Predictive performance of interferon-gamma release assays and the tuberculin skin test for incident tuberculosis: an individual participant data meta-analysis.

Background: Evidence on the comparative performance of purified protein derivative tuberculin skin tests (TST) and interferon-gamma release assays (IGRA) for predicting incident active tuberculosis (TB) remains conflicting. We conducted an individual participant data meta-analysis to directly compare the predictive performance for incident TB disease between TST and IGRA to inform policy. Methods: We searched Medline and Embase from 1 January 2002 to 4 September 2020, and studies that were included in previous systematic reviews. We included prospective longitudinal studies in which participants received both TST and IGRA and estimated performance as hazard ratios (HR) for the development of all diagnoses of TB in participants with dichotomised positive test results compared to negative results, using different thresholds of positivity for TST. Secondary analyses included an evaluation of the impact of background TB incidence. We also estimated the sensitivity and specificity for predicting TB. We explored heterogeneity through pre-defined sub-group analyses (e.g. country-level TB incidence). Publication bias was assessed using funnel plots and Egger's test. This review is registered with PROSPERO, CRD42020205667. Findings: We obtained data from 13 studies out of 40 that were considered eligible (N = 32,034 participants: 36% from countries with TB incidence rate ≥100 per 100,000 population). All reported data on TST and QuantiFERON Gold in-Tube (QFT-GIT). The point estimate for the TST was highest with higher cut-offs for positivity and particularly when stratified by bacillus Calmette-Guérin vaccine (BCG) status (15 mm if BCG vaccinated and 5 mm if not [TST5/15 mm]) at 2.88 (95% CI 1.69-4.90). The pooled HR for QFT-GIT was higher than for TST at 4.15 (95% CI 1.97-8.75). The difference was large in countries with TB incidence rate <100 per 100,000 population (HR 10.38, 95% CI 4.17-25.87 for QFT-GIT VS. HR 5.36, 95% CI 3.82-7.51 for TST5/15 mm) but much of this difference was driven by a single study (HR 5.13, 95% CI 3.58-7.35 for TST5/15 mm VS. 7.18, 95% CI 4.48-11.51 for QFT-GIT, when excluding the study, in which all 19 TB cases had positive QFT-GIT results). The comparative performance was similar in the higher burden countries (HR 1.61, 95% CI 1.23-2.10 for QFT-GIT VS. HR 1.72, 95% CI 0.98-3.01 for TST5/15 mm). The predictive performance of both tests was higher in countries with TB incidence rate <100 per 100,000 population. In the lower TB incidence countries, the specificity of TST (76% for TST5/15 mm) and QFT-GIT (74%) for predicting active TB approached the minimum World Health Organization target (≥75%), but the sensitivity was below the target of ≥75% (63% for TST5/15 mm and 65% for QFT-GIT). The absolute differences in positive and negative predictive values between TST15 mm and QFT-GIT were small (positive predictive values 2.74% VS. 2.46%; negative predictive values 99.42% VS. 99.52% in low-incidence countries). Egger's test did not show evidence of publication bias (0.74 for TST15 mm and p = 0.68 for QFT-GIT). Interpretation: IGRA appears to have higher predictive performance than the TST in low TB incidence countries, but the difference was driven by a single study. Any advantage in clinical performance may be small, given the numerically similar positive and negative predictive values. Both IGRA and TST had lower performance in countries with high TB incidence. Test choice should be contextual and made considering operational and likely clinical impact of test results. Funding: YH, IA, and MXR were supported by the National Institute for Health and Care Research (NIHR), United Kingdom (RP-PG-0217-20009). MQ was supported by the Medical Research Council [MC_UU_00004/07].

Infant BCG vaccination and risk of pulmonary and extrapulmonary tuberculosis throughout the life course: a systematic review and individual participant data meta-analysis.

