TB Modeling and Translational Epi Group

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- February 2018 -

Risk factors associated with cluster size of Mycobacterium tuberculosis (Mtb) of different RFLP lineages in Brazil. (2018). Peres RL., Vinhas SA., Ribeiro FKC., Palaci M., do Prado TN., Reis-Santos B., Zandonade E., Suffys PN., Golub JE., Riley LW., Maciel EL, BMC infectious diseases, 18, 71

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BACKGROUND: Tuberculosis (TB) transmission is influenced by patient-related risk, environment and bacteriological factors. We determined the risk factors associated with cluster size of IS6110 RFLP based genotypes of Mycobacterium tuberculosis (Mtb) isolates from Vitoria, Espirito Santo, Brazil. METHODS: Cross-sectional study of new TB cases identified in the metropolitan area of Vitoria, Brazil between 2000 and 2010. Mtb isolates were genotyped by the IS6110 RFLP, spoligotyping and RD(Rio). The isolates were classified according to genotype cluster sizes by three genotyping methods and associated patient epidemiologic characteristics. Regression Model was performed to identify factors associated with cluster size. RESULTS: Among 959 Mtb isolates, 461 (48%) cases had an isolate that belonged to an RFLP cluster, and six clusters with ten or more isolates were identified. Of the isolates spoligotyped, 448 (52%) were classified as LAM and 412 (48%) as non-LAM. Our regression model found that 6-9 isolates/RFLP cluster were more likely belong to the LAM family, having the RD(Rio) genotype and to be smear-positive (adjusted OR = 1.17, 95% CI 1.08-1.26; adjusted OR = 1.25, 95% CI 1.14-1.37; crude OR = 2.68, 95% IC 1.13-6.34; respectively) and living in a Serra city neighborhood decrease the risk of being in the 6-9 isolates/RFLP cluster (adjusted OR = 0.29, 95% CI, 0.10-0.84), than in the others groups. Individuals aged 21 to 30, 31 to 40 and > 50 years were less likely of belonging the 2-5 isolates/RFLP cluster than unique patterns compared to individuals < 20 years of age (adjusted OR = 0.49, 95% CI 0.28-0.85, OR = 0.43 95% CI 0.24-0.77and OR = 0. 49, 95% CI 0.26-0.91), respectively. The extrapulmonary disease was less likely to occur in those infected with strains in the 2-5 isolates/cluster group (adjustment OR = 0.45, 95% CI 0.24-0.85) than unique patterns. CONCLUSIONS: We found that a large proportion of new TB infections in Vitoria is caused by prevalent Mtb genotypes belonging to the LAM family and RD(Rio) genotypes. Such information demonstrates that some genotypes are more likely to cause recent transmission. Targeting interventions such as screening in specific areas and social risk groups, should be a priority for reducing transmission.

- January 2018 -

Gender-based violence screening methods preferred by women visiting a public hospital in Pune, India. (2018). Suryavanshi N., Naik S., Waghmare S., Gupte N., Khan S., Mave V., Deluca A., Gupta A., Golub J., Bollinger RC., Shankar A, BMC women's health, 18, 19

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BACKGROUND: Gender-based violence (GBV) is a major global public health concern and is a risk factor for adverse health outcomes. Early identification of GBV is crucial for improved health outcomes. Interactions with health care providers may provide a unique opportunity for routine GBV screening, if a safe, confidential environment can be established. METHODS: Between November 2014 and February 2015, a cross-sectional, observational study was conducted where women were interviewed about their opinions concerning GBV screening in a tertiary health care setting in Pune, India. Trained counsellors interviewed 300 women at different out-patient and in-patient departments using a semi-structured questionnaire. RESULTS: Twenty-three percent of these women reported experiencing GBV in their life. However, 90% of women said they had never been asked about GBV in a health care setting. Seventy-two percent expressed willingness to be asked about GBV by their health care providers, with the preferred provider being nurses or counsellors. More than half (53%) women reported face-to-face interview as the most preferred method for screening. There were no major differences in these preferences by GBV history status. CONCLUSIONS: Our study provides evidence for preferred GBV screening methods and optimal provider engagement as perceived by women attending a public hospital.

