Determining the importance of different locations to Mycobacterium tuberculosis transmission in high tuberculosis burden settings

Lead Research Organisation: London Sch of Hygiene and Trop Medicine
Department Name: Epidemiology and Population Health

Abstract

Over nine and a half million people worldwide developed tuberculosis (TB) in 2014, and 1.5 million died from the disease. Current control strategies are insufficient, with global TB incidence falling by only 1-2% per year. Despite its importance as a global public health problem, very little is known about where Mycobacterium tuberculosis transmission (M.tb., the bacterium that causes the majority of TB disease) occurs, particularly in high burden countries such as South Africa. This is primarily because it is difficult to know whether someone has been recently infected, and it can be decades between infection and disease. Studies of social contacts have been useful in giving some indication of which locations may be important to M.tb. transmission. However, these studies are insufficient to estimate where the majority of transmission occurs, for three main reasons:

1) There is a lot of variation in the infectiousness of people with TB disease, and in how susceptible people are to infection and disease (e.g. people living with HIV are at increased risk). For this reason, chance meetings between the most infectiousness and susceptible people are likely be very important to overall transmission in a population. These meetings are most likely to occur in the places where numbers of new people met are highest, but these locations may not be the places where people spend most time, or where people meet the most other people per visit.
2) Transmission is likely to occur more often in crowded, badly ventilated buildings with little natural light.
3) Transmission is likely to be more common in places that are both visited by people with TB, and also visited by the people most susceptible to TB (e.g. clinics).

In this study, we will develop a better understanding of where M.tb. transmission occurs in high TB burden countries, and use this information to inform strategies to reduce TB death and suffering. We will use Cape Town, South Africa, as a case study. We have four main tasks:

1) Develop a model of people's contacts and infection transmission to investigate how variation in susceptibility and infectiousness affects where transmission occurs, for M.tb. and other infections.
2) Collect new data using questionnaires that will allow us to estimate the proportion of contacts that are between people who have not met before, by location. We will also collect data on the levels of ventilation and natural light in different types of location.
3) Using the new data we have collected, as well as existing data, build a model of M.tb. transmission by location. Using this model, we will estimate the proportion of transmission that occurs in different locations in Cape Town.
4) Adapt the model to represent contact patterns, susceptibility levels (e.g. HIV prevalence), and levels of M.tb. transmission in other high burden sub-Saharan African settings. We can then estimate in what types of location transmission may be common in other countries. We will also investigate what the most effective locations are to target using infection control interventions (e.g. improving ventilation or installing ultraviolet (U.V.) lights).

This study will help to fill a major gap in our understanding of TB: where does transmission occur? This has very real, practical implications. Trials of U.V. lights suggest that they may reduce transmission by 70-80%, and improving ventilation can also be very effective in preventing infections. These infection control measures are often implemented in TB clinics, but we currently do not know where else they should be targeted. Our results will inform the targeting of infection control measures, and if successful, should lead to reductions in M.tb. transmission, and in TB death and suffering. Our new understanding should also contribute to meeting the 2025 WHO End TB Strategy targets in high TB burden settings, the settings most in need of novel, innovative, and cost effective prevention strategies.

Technical Summary

Currently, little is known about where M.tb. transmission occurs in high incidence settings, limiting the potential effectiveness of infection control interventions. The aim of this study is to estimate the proportion of transmission that occurs in different locations in Cape Town and other high incidence, sub-Saharan African settings, and to investigate the implications for TB control. There are four objectives:

1) Use network modelling to determine the effect of variation in infectiousness and susceptibility on the contribution of different location types to transmission.
2) Conduct primary data collection and analysis to inform model parameterisation. This objective has three parts: A. Estimate numbers of unique and repeat contacts by location (primary data collection using a questionnaire). B. Determine the suitability of different types of location for M.tb. transmission (data collection in buildings, including measuring CO2 and UV levels). C. Determine how contacts vary between people with different levels of behavioural and biological susceptibility to M.tb. infection and progression, by location (analysis of existing data).
3) Develop an individual-based model of contact behaviour and M.tb. transmission, and estimate the proportion of transmission that occurs in different locations in Cape Town.
4) Generalise the model to other settings, and investigate the impact of location-based infection control measures on M.tb. incidence and mortality.

This study will directly address two of the WHO's research priorities: determining effects of infection control in 1) healthcare facilities and 2) other settings. Our findings will be of interest to international policy makers, and our results will be useful in informing and improving the effectiveness of infection control interventions. This understanding should contribute to meeting the 2025 WHO End TB Strategy Targets, in the high TB burden settings most in need of novel and innovative prevention strategies.