BACKGROUND: BCG vaccines are given to more than 100 million children every year, but there is considerable debate regarding the effectiveness of BCG vaccination in preventing tuberculosis and death, particularly among older children and adults. We therefore aimed to investigate the age-specific impact of infant BCG vaccination on tuberculosis (pulmonary and extrapulmonary) development and mortality. METHODS: In this systematic review and individual participant data meta-analysis, we searched MEDLINE, Web of Science, BIOSIS, and Embase without language restrictions for case-contact cohort studies of tuberculosis contacts published between Jan 1, 1998, and April 7, 2018. Search terms included "mycobacterium tuberculosis", "TB", "tuberculosis", and "contact". We excluded cohort studies that did not provide information on BCG vaccination or were done in countries that did not recommend BCG vaccination at birth. Individual-level participant data for a prespecified list of variables, including the characteristics of the exposed participant (contact), the index case, and the environment, were requested from authors of all eligible studies. Our primary outcome was a composite of prevalent (diagnosed at or within 90 days of baseline) and incident (diagnosed more than 90 days after baseline) tuberculosis in contacts exposed to tuberculosis. Secondary outcomes were pulmonary tuberculosis, extrapulmonary tuberculosis, and mortality. We derived adjusted odds ratios (aORs) using mixed-effects, binary, multivariable logistic regression analyses with study-level random effects, adjusting for the variable of interest, baseline age, sex, previous tuberculosis, and whether data were collected prospectively or retrospectively. We stratified our results by contact age and Mycobacterium tuberculosis infection status. This study is registered with PROSPERO, CRD42020180512. FINDINGS: We identified 14 927 original records from our database searches. We included participant-level data from 26 cohort studies done in 17 countries in our meta-analysis. Among 68 552 participants, 1782 (2·6%) developed tuberculosis (1309 [2·6%] of 49 686 BCG-vaccinated participants vs 473 [2·5%] of 18 866 unvaccinated participants). The overall effectiveness of BCG vaccination against all tuberculosis was 18% (aOR 0·82, 95% CI 0·74-0·91). When stratified by age, BCG vaccination only significantly protected against all tuberculosis in children younger than 5 years (aOR 0·63, 95% CI 0·49-0·81). Among contacts with a positive tuberculin skin test or IFNγ release assay, BCG vaccination significantly protected against tuberculosis among all participants (aOR 0·81, 95% CI 0·69-0·96), participants younger than 5 years (0·68, 0·47-0·97), and participants aged 5-9 years (0·62, 0·38-0·99). There was no protective effect among those with negative tests, unless they were younger than 5 years (0·54, 0·32-0·90). 14 cohorts reported on whether tuberculosis was pulmonary or extrapulmonary (n=57 421). BCG vaccination significantly protected against pulmonary tuberculosis among all participants (916 [2·2%] in 41 119 vaccinated participants vs 334 [2·1%] in 16 161 unvaccinated participants; aOR 0·81, 0·70-0·94) but not against extrapulmonary tuberculosis (106 [0·3%] in 40 318 vaccinated participants vs 38 [0·2%] in 15 865 unvaccinated participants; 0·96, 0·65-1·41). In the four studies with mortality data, BCG vaccination was significantly protective against death (0·25, 0·13-0·49). INTERPRETATION: Our results suggest that BCG vaccination at birth is effective at preventing tuberculosis in young children but is ineffective in adolescents and adults. Immunoprotection therefore needs to be boosted in older populations. FUNDING: National Institutes of Health.

Mycobacterium tuberculosis progresses through two phases of latent infection in humans.

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 < 0.001, assuming an 18 h generation time equal to log phase M. tuberculosis, with latency period modeled as a continuous variable). Alternatively, assuming a fixed mutation rate, the generation time increases over the latency duration. Mutations indicative of oxidative stress do not increase with increasing latency duration suggesting a lack of host or bacterial derived mutational stress. These results suggest that M. tuberculosis enters a quiescent state during latency, decreasing the risk for mutational drug resistance and increasing generation time, but potentially increasing bacterial tolerance to drugs that target actively growing bacteria.

Using Cure Models to Estimate the Serial Interval of Tuberculosis With Limited Follow-up.

