Incidence and risk factors of tuberculosis among 420 854 household contacts of patients with tuberculosis in the 100 Million Brazilian Cohort (2004-18): a cohort study.

BACKGROUND: Although household contacts of patients with tuberculosis are known to be particularly vulnerable to tuberculosis, the published evidence focused on this group at high risk within the low-income and middle-income country context remains sparse. Using nationwide data from Brazil, we aimed to estimate the incidence and investigate the socioeconomic and clinical determinants of tuberculosis in a cohort of contacts of tuberculosis patients. METHODS: In this cohort study, we linked individual socioeconomic and demographic data from the 100 Million Brazilian Cohort to mortality data and tuberculosis registries, identified contacts of tuberculosis index patients diagnosed from Jan 1, 2004 to Dec 31, 2018, and followed up the contacts until the contact's subsequent tuberculosis diagnosis, the contact's death, or Dec 31, 2018. We investigated factors associated with active tuberculosis using multilevel Poisson regressions, allowing for municipality-level and household-level random effects. FINDINGS: We studied 420 854 household contacts of 137 131 tuberculosis index patients. During the 15 years of follow-up (median 4·4 years [IQR 1·9-7·6]), we detected 8953 contacts with tuberculosis. The tuberculosis incidence among contacts was 427·8 per 100 000 person-years at risk (95% CI 419·1-436·8), 16-times higher than the incidence in the general population (26·2 [26·1-26·3]) and the risk was prolonged. Tuberculosis incidence was associated with the index patient being preschool aged (<5 years; adjusted risk ratio 4·15 [95% CI 3·26-5·28]) or having pulmonary tuberculosis (2·84 [2·55-3·17]). INTERPRETATION: The high and sustained risk of tuberculosis among contacts reinforces the need to systematically expand and strengthen contact tracing and preventive treatment policies in Brazil in order to achieve national and international targets for tuberculosis elimination. FUNDING: Wellcome Trust and Brazilian Ministry of Health.

Validation of the use of dried blood spots in a chikungunya virus IgG serological assay.

Dried blood spot (DBS) sampling is a simple, fast, and minimally invasive blood collection method that is particularly useful for diagnostic or epidemiological studies in hard-to-reach populations. Nevertheless, the use of DBS in assays that have been optimized with gold-standard samples (serum or plasma) must be optimized to yield reliable results. Here, we describe the validation of DBS in a commercial assay to measure IgG against chikungunya virus (CHIKV IgG ELISA; Euroimmun, Lübeck, Germany). During a health survey of people experiencing homelessness in Salvador, Brazil, between September 2021 and February 2022, a subset (75/523; 14.3%) of the study participants had paired capillary (for DBS preparation) and venous (for serum separation) blood samples collected. A pilot optimization test was initially performed with 17 paired samples to compare the CHIKV IgG ELISA absorbance values between serum and three different dilutions of DBS. Based on the preliminary results, the best DBS dilution was selected for a final evaluation comparing paired serum and DBS samples from 58 participants. The sensitivity and specificity of the CHIKV ELISA of DBS compared to sera were 100% (95% C.I.: 85.8-100%) and 100% (95% C.I.: 93-100%), respectively. In the linear regression analysis, a coefficient of determination (R2) value of 0.98 indicated the excellent performance of DBS in predicting the serum levels of IgG CHIKV antibodies. Our findings suggest that DBS at an optimized dilution is reliable for investigating the prevalence of CHIKV IgG antibodies during population surveys in the commercial assay tested here.

Estimating underreporting of leprosy in Brazil using a Bayesian approach.

