New Tuberculosis Framework May Improve Research, Clinical Care

A new framework may better characterize the early stages of tuberculosis (TB) and improve research and clinical care, an international team of researchers said.

Turning against the current "active" or "latent" classification of TB, the International Consensus for Early TB (ICE-TB) group released a five-state system that distinguishes disease from infection, clinical versus subclinical states, and the degree of likely infectiousness.

The framework includes four disease states, including clinical TB (with symptoms) and subclinical TB (without symptoms), with each of these categorized as either infectious or non-infectious. The fifth state is TB infection that has not progressed to disease.

"The presence of viable Mycobacterium tuberculosis and an associated host response are prerequisites for all states of infection and disease," wrote Hanif Esmail, PhD, of University College London, and co-authors. Their position paper was published in Lancet Respiratory Medicine.

Esmail and colleagues noted that the simple binary view of latent infection and active disease had been key to case detection and standardized treatment of symptomatic individuals -- preventing millions of TB deaths worldwide in the last few decades -- but "it had less of an impact on transmission and disease incidence, possibly because millions of individuals with tuberculosis do not present to health facilities or receive care."

The ICE-TB group stressed the need for improvement in diagnostic tools and for a TB framework to be flexible as new research emerges.

"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," said Esmail in a press release. "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."

Keertan Dheda, MBBCh, PhD, of the London School of Hygiene and Tropical Medicine in England, and Giovanni Battista Migliori, MD, of Istituti Clinici Scientifici Maugeri IRCCS in Tradate, Italy, agreed that people with subclinical TB could "could probably receive shorter effective 2-month treatment regimens."

"The authors must be commended on tackling a difficult and controversial area, and choosing a classification that is workable in the real world, including tuberculosis-endemic countries," the duo wrote in an invited editorial. They did caution, however, that there is no established method for determining the level of infectiousness in subclinical TB.

Around the globe, TB is the leading cause of death from an infectious disease. The M. tuberculosis bacteria tend to attack the lungs, but other organs -- kidney, spine, and brain, for example -- may be affected. A TB vaccine has been available for over a century, and drug treatments for nearly that long. A minority of infected individuals will go on to develop symptomatic disease, the presentation of which varies widely and may not always include cough.

The CDC estimates that up to 13 million Americans live with latent TB infection -- a population that would be split between infection and subclinical disease groups according to the new ICE-TB model.

"This classification moves the field forward, as the framework can be validated and moves the research fraternity closer to standardized definitions that will facilitate research, assist diagnostic product development, and accelerate the development of new interventions," according to Dheda and Migliori.

"The suggested framework is sufficiently simple, which will be useful in the real world, covers all forms of active tuberculosis (including extrapulmonary tuberculosis and tuberculosis in children), will likely advance active case-finding (largely based on the presence of signs and symptoms) and improve recording instances of subclinical tuberculosis in national tuberculosis registers (the recording of which is currently not accommodated)," they wrote.

The arrival of ICE-TB may also have implications for ongoing TB vaccine development.

The ICE-TB framework was developed by an international, multidisciplinary group participating in two rounds of surveys. Participants represented the World Health Organization (WHO) regions of Africa, the Americas, Europe, the Eastern Mediterranean, South-East Asia, and the Western Pacific. Just over half of the represented countries were low-income.

The 71-person group reached a final consensus on conceptual states, related terminology, and research gaps in TB during an in-person symposium in 2023.

"This new classification will provide a foundation for research and progress in diagnosis and treatment across the full spectrum of tuberculosis to reduce the global burden of morbidity and mortality," wrote Lancet Respiratory Medicine journal staff in their own editorial.