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Little is known about the physiology of latent Mycobacterium tuberculosis infection. We studied the mutational rates of 24 index tuberculosis (TB) cases and their latently infected household contacts who developed active TB up to 5.25 years later, as an indication of bacterial physiological state and possible generation times during latent TB infection in humans. Here we report that the rate of new mutations in the M. tuberculosis genome decline dramatically after two years of latent infection (two-sided p, Here, Colangeli et al. use a human household contact cohort to measure the rate of mutation and evolution of Mycobacterium tuberculosis strains and find that long term latency is characterized by reduced mutation rates compared to latency in the first year, coinciding with clinical risk of developing active TB.

Molecular epidemiologic studies have shown that the dynamics of tuberculosis transmission varies geographically. We sought to determine which strains of Mycobacterium tuberculosis (MTB) were infecting household contacts (HHC), and which were causing clusters of tuberculosis (TB) disease in Vitoria-ES, Brazil. A total of 741 households contacts (445 TST +) and 139 index cases were characterized according to the proportion of contacts in each household that had a tuberculin skin test positive: low (LT) (≤40% TST+), high (HT) (≥70% TST+) and (40–70% TST+) intermediate (IT) transmission. IS 6110 -RFLP and spoligotyping analysis were performed only 139 MTB isolates from index cases and 841 community isolates. Clustering occurred in 45% of the entire study population. There was no statistically significant association between MTB household transmission category and clustering. Within the household study population, the proportion of clusters in HT and LT groups was similar (31% and 36%, respectively; p = 0.82). Among index cases isolates associated with households demonstrating TST conversion, the frequency of unique pattern genotypes was higher for index cases of the LT compared to HT households (p = 0.03). We concluded that clusters and lineages associated with MTB infection in HT households had no proclivity for increased transmission of TB in the community.

Household contact studies, a mainstay of tuberculosis transmission research, often assume that tuberculosis-infected household contacts of an index case were infected within the household. However, strain genotyping has provided evidence against this assumption. Understanding the household versus community infection dynamic is essential for designing interventions. The misattribution of infection sources can also bias household transmission predictor estimates. We present a household-community transmission model that estimates the probability of community infection, that is, the probability that a household contact of an index case was actually infected from a source outside the home and simultaneously estimates transmission predictors. We show through simulation that our method accurately predicts the probability of community infection in several scenarios and that not accounting for community-acquired infection in household contact studies can bias risk factor estimates. Applying the model to data from Vitoria, Brazil, produced household risk factor estimates similar to two other standard methods for age and sex. However, our model gave different estimates for sleeping proximity to index case and disease severity score. These results show that estimating both the probability of community infection and household transmission predictors is feasible and that standard tuberculosis transmission models likely underestimate the risk for two important transmission predictors. Copyright © 2017 John Wiley & Sons, Ltd.

Household contact studies of tuberculosis (TB) are a common way to study disease transmission dynamics. However these studies lack a mechanism for accounting for community transmission, which is known to be significant, particularly in high burden settings. We illustrate a statistical approach for estimating both the correlates with transmission of TB in a household setting and the probability of community transmission using a modified Bayesian mixed-effects model. This is applied to two household contact studies in Vitória, Brazil from 2008-2013 and Kampala, Uganda from 1995-2004 that enrolled households with an individual that was recently diagnosed with pulmonary TB. We estimate the probability of community transmission to be higher in Uganda (ranging from 0.21 to 0.69, depending on HHC age and HIV status of the index case) than in Brazil (ranging from 0.13 for young children to 0.50 in adults). These estimates are consistent with a higher overall burden of disease in Uganda compared to Brazil. Our method also estimates an increasing risk of community-acquired TB with age of the household contact, consistent with existing literature. This approach is a useful way to integrate the role of the community in understanding TB disease transmission dynamics in household contact studies.

Background Epidemiologic data suggests that only a minority of tuberculosis (TB) patients are infectious. Cough aerosol sampling is a novel quantitative method to measure TB infectiousness. Methods We analyzed data from three studies conducted in Uganda and Brazil over a 13-year period. We included sputum acid fast bacilli (AFB) and culture positive pulmonary TB patients and used a cough aerosol sampling system (CASS) to measure the number of colony-forming units (CFU) of Mycobacterium tuberculosis in cough-generated aerosols as a measure for infectiousness. Aerosol data was categorized as: aerosol negative (CFU = 0) and aerosol positive (CFU > 0). Logistic regression models were built to identify factors associated with aerosol positivity. Results M. tuberculosis was isolated by culture from cough aerosols in 100/233 (43%) TB patients. In an unadjusted analysis, aerosol positivity was associated with fewer days of antituberculous therapy before CASS sampling (p = .0001), higher sputum AFB smear grade (p = .01), shorter days to positivity in liquid culture media (p = .02), and larger sputum volume (p = .03). In an adjusted analysis, only fewer days of TB treatment (OR 1.47 per 1 day of therapy, 95% CI 1.16-1.89; p = .001) was associated with aerosol positivity. Conclusion Cough generated aerosols containing viable M. tuberculosis, the infectious moiety in TB, are detected in a minority of TB patients and rapidly become non-culturable after initiation of antituberculous treatment. Mechanistic studies are needed to further elucidate these findings., In this aggregated analysis of three cohorts of sputum smear and culture positive pulmonary TB patients, we found that only a minority of individuals have viable aerosolized M. tuberculosis, the infectious moeity in TB. Infectiousness is markedly reduced shortly after antituberculous therapy is initiated, as indicated by a sharp decrease in M. tuberculosis growth in cultures of cough-generated aerosols.

