New classification of tuberculosis to support efforts to eliminate the disease

25 Mar 2024
A scanning electron micrograph showing numerous rod-shaped Mycobacterium tuberculosis bacteria
25 Mar 2024

A new way to classify tuberculosis (TB) that aims to improve focus on the early stages of the disease has been presented by an international team led by researchers at University College London (UCL), the London School of Hygiene & Tropical Medicine (LSHTM), The Walter and Eliza Hall Institute (WEHI), the Centre for Infectious Diseases Research in Africa (CIDRI-Africa) at the University of Cape Town, Imperial College London and the South African Medical Research Council.

The new framework, published in The Lancet Respiratory Medicine, seeks to replace the approach of the last half century of defining TB as either active (i.e., causing illness and potentially infectious to others) or latent (being infected with the bacterium that causes TB [M. tuberculosis] but well and not infectious to others) – an approach researchers say is limiting progress in eradicating the disease. Of note, large surveys conducted in over 20 countries recently have shown than many people with infectious TB feel well. 

Under the new classification, there are four disease states: clinical (with symptoms) and subclinical (without symptoms), with each of these classed as either infectious or non-infectious. The fifth state is M. tuberculosis infection that has not progressed to disease – that is, M. tuberculosis may be present in the body and alive, but there are no signs of the disease that are visible to the naked eye, for example with imaging.

The researchers say they hope the International Consensus for Early TB (ICE-TB) framework, developed by a diverse group of 64 experts, will help lead to better diagnosis and treatment of the early stages of TB which have historically been overlooked in research.

TB remains the world’s most deadly infectious disease currently and has caused over one billion deaths in the last 200 years. An estimated three million cases a year are not reported to health systems and more than half of these cases will be asymptomatic.

Prof. Rein Houben (LSHTM), co-lead author of the paper, said: “We are not on the right trajectory with TB. We have not seen the steep declines in burden that have occurred with other infectious diseases such as HIV and malaria despite millions receiving TB treatment.

“The old concepts of active versus latent TB worked when the focus was to treat people who had become very sick. But to get closer to eradicating the disease, we need to stop transmission, and look at earlier disease states, and identify people who may be infectious for months or years before developing any symptoms.

“For the last decade people in the field have said a different system is needed but there was no agreement on the states or terminology. We have taken the next step and we hope that this new framework is adopted widely.”

The framework was developed via a Delphi process designed to reach a consensus among a diverse group. The process began with a scoping review of papers and online surveys of experts and culminated in a two-day meeting in Cape Town, South Africa, of researchers from a range of disciplines as well as policymakers, clinicians, and TB survivors. 

“One key finding in the consensus is moving the disease threshold” said Dr Anna Coussens co-lead author from CIDRI-Africa and WEHI “and acknowledge that disease does not just start with symptoms or transmission, but when tissue is damaged.

“In time we hope our framework can contribute to TB elimination by leading to improved early diagnosis and treatment, optimising patient outcomes and minimising transmission.”

The researchers noted that the disease process was non-linear – that people may fluctuate between infectious and non-infectious states, and between the presence and absence of symptoms or signs. 

They also said that better diagnostic tools were needed to identify many of the TB states. For instance, there is currently no test to detect a viable TB infection (i.e., one where the bacteria are physiologically active), as opposed to a non-viable infection or recent infection that has cleared. 

Dr Hanif Esmail co-lead author from CIDRI-Africa and UCL said: “The binary paradigm of active disease versus latent infection has resulted in a one-size-fits-all antibiotic treatment for disease, but designed for those with the most severe form of disease. This leads to potential over-treatment of individuals with subclinical TB.”

“A key research priority now is to identify the best combination, dosage and duration of antibiotics to treat each TB state, as well as the benefits of treating the subclinical states.

The international team involved stakeholders from 19 countries including the International Union Against TB and Lung Disease, The StopTB partnership, World Health Organization, FIND, National TB Programmes, TB Proof, and researchers from a number of universities. 

The work was supported by Wellcome, the National Institutes of Health/RePORT RSA, the Bill and Melinda Gates Foundation, the Medical Research Council, the European Research Council, and the National Health and Medical Research Council.

Read the paper at 
Coussens, A. K. et al. Classification of early tuberculosis states to guide research for improved care and prevention: an international Delphi consensus exercise. Lancet Respir. Med. (2024) doi:10.1016/S2213-2600(24)00028-6.

Mycobacterium tuberculosis Bacteria” by National Institute of Allergy and Infectious Diseases, National Institutes of Health is licenced under CC BY-NC 2.0 DEED / rotated from original