Tuberculosis (TB) continues to spread in South Africa at alarming rates, possibly because some people may have the disease without TB symptoms and may unknowingly be passing on the bug, writes Elri Voigt for Spotlight.
The tenacious bug has survived and thrived for millennia, even though the disease, caused by the bacterium Mycobacterium tuberculosis, can be cured by antibiotics.
The bug has adapted extremely well to evade our immune systems and spread through tiny droplets in the air. Inhaling these droplets doesn’t automatically mean it will flourish in the lungs and cause the disease. In fact, only around one in 10 people exposed to the bug will go on to develop TB.
While we know a good deal about the disease and its complicated interactions with the human body, there are still big gaps in our understanding. Fortunately, some important research into these is continuing, despite cuts to medical research funding from the US Government – one of the largest funders of these studies for the past decade.
On arguably the most exciting frontier, scientists have recently been lifting the lid on what may be one of the most effective weapons in the bug’s armoury – stealth, and the fact that someone might have TB in their lungs but be unaware of it.
We look at “asymptomatic TB”, and unpack its far-reaching implications for our ongoing battle against this age-old illness.
Reality of the disease
Classic TB symptoms are persistent cough, night sweats, fever, fatigue, chest pain, and weight loss. Asymptomatic TB is where the bug is active in the body, but it is not, or not yet, resulting in these symptoms.
Yet the reality is often more complicated. Instead of a simple on-off switch, TB disease manifests in various ways. The precise symptoms and their severity can differ widely from person to person. When symptoms are mild, it can be particularly difficult to distinguish TB from other infections, or even to identify them as anything unusual.
Yet even without clear symptoms, TB might silently be causing damage to the lungs, which could lead to irritation and inflammation, resulting in symptoms months, or even years, down the line.
Precisely because asymptomatic disease often presents without symptoms, TB may go undetected for longer, resulting in more damage to the lungs and leading to someone eventually becoming sicker.
To further complicate matters, asymptomatic TB itself presents as a spectrum of disease, says Thomas Scriba, a Professor of Immunology at the South African Tuberculosis Vaccine Initiative at the University of Cape Town. Some people with active TB disease and no symptoms may have mild illness, while others with active TB disease and no symptoms may have more severe disease.
Inflammation is considered a good indicator of how intensely the immune system is responding to a threat, like an infection with TB.
Scriba was involved in research (for now only published as a preprint) suggesting that, on average, asymptomatic TB causes less inflammation than symptomatic disease. TB disease typically causes inflammation in the lungs and lymph nodes around the lungs, which in turn is responsible for some of the classic TB symptoms. It thus fits that a lack of symptoms should go hand in hand with lower levels of inflammation.
And then there is the risk to others. While one person’s TB might be mild or asymptomatic, they might transmit the bug to someone else in whose body the bug causes life-threatening illness.
Many infections have an asymptomatic component, says Scriba. With the SARS-CoV-2 virus, some people get very ill, others just have “the sniffles” or lose their sense of taste but are otherwise fine, and some are completely asymptomatic. This asymptomatic group contributed to the spread of SARS-CoV-2, though we don’t have a clear picture of how much. A similar dynamic may be at play with TB.
Lack of symptoms or lack of reporting?
A further complication is that symptom reporting for TB can be unreliable for a number of reasons, said Dr Keertan Dheda, a leading TB researcher, in a recent commentary in The Lancet. These include recall bias and TB stigma. He cited community-based TB prevalence surveys where about half of people with confirmed TB said they have no symptoms.
Part of the challenge is how one defines what qualifies as TB symptoms and what does not. It would, after all, be absurd for everyone with a slight cough and some fatigue to suspect they have TB. Set the threshold for symptoms to low and you throw the net too wide – set the threshold too high and you’ll miss cases.
There is yet a further complexity in that asymptomatic TB may have its own set of more subtle symptoms.
“The take-home message really is we can’t wait for people to develop symptoms and then to self-present for care, because there are some who are not experiencing symptoms or noticing symptoms and are not presenting for care but who also have TB and are probably transmitting (it) onwards. And so, fuelling the epidemic in that way,” Scriba says.
How infectious is it?
