Unacceptable levels of Mycobacterium tuberculosis transmission are noted in high burden settings and a renewed focus on reducing person-to-person transmission in these communities is needed. We review recent developments in the understanding of airborne transmission. We outline approaches to measure transmission in populations and trials and describe the Wells-Riley equation, which is used to estimate transmission risk in indoor spaces. Present research priorities include the identification of effective strategies for tuberculosis infection control, improved understanding of where transmission occurs and the transmissibility of drug-resistant strains, and estimates of the effect of HIV and antiretroviral therapy on transmission dynamics. When research is planned and interventions are designed to interrupt transmission, resource constraints that are common in high burden settings-including shortages of health-care workers-must be considered.

Wellcome Trust, UK National Institute for Health Research, Medical Research Council, Public Health England.

Multiple imputation with delta adjustment provides a flexible and transparent means to impute univariate missing data under general missing-not-at-random mechanisms. This facilitates the conduct of analyses assessing sensitivity to the missing-at-random (MAR) assumption. We review the delta-adjustment procedure and demonstrate how it can be used to assess sensitivity to departures from MAR, both when estimating the prevalence of a partially observed outcome and when performing parametric causal mediation analyses with a partially observed mediator. We illustrate the approach using data from 34,446 respondents to a tuberculosis and human immunodeficiency virus (HIV) prevalence survey that was conducted as part of the Zambia–South Africa TB and AIDS Reduction Study (2006–2010). In this study, information on partially observed HIV serological values was supplemented by additional information on self-reported HIV status. We present results from 2 types of sensitivity analysis: The first assumed that the degree of departure from MAR was the same for all individuals with missing HIV serological values; the second assumed that the degree of departure from MAR varied according to an individual's self-reported HIV status. Our analyses demonstrate that multiple imputation offers a principled approach by which to incorporate auxiliary information on self-reported HIV status into analyses based on partially observed HIV serological values.

The emergence and expansion of the multidrug-resistant tuberculosis epidemic is a threat to the global control of tuberculosis. Multidrug-resistant tuberculosis is the result of the selection of resistance-conferring mutations during inadequate antituberculosis treatment. However, HIV has a profound effect on the natural history of tuberculosis, manifesting in an increased rate of disease progression, leading to increased transmission and amplification of multidrug-resistant tuberculosis. Interventions specific to HIV-endemic areas are urgently needed to block tuberculosis transmission. These interventions should include a combination of rapid molecular diagnostics and improved chemotherapy to shorten the duration of infectiousness, implementation of infection control measures, and active screening of multidrug-resistant tuberculosis contacts, with prophylactic regimens for individuals without evidence of disease. Development and improvement of the efficacy of interventions will require a greater understanding of the factors affecting the transmission of multidrug-resistant tuberculosis in HIV-endemic settings, including population-based molecular epidemiology studies. In this Series article, we review what we know about the transmission of multidrug-resistant tuberculosis in settings with high burdens of HIV and define the research priorities required to develop more effective interventions, to diminish ongoing transmission and the amplification of drug resistance.

SUMMARYGlobally, the rates of decline in tuberculosis (TB) incidence are disappointing, but in line with model predictions regarding the likely impact of the DOTS strategy. Here, we review evidence from basic epidemiology, molecular epidemiology and modelling, all of which suggest that, in high-burden settings, the majority of Mycobacterium tuberculosis transmission may occur in indoor congregate settings. We argue that mass environmental modifications in these places might have a significant impact on TB control and suggest a research agenda that might inform interventions of this nature. The necessary technology exists and, critically, implementation would not be dependent on health care workers who are in short supply in the communities worst affected by TB.

Infection prevention and control (IPC) measures to reduce transmission of drug-resistant and drug-sensitive tuberculosis (TB) in health facilities are well described but poorly implemented. The implementation of TB IPC has been assessed primarily through quantitative and structured approaches that treat administrative, environmental, and personal protective measures as discrete entities. We present an ongoing project entitled Umoya omuhle ("good air"), conducted in two provinces of South Africa, that adopts an interdisciplinary, 'whole systems' approach to problem analysis and intervention development for reducing nosocomial transmission of Mycobacterium tuberculosis (Mtb) through improved IPC. We suggest that TB IPC represents a complex intervention that is delivered within a dynamic context shaped by policy guidelines, health facility space, infrastructure, organisation of care, and management culture. Methods drawn from epidemiology, anthropology, and health policy and systems research enable rich contextual analysis of how nosocomial Mtb transmission occurs, as well as opportunities to address the problem holistically. A 'whole systems' approach can identify leverage points within the health facility infrastructure and organisation of care that can inform the design of interventions to reduce the risk of nosocomial Mtb transmission.

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SUMMARYSETTING: Molecular epidemiology suggests that most Mycobacterium tuberculosis transmission in high-burden settings occurs outside the home.OBJECTIVE: To estimate the risk of M. tuberculosis transmission inside public buildings in a high TB burden community in KwaZulu-Natal, South Africa.DESIGN: Carbon dioxide (CO2) sensors were placed inside eight public buildings. Measurements were used with observations of occupancy to estimate infection risk using an adaptation of the Wells-Riley equation. Ventilation modelling using CONTAM was used to examine the impact of low-cost retrofits on transmission in a health clinic.RESULTS: Measurements indicate that infection risk in the church, classroom and clinic waiting room would be high with typical ventilation, occupancy levels and visit durations. For example, we estimated that health care workers in a clinic waiting room had a 16.9–24.5% annual risk of M. tuberculosis infection. Modelling results indicate that the simple addition of two new windows allowing for cross-ventilation, at a cost of US$330, would reduce the annual risk to health care workers by 57%.CONCLUSIONS: Results indicate that public buildings in this community have a range of ventilation and occupancy characteristics that may influence transmission risks. Simple retrofits may result in dramatic reductions in M. tuberculosis transmission, and intervention studies should therefore be considered.