Asymptomatic tuberculosis and implications for programmatic action

Not all individuals who have tuberculosis (TB) present to health services with symptoms or declare that they are sick. Thus, people with asymptomatic forms of disease – sometimes referred to as subclinical TB – may only be identified during screening or during TB prevalence surveys. Recent reviews estimated that about half of people with TB detected by national TB prevalence surveys had bacteriologically confirmed disease but reported no classical TB symptoms (e.g. persistent cough) when questioned (1–5).

The natural history of TB remains incompletely understood. Current thinking sees asymptomatic TB as a stage on a continuum that moves from infection with Mycobacterium tuberculosis complex to clinical disease. Although both progression and reversion between these states are known to occur, less is known about what causes these events to happen and at what rate. Studies of these phenomena have not adequately described the symptom status of participants (6, 7).

What is the public health significance of asymptomatic TB?

Interest in the public health significance of asymptomatic TB has increased in recent years, owing to a growing emphasis on screening and earlier diagnosis. The World Health Organization (WHO) released its first compilation of evidence-based recommendations for TB screening in 2013, and updated them in 2021 (8–11). WHO has also released guidance on TB disease prevalence surveys and surveillance; the guidance also touches on active case finding for TB (12, 13). TB screening and active case finding for TB were enshrined in the End TB Strategy after 2015 (14).

One of the main questions regarding the public health significance of asymptomatic TB is whether it is worth focusing on it as distinct from other forms of TB disease that are known to cause people to become sick or disabled, or to die. One important implication of people with asymptomatic TB not feeling sick is that they do not present for care. Unless active case finding with symptom-agnostic tools is used, then diagnosis of such people would be missed. There is important uncertainty about the outcomes of asymptomatic TB. If a large proportion resolves spontaneously, then the burden of illness associated with asymptomatic TB may be minimal. Conversely, untreated asymptomatic TB may contribute to the pathology associated with severe clinical TB (e.g. cavitation); therefore, delays in starting treatment will influence outcomes in such patients.

Another key question is whether asymptomatic TB matters for transmission of TB. There is uncertainty about the duration of infectiousness of asymptomatic TB and therefore about its contribution to transmission if it is not treated. It is likely that individuals with asymptomatic, pulmonary, bacteriologically confirmed TB contribute substantively to TB transmission and the global burden of TB disease (15), even if they have minimal or no cough. Analysis of data from 14 countries in Africa and Asia suggests that about two thirds of global TB transmission may be from asymptomatic TB (95% prediction interval: 27–92%) (16).

Defining asymptomatic TB

The current WHO definition of notifiable TB does not distinguish between symptomatic and asymptomatic disease (13). Nevertheless, asymptomatic TB is increasingly recognized as relevant to current discussions on surveillance, infection control, TB elimination and more. In addition to helping enumeration and surveillance, standard definitions of asymptomatic TB can eventually also guide the choice of diagnostic tests (e.g. expansion of the use of chest X-ray) and treatments offered. Defining asymptomatic TB will also signal the importance of the condition in programmatic management.

In October 2024, WHO convened a consultation with a broad constituency, including national TB programme staff, civil society, and technical and funding agencies. The aims were to develop a definition of asymptomatic TB relevant for TB programmes and research, and to identify research gaps and set priorities that are critical for WHO guidance. As a result of this consultation, asymptomatic TB was defined – split into bacteriologically confirmed and unconfirmed – resulting in subsets of current WHO definitions (Table 1). The new definitions are intended to be practical to implement but explicit enough to serve their purpose. The main distinguishing criterion at this point would be a bacteriological test (e.g. a WHO-recommended rapid diagnostic test, culture or smear microscopy). WHO will disseminate these definitions for programmes to use, and will also develop guidance on their operationalization.

Table 1 Definitions of asymptomatic TB following a WHO consultation 2024 (compared with the current TB definitions according to the latest WHO guidance (13))

Estimating the burden of asymptomatic TB

Recent literature on the natural history of TB, especially in relation to the progression and reversion of symptom status, has raised important questions about the most appropriate interpretation of TB incidence (17). For the 29 countries whose burden estimates are informed by national TB prevalence surveys in particular (which account for about two thirds of global TB incidence), existing estimates of TB incidence and mortality already incorporate the incidence of asymptomatic TB. These estimates are based on an assumed natural history in which most people with asymptomatic TB ultimately develop symptoms. By contrast, recent modelling using data on the natural history of TB from the pre-chemotherapy era, coupled with contemporary data from national TB prevalence surveys, has raised the possibility that about half of those with asymptomatic TB may never develop symptoms. Further work in relation to this modelling is currently underway; for example, to consider how inferences from cohorts from the pre-chemotherapy era may apply to contemporary settings.

In September 2024, WHO convened the Global Task Force on TB Impact Measurement (18). The meeting included discussion of the implications of asymptomatic TB for incidence estimation. A key outcome of this meeting was strong consensus for the following approach to burden estimation:

• first, for country-specific incidence estimates, WHO would publish estimates that would be consistent with the incidence of symptomatic TB (this would ensure continuity with previous estimates, while also being more relevant for most current TB programmes, which are focused on optimizing services for symptomatic TB); and
• second, WHO would publish “complementary” estimates to recognize the importance of asymptomatic TB for transmission (in particular, an estimate of the global prevalence of TB, stratified by asymptomatic and symptomatic TB); work to develop these estimates is ongoing, in parallel with collaborative work to validate recently published estimates for natural history parameters.

What are the programmatic implications to detect and treat asymptomatic TB?

WHO is currently reviewing its guidance to determine what changes will be needed for countries to accommodate asymptomatic TB in programmatic actions, and to define research needs to enhance knowledge about the condition.

In terms of surveillance, programmes that have digital case-based reporting may consider the inclusion of data variables to register the presence or absence of symptoms during TB screening.

Diagnostic approaches currently remain focused on available technologies (e.g. microscopy, culture and molecular options). Although most people with asymptomatic TB are expected to have a pulmonary localization, it is possible that they only have extrapulmonary forms of disease. For forms of asymptomatic TB that are bacteriologically unconfirmed using available tests, the diagnosis would rest on chest radiography findings or other imaging (e.g. computed tomography) and histopathological examination, supported by a personal history that is suggestive of contact with or previous history of TB.

Current WHO recommendations on TB treatment do not distinguish between people who have symptoms and those who have asymptomatic TB; new research is needed to determine whether asymptomatic TB can be treated effectively with regimens of different composition or duration. Other recommendations on TB screening and infection prevention and control would also need to be adapted to better reflect the eventuality of asymptomatic TB.

References

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2. Teo AKJ, MacLean EL, Fox GJ. Subclinical tuberculosis: a meta-analysis of prevalence and scoping review of definitions, prevalence and clinical characteristics. Eur Respir Rev. 2024;33. doi: https://doi.org/10.1183/16000617.0208-2023.

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