Asymptomatic Tuberculosis: A Key Challenge in Disease Transmission

TB QUEST, a European field study, investigates how asymptomatic tuberculosis contributes to transmission and helps improve prevention and disease control.

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As we celebrate World Tuberculosis Day (24 March), it is important to recognize the progress and challenges in the fight against tuberculosis, the disease caused by the bacteria Mycobacterium tuberculosis. Over the past decade, global efforts against tuberculosis have delivered meaningful advances, including expanded access to rapid molecular diagnostics, shorter and more effective treatment regimens, especially for drug resistant tuberculosis, and strengthened political and scientific commitment. These advances have improved case detection, treatment outcomes, and preventive therapy coverage, reinforcing tuberculosis as a central priority in global health. However, persistent knowledge and funding gaps continue to limit the impact and coverage of these public health interventions.

Asymptomatic tuberculosis is a relatively new scientific discovery and a deeper understanding of this disease state could carry significant implications for disease control

Tuberculosis control has traditionally relied on a binary classification of the disease into two tuberculosis states, the so-called “latent” tuberculosis infection and “active” tuberculosis disease. In the last few years, however, several studies have challenged this dichotomous paradigm, suggesting instead that tuberculosis exists along a spectrum of disease. Within this continuum, some individuals have asymptomatic tuberculosis, where Mycobacterium tuberculosis is present and detectable but the individual does not report the typical tuberculosis symptoms, including cough, fever, weight loss, or night sweats. Asymptomatic tuberculosis is a relatively new scientific discovery and a deeper understanding of this disease state could carry significant implications for disease control. That’s where our TB QUEST team comes in.

From left to right: Amuly Chilopola, clinical coordinator of the study, discussing screening and treatment plans with the TB QUEST clinical team; in Manhiça. Joanna Ehrlich, a Research Fellow and scientific coordinator with the TB QUEST project working with the field team to collect data from trackers that objectively monitor symptoms of the project’s patients. Amuly Chilopola carries the portable X-ray machine to the clinic for another day of TB QUEST screenings.

Modeling studies have suggested that up to 68% of global tuberculosis transmission could be attributed to an asymptomatic source. However, there is currently not a single study that shows a secondary tuberculosis case originating from an asymptomatic tuberculosis case. So, the vital question to answer is: does asymptomatic tuberculosis play an important role in global tuberculosis transmission? Excitingly, the epidemiological design of TB QUEST will identify whether asymptomatic tuberculosis transmits similarly to symptomatic tuberculosis with very strong certainty. Recognizing asymptomatic tuberculosis transmission could change global tuberculosis control efforts, highlighting the limitations of symptoms-based case-finding strategies and the urgent need for more sensitive detection methods.

Recognizing asymptomatic tuberculosis transmission could change global tuberculosis control efforts, highlighting the limitations of symptoms-based case-finding strategies and the urgent need for more sensitive detection methods

Diagnosing asymptomatic tuberculosis is far less simple than symptomatic tuberculosis. Despite these difficulties, recent prevalence surveys have uncovered that around 50% of tuberculosis cases are asymptomatic. TB QUEST will also provide key insights to optimize the detection of asymptomatic tuberculosis, combining artificial-intelligence (AI) software, radiological evaluations and bacteriological tests.

Pushing the boundaries of what is known

Researchers at ISGlobal in Barcelona, Spain and the Centro de Investigação de Saúde de Manhiça (CISM) in Manhiça, Mozambique are working together to bridge the research gap through the TB QUEST project, funded by the European Research Council (ERC) and led by Alberto Garcia-Basteiro. Pushing the boundaries of what is known, the TB QUEST project will answer these key questions about asymptomatic tuberculosis and help us understand the role of asymptomatic disease within the natural history of tuberculosis disease development.

Next generation diagnostics, treatment, and active case finding strategies depend heavily on what we know about asymptomatic transmission

Using the highest scientific standards and technological advances, TB QUEST design will allow for maximizing the scientific outputs from the study:

• Firstly, a very large sample of HIV+ participants is being screened, which will provide the number of asymptomatic and symptomatic cases required to observe sufficient secondary transmission, leading to high statistical power and a true representation of variability.
• Secondly, exciting advances in genomic epidemiological methods will help us identify asymptomatic tuberculosis transmission links with strong certainty, and understand the timing and circumstances surrounding transmission events.
• Thirdly, we will identify and explore clinical considerations for multiple asymptomatic tuberculosis phenotypes, including newly postulated stages that may evade common screening strategies using chest x-ray.
• Finally, the inclusion of new, cutting edge tools using AI software will contribute to the objective characterization of asymptomatic tuberculosis, solidifying our understanding of the disease stage within the natural history of tuberculosis.

All in all, it is time to stop focusing solely on the tuberculosis that willingly shows itself to us through symptoms. On this World Tuberculosis Day, we are reminded why this shift in focus is so urgent. Next generation diagnostics, treatment, and active case finding strategies depend heavily on what we know about asymptomatic transmission, which is where the project gets its name: a quest is defined as a search or pursuit made to find or obtain something. TB QUEST searches for the responses to these vital queries and the results will reveal the best path forward for accelerating progress towards tuberculosis elimination.