Serial interval (SI), defined as the time between symptom onset in an infector and infectee pair, is commonly used to understand infectious diseases transmission. Slow progression to active disease, as well as the small percentage of individuals who will eventually develop active disease, complicate the estimation of the SI for tuberculosis (TB). In this paper, we showed via simulation studies that when there is credible information on the percentage of those who will develop TB disease following infection, a cure model, first introduced by Boag in 1949, should be used to estimate the SI for TB. This model includes a parameter in the likelihood function to account for the study population being composed of those who will have the event of interest and those who will never have the event. We estimated the SI for TB to be approximately 0.5 years for the United States and Canada (January 2002 to December 2006) and approximately 2.0 years for Brazil (March 2008 to June 2012), which might imply a higher occurrence of reinfection TB in a developing country like Brazil.

Cross-validation of existing signatures and derivation of a novel 29-gene transcriptomic signature predictive of progression to TB in a Brazilian cohort of household contacts of pulmonary TB.

The goal of this study was to identify individuals at risk of progression and reactivation among household contacts (HHC) of pulmonary TB cases in Vitoria, Brazil. We first evaluated the predictive performance of six published signatures on the transcriptional dataset obtained from peripheral blood mononuclear cell samples from HHC that either progressed to TB disease or not (non-progressors) during a five-year follow-up. The area under the curve (AUC) values for the six signatures ranged from 0.670 to 0.461, and the PPVs did not reach the WHO published target product profiles (TPPs). We therefore used as training cohort the earliest time-point samples from the African cohort of adolescents (GSE79362) and applied an ensemble feature selection pipeline to derive a novel 29-gene signature (PREDICT29). PREDICT29 was tested on 16 progressors and 21 non-progressors. PREDICT29 performed better in segregating progressors from non-progressors in the Brazil cohort with the area under the curve (AUC) value of 0.911 and PPV of 20%. This proof of concept study demonstrates that PREDICT29 can predict risk of progression/reactivation to clinical TB disease in recently exposed individuals at least 5 years prior to disease development. Upon validation in larger and geographically diverse cohorts, PREDICT29 can be used to risk-stratify recently infected for targeted therapy.

Partitioning the risk of tuberculosis transmission in household contact studies.

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.

Host Determinants of Infectiousness in Smear-Positive Patients With Pulmonary Tuberculosis.

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.

Further evidence of Mycobacterium tuberculosis in the sputum of culture-negative pulmonary tuberculosis suspects using an ultrasensitive molecular assay.

BACKGROUND: Rapid diagnosis of pulmonary tuberculosis (TB) is critical to TB control. However, many patients with paucibacillary TB disease remain undiagnosed. Current TB elimination goals require new tools to diagnose early disease. We evaluated performance of the Totally Optimized PCR (TOP) TB assay, a novel ultrasensitive molecular test. METHODS: We assessed analytical specificity against nontuberculous mycobacteria (NTM), and estimated the diagnostic accuracy of TOP in a pilot study in Brazil (n = 46) and a cross-sectional study in Boston (n = 60). We compared TOP results to culture and a composite reference standard (CRS). RESULTS: TOP exhibited no cross-reactivity against NTM. We tested 132 respiratory specimens from 106 patients with suspected pulmonary TB. The pilot demonstrated feasibility and 100% (95% CI 85-100) sensitivity in predominantly smear-positive specimens; TOP's specificity against solid media culture was low (58%, 37-77) but improved against a CRS (93%, 68-100). Similarly, when using the CRS in the Boston study, TOP (88%, 1-99) had greater sensitivity than solid or liquid media culture (25%, 3-65) and similar specificity (both 100%, 93-100). CONCLUSIONS: The TOP assay enables detection of M. tuberculosis in culture-negative paucibacillary disease. While the use of TOP for the diagnosis of paucibacillary disease will require further clinical validation, its high sensitivity indicate a more immediate utility as a rule out TB test.

Transmission phenotype of Mycobacterium tuberculosis strains is mechanistically linked to induction of distinct pulmonary pathology.