BACKGROUND: Leprosy remains concentrated among the poorest communities in low-and middle-income countries and it is one of the primary infectious causes of disability. Although there have been increasing advances in leprosy surveillance worldwide, leprosy underreporting is still common and can hinder decision-making regarding the distribution of financial and health resources and thereby limit the effectiveness of interventions. In this study, we estimated the proportion of unreported cases of leprosy in Brazilian microregions. METHODOLOGY/PRINCIPAL FINDINGS: Using data collected between 2007 to 2015 from each of the 557 Brazilian microregions, we applied a Bayesian hierarchical model that used the presence of grade 2 leprosy-related physical disabilities as a direct indicator of delayed diagnosis and a proxy for the effectiveness of local leprosy surveillance program. We also analyzed some relevant factors that influence spatial variability in the observed mean incidence rate in the Brazilian microregions, highlighting the importance of socioeconomic factors and how they affect the levels of underreporting. We corrected leprosy incidence rates for each Brazilian microregion and estimated that, on average, 33,252 (9.6%) new leprosy cases went unreported in the country between 2007 to 2015, with this proportion varying from 8.4% to 14.1% across the Brazilian States. CONCLUSIONS/SIGNIFICANCE: The magnitude and distribution of leprosy underreporting were adequately explained by a model using Grade 2 disability as a marker for the ability of the system to detect new missing cases. The percentage of missed cases was significant, and efforts are warranted to improve leprosy case detection. Our estimates in Brazilian microregions can be used to guide effective interventions, efficient resource allocation, and target actions to mitigate transmission.

Investigating extradomiciliary transmission of tuberculosis: An exploratory approach using social network patterns of TB cases and controls and the genotyping of Mycobacterium tuberculosis.

Extradomiciliary contacts have been overlooked in the study of TB transmission due to difficulties in identifying actual contacts in large populations. Complex network analysis provides a framework to model the structure of contacts, specially extradomiciliary ones. We conducted a study of incident sputum-positive TB cases and healthy controls occurring in a moderate TB burden city. Cases and controls were interviewed to obtain data regarding the usual locations of residence, work, study, and leisure. Mycobacterium tuberculosis isolated from sputum was genotyped. The collected data were used to build networks based on a framework of putative social interactions indicating possible TB transmission. A user-friendly open source environment (GraphTube) was setup to extract information from the collected data. Networks based on the likelihood of patient-patient, patient-healthy, and healthy-healthy contacts were setup, depending on a constraint of geographical distance of places attended by the volunteers. Using a threshold for the geographical distance of 300 m, the differences between TB cases and controls are revealed. Several clusters formed by social network nodes with high genotypic similarity were characterized. The developed framework provided consistent results and can be used to support the targeted search of potentially infected individuals and to help to understand the TB transmission.

Effect of a conditional cash transfer programme on leprosy treatment adherence and cure in patients from the nationwide 100 Million Brazilian Cohort: a quasi-experimental study.

BACKGROUND: Indirect financial costs and barriers to health-care access might contribute to leprosy treatment non-adherence. We estimated the association of the Brazilian conditional cash transfer programme, the Programa Bolsa Família (PBF), on leprosy treatment adherence and cure in patients in Brazil. METHODS: In this quasi-experimental study, we linked baseline demographic and socioeconomic information for individuals who entered the 100 Million Brazilian Cohort between Jan 1, 2007, and Dec 31, 2014, with the PBF payroll database and the Information System for Notifiable Diseases, which includes nationwide leprosy registries. Individuals were eligible for inclusion if they had a household member older than 15 years and had not received PBF aid or been diagnosed with leprosy before entering the 100 Million Brazilian Cohort; they were excluded if they were partial receivers of PBF benefits, had missing data, or had a monthly per-capita income greater than BRL200 (US$50). Individuals who were PBF beneficiaries before leprosy diagnosis were matched to those who were not beneficiaries through propensity-score matching (1:1) with replacement on the basis of baseline covariates, including sex, age, race or ethnicity, education, work, income, place of residence, and household characteristics. We used logistic regression to assess the average treatment effect on the treated of receipt of PBF benefits on leprosy treatment adherence (six or more multidrug therapy doses for paucibacillary cases or 12 or more doses for multibacillary cases) and cure in individuals of all ages. We stratified our analysis according to operational disease classification (paucibacillary or multibacillary). We also did a subgroup analysis of paediatric leprosy restricted to children aged up to 15 years. FINDINGS: We included 11 456 new leprosy cases, of whom 8750 (76·3%) had received PBF before diagnosis and 2706 (23·6%) had not. Overall, 9508 (83·0%) patients adhered to treatment and 10 077 (88·0%) were cured. After propensity score matching, receiving PBF before diagnosis was associated with adherence to treatment (OR 1·22, 95% CI 1·01-1·48) and cure (1·26, 1·01-1·58). PBF receipt did not significantly improve treatment adherence (1·37, 0·98-1·91) or cure (1·12, 0·75-1·67) in patients with paucibacillary leprosy. For patients with multibacillary disease, PBF beneficiaries had better treatment adherence (1·37, 1·08-1·74) and cure (1·43, 1·09-1·90) than non-beneficiaries. In the propensity score-matched analysis in 2654 children younger than 15 years with leprosy, PBF exposure was not associated with leprosy treatment adherence (1·55, 0·89-2·68) or cure (1·57, 0·83-2·97). INTERPRETATION: Our results suggest that being a beneficiary of the PBF, which facilitates cash transfers and improved access to health care, is associated with greater leprosy multidrug therapy adherence and cure in multibacillary cases. These results are especially relevant for patients with multibacillary disease, who are treated for a longer period and have lower cure rates than those with paucibacillary disease. FUNDING: CONFAP/ESRC/MRC/BBSRC/CNPq/FAPDF-Doenças Negligenciadas, the UK Medical Research Council, the Wellcome Trust, and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-Brazil (CAPES).