Planned Impact

There is an increasing interest in using location-based infection control interventions to reduce Mycobacterium tuberculosis (M.tb.) transmission, as a means of reducing morbidity and mortality due to tuberculosis disease (TB). The World Health Organization (WHO) has prioritised quantifying the effects of infection control strategies in 1) health care facilities and 2) other settings (congregate settings and households) as two of its key research priorities. Recent trials of ultraviolet germicidal irradiation devices have shown 70-80% reductions in M.tb. transmission to guinea pigs from TB patients in clinics. Improving ventilation can also be highly effective in reducing transmission, and can cost little in warm climates. Current understanding of where M.tb. transmissions occurs in high tuberculosis burden settings is poor however, impeding the effective implementation of location-based infection control measures. For this reason, one of the Stop TB Partnership's high priority questions is "What are the relative contributions of the various foci of TB transmission (e.g. household, community, nosocomial transmission) at the population level?"

This study will improve understanding of transmission by location in Cape Town, South Africa, and other high burden settings. This will enable the potential impact of location-based infection control measures in clinics and other locations to be determined, and will allow the most effective locations to target with infection control measures to be identified. Our findings will therefore be of interest to the National TB Control programmes in South Africa and other high burden countries, as well as the WHO and other global policy makers. The manufacturers of UVGI systems may also benefit, through an increased demand for their products.

In addition to improving understanding of where M.tb. transmission occurs, this study will also lead to an improved understanding of where transmission occurs for other infections that are transmitted directly between humans. In particular, through objective 1, we will investigate the role that variation in infectiousness and susceptibility plays on transmission by location. This may lead to the improvement of transmission models of infections such as influenza, and improved recommendations of the infection control measures (e.g. school closures) that should be employed during epidemics, leading to reduced morbidity and mortality.

More effective TB control measures will also have a wider societal impact. Informed targeting of location-based interventions has the potential to greatly increase both the impact and cost-effectiveness of control measures, ensuring that optimum use is made of the limited resources available for TB care and control. It will also reduce onward transmission of M.tb., reducing the incidence and prevalence of TB disease, contributing towards the WHO goal of TB elimination, and reducing the large economic cost to high incidence countries of reduced productivity due to TB disease.

Publications

10 25 50
 
Description As a result of this award, we now have a greatly improved understanding of the role that transmission in clinics may play in tuberculosis disease incidence in settings with high burdens of both tuberculosis and HIV. Existing empirical data showed that only a small proportion of overall indoor contact time occurs in clinics, which would suggest that they are not important sites of transmission. Using mathematical modelling, we demonstrated that transmission in clinics is likely to be higher because of increased rates of clinic visiting in people with infectious tuberculosis and/or HIV. This can greatly increase the proportion of tuberculosis that results from transmission in clinics.
See McCreesh, Nicky, et al. "Tuberculosis from transmission in clinics in high HIV settings may be far higher than contact data suggest." International Journal of Tuberculosis and Lung Disease (2019).

During the award we also invented a novel method for estimating social age-mixing patterns that is relevant for the transmission of airborne diseases such as tuberculosis and measles. Current models rely on age-mixing patterns calculated from 'close' contacts only, which are not that relevant contacts for airborne diseases. Our method should improve the accuracy of estimates from mathematical models of airborne disease, and therefore allow identification of more effective interventions to prevent Mtb transmission.
See McCreesh, Nicky, et al. "Estimating age-mixing patterns relevant for the transmission of airborne infections." Epidemics 28 (2019): 100339

The award has also led to ongoing collaborations and funded grants between White and McCreesh and the Africa Health Research Institute in South Africa
• 2019: NIH Research grant. "Defining drivers of TB transmission in the era of universal ART, and implications for finding the walking well". Co-investigators include White and McCreesh. £1.5M for 5 years
• 2017: ESRC Research grant. 'Infection prevention and control for drug-resistant tuberculosis in South Africa in the era of decentralised care: a whole systems approach'. Co-investigators include White and McCreesh. £2M for 42 months.
and a grant applications leading from this award are currently being considered by the MRC and the Wellcome Trust.
Exploitation Route The findings of this award have been presented at international conferences, including at the 2018 and 2019 Union World Conferences on Lung Health, and have been published as peer-reviewed research articles. These dissemination activities have allowed researchers in healthcare and other sectors to benefit from the outcomes of this research.
Data collected as part of this award are currently being cleaned and analysed. Following this, the datasets will be made publicly available, allowing them to be used by other researchers. The code of a novel individual-based model of Mycobacterium transmission locations will also be made publicly available.
Sectors Healthcare

 
Description Evidence and input from our group was used to update the gender focus from women to men in The Global Fund's Technical Brief on Tuberculosis, Gender and Human Rights
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in other policy documents
Impact Impacts pending, but should lead to more efficient resource allocation by Global Fund (evidence lacking at this stage)
 
Description Impact on South African Government National TB Strategic Plan Policies 2017-2021
Geographic Reach National 
Policy Influence Type Citation in other policy documents
Impact Impact forthcoming, but substantial impact expected in all areas checked.
 