One of the big scientific unknowns about asymptomatic TB is how infectious it is. Scriba says there haven’t been any large, well-designed studies looking at this yet. “Studying the successful transmission of TB from person to person is not easy and requires very large and expensive studies,” he says.
Based on what we know in general, Scriba says that usually the amount of TB bacteria that can be detected in sputum correlates with infectiousness. So the more TB bacteria someone has in their sputum, the more likely they will transmit the disease when they cough or breathe.
Because there have been people in studies who are asymptomatic but test positive for TB through sputum-based smear microscopy, which requires a lot of TB bug to be present for a positive result, researchers like Scriba think it’s highly likely that some people with asymptomatic TB are contributing to TB transmission. The big unknown is by how much.
How prevalent is it?
There is also significant uncertainty about how common asymptomatic TB is, although some rough numbers have been emerging.
Global figures from a systematic review and meta-analysis of TB prevalence surveys from Africa and Asia found that around 50% of people diagnosed with TB did not report any symptoms.
Simon Mendelsohn, a clinical investigator at the SA Tuberculosis Vaccine Initiative, cautions that this might be an underestimate because of how these surveys are conducted. On a webinar in January, he said there is usually a pre-screening component to surveys, where participants are asked about symptoms and have their chests X-rayed.
If they are negative on both counts, they aren’t investigated further, meaning those with asymptomatic TB or mild TB disease might be going undetected.
South Africa’s first National TB prevalence survey found that just more than half of the participants with TB that was confirmed through molecular testing had not reported having symptoms.
Changes to TB testing
Until just a few years ago, South Africa’s strategy for testing people for TB relied largely on waiting for them to report to clinics with symptoms, or because they were identified during screening drives. This approach meant that asymptomatic TB was going largely undetected and untreated.
But as it became clear that this approach was missing many cases, and evidence mounted of the substantial burden of asymptomatic TB, pressure grew for a more active approach to detection. For example, in a commentary published in April 2021, Dr Yogan Pillay, then with the Clinton Health Access Initiative, argued: “For asymptomatic TB, screening and testing of all TB contacts should be expanded and … digital hand-held portable X-ray machines should be considered.”
As Spotlight outlined previously, an important shift occurred with the introduction of the country’s targeted universal testing (TUT) strategy, which involves testing high-risk people, whether or not they have symptoms.
High risk is typically defined as household or close contacts of people diagnosed with TB, those with HIV, and people who have had TB disease within the past two years. TUT was shown to improve TB detection in a landmark study first reported in late 2020.
Linked to the TUT strategy, there is also the EndTB campaign launched by the National Department of Health on World TB Day in 2025. The aim is to conduct 5m TB tests in 12 months – since this number is much larger than the number of people with TB symptoms, it will include lots of people who do not have symptoms.
Since the campaign started, around 2.9m people have been tested for TB and around 150 000 tested positive, according to an NICD dashboard. Though the 5m target will be missed, it looks as though more TB tests will be done this year than in any other year in the past decade.
But there are also some concerns about how well the TUT programme is working. According to estimates from the Thembisa model, around 1.2m HIV+ people were tested for TB in 2024 as part of the TUT programme. Of those, only about 12 000 (one in 94) started TB treatment.
Dr Leigh Johnson, lead developer of the model, cautions, however, that these estimates are highly uncertain. Either way, there is a suggestion that at least the HIV part of the TUT programme could probably be better targeted.
Will we get better tests?
One challenge in testing for TB is that the accuracy of most tests depends on whether people can cough up sputum and how much bacteria there are in the sputum sample. As it is, many TB cases treated in South Africa are not confirmed with a laboratory test.
Our lab tests are more likely to miss TB in people with HIV, since the concentration of bacteria is lower in their sputum samples. On average, the bacterial load is also lower in samples from people with asymptomatic TB.
As Scriba points out, there simply isn’t a diagnostic test yet that will be able to detect all cases of asymptomatic TB.
There is also a question of what screening to do before asking someone to provide a sputum sample for molecular testing. Here there is evidence that screening with chest X-rays and symptoms is better than either are on its own.
