccine efficacy was 12% (-2 to 24%) as compared to 9% (-16 to 29%) for the 5-year follow up. Vaccine efficacy was higher in Salvador (19%, 3 to 33%) than in Manaus (1%, -27 to 27%) with the highest vaccine efficacy in children from Salvador aged <11 years at revaccination (33%, 3 to 54%). The findings are in line with the hypothesis that BCG vaccination offers higher efficacy in low NTMb prevalence, and show that revaccination with BCG can offer weak protection in selected subgroups.

Effectiveness and cost-effectiveness of first BCG vaccination against tuberculosis in school-age children without previous tuberculin test (BCG-REVAC trial): a cluster-randomised trial

BACKGROUNDnNeonatal BCG vaccination is part of routine vaccination schedules in many developing countries; vaccination at school age has not been assessed in trials in low-income and middle-income countries. Catch-up BCG vaccination of school-age children who missed neonatal BCG vaccination could be indicated if it confers protection and is cost-effective. We did a cluster-randomised trial (BCG REVAC) to estimate the effectiveness (efficacy given in routine settings) of school-age vaccination.nnnMETHODSnWe assessed the effectiveness of BCG vaccination in school-age children (aged 7-14 years) with unknown tuberculin status who did not receive neonatal BCG vaccination (subpopulation of the BCG REVAC cluster-randomised trial), between July, 1997, and June, 2006, in Salvador, Brazil, and between January, 1999, and December, 2007, in Manaus, Brazil. 763 schools were randomly assigned into BCG vaccination group or a not-vaccinated control group. Neither allocation nor intervention was concealed. Incidence of tuberculosis was the primary outcome. Cases were identified via the Brazilian Tuberculosis Control Programme. Study staff were masked to vaccination status when identified cases were linked to the study population. We estimated cost-effectiveness in Salvador by comparison of the cost for vaccination to prevent one case of tuberculosis (censored at 9 years) with the average cost of treating one case of tuberculosis. Analysis of all included children was by intention to treat. For calculation of the incidence rate we used generalised estimating equations and correlated observations over time.nnnFINDINGSnWe randomly assigned 20,622 children from 385 schools to the BCG vaccination group and 18,507 children from 365 schools to the control group. The crude incidence of tuberculosis was 54·9 (95% CI 45·3-66·7) per 100,000 person-years in the BCG vaccination group and 72·7 (62·8-86·8) per 100,000 person-years in the control group. The overall vaccine effectiveness of a first BCG vaccination at school age was 25% (3-43%). In Salvador, where vaccine effectiveness was 34% (8-53%), vaccination of 381 children would prevent one case of tuberculosis and was cheaper than treatment. The frequency of adverse events was very low with only one axillary lymphadenitis and one ulcer greater than 1 cm in 11,980 BCG vaccinations.nnnINTERPRETATIONnVaccination of school-age children without previous tuberculin testing can reduce the incidence of tuberculosis and could reduce the costs of tuberculosis control. Restriction of BCG vaccination to the first year of life is not in the best interests of the public nor of programmes for tuberculosis control.nnnFUNDINGnUK Department for International Development, National Health Foundation.

Is routine dengue vector surveillance in central Brazil able to accurately monitor the Aedes aegypti population? Results from a pupal productivity survey.

Objectiveu2002 To assess how well the Aedes aegypti infestation rapid survey, Levantamento Rapido de Indice para Aedes aegypti (LIRAa), is able to accurately estimate dengue vector densities and target the most important breeding sites in Goiania, Brazil.

Causes of variation in BCG vaccine efficacy: examining evidence from the BCG REVAC cluster randomized trial to explore the masking and the blocking hypotheses.

BCG protection varies and in some places (nearest the equator) is low or absent. Understanding this variation can inform the efforts to develop new vaccines against tuberculosis. Two main hypotheses are used to explain this variation: under masking, new vaccines are unlikely to increase protection; under blocking new vaccines have a greater potential to be effective when BCG is not. We conducted a cluster randomized trial to explored the masking and blocking hypotheses by studying BCG vaccine efficacy of neonatal vaccination and when administered for the first or a second (revaccination) time at school age in two sites (Manaus close and Salvador further south from the equator). Seven hundred and sixty three state schools were matched on socio economic characteristics of the neighborhood and 239,934 children were randomized to vaccine (BCG vaccination at school age) or control group. Protection by first BCG vaccination at school age was high in Salvador (34%, 95% CI 7-53%, p=0.017) but low in Manaus (8%, 95% CI t0 39-40%, p=0.686). For revaccination at school age, protection was modest in Salvador (19%, 95% CI 3-33%, p=0.022) and absent in Manaus (1%, 95% CI to 27-23%, p=0.932). Vaccine efficacy for neonatal vaccination was similar in Salvador (40%, 95% CI 22-54%, p<0.001) and Manaus (36%, 95% CI 11-53%, p=0.008). Variation in BCG efficacy was marked when vaccine was given at school age but absent at birth, which points towards blocking as the dominant mechanism. New tuberculosis vaccines that overcome or by pass this blocking effect could confer protection in situations where BCG is not protective.

