TB transmission is associated with prolonged stay in a low socio-economic, high burdened TB and HIV community in Cape Town, South Africa

Abstract Background While several studies have assessed the associations between biological factors and tuberculosis (TB) transmission, our understanding of the associations between TB transmission and social and economic factors remains incomplete. We aimed to explore associations between community TB transmission and socio-economic factors within a high TB-HIV burdened setting. Methods We conducted a cross-sectional molecular epidemiology study among adult patients attending a routine TB clinic. Demographic and clinical data were extracted from TB registers and clinical folders; social and economic data were collected using interviewer-administered questionnaires; Mycobacterium tuberculosis isolates were genotyped and classified as clustered/non-clustered using IS6110-based Restriction Fragment Length Polymorphism. Composite “social” and “economic” scores were generated from social and economic data. Data were analyzed using StataCorp version 15.0 software. Stratified, bivariable analyses were performed using chi-squared. Wilcoxon signed rank tests; univariable and multivariable logistic regression models were developed to explore associations in the social, economic, traditional and composite TB risk factors with TB transmission. Results Of the 505 patient Mtb  strains, 348(69%) cases were classified as clustered and 157(31%) were non-clustered. Clustered cases were more likely to have lived longer in the study community, (odds ratio [OR] = 1.05, 95% Confidence interval [C.I]:1.02–1.09, p = 0.006); in the same house (OR = 1.04, C.I: 0.99–1.08, p = 0.06); and had increased household crowding conditions (i.e fewer rooms used for sleeping, OR = 0.45, C.I:0.21–0.95, p = 0.04). Although a higher proportion of clustered cases had a low economic score, no statistically significant association was found between clustering and either the economic score (p = 0.13) or social score (p = 0.26). Conclusions We report a novel association between Mtb transmission and prolonged stay within a high burdened community. Transmission was also associated with fewer rooms for sleeping in a household. Increased social interaction and prolonged residence in a high burdened community are important factors linked to Mtb transmission, possibly due to increased probability of higher effective contact rates. The possible importance of degrees of poverty within low socio-economic setting warrants further study

High Prevalence of inhA Promoter Mutations among Patients with Drug-Resistant Tuberculosis in KwaZulu-Natal, South Africa

Background Drug-resistant tuberculosis (TB) remains extremely difficult to treat because there are often few remaining active medications and limited diagnostic options to detect resistance. Resistance to isoniazid is typically caused by mutations in either katG or the inhA promoter. inhA mutations confer low-level resistance to isoniazid and cross-resistance to ethionamide while katG mutations confer high-level isoniazid resistance and no cross-resistance. Line Probe Assays (LPAs) that detect mutations in katG and inhA are currently performed on all positive TB cultures in KwaZulu-Natal province, South Africa, but the frequency of inhA mutations in drug-resistant TB patients has not been examined. Methods We sought to determine the proportion of patients who could potentially benefit from high-dose isoniazid and who may be resistant to ethionamide. We reviewed 994 LPA (Hain MTBDRplus) results at the TB reference laboratory in KwaZulu-Natal to determine the frequency of mutations in either katG or the inhA promoter. We stratified these results by drug-resistance category (i.e., MDR-TB, pre-XDR-TB, and XDR-TB) as determined by phenotypic drug-susceptibility testing. Results Among MDR- and XDR-TB isolates, the prevalence of inhA mutations without a concurrent katG mutation was 14.8% and 10.3% respectively. The prevalence of inhA mutations with OR without a katG mutation was 30.3% and 82.8%, respectively. Conclusion More than 10% of patients with MDR- and XDR-TB may benefit from high-dose isoniazid. Although ethionamide is empirically included in all MDR- and XDR-TB regimens, nearly a third of MDR-TB patients and a majority of XDR-TB patients likely have resistance to ethionamide. Laboratories performing line probe assays should report specific band patterns so that clinicians may adjust treatment regimens accordingly

TB transmission is associated with prolonged stay in a low socio-economic, high burdened TB and HIV community in Cape Town, South Africa

Background While several studies have assessed the associations between biological factors and tuberculosis (TB) transmission, our understanding of the associations between TB transmission and social and economic factors remains incomplete. We aimed to explore associations between community TB transmission and socio-economic factors within a high TB-HIV burdened setting. Methods We conducted a cross-sectional molecular epidemiology study among adult patients attending a routine TB clinic. Demographic and clinical data were extracted from TB registers and clinical folders; social and economic data were collected using interviewer-administered questionnaires; Mycobacterium tuberculosis isolates were genotyped and classified as clustered/non-clustered using IS6110-based Restriction Fragment Length Polymorphism. Composite “social” and “economic” scores were generated from social and economic data. Data were analyzed using StataCorp version 15.0 software. Stratified, bivariable analyses were performed using chi-squared. Wilcoxon signed rank tests; univariable and multivariable logistic regression models were developed to explore associations in the social, economic, traditional and composite TB risk factors with TB transmission. Results Of the 505 patient Mtb  strains, 348(69%) cases were classified as clustered and 157(31%) were non-clustered. Clustered cases were more likely to have lived longer in the study community, (odds ratio [OR] = 1.05, 95% Confidence interval [C.I]:1.02–1.09, p = 0.006); in the same house (OR = 1.04, C.I: 0.99–1.08, p = 0.06); and had increased household crowding conditions (i.e fewer rooms used for sleeping, OR = 0.45, C.I:0.21–0.95, p = 0.04). Although a higher proportion of clustered cases had a low economic score, no statistically significant association was found between clustering and either the economic score (p = 0.13) or social score (p = 0.26). Conclusions We report a novel association between Mtb transmission and prolonged stay within a high burdened community. Transmission was also associated with fewer rooms for sleeping in a household. Increased social interaction and prolonged residence in a high burdened community are important factors linked to Mtb transmission, possibly due to increased probability of higher effective contact rates. The possible importance of degrees of poverty within low socio-economic setting warrants further study