For example, in a small South African study published in The Lancet, of 979 household contacts of TB patients, researchers found that symptom screening alone would miss about eight in every 10 cases, chest X-ray screening alone would miss three, and symptom and chest X-ray screening combined would miss only two.
According to a meta-analysis by Mendelsohn and others, symptom screening has a sensitivity of only about 50%. X-rays was estimated at around 62% and the two combined were at 67%. Sensitivity refers to a test’s ability to correctly indicate the presence of a bug in a test sample.
There are still many unanswered questions here, says Mendelsohn, like the cost implications of performing universal sputum testing versus using pre-screening approaches of symptoms or chest X-ray.
Because of cost constraints, there might be a role for universal sputum testing in high-risk groups instead of pre-screening them.
One of the ways in which researchers are hoping to improve the identification of asymptomatic TB is by using blood-based biomarkers. These are tests that look for a specific marker in someone’s blood that is caused by the TB bacterium or the body’s response to it.
A well-known type of blood-based biomarker test for TB is the interferon gamma release assay. However, this type of test has limited value since it can only show you if someone has been exposed to TB before, not if they currently have the disease.
There were hopes that an inflammatory marker called C-Reactive Protein might help us distinguish between asymptomatic TB and non-TB, but findings from a recent study on the approach were underwhelming.
Scriba says that there isn’t currently a clear front runner for an asymptomatic TB test, but it is important that researchers keep looking.
A large asymptomatic TB study is starting later this year in South Africa and Indonesia. It will contain a sub-study evaluating how well several novel TB tests are able to detect asymptomatic TB. The researchers plan to evaluate tongue swabs, a bio-aerosol collection face-mask, exhaled breath condensate, and two blood tests.
How is it treated?
Under SA's TB treatment guidelines, everyone diagnosed with TB – symptomatic or not – is treated using the same six-month course. Treatment for Drug Resistant forms of TB can take longer.
People typically become non-infectious within a few weeks of starting the standard treatment. As with symptomatic TB, treatment of asymptomatic TB should thus prevent further transmission of the bug.
One idea is that people with asymptomatic TB, who are not very ill, could be cured with a shorter treatment course, possibly with fewer medicines than the standard four antibiotics used for symptomatic disease. However, it isn’t yet clear how to identify who meets the criteria of less-severe disease, and if you could identify them, which combination of medicines you’d use to treat them, and for how long.
Based on the success of TB preventative therapy, where someone exposed to TB takes one or two antibiotics to kill the bug before they become ill, Scriba suggests that mild asymptomatic TB might be cured with simpler, shorter regimens. Ultimately, large, well-designed clinical trials are needed to answer such questions.
There is also a more immediate concern. Preventative therapy is sufficient for the treatment of healthy people with latent TB infection – where the body essentially has the bug under control. However, it may not to be sufficient for people with asymptomatic TB, where, even though there are no symptoms, there is already disease and the immune system does not have the bug under control.
The fear around accidentally treating people with asymptomatic TB with TB preventative therapy is twofold. First, it may not work for that person since the drug combination is not strong and varied enough. Second, it might encourage the development of drug resistance.
How we should deal with this risk, and how big this risk actually is, is unclear at this point.
And then there is the exciting possibility of a new TB vaccine – M72 – which has already shown potential for preventing development of the disease in people with latent TB infection in a large phase 2 clinical trial.
The vaccine is being assessed in a massive phase 3 study, partly being conducted in South Africa. It is likely that a vaccine that prevents active TB disease will also provide some protection against asymptomatic TB.
There are many unanswered questions about asymptomatic TB. We don’t know exactly how many people have it or how infectious it is. We don’t know the optimal way to treat it, or how much it is contributing to TB transmission in South Africa.
But what we do know is that there are many people with asymptomatic TB and that we won’t find them if we rely mostly on symptom screening. If we want to combat TB more effectively, investing in research on asymptomatic TB is non-negotiable.
See more from MedicalBrief archives:
SA and Indonesia collaborate on asymptomatic TB study
Digital X-rays increase TB detection in asymptomatic South Africans
Shorter, simpler DR-TB regimen in the pipeline for South Africa
Most TB patients don't have persistent cough – global study
Blood biomarker able to predict risk for TB disease progression