Metformin Use Reverses the Increased Mortality Associated With Diabetes Mellitus During Tuberculosis Treatment. (2018). Degner NR., Wang JY., Golub JE., Karakousis PC, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 66, 198-205

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Background: The global type 2 diabetes mellitus (DM) epidemic threatens progress made in reducing tuberculosis (TB)-related mortality worldwide. Previous clinical studies have not fully evaluated potential confounding variables in addressing the impact of DM on TB treatment outcomes. The antidiabetic agent metformin regulates autophagy and may play a role as a host-directed therapeutic adjuvant to antitubercular treatment. Methods: We conducted a retrospective cohort study comprising patients aged >/=13 years undergoing treatment for culture-confirmed, drug-susceptible pulmonary TB. We assessed the effect of DM on mortality during TB treatment and 2-month TB sputum-culture conversion. We also evaluated the effect of metformin use on survival during TB treatment. Results: Among 2416 patients undergoing TB treatment, after adjusting for age, sex, chronic kidney disease, cancer, hepatitis C, tobacco use, cavitary disease, and treatment adherence, patients with DM had 1.91 times higher odds (95% confidence interval [CI], 1.51-2.40) of death during TB treatment than patients without DM, and 1.72 (95% CI, 1.25-2.38) times higher odds of remaining culture-positive at 2 months. Metformin use in patients with DM was significantly associated with decreased mortality during TB treatment (hazard ratio, 0.56 [95% CI, .39-.82]), and metformin users had similar mortality as patients without DM. Conclusions: This study suggests that despite multiple potential confounding variables, DM poses an increased risk of adverse TB treatment outcomes. There was a significant association between metformin use and decreased mortality during TB treatment, suggesting a potential role for this agent as adjunctive, host-directed therapy.

Brief Report: "Give Me Some Time": Facilitators of and Barriers to Uptake of Home-Based HIV Testing During Household Contact Investigation for Tuberculosis in Kampala, Uganda. (2018). Armstrong-Hough M., Ggita J., Ayakaka I., Dowdy D., Cattamanchi A., Haberer JE., Katamba A., Davis JL, Journal of acquired immune deficiency syndromes (1999), 77, 400-404

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BACKGROUND: Integrating home-based HIV counseling and testing (HCT) with tuberculosis (TB) evaluation could improve the uptake of HIV testing among household contacts of patients with active TB. We sought to identify the facilitators of and barriers to HCT during household contact investigation for TB in Kampala, Uganda. METHODS: We nested semi-structured interviews with 28 household contacts who were offered home-based HCT in a household-randomized trial of home-based strategies for TB contact investigation. Respondents reflected on their experiences of the home visit, the social context of the household, and their decision to accept or decline HIV testing. We used content analysis to identify and evaluate facilitators of and barriers to testing, then categorized the emergent themes using the Capability, Opportunity, Motivation, and Behavior (COM-B) model. RESULTS: Facilitators included a preexisting desire to confirm HIV status or to show support for the index TB patient; a perception that home-based services are convenient; and positive perceptions of lay health workers. Key barriers included fear of results and feeling psychologically unprepared to receive results. The social influence of other household members operated as both a facilitator and a barrier. CONCLUSIONS: Preexisting motivation, psychological readiness to test, and the social context of the household are major contributors to the decision to test for HIV at home. Uptake might be improved by providing normalizing information about HCT before the visit, by offering a second HCT opportunity, by offering self-tests with follow-up counseling, or by introducing HCT using "opt-out" language.

Prevalence of dysglycemia and clinical presentation of pulmonary tuberculosis in Western India. (2018). Mave V., Meshram S., Lokhande R., Kadam D., Dharmshale S., Bharadwaj R., Kagal A., Pradhan N., Deshmukh S., Atre S., Sahasrabudhe T., Barthwal M., Meshram S., Kakrani A., Kulkarni V., Raskar S., Suryavanshi N., Shivakoti R., Chon S., Selvin E., Gupte A., Gupta A., Gupte N., Golub JE, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 21, 1280-1287