Prevalence and Risk Factors of Hookworm-Related Cutaneous Larva Migrans (HrCLM) in a Resource-Poor Community in Manaus, Brazil

Background Hookworm-related cutaneous larva migrans (HrCLM) is a neglected tropical skin disease associated with significant clinical pathology. Little knowledge exists about prevalence and risk factors of HrCLM in endemic regions. Methodology/ Principal Findings To understand the epidemiology of HrCLM in Amazonia, we conducted a cross-sectional study in a resource-poor township in Manaus, Brazil. HrCLM was diagnosed in 8.2% (95% CI, 6.3–10.1%) of the study population (N = 806) with a peak prevalence of 18.2% (95% CI, 9.3–27.1%) in children aged 10–14. Most of the tracks (62.4%) were located on the feet, and 10.6% were superinfected. HrCLM was associated independently with age under 15, male sex, presence of animal faeces on the compound, walking barefoot on sandy ground and poverty. Conclusions/ Significance HrCLM is common in resource-poor communities in Amazonia and is related to poverty. To reduce the disease burden caused by HrCLM, living conditions have to be improved.

Prevalence of pediculosis capitis in children from a rural school in Yucatan, Mexico

We conducted an analytical cross-sectional survey to estimate the prevalence of and factors associated with active head lice infestation. In total 140 children, aged 6 to 16-years, from a public school in rural Yucatan, Mexico, were examined by wet-combing. A structured questionnaire was used to collect information on individuals and the conditions in the surrounding environment. Head lice infestation was found in 19 out of the 140 children tested (13.6%) and this was associated with both lower income (OR 9.9, 95% CI 2.15-45.79, p = 0.003) and a higher frequency of hair washing (OR 8, 95% CI 1.58-50, p = 0.012). Intersectoral control programs that take into account the socioeconomic differences of children should be implemented.

BCG vaccination in England since 2005: a survey of policy and practice

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.

Quantification of radiation retinopathy after beam proton irradiation in centrally located choroidal melanoma

PurposeTo localize and quantify ischemic changes induced by proton beam irradiation of central choroidal melanoma and to identify baseline predictors correlated with the extent of ischemic changes.MethodsRetrospective chart review of patients with central choroidal melanoma treated by proton beam irradiation and conducted widefield fluorescein angiography (≥u200920xa0months after radiation therapy). Quantification and location of ischemic areas and correlation to baseline predictors. Multiple linear regression model was performed for analyses.ResultsTwenty-five eyes from 25 patients were included in final analysis. Mean largest basal tumor area was 56.6u2009±u200940.0xa0mm2 and mean maximal tumor prominence 2.5u2009±u20091.4xa0mm. Mean total radiated area was 339.1u2009±u200968.3xa0mm2. All patients showed ischemic changes. Mean ischemic area was 387.6u2009±u2009123.3xa0mm2 and mean ischemic index (ischemic area/total visible area) was 0.53u2009±u20090.23. Twenty-two patients (88%) presented ischemic changes outside of the irradiation field, which comprised of 23% of total ischemic area. Mean angular distance between lateral border of irradiation field and ischemic area outside of the radiated area was 44.8u2009±u200936.5°. Multivariable analysis revealed a positive correlation of total ischemic area with total radiated area (pu2009=u20090.02) and initial sonographic tumor prominence (pu2009=u20090.02).ConclusionsIschemic changes induced by proton beam irradiation of central choroidal melanoma were localized and quantified. Ischemic changes exceed the tumor area distinctly and are found also outside of the irradiation field in the majority of patients. Size of irradiation area and tumor prominence are positively correlated with extent of ischemic area.

Neovascular glaucoma after proton beam therapy of choroidal melanoma: incidence and risk factors