In a study of household contacts (HHC), households were categorized into High (HT) and Low (LT) transmission groups based on the proportion of HHC with a positive tuberculin skin test. The Mycobacterium tuberculosis (Mtb) strains from HT and LT index cases of the households were designated Mtb-HT and Mtb-LT, respectively. We found that C3HeB/FeJ mice infected with Mtb-LT strains exhibited significantly higher bacterial burden compared to Mtb-HT strains and also developed diffused inflammatory lung pathology. In stark contrast, a significant number of mice infected with Mtb-HT strains developed caseating granulomas, a lesion type with high potential to cavitate. None of the Mtb-HT infected animals developed diffused inflammatory lung pathology. A link was observed between increased in vitro replication of Mtb-LT strains and their ability to induce significantly high lipid droplet formation in macrophages. These results support that distinct early interactions of Mtb-HT and Mtb-LT strains with macrophages and subsequent differential trajectories in pathological disease may be the mechanism underlying their transmission potential.

Cough-aerosol cultures of Mycobacterium tuberculosis in the prediction of outcomes after exposure. A household contact study in Brazil.

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 (<10 CFU) and 33% high aerosols (≥10 CFU). Of their 230 contacts, the proportion with a TST ≥10 mm at 8 weeks was 59%, 65% and 75%, respectively (p = 0.34). Contacts of high aerosol cases had greater IGRA readouts (median 4.6 IU/mL, IQR 0.02-10) when compared to those with low (0.8, 0.2-10) or no aerosol (0.1, 0-3.7; p = 0.08). IGRA readouts in TST converters of high aerosol cases (median 20 IU/mL, IQR 10-24) were larger than those from aerosol-negative (0.13, 0.04-3; p = o.o2). 8/9 (89%) culture+ secondary TB cases occurred in contacts of aerosol+ cases. CONCLUSION: Aerosol CFU predicts quantitatively IGRA readouts among household contacts of smear positive TB cases. Our results strengthen the argument of using cough aerosols to guide targeted preventive treatment strategies, a necessary component of current TB elimination projections.

Author Correction: Genome-wide analysis of multi- and extensively drug-resistant Mycobacterium tuberculosis.

In the version of this article initially published, the URL listed for TubercuList was incorrect. The correct URL is https://mycobrowser.epfl.ch/. The error has been corrected in the HTML and PDF versions of the article.

Comparison of different treatments for isoniazid-resistant tuberculosis: an individual patient data meta-analysis.

BACKGROUND: Isoniazid-resistant, rifampicin-susceptible (INH-R) tuberculosis is the most common form of drug resistance, and is associated with failure, relapse, and acquired rifampicin resistance if treated with first-line anti-tuberculosis drugs. The aim of the study was to compare success, mortality, and acquired rifampicin resistance in patients with INH-R pulmonary tuberculosis given different durations of rifampicin, ethambutol, and pyrazinamide (REZ); a fluoroquinolone plus 6 months or more of REZ; and streptomycin plus a core regimen of REZ. METHODS: Studies with regimens and outcomes known for individual patients with INH-R tuberculosis were eligible, irrespective of the number of patients if randomised trials, or with at least 20 participants if a cohort study. Studies were identified from two relevant systematic reviews, an updated search of one of the systematic reviews (for papers published between April 1, 2015, and Feb 10, 2016), and personal communications. Individual patient data were obtained from authors of eligible studies. The individual patient data meta-analysis was performed with propensity score matched logistic regression to estimate adjusted odds ratios (aOR) and risk differences of treatment success (cure or treatment completion), death during treatment, and acquired rifampicin resistance. Outcomes were measured across different treatment regimens to assess the effects of: different durations of REZ (≤6 months vs >6 months); addition of a fluoroquinolone to REZ (fluoroquinolone plus 6 months or more of REZ vs 6 months or more of REZ); and addition of streptomycin to REZ (streptomycin plus 6 months of rifampicin and ethambutol and 1-3 months of pyrazinamide vs 6 months or more of REZ). The overall quality of the evidence was assessed using GRADE methodology. FINDINGS: Individual patient data were requested for 57 cohort studies and 17 randomised trials including 8089 patients with INH-R tuberculosis. We received 33 datasets with 6424 patients, of which 3923 patients in 23 studies received regimens related to the study objectives. Compared with a daily regimen of 6 months of (H)REZ (REZ with or without isoniazid), extending the duration to 8-9 months had similar outcomes; as such, 6 months or more of (H)REZ was used for subsequent comparisons. Addition of a fluoroquinolone to 6 months or more of (H)REZ was associated with significantly greater treatment success (aOR 2·8, 95% CI 1·1-7·3), but no significant effect on mortality (aOR 0·7, 0·4-1·1) or acquired rifampicin resistance (aOR 0·1, 0·0-1·2). Compared with 6 months or more of (H)REZ, the standardised retreatment regimen (2 months of streptomycin, 3 months of pyrazinamide, and 8 months of isoniazid, rifampicin, and ethambutol) was associated with significantly worse treatment success (aOR 0·4, 0·2-0·7). The quality of the evidence was very low for all outcomes and treatment regimens assessed, owing to the observational nature of most of the data, the diverse settings, and the imprecision of estimates. INTERPRETATION: In patients with INH-R tuberculosis, compared with treatment with at least 6 months of daily REZ, addition of a fluoroquinolone was associated with better treatment success, whereas addition of streptomycin was associated with less treatment success; however, the quality of the evidence was very low. These results support the conduct of randomised trials to identify the optimum regimen for this important and common form of drug-resistant tuberculosis. FUNDING: World Health Organization and Canadian Institutes of Health Research.