Drivers of Tuberculosis Transmission.

Measuring tuberculosis transmission is exceedingly difficult, given the remarkable variability in the timing of clinical disease after Mycobacterium tuberculosis infection; incident disease can result from either a recent (ie, weeks to months) or a remote (ie, several years to decades) infection event. Although we cannot identify with certainty the timing and location of tuberculosis transmission for individuals, approaches for estimating the individual probability of recent transmission and for estimating the fraction of tuberculosis cases due to recent transmission in populations have been developed. Data used to estimate the probable burden of recent transmission include tuberculosis case notifications in young children and trends in tuberculin skin test and interferon γ-release assays. More recently, M. tuberculosis whole-genome sequencing has been used to estimate population levels of recent transmission, identify the distribution of specific strains within communities, and decipher chains of transmission among culture-positive tuberculosis cases. The factors that drive the transmission of tuberculosis in communities depend on the burden of prevalent tuberculosis; the ways in which individuals live, work, and interact (eg, congregate settings); and the capacity of healthcare and public health systems to identify and effectively treat individuals with infectious forms of tuberculosis. Here we provide an overview of these factors, describe tools for measurement of ongoing transmission, and highlight knowledge gaps that must be addressed

Evaluating strategies for control of tuberculosis in prisons and prevention of spillover into communities: An observational and modeling study from Brazil

Background It has been hypothesized that prisons serve as amplifiers of general tuberculosis (TB) epidemics, but there is a paucity of data on this phenomenon and the potential population-level effects of prison-focused interventions. This study (1) quantifies the TB risk for prisoners as they traverse incarceration and release, (2) mathematically models the impact of prison-based interventions on TB burden in the general population, and (3) generalizes this model to a wide range of epidemiological contexts. Methods and findings We obtained individual-level incarceration data for all inmates (n = 42,925) and all reported TB cases (n = 5,643) in the Brazilian state of Mato Grosso do Sul from 2007 through 2013. We matched individuals between prisoner and TB databases and estimated the incidence of TB from the time of incarceration and the time of prison release using Cox proportional hazards models. We identified 130 new TB cases diagnosed during incarceration and 170 among individuals released from prison. During imprisonment, TB rates increased from 111 cases per 100,000 person-years at entry to a maximum of 1,303 per 100,000 person-years at 5.2 years. At release, TB incidence was 229 per 100,000 person-years, which declined to 42 per 100,000 person-years (the average TB incidence in Brazil) after 7 years. We used these data to populate a compartmental model of TB transmission and incarceration to evaluate the effects of various prison-based interventions on the incidence of TB among prisoners and the general population. Annual mass TB screening within Brazilian prisons would reduce TB incidence in prisons by 47.4% (95% Bayesian credible interval [BCI], 44.4%–52.5%) and in the general population by 19.4% (95% BCI 17.9%–24.2%). A generalized model demonstrates that prison-based interventions would have maximum effectiveness in reducing community incidence in populations with a high concentration of TB in prisons and greater degrees of mixing between ex-prisoners and community members. Study limitations include our focus on a single Brazilian state and our retrospective use of administrative databases. Conclusions Our findings suggest that the prison environment, more so than the prison population itself, drives TB incidence, and targeted interventions within prisons could have a substantial effect on the broader TB epidemic

Genetic composition and evolution of the prevalent Mycobacterium tuberculosis lineages 2 and 4 in the Chinese and Zhejiang Province populations

