Tuberculosis (TB) remains one of the leading causes of death from infectious diseases worldwide. It is estimated that approximately one quarter of the world’s population is infected with Mycobacterium tuberculosis without showing symptoms or being contagious. This condition, now referred to as tuberculosis infection (previously known as latent tuberculosis infection), represents an important reservoir of future TB disease cases.
To identify infected individuals, health programmes primarily rely on two types of tests: the Tuberculin Skin Test (TST) and Interferon-Gamma Release Assays (IGRAs). These tests detect an immune response directed against the tuberculosis bacterium but generally do not determine which individuals will subsequently develop active TB disease.
One of the major challenges faced by National Tuberculosis Programmes is therefore identifying, among individuals with a positive test result, those at highest risk of progressing to active TB. Improved risk stratification could help target preventive treatment more effectively, optimize the use of healthcare resources, and contribute to reducing disease transmission.
A study published in Clinical Microbiology and Infection provides new evidence on the relationship between the magnitude of immune responses measured by these tests and the risk of developing TB disease following recent exposure.
This work was conducted as part of the APRECIT project (Improving the Management of Tuberculosis Infection), implemented by the Institut Pasteur de Madagascar, the Centre Pasteur du Cameroun, the National Tuberculosis Programmes of Madagascar and Cameroon, and Fondation Mérieux.
Better understanding the risk of disease progression
Household contacts of patients with pulmonary tuberculosis represent one of the populations at highest risk of both infection and progression to disease.
Between 2020 and 2022, research teams, in collaboration with the National Tuberculosis Programmes of Madagascar and Cameroon, conducted a large-scale tuberculosis infection screening campaign among 1,659 household contacts of pulmonary TB patients. Participants were then followed for 18 months to better understand factors associated with progression to active TB disease.
Researchers focused on the tests currently used to detect tuberculosis infection, particularly the Tuberculin Skin Test (TST) and Interferon-Gamma Release Assays (IGRAs), which are generally interpreted using a simple positive-or-negative approach.
An association between immune response magnitude and tuberculosis risk
The findings suggest that tuberculosis infection tests may provide more information than their simple positive-or-negative interpretation.
Among household contacts recently exposed to a patient with pulmonary tuberculosis, the risk of developing TB disease was not uniform among individuals with positive test results. While the TST is routinely interpreted using a positivity threshold of 10 mm of induration, the APRECIT study found that participants with an induration of 14 mm or greater had a significantly higher risk (approximately four times greater) of developing tuberculosis during the subsequent 18 months.
Similar findings were observed with IGRA tests. While currently used commercial thresholds showed limited ability to identify individuals at highest risk, exploratory analyses suggested that the highest immune responses were associated with a nearly six-fold increased risk of progression to disease. These findings, however, require confirmation in additional studies.
Overall, the results suggest that the magnitude of immune responses measured by tuberculosis infection tests may provide additional information for better characterizing the risk of disease progression among recently exposed individuals.
Findings that could help improve tuberculosis prevention strategies
Tuberculosis preventive treatment is a key tool for reducing the incidence of disease. However, its implementation remains challenging in many high-burden settings, particularly because of the large number of individuals potentially eligible for treatment.
The study also explored the programmatic and economic implications of prevention strategies based on different immune response thresholds. Results indicate that the thresholds used to define at-risk populations can influence both the number of individuals eligible for preventive treatment and the associated costs.
These findings contribute to ongoing discussions on how to optimize tuberculosis prevention strategies in high-burden countries.
Operational research supporting public health policies
Conducted under real-world conditions and in close collaboration with National Tuberculosis Programmes, this study illustrates the contribution of operational research to generating evidence capable of informing public health policies.
The authors emphasize, however, that tuberculosis infection tests alone cannot distinguish infection from early disease at the individual level, and that further studies will be needed to confirm these findings in other epidemiological settings.
“In Madagascar, tuberculosis preventive treatment has historically been limited to people living with HIV and children under 15 years of age. This creates a major gap for household contacts over the age of 15 of a bacteriologically confirmed TB case, who are not eligible for TPT, even when active tuberculosis has been formally ruled out through clinical assessment and chest radiography.
The findings of the APRECIT study represent a major turning point. They allow us to reinterpret the tuberculin skin test and interferon-gamma release assays by demonstrating their strong predictive value. Knowing that these tests can predict the development of active tuberculosis within the following 18 months among household contacts (at a stage when both clinical examination and chest radiography remain unremarkable) is a decisive step towards changing our clinical and public health practices.”
Prof. Michel TIARAY HARISON
Head of the National Tuberculosis Control Programme, Madagascar.
Scientific reference
Ratovoson R., Donkeng V., Ranaivomanana P. et al. Association between immune response magnitude to tuberculosis infection tests and short-term disease risk: a prospective cohort study. Clinical Microbiology and Infection, 2026.
Funding
The APRECIT project was supported by L’Initiative. Implemented in partnership with the National Tuberculosis Programmes, research institutions, and public health stakeholders in Madagascar and Cameroon, the project aimed to generate evidence to improve tuberculosis prevention and support data-driven strategies in high-burden settings.