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SETTING: Pune, India. OBJECTIVES: To estimate the prevalence and risk factors of pre-diabetes mellitus (DM) and DM, and its associations with the clinical presentation of tuberculosis (TB). DESIGN: Screening for DM was conducted among adults (age >/= 18 years) with confirmed TB between December 2013 and January 2017. We used multinomial regression to evaluate the risk factors for pre-DM (glycated hemoglobin [HbA1c] >/= 5.7-6.5% or fasting glucose 100-125 mg/dl) and DM (HbA1c >/= 6.5% or fasting glucose >/= 126 mg/dl or random blood glucose > 200 mg/dl or self-reported DM history/treatment) and the association of dysglycemia with the severity of TB disease. RESULTS: Among 1793 participants screened, 890 (50%) had microbiologically confirmed TB. Of these, 33% had pre-DM and 18% had DM; 41% were newly diagnosed. The median HbA1c level among newly diagnosed DM was 7.0% vs. 10.3% among known DM (P < 0.001). DM (adjusted OR [aOR] 4.94, 95%CI 2.33-10.48) and each per cent increase in HbA1c (aOR 1.42, 95%CI 1.01-2.01) was associated with >1+ smear grade or

The significance of cytomegalovirus in children with pneumonia admitted for mechanical ventilation. (2018). Gupte AN., Mave V., Meshram S., Lokhande R., Kadam D., Dharmshale S., Bharadwaj R., Kagal A., Pradhan N., Deshmukh S., Atre S., Sahasrabudhe T., Barthwal M., Meshram S., Kakrani A., Kulkarni V., Raskar S., Suryavanshi N., Shivakoti R., Chon S., Selvin E., Gupte N., Gupta A., Golub JE, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 21, 800-806

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BACKGROUND: The pathogenic role of cytomegalovirus (CMV) among children with pneumonia is not clear. OBJECTIVES AND DESIGN: We describe the outcome of children on mechanical ventilation with 'probable' CMV-related pneumonitis (CMV DNA polymerase chain reaction [PCR] positive as well as clinical and imaging features of CMV on ganciclovir) and children with pneumonia and CMV infection (CMV DNA PCR-positive without clinical and imaging features of CMV and not on ganciclovir therapy) at a paediatric intensive care unit in South Africa between 2011 and 2013. CMV viral loads were measured in non-bronchoscopic bronchoalveolar lavage fluid (NBBALF), plasma and whole-blood samples. RESULTS: Of the 97 children enrolled, 38 had CMV-related pneumonitis, 27 had pneumonia and CMV infection and 32 had pneumonia without CMV infection (negative CMV DNA PCR). Survival in the three groups was respectively 73.7% (P < 0.05), 92.6% (P < 0.05) and 88.0%. The difference in outcome could be accounted for by variance in the prevalence of human immunodeficiency virus (HIV) infection (respectively 60.5% and 29.6%, P < 0.05). A higher CMV viral load in NBBALF and plasma was seen in cases of CMV-related pneumonitis than in pneumonia with CMV infection: respectively log 5.20 vs. log 4.10 (P < 0.05) and 4.56 vs. 3.47 (P < 0.05). CONCLUSIONS: HIV-infected children on mechanical ventilation with CMV-related pneumonitis on ganciclovir have poor outcomes. Randomised placebo-controlled studies on ganciclovir are required.

Secondhand Smoke Exposure and Validity of Self-Report in Low-Income Women and Children in India. (2018). Elf JL., Kinikar A., Khadse S., Mave V., Gupte N., Kulkarni V., Patekar S., Raichur P., Cohen J., Breysse PN., Gupta A., Golub JE, Pediatrics, 141, S118-S129

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BACKGROUND: There is limited validation of self-reported measures for secondhand smoke (SHS) exposure in low- and middle-income countries. We evaluated the validity of standard self-reported measures among women and children in urban India. METHODS: Structured questionnaires were administered, and household air and hair samples were analyzed for nicotine concentration. RESULTS: In total, 141 households of 70 child and 71 adult participants were included. Air nicotine was detected in 72 (51%) homes, and 35 (75%) child and 12 (56%) adult participants had detectable hair nicotine. Correlation between air and hair nicotine was significant in children (r = 0.5; P = .0002) but not in adults (r = -0.1; P = .57). Poor correlation was found between self-reported measures of exposure and both air and hair nicotine. No questions were significantly correlated with hair nicotine, and the highest-magnitude correlation with air nicotine was for how often someone smoked inside for adults (r = 0.4; P = .10) and for home preparation of mishri (a smokeless tobacco product prepared for consumption by roasting) for children (r = 0.4; P = .39). The highest value for sensitivity by using air nicotine as the gold standard was for whether people smelled other families preparing mishri (47%; 95% confidence interval: 31-62) and prepared mishri in their own homes (50%; 95% confidence interval: 19-81). CONCLUSIONS: These results raise caution in using or evaluating self-reported SHS exposure in these communities. More appropriate questions for this population are needed, including mishri preparation as a source of SHS exposure.