The Epistem Genedrive assay rapidly detects the Mycobacterium tuberculosis complex from sputum and is currently available for clinical use. However, the analytical and clinical performance of this test has not been fully evaluated. The analytical limit of detection (LOD) of the Genedrive PCR amplification was tested with genomic DNA; the performance of the complete (sample processing plus amplification) system was tested by spiking M. tuberculosis mc 2 6030 cells into distilled water and M. tuberculosis -negative sputum. Specificity was tested using common respiratory pathogens and nontuberculosis mycobacteria. A clinical evaluation enrolled adults with suspected pulmonary tuberculosis, obtained three sputum samples from each participant, and compared the accuracy of the Genedrive to that of the Xpert MTB/RIF assay using M. tuberculosis cultures as the reference standard. The Genedrive assay had an LOD of 1 pg/μl (100 genomic DNA copies/reaction). The LODs of the system were 2.5 × 10 4 CFU/ml and 2.5 × 10 5 CFU/ml for cells spiked into water and sputum, respectively. False-positive rpoB probe signals were observed in 3/32 (9.4%) of the negative controls and also in few samples containing Mycobacterium abscessus , Mycobacterium gordonae , or Mycobacterium thermoresistibile . In the clinical study, among 336 analyzed participants, the overall sensitivities for the tuberculosis case detection of Genedrive, Xpert, and smear microscopy were 45.4% (95% confidence interval [CI], 35.2% to 55.8%), 91.8% (95% CI, 84.4% to 96.4%), and 77.3% (95% CI, 67.7% to 85.2%), respectively. The sensitivities of Genedrive and Xpert for the detection of smear-microscopy-negative tuberculosis were 0% (95% CI, 0% to 15.4%) and 68.2% (95% CI, 45.1% to 86.1%), respectively. The Genedrive assay did not meet performance standards recommended by the World Health Organization for a smear microscopy replacement tuberculosis test. Epistem is working on modifications to improve the assay.

Background Mycobacterium tuberculosis cultures of cough-generated aerosols from patients with pulmonary tuberculosis (TB) are a quantitative method to measure infectiousness and to predict secondary outcomes in exposed contacts. However, their reproducibility has not been established. Objective To evaluate the predictive value of colony-forming units (CFU) of M.Tuberculosis in cough aerosols on secondary infection and disease in household contacts in Brazil. Methods Adult sputum smear+ and culture+ pulmonary TB cases underwent a standard evaluation and were categorized according to aerosol CFU. We evaluated household contacts for infection at baseline and at 8 weeks with TST and IGRA, and secondary disease. Results We enrolled 48 index TB cases; 40% had negative aerosols, 27% low aerosols (

Globally, the prevalence of tuberculosis (TB) disease is higher in males. This study examined the effect of sex and age onMycobacterium tuberculosis(Mtb) infection. Demographic and exposure data were collected on household contacts of sputum smear-positive pulmonary TB patients in Brazil. Contacts with tuberculin skin test induration ⩾10 mm at baseline or 12 weeks were considered Mtb infected. The study enrolled 917 household contacts from 160 households; 508 (55.4%) were female, median age was 21.0 years (range 0.30–87.0) and 609 (66.4%) had Mtb infection. The proportion infected increased with age from 63.3% in girls P= 0.02) and between ages 0–4 and 15–39 years among male contacts (OR 2.7, 95% CI 0.83–8.9 and 1.1, 95% CI 0.99–1.3 per 5-year age increase;P= 0.10, 0.07, respectively). The study suggests that the age at which Mtb infection increases most is different in females compared with males. Studies are needed to explore whether these findings are due to differences in host susceptibility, exposure outside the household or other factors.