Effectiveness of a conditional cash transfer programme on TB cure rate: a retrospective cohort study in Brazil.

BACKGROUND: Despite the efforts of the National Tuberculosis Programme, TB cure rates in Brazil are sub-optimal. The End TB Strategy for post-2015 identifies conditional cash transfer interventions as powerful tools to improve TB control indicators, including TB cure rate. This study aims to inform the new policy by evaluating the role of the Bolsa Familia Programme (BFP), one of the largest conditional cash transfer programmes in the world, on TB cure rates in Brazil. METHODS: We undertook a retrospective cohort study, based on an unprecedented record linkage of socioeconomic and health data, to compare cases of patients newly diagnosed with TB in 2010 receiving BFP cash benefits (n=5788) with those who did not (n=1467) during TB treatment. We used Poisson regression with robust variance to estimate the relative risks for TB cure adjusted for known confounders. RESULTS: The cure rate among patients exposed to BFP during TB treatment was 82.1% (4752/5788), 5.2% higher than among those not exposed. This was confirmed after controlling for TB type, diabetes mellitus, HIV status and other relevant clinical and socioeconomic covariates (RR=1.07, 95% CI 1.04 to 1.11 for cure rates among BFP beneficiaries). This association seemed higher for patients not under directly observed treatment (RR=1.11; 95% CI 1.05 to 1.16). CONCLUSIONS: Although further research is needed, this study suggests that conditional cash transfer programmes can contribute to improve TB cure rate in Brazil.

SNP typing reveals similarity in Mycobacterium tuberculosis genetic diversity between Portugal and Northeast Brazil.

Human tuberculosis is an infectious disease caused by bacteria from the Mycobacterium tuberculosis complex (MTBC). Although spoligotyping and MIRU-VNTR are standard methodologies in MTBC genetic epidemiology, recent studies suggest that Single Nucleotide Polymorphisms (SNP) are advantageous in phylogenetics and strain group/lineages identification. In this work we use a set of 79 SNPs to characterize 1987 MTBC isolates from Portugal and 141 from Northeast Brazil. All Brazilian samples were further characterized using spolygotyping. Phylogenetic analysis against a reference set revealed that about 95% of the isolates in both populations are singly attributed to bacterial lineage 4. Within this lineage, the most frequent strain groups in both Portugal and Brazil are LAM, followed by Haarlem and X. Contrary to these groups, strain group T showed a very different prevalence between Portugal (10%) and Brazil (1.5%). Spoligotype identification shows about 10% of mis-matches compared to the use of SNPs and a little more than 1% of strains unidentifiability. The mis-matches are observed in the most represented groups of our sample set (i.e., LAM and Haarlem) in almost the same proportion. Besides being more accurate in identifying strain groups/lineages, SNP-typing can also provide phylogenetic relationships between strain groups/lineages and, thus, indicate cases showing phylogenetic incongruence. Overall, the use of SNP-typing revealed striking similarities between MTBC populations from Portugal and Brazil.