- December 2017 -

Integrating social justice concerns into economic evaluation for healthcare and public health: A systematic review. (2017). Dukhanin V., Searle A., Zwerling A., Dowdy DW., Taylor HA., Merritt MW, Social science & medicine (1982), 198, 27-35

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Social justice is the moral imperative to avoid and remediate unfair distributions of societal disadvantage. In priority setting in healthcare and public health, social justice reaches beyond fairness in the distribution of health outcomes and economic impacts to encompass fairness in the distribution of policy impacts upon other dimensions of well-being. There is an emerging awareness of the need for economic evaluation to integrate all such concerns. We performed a systematic review (1) to describe methodological solutions suitable for integrating social justice concerns into economic evaluation, and (2) to describe the challenges that those solutions face. To be included, publications must have captured fairness considerations that (a) involve cross-dimensional subjective personal life experience and (b) can be manifested at the level of subpopulations. We identified relevant publications using an electronic search in EMBASE, PubMed, EconLit, PsycInfo, Philosopher's Index, and Scopus, including publications available in English in the past 20 years. Two reviewers independently appraised candidate publications, extracted data, and synthesized findings in narrative form. Out of 2388 publications reviewed, 26 were included. Solutions sought either to incorporate relevant fairness considerations directly into economic evaluation or to report them alongside cost-effectiveness measures. The majority of reviewed solutions, if adapted to integrate social justice concerns, would require their explicit quantification. Four broad challenges related to the implementation of these solutions were identified: clarifying the normative basis; measuring and determining the relative importance of criteria representing that basis; combining the criteria; and evaluating trade-offs. All included solutions must grapple with an inherent tension: they must either face the normative and operational challenges of quantifying social justice concerns or accede to offering incomplete policy guidance. Interdisciplinary research and broader collaborations are crucial to address these challenges and to support due attention to social justice in priority setting.

Impact of Targeted Tuberculosis Vaccination Among a Mining Population in South Africa: A Model-Based Study. (2017). Shrestha S., Chihota V., White RG., Grant AD., Churchyard GJ., Dowdy DW, American journal of epidemiology, 186, 1362-1369

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Optimizing the use of new tools, such as vaccines, may play a crucial role in reaching global targets for tuberculosis (TB) control. Some of the most promising candidate vaccines target adults, although high-coverage mass vaccinations may be logistically more challenging among this population than among children. Vaccine-delivery strategies that target high-risk groups or settings might yield proportionally greater impact than do those that target the general population. We developed an individual-based TB transmission model representing a hypothetical population consisting of people who worked in South African gold mines or lived in associated labor-sending communities. We simulated the implementation of a postinfection adult vaccine with 60% efficacy and a mean effect duration of 10 years. We then compared the impact of a mine-targeted vaccination strategy, in which miners were vaccinated while in the mines, with that of a community-targeted strategy, in which random individuals within the labor-sending communities were vaccinated. Mine-targeted vaccination averted an estimated 0.37 TB cases per vaccine dose compared with 0.25 for community-targeted vaccination, for a relative efficacy of 1.46 (95% range, 1.13-1.91). The added benefit of mine-targeted vaccination primarily reflected the disproportionate demographic burden of TB among the population of adult males as a whole. As novel vaccines for TB are developed, venue-based vaccine delivery that targets high-risk demographic groups may improve both vaccine feasibility and the impact on transmission.