Genome-wide analysis of multi- and extensively drug-resistant Mycobacterium tuberculosis.

To characterize the genetic determinants of resistance to antituberculosis drugs, we performed a genome-wide association study (GWAS) of 6,465 Mycobacterium tuberculosis clinical isolates from more than 30 countries. A GWAS approach within a mixed-regression framework was followed by a phylogenetics-based test for independent mutations. In addition to mutations in established and recently described resistance-associated genes, novel mutations were discovered for resistance to cycloserine, ethionamide and para-aminosalicylic acid. The capacity to detect mutations associated with resistance to ethionamide, pyrazinamide, capreomycin, cycloserine and para-aminosalicylic acid was enhanced by inclusion of insertions and deletions. Odds ratios for mutations within candidate genes were found to reflect levels of resistance. New epistatic relationships between candidate drug-resistance-associated genes were identified. Findings also suggest the involvement of efflux pumps (drrA and Rv2688c) in the emergence of resistance. This study will inform the design of new diagnostic tests and expedite the investigation of resistance and compensatory epistatic mechanisms.

Intensity of exposure to pulmonary tuberculosis determines risk of tuberculosis infection and disease.

Household contacts of pulmonary tuberculosis (TB) patients are at increased risk of TB infection and disease. However, their risk in relation to the intensity of exposure remains unknown.We studied smear-positive TB cases and their household contacts in Vitória, Brazil. We collected clinical, demographic and radiographic information from TB cases, and obtained tuberculin skin test (TST) and QuantiFERON-TB Gold (QFT) results from household contacts. We measured intensity of exposure using a proximity score and sleep location in relation to the TB index case and defined infection by TST ≥10 mm or QFT ≥0.35 UI·mL-1 We ascertained secondary TB cases by reviewing local and nationwide case registries.We included 160 TB index cases and 894 household contacts. 464 (65%) had TB infection and 23 (2.6%) developed TB disease. Risk of TB infection and disease increased with more intense exposures. In an adjusted analysis, the proximity score was associated with TB disease (OR 1.61, 95% CI 1.25-2.08; p<0.000); however, its diagnostic performance was only moderate.Intensity of exposure increased risk of TB infection and disease among household contacts; however, its diagnostic performance was still suboptimal. A biomarker to target preventive therapy is urgently needed in this at-risk population.

Incident Mycobacterium tuberculosis infection in household contacts of infectious tuberculosis patients in Brazil.

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.

Strains of Mycobacterium tuberculosis transmitting infection in Brazilian households and those associated with community transmission of tuberculosis.

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. IS6110-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.

Extensions to Bayesian generalized linear mixed effects models for household tuberculosis transmission.

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 Wiley & Sons, Ltd.