Background There are seven human-adaptation lineages of Mycobacterium tuberculosis (Mtb). Tuberculosis (TB) dissemination is strongly influenced by human movements and host genetics. The detailed lineage distribution evolution of Mtb in Zhejiang Province is unknown. We aim to determine how different sub-lineages are transmitted and distributed within China and Zhejiang Province. Methods We analysed whole-genome sequencing data for a worldwide collection of 1154 isolates and a provincial collection of 1296 isolates, constructed the best-scoring maximum likelihood phylogenetic tree. Bayesian evolutionary analysis was used to calculate the latest common ancestor of lineages 2 and 4. The antigenic diversity of human T cell epitopes was evaluated by calculating the pairwise dN/dS ratios. Results Of the Zhejiang isolates, 964 (74.38%) belonged to lineage 2 and 332 (25.62%) belonged to lineage 4. The distributions of the sub-lineages varied across the geographic regions of Zhejiang Province. L2.2 is the most ancient sub-lineage in Zhejiang, first appearing approximately 6897 years ago (95% highest posterior density interval (HDI): 6513–7298). L4.4 is the most modern sub-lineage, first appearing approximately 2217 years ago (95% HDI: 1864–2581). The dN/dS ratios showed that the epitope and non-epitope regions of lineage 2 strains were significantly (P < 0.001) more conserved than those of lineage 4. Conclusions An increase in the frequency of lineage 4 may reflect its successful transmission over the last 20 years. The recent common ancestors of the sub-lineages and their transmission routes are relevant to the entry of humans into China and Zhejiang Province. Diversity in T cell epitopes may prevent Mycobacterium tuberculosis from being recognized by the immune system

Experimental Tuberculosis in the Wistar Rat: A Model for Protective Immunity and Control of Infection

BACKGROUND: Despite the availability of many animal models for tuberculosis (TB) research, there still exists a need for better understanding of the quiescent stage of disease observed in many humans. Here, we explored the use of the Wistar rat model for the study of protective immunity and control of Mycobacterium tuberculosis (Mtb) infection. METHODOLOGY/PRINCIPAL FINDINGS: The kinetics of bacillary growth, evaluated by the colony stimulating assay (CFU) and the extent of lung pathology in Mtb infected Wistar rats were dependent on the virulence of the strains and the size of the infecting inoculums. Bacillary growth control was associated with induction of T helper type 1 (Th1) activation, the magnitude of which was also Mtb strain and dose dependent. Histopathology analysis of the infected lungs demonstrated the formation of well organized granulomas comprising epithelioid cells, multinucleated giant cells and foamy macrophages surrounded by large numbers of lymphocytes. The late stage subclinical form of disease was reactivated by immunosuppression leading to increased lung CFU. CONCLUSION: The Wistar rat is a valuable model for better understanding host-pathogen interactions that result in control of Mtb infection and potentially establishment of latent TB. These properties together with the ease of manipulation, relatively low cost and well established use of rats in toxicology and pharmacokinetic analyses make the rat a good animal model for TB drug discovery

Correction to: Genetic composition and evolution of the prevalent Mycobacterium tuberculosis lineages 2 and 4 in the Chinese and Zhejiang Province populations

No abstract was provided by the editors of this work

Evolution of epidemiologic methods and concepts in selected textbooks of the 20th century

Summary: Textbooks are an expression of the state of development of a discipline at a given moment in time. By reviewing eight epidemiology textbooks published over the course of a century, we have attempted to trace the evolution of five epidemiologic concepts and methods: study design (cohort studies and case-control studies), confounding, bias, interaction and causal inference. Overall, these eight textbooks can be grouped into three generations. Greenwood (1935) and Hill (first edition 1937; version reviewed 1961)'s textbooks belong to the first generation, "early epidemiology”, which comprise early definitions of bias and confounding. The second generation, "classic epidemiology”, represented by the textbooks of Morris (first edition 1957; version reviewed 1964), MacMahon & Pugh (first edition 1960; version reviewed 1970), Susser (1973), and Lilienfeld & Lilienfeld (first edition 1976; version reviewed 1980), clarifies the properties of cohort and case-control study designs and the theory of disease causation. Miettinen (1985) and Rothman (1986)'s textbooks belong to a third generation, "modern epidemiology”, presenting an integrated perspective on study designs and their measures of outcome, as well as distinguishing and formalizing the concepts of confounding and interaction. Our review demonstrates that epidemiology, as a scientific discipline, is in constant evolution and transformation. It is likely that new methodological tools, able to assess the complexity of the causes of human health, will be proposed in future generations of textbook

Molecular Epidemiology of Multidrug-Resistant Tuberculosis, New York City, 1995–1997

From January 1, 1995, to December 31, 1997, we reviewed records of all New York City patients who had multidrug-resistant tuberculosis (MDRTB); we performed insertion sequence (IS) 6110-based DNA genotyping on the isolates. Secondary genotyping was performed for low IS6110 copy band strains. Patients with identical DNA pattern strains were considered clustered. From 1995 through 1997, MDRTB was diagnosed in 241 patients; 217 (90%) had no prior treatment history, and 166 (68.9%) were born in the United States or Puerto Rico. Compared with non-MDRTB patients, MDRTB patients were more likely to be born in the United States, have HIV infection, and work in health care. Genotyping results were available for 234 patients; 153 (65.4%) were clustered, 126 (82.3%) of them in eight clusters of >4 patients. Epidemiologic links were identified for 30 (12.8%) patients; most had been exposed to patients diagnosed before the study period. These strains were likely transmitted in the early 1990s when MDRTB outbreaks and tuberculosis transmission were widespread in New York