Multidrug-resistant tuberculosis in India: looking back, thinking ahead. (2017). Fojo AT., Dowdy DW, The Lancet. Public health, 2, e8-e9

Estimated clinical impact of the Xpert MTB/RIF Ultra cartridge for diagnosis of pulmonary tuberculosis: A modeling study. (2017). Kendall EA., Schumacher SG., Denkinger CM., Dowdy DW, PLoS medicine, 14, e1002472

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BACKGROUND: The Xpert MTB/RIF (Xpert) assay offers rapid and accurate diagnosis of tuberculosis (TB) but still suffers from imperfect sensitivity. The newer Xpert MTB/RIF Ultra cartridge has shown improved sensitivity in recent field trials, but at the expense of reduced specificity. The clinical implications of switching from the existing Xpert cartridge to the Xpert Ultra cartridge in different populations remain uncertain. METHODS AND FINDINGS: We developed a Markov microsimulation model of hypothetical cohorts of 100,000 individuals undergoing diagnostic sputum evaluation with Xpert for suspected pulmonary TB, in each of 3 emblematic settings: an HIV clinic in South Africa, a public TB center in India, and an adult primary care setting in China. In each setting, we used existing data to project likely diagnostic results, treatment decisions, and ultimate clinical outcomes, assuming use of the standard Xpert versus Xpert Ultra cartridge. Our primary outcomes were the projected number of additional unnecessary treatments generated, the projected number of TB deaths averted, and the projected number of unnecessary treatments generated per TB death averted, if standard Xpert were switched to Xpert Ultra. We also simulated alternative approaches to interpreting positive results of the Ultra cartridge's semi-quantitative trace call. Extensive sensitivity and uncertainty analyses were performed to evaluate the drivers and generalizability of projected results. In the Indian TB center setting, replacing the standard Xpert cartridge with the Xpert Ultra cartridge was projected to avert 0.5 TB deaths (95% uncertainty range [UR]: 0, 1.3) and generate 18 unnecessary treatments (95% UR: 10, 29) per 1,000 individuals evaluated-resulting in a median ratio of 38 incremental unnecessary treatments added by Ultra per incremental death averted by Ultra compared to outcomes using standard Xpert (95% UR: 12, indefinite upper bound). In the South African HIV care setting-where TB mortality rates are higher and Ultra's improved sensitivity has greater absolute benefit-this ratio improved to 7 unnecessary treatments per TB death averted (95% UR: 2, 43). By contrast, in the Chinese primary care setting, this ratio was much less favorable, at 372 unnecessary treatments per TB death averted (95% UR: 75, indefinite upper bound), although the projected number of unnecessary treatments using Xpert Ultra was lower (with a possibility of no increased overtreatment) when using specificity data only from lower-burden settings. Alternative interpretations of the trace call had little effect on these ratios. Limitations include uncertainty in key parameters (including the clinical implications of false-negative results), the exclusion of transmission effects, and restriction of this analysis to adult pulmonary TB. CONCLUSIONS: Switching from the standard Xpert cartridge to the Xpert Ultra cartridge for diagnosis of adult pulmonary TB may have different consequences in different clinical settings. In settings with high TB and HIV prevalence, Xpert Ultra is likely to offer considerable mortality benefit, whereas in lower-prevalence settings, Xpert Ultra will likely result in considerable overtreatment unless the possibility of higher specificity of Ultra in lower-prevalence settings in confirmed. The ideal use of the Ultra cartridge may therefore involve a more nuanced, setting-specific approach to implementation, with priority given to populations in which the anticipated prevalence of TB (and HIV) is the highest.

Mathematical Modeling of "Chronic" Infectious Diseases: Unpacking the Black Box. (2017). Fojo AT., Kendall EA., Kasaie P., Shrestha S., Louis TA., Dowdy DW, Open forum infectious diseases, 4, ofx172

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Background: Mathematical models are increasingly used to understand the dynamics of infectious diseases, including "chronic" infections with long generation times. Such models include features that are obscure to most clinicians and decision-makers. Methods: Using a model of a hypothetical active case-finding intervention for tuberculosis in India as an example, we illustrate the effects on model results of different choices for model structure, input parameters, and calibration process. Results: Using the same underlying data, different transmission models produced different estimates of the projected intervention impact on tuberculosis incidence by 2030 with different corresponding uncertainty ranges. We illustrate the reasons for these differences and present a simple guide for clinicians and decision-makers to evaluate models of infectious diseases. Conclusions: Mathematical models of chronic infectious diseases must be understood to properly inform policy decisions. Improved communication between modelers and consumers is critical if model results are to improve the health of populations.