BACKGROUND: Household contacts of smear-positive tuberculosis (TB) patients are at increased risk of TB infection, however the risk of TB infection and disease in relation to the intensity of exposure remains unknown. METHODS: In the setting of a household contact study in Vitoria, Brazil, we studied smear positive, culture-proven pulmonary TB cases and their household contacts (HHCs). Tuberculin skin test (TST) and QuantiFERON-TB Gold (QFT) were performed on HHCs. Clinical, demographic and radiographic variables were obtained. Intensity of exposure was measured using the Mandalakas score and the sleep location in relation to the index TB case. TB infection was defined by TST ≥ 1o mm or QFT ≥ 0.35 UI/ml. Secondary TB cases were identified by reviewing local and nationwide databases 21 months after conclusion of enrollment. Generalized estimating equations (GEE) models were constructed to evaluate the association between intensity of exposure and TB infection and disease. RESULTS: 160 TB index cases and 894 HHCs were included. TB infection defined by both TST and QFT was more common with high intensity exposures. TST+/IGRA- discordance was associated with less intense exposures measured by the modified Mandalakas score (p < 0.000). 23 (2.6%) of exposed household contacts developed secondary incident TB. The modified Mandalakas score was associated with increased risk of TB disease (OR 1.65 95% CI 1.25 – 2.08 p < 0.000). Diagnostic performance of the modified Mandalakas score was poor to predict TB infection and moderate for TB disease. CONCLUSION: Intensity of exposure improved TST+/IGRA+ concordance and increased risk of TB disease among HHCs, however their diagnostic performance is still suboptimal. A biomarker to guide preventive therapy is urgently needed in this at-risk population.

Background In household contact investigations of tuberculosis (TB), a second tuberculin skin test (TST) obtained several weeks after a first negative result consistently identifies individuals that undergo TST conversion. It remains unclear whether this delay in M. tuberculosis infection is related to differences in the infectious exposure, TST boosting, partial host resistance, or some other factor. Methods We conducted a household contact study Vitória, Brazil. Between 2008 and 2013, we identified culture-positive pulmonary TB patients and evaluated their household contacts with both a TST and interferon gamma release assay (IGRA), and identified TST converters at 8–12 weeks post study enrollment. Contacts were classified as TST-positive (≥10 mm) at baseline, TST converters, or persistently TST-negative. We compared TST converters to TST-positive and to TST-negative contacts separately, using generalized estimating equations. Results We enrolled 160 index patients and 838 contacts; 523 (62.4%) were TST+, 62 (7.4%) TST converters, and 253 (30.2%) TST−. TST converters were frequently IGRA− at 8–12 weeks. In adjusted analyses, characteristics distinguishing TST converters from TST+ contacts (no contact with another TB patient and residence ownership) were different than those differentiating them from TST− contacts (stronger cough in index patient and contact BCG scar). Conclusions The individual risk and timing of M. tuberculosis infection within households is variable and dependent on index patient, contact and environmental factors within the household, and the surrounding community. Our findings suggest a threshold effect in the risk of infection in humans. Electronic supplementary material The online version of this article (doi:10.1186/s12879-017-2675-3) contains supplementary material, which is available to authorized users.

Household contact studies, a mainstay of tuberculosis transmission research, often assume that tuberculosis-infected household contacts of an index case were infected within the household. However, strain genotyping has provided evidence against this assumption. Understanding the household versus community infection dynamic is essential for designing interventions. The misattribution of infection sources can also bias household transmission predictor estimates. We present a household-community transmission model that estimates the probability of community infection, that is, the probability that a household contact of an index case was actually infected from a source outside the home and simultaneously estimates transmission predictors. We show through simulation that our method accurately predicts the probability of community infection in several scenarios and that not accounting for community-acquired infection in household contact studies can bias risk factor estimates. Applying the model to data from Vitória, Brazil, produced household risk factor estimates similar to two other standard methods for age and sex. However, our model gave different estimates for sleeping proximity to index case and disease severity score. These results show that estimating both the probability of community infection and household transmission predictors is feasible and that standard tuberculosis transmission models likely underestimate the risk for two important transmission predictors. Copyright © 2017 John WileySons, Ltd.

Rationale The degree to which tuberculosis (TB) is transmitted between persons is variable. Identifying the factors that contribute to transmission could provide new opportunities for TB control. Transmission is influenced by host, bacterial and environmental factors. However, distinguishing their individual effects is problematic because measures of disease severity are tightly correlated, and assessing the virulence of Mycobacterium tuberculosis isolates is complicated by epidemiological and clinical confounders. Objectives To overcome these problems, we investigated factors potentially associated with TB transmission within households. Methods We evaluated patients with smear-positive (≥2+), pulmonary TB and classified M. tuberculosis strains into single nucleotide polymorphism genetic cluster groups (SCG). We recorded index case, household contact, and environmental characteristics and tested contacts with tuberculin skin test (TST) and interferon-gamma release assay. Households were classified as high (≥70% of contacts with TST≥10 mm) and low (≤40%) transmission. We used logistic regression to determine independent predictors. Result From March 2008 to June 2012, we screened 293 TB patients to enroll 124 index cases and their 731 contacts. There were 23 low and 73 high transmission households. Index case factors associated with high transmission were severity of cough as measured by a visual analog cough scale (VACS) and the Leicester Cough Questionnaire (LCQ), and cavitation on chest radiograph. SCG 3b strains tended to be more prevalent in low (27.3%) than in high (12.5%) transmission households (p = 0.11). In adjusted models, only VACS (p