Beyond latent and active tuberculosis

17 Nov 2023

Researchers from the MRC Clinical Trials Unit at UCL have published the first study to systematically review how scientists and medical professionals characterise the different stages of tuberculosis (TB), beyond the binary of latent or active. The team have used this evidence to inform an overarching framework that incorporates multiple states of TB, to help guide research and public health management aiming to eliminate the disease. The study was published today in eClinicalMedicine.

TB causes 1.6 million deaths every year. For decades, TB elimination priorities, diagnostic approaches and treatments have been based on an understanding of TB existing in two distinct states: latent, non-infectious and asymptomatic infection or active, infectious and symptomatic disease.

But while this is a useful model, it does not account for how the disease progresses between these two extremes and can mean some patients are missed by healthcare systems. For example, some individuals with early TB may be infectious without showing any symptoms. They can be an important source of transmission around the community, but would not be identified by symptom-based screening programmes.

Recently, there has been a growing recognition that TB exists on a spectrum. Several published papers have proposed that there are multiple states of infection and disease, but authors have approached this from different perspectives, for example, focusing on immunology, microbiology, or public health.

Standardising the definitions and diagnostic criteria for these different states will help make further progress towards eliminating TB through targeted research and drug development, better clinical practice, and improved case-finding public health initiatives.

This study is the first to map the multiple ways that researchers have conceptualised different states of TB, beyond the latent or active binary. The team used key words to systematically search the databases MEDLINE, Embase and EMcare for reviews published in scientific journals between 1946 and September 2023. They identified 40 reviews, all published from 2009 onwards, which explicitly described more than two states of TB infection and disease.

Different reviews used different terminology, definitions and diagnostic criteria, but the team identified eight broad conceptual themes that were used to categorise states of TB:

State 0: TB infection has been eliminated with innate immune response.
State I: TB infection has been eliminated with acquired immune response.
State II: TB infection has not been eliminated but is controlled by the immune system.
State III: TB infection is not controlled by the immune system.
State IV: Individual has tested positive for TB-causing bacteria but has no symptoms of TB disease.
State V: Individual has signs or symptoms of TB disease.
State VI: Individual has severe TB disease, identified by severe symptoms, X-ray imaging or bacteria culture tests.
State VII: Individual has a previous history of TB

The study has led to and supported the development of the First International Symposium on New Concepts in Early TB Disease (ICE-TB), a meeting of TB experts which aimed to reach consensus on a framework for multiple TB states. Hanif Esmail and Asad Zaidi from the MRC CTU at UCL presented findings from the symposium at the Union World Conference on Lung Health 2023 on Friday 17^th November.

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