- November 2017 -

Indoor air pollution from secondhand tobacco smoke, solid fuels, and kerosene in homes with active tuberculosis disease in South Africa. (2017). Elf JL., Eke O., Rakgokong M., Variava E., Baliram Y., Motlhaoleng K., Lebina L., Shapiro AE., Breysse PN., Golub JE., Martinson N, BMC research notes, 10, 591

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OBJECTIVES: Secondhand tobacco smoke (SHS), use of solid fuels, and kerosene may play an important role in perpetuating the tuberculosis (TB) epidemic. The purpose of this study was to explore the prevalence of household air pollution (HAP) from these sources in homes of someone with TB in a high HIV-prevalence setting. A convenience sample of homes and household members participating in an ongoing active case-finding study in Matlosana district townships surrounding Klerksdorp, South Africa were included. RESULTS: We found a high prevalence of air pollution from SHS, solid fuels, and kerosene among individuals in homes with a case of prevalent active TB disease in Klerksdorp, South Africa. Adults in 40% of homes reported a daily smoker in the home, and 70% of homes had detectable air nicotine. In homes with a history of previous TB (prior to but not including the index case) as compared to those without previous TB, both SHS (83% vs. 65%, respectively) and solid/kerosene fuel use for more than 1 h/day (27% vs. 21%, respectively) were more prevalent. Larger studies are needed to estimate the risk of TB from these types of air pollution in HIV infected individuals and settings with high HIV prevalence.

Is it time for Brazil to prioritize TB preventive therapy for all people living with HIV? (2017). Maciel EL., Prado TND., Andrade KB., Golub JE, The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases, 22, 74-75

What We Know About Tuberculosis Transmission: An Overview. (2017). Churchyard G., Kim P., Shah NS., Rustomjee R., Gandhi N., Mathema B., Dowdy D., Kasmar A., Cardenas V, The Journal of infectious diseases, 216, S629-S635

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Tuberculosis remains a global health problem with an enormous burden of disease, estimated at 10.4 million new cases in 2015. To stop the tuberculosis epidemic, it is critical that we interrupt tuberculosis transmission. Further, the interventions required to interrupt tuberculosis transmission must be targeted to high-risk groups and settings. A simple cascade for tuberculosis transmission has been proposed in which (1) a source case of tuberculosis (2) generates infectious particles (3) that survive in the air and (4) are inhaled by a susceptible individual (5) who may become infected and (6) then has the potential to develop tuberculosis. Interventions that target these events will interrupt tuberculosis transmission and accelerate the decline in tuberculosis incidence and mortality. The purpose of this article is to provide a high-level overview of what is known about tuberculosis transmission, using the tuberculosis transmission cascade as a framework, and to set the scene for the articles in this series, which address specific aspects of tuberculosis transmission.

Research Roadmap for Tuberculosis Transmission Science: Where Do We Go From Here and How Will We Know When We're There? (2017). Auld SC., Kasmar AG., Dowdy DW., Mathema B., Gandhi NR., Churchyard GJ., Rustomjee R., Shah NS, The Journal of infectious diseases, 216, S662-S668

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High rates of tuberculosis transmission are driving the ongoing global tuberculosis epidemic, and there is a pressing need for research focused on understanding and, ultimately, halting transmission. The ongoing tuberculosis-human immunodeficiency virus (HIV) coepidemic and rising rates of drug-resistant tuberculosis in parts of the world add further urgency to this work. Success in this research will require a concerted, multidisciplinary effort on the part of tuberculosis scientists, clinicians, programs, and funders and must span the research spectrum from biomedical sciences to the social sciences, public health, epidemiology, cost-effectiveness analyses, and operations research. Heterogeneity of tuberculosis disease, both among individual patients and among communities, poses a substantial challenge to efforts to interrupt transmission. As such, it is likely that effective interventions to stop transmission will require a combination of approaches that will vary across different epidemiologic settings. This research roadmap summarizes key gaps in our current understanding of transmission, as laid out in the preceding articles in this series. We also hope that it will be a call to action for the global tuberculosis community to make a sustained commitment to tuberculosis transmission science. Halting transmission today is an essential step on the path to end tuberculosis tomorrow.

