Over the past decade, there’s been growing evidence that people can have TB without any symptoms. But there is still much uncertainty over how such asymptomatic TB functions in the body and how infectious it is. An ambitious study, to be conducted in South Africa and Indonesia, is trying to find some answers, writes Elri Voigt for Spotlight.
TB, caused by a tenacious bacterium, has plagued the world for many centuries, and while we have treatments that can cure the disease, they typically take six months and involve a minimum of three different antibiotics. Meanwhile, for complex reasons to do with how effectively the bug has evolved, TB keeps spreading and rates of new infections remain stubbornly high.
Our knowledge of TB has expanded substantially over the past decade, but with new knowledge comes new questions. Maybe most notably, the binary distinction between latent TB infection and TB disease has broken down.
The former is when there is TB bacteria in the body, but it is fully under control; disease is when it is not. There is increasing evidence of an in-between stage where a person has no symptoms, but the bacteria is active in the body and the person might be infectious.
The WHO has dubbed this asymptomatic TB. It has also been called sub-clinical TB.
While we know there is a lot of asymptomatic TB out there, the problem is we don’t know about it, like how infectious it is, and how best to test for and treat it.
What we do know is that because many people have asymptomatic TB, this has huge implications and could largely explain why it’s so hard to get the disease under control, Thomas Scriba, a professor of immunology at the University of Cape Town, told Spotlight.
To learn more about how asymptomatic TB works, the Africa Health Research Institute (AHRI) in KwaZulu-Natal has now partnered with the Research Centre for Care and Control of Infectious Diseases at Padjadjaran University in Indonesia to conduct what might well be the largest study on the issue so far.
Both countries are on the WHO list of countries with the highest TB burdens. In 2023, according to data from the WHO’s Global TB report, TB incidence in South Africa was at 427 per 100 000, while in Indonesia it stood at 387 per 100 000.
Several other universities and research institutions will be involved in the study, including the Desmond Tutu Health Foundation, the South African Centre for Epidemiological Modelling and Analysis, the London School of Hygiene and Tropical Medicine, Wits Diagnostic Innovation Hub, University of Alabama at Birmingham, Radboud University Medical Centre, and the University of Otago.
90 000 people
For the study, called Asymptomatic TB Transmission in Indonesia and South Africa (ATTIS), the researchers aim to recruit 90 000 people from households with children – 60 000 people in Indonesia and 30 000 in South Africa. It is a type of cohort study, where the main aim is to monitor these 90 000 people over a few years, some more closely than others.
“The study is trying to figure out: are these people with asymptomatic TB transmitting it to other people? Are they contributing to the transmission and the disease? Is it the missing puzzle piece in the control of TB in many countries?” said Professor Limakatso Lebina, AHRI’s director for clinical trials and one of the ATTIS study co-leads.
The four main aims of the study are to understand how TB spreads from people who are asymptomatic, test novel diagnostic tools to see how well they detect asymptomatic TB, create a biobank to study how the immune system responds to asymptomatic TB, and finally, to investigate the impact asymptomatic TB has on TB transmission and incidence more generally. This will be investigated through a core study and three sub-studies.
“We hope to start enrolling in South Africa in February 2026, and in Indonesia in April 2026. We plan to screen for 18 months in each country to achieve the study numbers we think we will need,” said Professor Emily Wong, AHRI and University of Alabama Birmingham faculty member and another co-lead on the ATTIS study.
Then there will be several months of follow-up.
“We plan to provide the main analysis by the end of the three-year grant period. As with any study, we’ll have a lot of additional analyses and those may extend beyond the grant period. But it is a very ambitious timeline, and we will aim to hit those milestones,” she added.
“But after about a year from now, we have a planned interim analysis to reassess the power of the study and the required scale and size. And so, we will have more precise timelines at that time as well.”
The budget for the study $19.5m, with half coming from the Gates Foundation and half from the Wellcome Trust.
The details
The study will start with a large-scale screening effort using two-person teams, comprising a nurse and a clinical researcher or research assistant. Lebina said between eight and 10 teams will go out into the King Cetshwanga and uMkhanyakude districts in northern KwaZulu-Natal to find people interested in participating.
They will then be screened for TB using three TB tests – GeneXpert Ultra (a type of molecular test), liquid culture, and digital chest X-ray. Based on the results, they will be split into three arms – those who don’t have TB, those with TB and TB symptoms, and those with asymptomatic TB.
Then the nurse and clinical researcher teams will go to the households of those adults and test the whole family, focusing specifically on the children – who will form part of the main study cohort.
Adults with asymptomatic TB will also be tested with several novel TB tests. “The plan is to test participants who have already been found with other tools or those found with chest X-ray to then see if these novel tools can pick up asymptomatic TB,” Lebina said.
While there will be a mechanism for adding any novel TB tests throughout the study’s duration, Wong said for now it would evaluate how well tongue swabs, a bio-aerosol collection facemask, exhaled breath condensate, as well as two blood tests, work at detecting asymptomatic TB.
