Know your tuberculosis epidemic–Is it time to add Mycobacterium tuberculosis immunoreactivity back into global surveillance?

Abstract

Tuberculosis (TB) still causes 1.5 million deaths globally each year. Over recent decades, slow and uneven declines in TB incidence have resulted in a falling prevalence of TB disease, which increasingly concentrates in vulnerable populations. Falling prevalence, while welcome, poses new challenges for TB surveillance. Cross-sectional disease surveys require very large sample sizes to accurately estimate disease burden, and even more participants to detect trends over time or identify high-risk areas or populations, making them prohibitively resource-intensive. In the past, tuberculin skin surveys measuring Mycobacterium tuberculosis (Mtb) immunoreactivity were widely used to monitor TB epidemiology in high-incidence settings, but were limited by challenges with both delivering and interpreting the test. Here we argue that the shifting epidemiology of tuberculosis, and the development of new tests for Mtb infection, make it timely and important to revisit the strategy of TB surveillance based on infection or immunoreactivity. Mtb infection surveys carry their own operational challenges and fundamental questions, for example: around survey design and frequency; which groups should be included; how the prevalence of immunoreactivity in a population should be used to estimate force of infection; how individual results should be interpreted and managed; and how surveillance can be delivered efficiently and ethically. However, if these knowledge gaps are addressed, the relative feasibility and lower costs of Mtb infection surveillance offer a powerful and affordable opportunity to better “know your TB epidemic”, understand trends, identify high-risk and underserved communities, and tailor public health responses to dynamic epidemiology.

Tuberculosis Immunoreactivity Surveillance in Malawi (Timasamala)—A protocol for a cross-sectional Mycobacterium tuberculosis immunoreactivity survey in Blantyre, Malawi

“…The approach to adults and adolescents with a positive test of TB infection is less clear; current Malawi guidelines do not routinely recommend TPT for adult and adolescent household contacts of people with TB; furthermore older participants in this study are not household contacts with a known, recent exposure but rather healthy community members who may have been exposed to TB years ago, who have a low risk of progression to TB disease [35,36] and an appreciable risk of side effects from preventive therapy [33]. Nevertheless as countries undergo epidemiological shifts towards TB elimination it becomes more important to understand the individual-and community-level risks and benefits of Mtb infection screening and treatment [6].…”

“…Existing methods of TB surveillance, predominantly based on TB disease rather than infection, do not meet these needs [6]. Diagnostic algorithms for TB disease may include symptom screening (insensitive and non-specific [7]), and diagnostic tests which are often expensive, challenging to operationalise, and may lack specificity (chest radiography) and/or sensitivity (microbiological tests of sputum).…”

“…However, with existing tools, prevalence surveys are extremely resource-intensive and imprecise at subnational levels, especially as prevalence falls. Thus, it is currently impractical to achieve district, or subdistrict-level spatial resolution, identify high-risk populations, or measure trends over time through repeated disease prevalence surveys [6].…”

“…Surveys of immunoreactivity to Mycobacterium tuberculosis (Mtb) or "latent TB infection" (LTBI), rather than TB disease, are an alternative way to monitor TB epidemiology [6]. Mtb immunoreactivity is defined by a positive T-cell-mediated immune response to Mtb antigen, measured using tests such as interferon gamma release assays (IGRAs) or tuberculin skin tests (TSTs), without any clinical or microbiological evidence of active TB disease [10].…”

“…Infection/ immunoreactivity surveys capture an earlier stage in TB pathophysiology prior to progression from infection to disease, and so may provide clearer insights into which groups are most exposed to TB transmission as well as providing an earlier indicator of changing TB epidemiology in a population. Infection prevalence is higher than disease prevalence, since only a minority of Mtb infections result in disease, providing greater power and precision from a smaller sample size [6]. Finally, in populations at high risk of progression from infection to disease (such as young children, and people living with HIV) there may be individual-level benefits to diagnosis and early treatment of Mtb infection [11,12].…”