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‘You will be positive for life’ is what clinicians often tell patients who test positive for Mtb exposure through common tests, the Tuberculin Skin Test (TST) and the Interferon Gamma Release Assay (IGRA), a blood test.

A shift from a negative to a positive TST or IGRA result is known as ‘conversion’ and is associated with Mtb exposure and an increased risk of TB progression. The belief that this response never shifts from positive back to negative, ‘reversion’, is so entrenched that clinicians don’t retest individuals. TB research, modelling studies and policy are also all informed by this belief.

Published in the journal European Respiratory Review, a comprehensive search of TB research spanning a hundred years, led by the Royal Melbourne Hospital’s Dr Katie Dale, an Epidemiologist in the Victorian Tuberculosis Program at the Doherty Institute, emphasises that the long-held belief that the immune response, or immunoreactivity, to Mtb never wanes was disproven more than a century ago.

“Our work found that, over the past 110 years, hundreds of studies have documented the loss of Mtb immunoreactivity in individuals and populations,” said Dr Dale.

“This evidence has been continuously overlooked, dismissed and downplayed; and this is unwarranted.”

An early 1913 study reported significant reversion risks, with 25 per cent of TST-positive patients testing negative within two years and over 50 per cent beyond that. More recently, a 2022 US study found that 37 per cent of children migrating to the US with a positive TST had reverted following arrival, and 58 per cent of those with a positive IGRA.

Population-level studies also reveal that reversion happens frequently, with studies finding lower proportions with positive immune responses in some retested populations, even in places where TB is prevalent.                                 

“Reversion clearly occurs, and we also present evidence that it is meaningful, that is, it is associated with a reduced TB risk, just as conversion is associated with an increased risk. Incorporating this evidence into our understanding is important for TB clinical care, research and policy at all levels,” added Dr Dale.

In clinical settings, understanding that reversion is associated with a decreased risk of TB progression emphasises the need for retesting and contemporary immunoreactivity assessments. This could reduce unnecessary treatment for individuals who may not be at risk and help identify individuals with strong responses following re-exposure or with conversion who may particularly benefit from treatment.

The Royal Melbourne Hospital’s Professor Justin Denholm, Medical Director of the Victorian Tuberculosis Program at the Doherty Institute and co-author, says acknowledging the changing nature of Mtb immunoreactivity is crucial.

“This study has gathered a wide array of knowledge to prove that Mtb immunoreactivity is not a static measure throughout life, and prospective evaluation of the clinical implications of reversion are now needed,” said Professor Denholm.

The paper also highlights the impacts for TB research, modelling and policy. Mtb immunoreactivity is used to understand TB risk in populations as well as individuals. The belief that a single exposure results in lifelong immunoreactivity and a ‘lifetime risk’ of TB has meant the importance of the cycle of Mtb infection and reinfection to the burden of TB has been underestimated.

“This has been a serious oversight for an infectious disease with the global magnitude of TB,” added Dr Dale.

The researchers hope their exploration will prompt a shift in how Mtb infection and TB risk are understood.

Dr Dale believes appreciating reversion and the shifting, dynamic nature of Mtb immunoreactivity is essential to ensure that TB clinical care, research and policy align with the existing evidence and better address the cycle of Mtb infection and reinfection sustaining the TB pandemic.

“More than one hundred years after it was first demonstrated, incorporating this evidence into common understanding is also clearly well overdue,” she said.

Peer review: Dale KD, Schwalb A, Coussens AK, et al. Overlooked, dismissed, and downplayed: reversion of Mycobacterium tuberculosis immunoreactivity. European Respiratory Review. (2024). https://doi.org/10.1183/16000617.0007-2024

Collaboration: This research involved international collaboration with the London School of Hygiene and Tropical Medicine (UK), Universidad Peruana Cayetano Heredia (Peru), Centre for Infectious Diseases Research in Africa and the University of Melbourne.