The tongue swabs will be tested for evidence of TB DNA in collaboration with the Wits Diagnostic Hub.
The face mask and exhaled breath condensate – a test where someone breathes into a metal straw that goes into a cold glass chamber and the resulting moisture is tested to detect TB – will be handled by the bio-aerosol group at the University of Cape Town.
The blood tests will be evaluated using a test looking for TB-specific T-cells that was developed by the South African Tuberculosis Vaccine Initiative (SATVI) group at UCT. These samples will also form part of the biobank the researchers will build to try to see what effect asymptomatic TB has on the body’s immune system.
One sub-study will look at adults who test negative for TB but have chest X-rays that indicate they might have TB. This group is of particular interest, Wong said, because currently there is no standardised way of treating them anywhere. They aim to enrol about 500 people in South Africa and 500 in Indonesia into this sub-study, and these individuals will be followed closely and retested for TB at regular intervals.
“This is a group that kind of gets neglected, but we suspect they’re at very high risk of developing microbiologically-confirmed TB in the future. So that’s the group our follow-up will focus on for one year to see how many of them develop culture microbiologically confirmed TB,” she said.
Finally, a sub-study will use mathematical modelling to determine the impact of asymptomatic TB on local and global transmission.
The South African Centre for Epidemiological Modelling and Analysis (SACEMA) at Stellenbosch University, and the London School of Hygiene and Tropical Medicine will help evaluate the results and do the relevant epidemiological modelling.
Lebina said that SACEMA will try to assess how much asymptomatic TB contributes to TB transmission in South Africa, as well as look at the cost-effectiveness of interventions targeting asymptomatic TB.
“The critical question that I think is not answered yet is how hard should we look and how much money we should spend looking [for asymptomatic TB],” Wong said. “So while this is not really a cost effectiveness study, I think defining the importance of identifying this group, its contribution to transmission and ongoing TB incidence, that’s really the gap that’s critical to fill.”
What we know about asymptomatic TB
South Africa’s SA’s TB Treatment guidelines currently do not have two separate treatment plans or approaches for someone who has TB and symptoms and someone with asymptomatic TB, Wong said.
“We already know that if someone has Gene Xpert positive TB, even if they don’t have symptoms, they should be treated. It may be that in future, other studies, not this study, have the chance to ask if that’s the appropriate treatment, if they could possibly be treated for shorter,” she said.
Currently, treating asymptomatic TB is what Scriba refers to as a “data-free zone”, as there haven’t yet been any large, well-designed trials on this. There are two studies from which we can draw insights when it comes to detecting asymptomatic TB.
In the context of a large screening study published in The Lancet Global Health, Scriba said it appears that X-rays looking for lung abnormalities suggestive of TB seem less effective at detecting asymptomatic TB than sputum-based tests.
In this study, 979 people who lived in a household where someone had TB were screened using a sputum test, where TB bacteria are detected by either a Gene Xpert test, Gene Xpert Ultra test or liquid culture: 51 people had microbiologically confirmed TB, of those, nine had symptoms and 42 were asymptomatic.
They were then X-rayed to see if any lung damage was present. Of the nine with TB symptoms, eight had an abnormal X-ray and one had a normal X-ray. Of the 42 asymptomatic people, one person did not have an X-ray done, while 23 had an abnormal X-ray and 18 had a normal X-ray.
Also not as effective in detecting asymptomatic TB are some of the blood markers that seem able to detect most cases of symptomatic TB. This is based on a pre-print of a study with which Scriba was involved.
For Scriba, the results from these two studies suggest that asymptomatic TB disease “on average is less severe than symptomatic disease”. However, this isn’t always the case, as many people who don’t have TB symptoms have severe lung damage and high inflammatory markers.
“And so, it occupies an intermediate position in the spectrum of disease that is TB,” he said.
All of this may suggest that some people with asymptomatic TB may potentially be cured with shorter treatment regimens, but that shouldn’t be taken as a blanket statement that can apply to all asymptomatic cases.
“I think it looks as if there will be people who may be cured by shorter treatment, but certainly not everyone. And so, it’s going to be a tricky issue, that’s why well-designed clinical trials would be required to answer that question,” Scriba said.
“It’s really critical that we think about the public health implications and don’t dawdle too long but actually come up with ways to manage TB, given this [asymptomatic TB],” he added.
“It means we have to put a lot more resources into active community screening and… really rethink this whole idea that we wait for people to come to clinics with respiratory symptoms, before testing for TB. Obviously, we must continue doing that, it’s really, really important. But we also need to test many more people who don’t yet have symptoms.”
– Additional reporting by Marcus Low
See more from MedicalBrief archives:
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SA to expedite TB diagnosis/treatment as cases continue to soar
Most TB patients don't have persistent cough – global study
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