PurposeTo analyze the risk factors for the development of neovascular glaucoma (NVG) of patients with choroidal melanoma after proton beam therapy (PBT).MethodClinical case series, retrospective study. We evaluated 629 consecutive patients receiving proton beam therapy for the treatment of a choroidal melanoma at the oncology service at Charité, Berlin and Helmholtz-Zentrum, Berlin between 05/1998 and 11/2008 regarding the development and risk factors of NVG. Patients with tumor resection, salvage proton beam therapy for recurrent disease and known glaucoma of other origin were excluded from the cohort.ResultsOf the 629 patients matching the inclusion criteria, 20.8% developed neovascularization of the iris after a mean time of 2.0xa0years (range 0.45 to 8.4xa0years) after PBT. Forty-seven percent of the patients with a neovascularization of the iris developed NVG after a mean time of 2.0xa0years after PBT, ranging from 5xa0months to 11.6xa0years. Univariate analysis revealed tumor height [pxa0<xa00.001, hazard ratio (HR): 2.71, 95% confidence interval (CI): 1.36–5.35 for tumors >6xa0mm ≤9xa0mm and 11.32 (4.03–31.73) for tumors >9xa0mm], distance of the tumor to the optic disc (pxa0<xa00.001, HR: 0.43, 95% CI: 0.24–0.77 for >0xa0mm ≤3xa0mm and HR: 0.13, 95% CI: 0.04–0.37 for >3xa0mm), dose to the ciliary body (pxa0<xa00.001, HR: 9.21, 95% CI: 5.08–16.71 (21–40 cobalt gray equivalents (CGE), HR 27.23, 95% CI: 6.33–116.97 (41–60 CGE)), dose to the optic disc (pxa0<xa00.001, HR: 3.53, 95% CI: 1.11–11.27 (21-40CGE), HR: 5.37, 95% CI: 2.72–10.63 (41-60CGE)), the irradiated length of the optic nerve (pxa0<xa00.001, HR: 4.48, 95% CI: 2.47–8.13) and diabetes mellitus (pxa0<xa00.05, HR: 2.53, 95% CI: 1.4–4.5) were found to be risk factors for the development of NVG. Multivariate regression analysis identified the dose to the ciliary body [pxa0<xa00.001, HR: 4.39, 95% CI: 2.28–8.44 (21–40 CGE), HR: 11.04, 95% CI: 1.97–61.69 (41–60 CGE)], the irradiated length of the optic nerve (pxa0<xa00.001, HR: 3.88, 95% CI: 2.11–7.16), the existence of diabetes mellitus (pxa0<xa00.01, HR: 1.28, 95% CI: 1.24–4.21) and tumor height [pxa0<xa00.05, HR: 2.28, 95% CI: 1.17–4.83 (>6xa0mm ≤9xa0mm), HR: 3.74, 95% CI: 1.05–13.23, (>9xa0mm)] to be independent risk factors for the development of NVG.ConclusionsIn the present analysis we found tumor height, dose to the ciliary body, irradiated length of the optic nerve and diabetes mellitus to be risk factors for the development of NVG. Whenever possible, critical structures of the anterior and posterior segment should be spared by beam shaping or changing of the beam entry angle.

Genetic variation and the risk of asthma: does it drive the differences in asthma prevalence among ethnic groups in North America?

[ Asthma is a complex disease and possiblymore than one disease. In North America, asthma prevalence differs among the white population (7.8%; 95% confidence interval [CI], 7.5%-8.1%), the black population (9.5%; 95% CI, 9.0%-10.1%), and the Latino population (14.2%; 95% CI, 12.5%-16.2%). The underlying factors driving the differences in prevalence are yet to be determined. Population attributable fractions (PAFs) or risks are used in epidemiology to estimate the proportion of risk in a population that can be attributed to a single risk factor or to a group of risk factors that are considered simultaneously. In the latter case, they are often called summary attributable risks. PAFs combine how strongly a risk factor is associated with a disease with the distribution of the risk factor within a population. The prevalence of a disease in a population depends on how common a risk factor is, as well as the susceptibility of a population to the risk factor. Hence, by comparing PAFs for the same risk factors in different populations, we can estimate howmuch a single risk factor or many risk factors contribute to the variation in the disease prevalence among populations. It has been estimated that 35% to 80% of the current variation in the risk of asthma is attributable to genetic variation. In North America, asthma prevalence has increased during the last decades and differs considerably across North American states and poverty levels. In fact, when asthma prevalence is examined within poverty levels, the difference between white and black North Americans disappears and the prevalence in Latinos, although still higher than in white or black North Americans, decreases with decreasing poverty. Clearly, the variation is not explained by genetics alone. Torgerson et al presented data from a genomewide association study in ethnically diverse North American populations. What is striking about the results is the similarity in the risk of asthma associated with certain single-nucleotide polymorphisms (SNPs) (almost all 95% CIs of odds ratios among the 3 groups overlap) and the moderate variation in risk allele frequencies among the different ethnic groups (Fig 1). We calculated the PAFs for each SNP and ethnicity as (OR 1/OR) allele frequencies in cases (Fig 1) and derived their CIs using a substitution method described by Greenland. We found that the number of asthma cases attributable to each SNP is different for the 3 ethnic groups. As such, when each SNP is considered separately, SNPs could explain different levels of asthma prevalence among different ethnicities. In each population, however, most CIs overlap, and few SNPs explain more than 20% of all asthma cases. Also, SNPs with high PAFs are almost equally frequent in all 3 populations. This finding suggests that it is unlikely