Designing and Evaluating Interventions to Halt the Transmission of Tuberculosis. (2017). Dowdy DW., Grant AD., Dheda K., Nardell E., Fielding K., Moore DAJ, The Journal of infectious diseases, 216, S654-S661

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To reduce the incidence of tuberculosis, it is insufficient to simply understand the dynamics of tuberculosis transmission. Rather, we must design and rigorously evaluate interventions to halt transmission, prioritizing those interventions most likely to achieve population-level impact. Synergy in reducing tuberculosis transmission may be attainable by combining interventions that shrink the reservoir of latent Mycobacterium tuberculosis infection (preventive therapy), shorten the time between disease onset and treatment initiation (case finding and diagnosis), and prevent transmission in key settings, such as the built environment (infection control). In evaluating efficacy and estimating population-level impact, cluster-randomized trials and mechanistic models play particularly prominent roles. Historical and contemporary evidence suggests that effective public health interventions can halt tuberculosis transmission, but an evidence-based approach based on knowledge of local epidemiology is necessary for success. We provide a roadmap for designing, evaluating, and modeling interventions to interrupt the process of transmission that fuels a diverse array of tuberculosis epidemics worldwide.

Measuring success: The challenge of social protection in helping eliminate tuberculosis. (2017). Shete PB., Dowdy DW, PLoS medicine, 14, e1002419

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In this Perspective on the research article by William Rudgard and colleagues, Priya Shete and coauthor discuss the challenges of measuring the impact of social protection programs such as cash transfers.

Drop-out from the tuberculosis contact investigation cascade in a routine public health setting in urban Uganda: A prospective, multi-center study. (2017). Armstrong-Hough M., Turimumahoro P., Meyer AJ., Ochom E., Babirye D., Ayakaka I., Mark D., Ggita J., Cattamanchi A., Dowdy D., Mugabe F., Fair E., Haberer JE., Katamba A., Davis JL, PloS one, 12, e0187145

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SETTING: Seven public tuberculosis (TB) units in Kampala, Uganda, where Uganda's national TB program recently introduced household contact investigation, as recommended by 2012 guidelines from WHO. OBJECTIVE: To apply a cascade analysis to implementation of household contact investigation in a programmatic setting. DESIGN: Prospective, multi-center observational study. METHODS: We constructed a cascade for household contact investigation to describe the proportions of: 1) index patient households recruited; 2) index patient households visited; 3) contacts screened for TB; and 4) contacts completing evaluation for, and diagnosed with, active TB. RESULTS: 338 (33%) of 1022 consecutive index TB patients were eligible for contact investigation. Lay health workers scheduled home visits for 207 (61%) index patients and completed 104 (50%). Among 287 eligible contacts, they screened 256 (89%) for symptoms or risk factors for TB. 131 (51%) had an indication for further TB evaluation. These included 59 (45%) with symptoms alone, 58 (44%) children <5, and 14 (11%) with HIV. Among 131 contacts found to be symptomatic or at risk, 26 (20%) contacts completed evaluation, including five (19%) diagnosed with and treated for active TB, for an overall yield of 1.7%. The cumulative conditional probability of completing the entire cascade was 5%. CONCLUSION: Major opportunities exist for improving the effectiveness and yield of TB contact investigation by increasing the proportion of index households completing screening visits by lay health workers and the proportion of at-risk contacts completing TB evaluation.

Linking Individual Natural History to Population Outcomes in Tuberculosis. (2017). Salvatore PP., Proano A., Kendall EA., Gilman RH., Dowdy DW, The Journal of infectious diseases, 217, 112-121

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Background: Substantial individual heterogeneity exists in the clinical manifestations and duration of active tuberculosis. We sought to link the individual-level characteristics of tuberculosis disease to observed population-level outcomes. Methods: We developed an individual-based, stochastic model of tuberculosis disease in a hypothetical cohort of patients with smear-positive tuberculosis. We conceptualized the disease process as consisting of 2 states-progression and recovery-including transitions between the 2. We then used a Bayesian process to calibrate the model to clinical data from the prechemotherapy era, thus identifying the rates of progression and recovery (and probabilities of transition) consistent with observed population-level clinical outcomes. Results: Observed outcomes are consistent with slow rates of disease progression (median doubling time: 84 days, 95% uncertainty range 62-104) and a low, but nonzero, probability of transition from disease progression to recovery (median 16% per year, 95% uncertainty range 11%-21%). Other individual-level dynamics were less influential in determining observed outcomes. Conclusions: This simplified model identifies individual-level dynamics-including a long doubling time and low probability of immune recovery-that recapitulate population-level clinical outcomes of untreated tuberculosis patients. This framework may facilitate better understanding of the population-level impact of interventions acting at the individual host level.

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