Description Our Group authored the WHO/TB MAC guidelines on the use of Modelling for Country Level TB Decision Making
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in other policy documents
URL http://tb-mac.org/tb-mac-resource/guidance-for-country-level-tb-modelling/
 
Description Aeras
Amount £150,000 (GBP)
Organisation Aeras 
Sector Charity/Non Profit
Country Global
Start 01/2017 
End 12/2018
 
Description ESRC Research grant, Antimicrobial Resistance Cross Council Initiative
Amount £2,000,000 (GBP)
Funding ID ES/P008011/1 
Organisation Economic and Social Research Council 
Sector Public
Country United Kingdom
Start 08/2017 
End 01/2021
 
Description Improving scientific and public health decision making by developing technologies to increase use of robust methods to calibrate and analyse complex mathematical models
Amount £494,109 (GBP)
Funding ID 218261/Z/19/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2020 
End 01/2023
 
Description Improving scientific and public health decision making by developing technologies to increase use of robust methods to calibrate and analyse complex mathematical models
Amount £451,991 (GBP)
Funding ID 218261/Z/19/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2020 
End 12/2022
 
Description Infection prevention and control for drug-resistant tuberculosis in South Africa in the era of decentralised care: a whole systems approach
Amount £1,739,991 (GBP)
Funding ID ES/P008011/1 
Organisation Economic and Social Research Council 
Sector Public
Country United Kingdom
Start 08/2017 
End 01/2021
 
Description USAID
Amount £285,897 (GBP)
Organisation United States Agency for International Development 
Sector Public
Country United States
Start 06/2017 
End 12/2017
 
Description USAID research project funding
Amount £285,896 (GBP)
Organisation United States Agency for International Development 
Sector Public
Country United States
Start 01/2017 
End 01/2018
 
Description supplementary ESRC funding
Amount £40,000 (GBP)
Organisation Economic and Social Research Council 
Sector Public
Country United Kingdom
Start 02/2018 
End 06/2018
 
Description Memorandum of understanding between LSHTM and Gates Medical Research Institute 
Organisation Bill and Melinda Gates Medical Research Institute
Country United States 
Sector Charity/Non Profit 
PI Contribution Providing scientific evidence for GMRI decision making
Collaborator Contribution Expected: - Scientific advice on research project - Training of LSHTM PhD student - Financial support of research projects - Training of high burden country researchers - modelling tools hosting
Impact Expected: - Research evidence and papers - Trained LSHTM PhD student - Financial support of research projects - Training of high burden country researchers - co-creation of methodological platform and consortia; - modelling tools hosted by GMRI
Start Year 2019
 
Description Changed South African Department Of Health Policy Announcement on TB screening in children 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Changed Paediatric TB policy announcement from screening all school age children, to screening under 5s (a more sensible policy based on TB epidemiology)
Year(s) Of Engagement Activity 2014
 
Description Press release - Targeting men could be key to beating TB 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Press release to disseminate knowledge on topic
Year(s) Of Engagement Activity 2016
URL http://blogs.lshtm.ac.uk/news/2015/12/18/targeting-men-could-be-key-to-beating-tb/#more-4602
 
Description Press release on drug-resistant latent TB 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Press release on drug-resistant latent TB. Much coverage eg Telegraph
Year(s) Of Engagement Activity 2019
URL https://www.telegraph.co.uk/global-health/science-and-disease/worryingly-high-number-people-infected...
 
Description Recommended age of BMG Vaccination - Modelling the Impact on global paediatric TB mortality. 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Press release to large room of journalists. Questions answered
Year(s) Of Engagement Activity 2017
 
Description Signatory on letter in The Times to Prime Minister May calling for attendance at UN General Assembly TB meeting 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Signatory on letter in The Times to Prime Minister May calling for attendance at UNGA meeting
Year(s) Of Engagement Activity 2018
 
Description Web feature: Ending TB: The Race To Control A Disease In Hiding 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact LSHTM web feature: Ending TB: The Race To Control A Disease In Hiding LSHTM Feature. Designed to engage global general public in TB, and efforts to control it globally
Year(s) Of Engagement Activity 2016
URL http://features.lshtm.ac.uk/project/ending-tb-the-race-to-control-a-disease-in-hiding
 
Description Work on TB patient costs attracted Kenyan media attention and was covered by a number of national TV stations 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Group work on TB patient costs attracted Kenyan media attention and was covered by a number of national TV stations
Year(s) Of Engagement Activity 2018
 
Description • The Correlate of Risk Targeted Intervention Study (CORTIS) Starts press release 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Press release and media briefing. Questions
Year(s) Of Engagement Activity 2016