Asymptomatic TB: A hidden challenge for TB control

Asymptomatic tuberculosis (TB) is common and biologically more complex than previously understood, with implications for treatment and care strategies. This is according to University of Cape Town (UCT) researchers, who have published new findings in Nature Communications that challenge current approaches to TB detection and control in South Africa.

The study was led by researchers at the South African Tuberculosis Vaccine Initiative (SATVI).

South Africa carries one of the world’s heaviest burdens of TB. It has recently become clear that many people with active TB do not recognise or report typical symptoms such as a cough, fever or weight loss. Studies have shown that over half of all TB cases identified in national surveys are asymptomatic and some community screening initiatives in South Africa have found that more than 80% of people with TB are asymptomatic. Despite its prevalence, asymptomatic TB remains poorly understood from a biological perspective, and current diagnostic tools developed for symptomatic patients perform poorly when screening for asymptomatic disease in communities.

“This represents a critical gap in TB control,” said Professor Thomas Scriba, co-director of SATVI and corresponding author on the study. “If we cannot effectively detect and diagnose asymptomatic TB in community settings, we cannot hope to control TB transmission at a population level. Our findings highlight why we need new approaches to asymptomatic TB screening and management.”

Two biologically distinct subtypes of asymptomatic TB

The most significant finding from this research is that asymptomatic TB is not a single disease entity. Using advanced transcriptomic (gene expression) and proteomic (protein) analysis of blood samples, researchers identified two distinct subtypes of asymptomatic TB with markedly different biological features and disease severity.

The two subtypes showed striking differences in key markers of disease severity. Individuals in the more severe asymptomatic cluster had higher bacterial loads in sputum (indicating more active disease), more chest radiographic abnormalities and more pronounced inflammatory profiles that resembled symptomatic TB cases. In contrast, the milder asymptomatic cluster had features more similar to individuals with early or long-term controlled infection. This heterogeneity suggests that asymptomatic TB patients fall along a spectrum of disease progression – some may be in early stages of infection with minimal inflammation, while others are on a more rapid pathway to symptomatic disease and likely with active bacterial shedding and suggest that different clinical management approaches may be warranted for these two groups.

“The findings raise the intriguing possibility that individuals with asymptomatic TB on different trajectories of progression or regression can be identified by their blood inflammatory profile.”

A critical implication of this work is that current blood-based biomarkers – diagnostic tests developed and validated in symptomatic patients – perform substantially worse when applied to asymptomatic TB screening. The study found that at 90% sensitivity, existing transcriptomic signatures achieved specificity below 50% for asymptomatic TB, well below the minimum performance standards recommended by the World Health Organization for screening tests. The research demonstrates that a one-size-fits-all approach is inadequate.

What this means for future research

The research has additional implications for TB transmission. All participants in the study with asymptomatic TB had microbiologically confirmed disease with detectable bacteria in sputum, and the majority in the more severe asymptomatic cluster were sputum smear-positive, indicating significant bacterial shedding. Recent studies have demonstrated that M. tuberculosis aerosol release can occur even without symptoms like coughing. The finding that asymptomatic TB includes individuals with substantial bacterial burdens and radiographic disease raises the likelihood that asymptomatic individuals could contribute meaningfully to TB transmission in communities.

“The discovery of biomarkers that distinguish between asymptomatic TB subtypes could inform clinical decision-making about the optimal treatment regimens.”

The findings also suggest that diagnostic biomarkers require optimisation specifically for asymptomatic TB screening rather than simple adaptation of existing TB tests developed for symptomatic TB. “Future research should investigate whether the two asymptomatic TB subtypes represent different prognoses, transmission risks or treatment needs. Additionally, clinical trials could determine whether the two subtypes respond differently to TB preventive therapy or full TB treatment. The discovery of biomarkers that distinguish between asymptomatic TB subtypes could inform clinical decision-making about the optimal treatment regimens,” said Professor Scriba.

Professor Mark Hatherill, the study’s co-author and SATVI director, commented: “The findings raise the intriguing possibility that individuals with asymptomatic TB on different trajectories of progression or regression can be identified by their blood inflammatory profile. Our next challenge is how to design rigorous, prospective studies to test this idea.”

About asymptomatic TB in South Africa

South Africa has the highest TB burden globally and faces a dual epidemic of TB and HIV. National TB prevalence surveys have documented that more than 50% of TB cases detected are asymptomatic. Community-based screening studies in South Africa have reported even higher proportions of asymptomatic TB, exceeding 80% in some studies. This means that tens of thousands of South Africans with active TB disease remain undetected in communities, potentially continuing to transmit infection. Improving detection and management of asymptomatic TB is critical to achieving South Africa’s TB control goals and contributing to global TB elimination.