Public health implications of the evolving understanding of tuberculosis natural history

Tuberculosis is an ancient disease that needs modern attention. According to the Global Tuberculosis Report from 2022, there were 6.4 million people newly diagnosed with tuberculosis (TB). Among them, 1.6 million people died (187,000 from HIV/TB coinfection) (1). Slow progress towards international goals has been impeded by the COVID-19 pandemic and associated disruption to health care services. The immediate impact includes a decrease in the number of people newly diagnosed with TB and the increased number of deaths in 2020 for the first time since 2005 (2,3).

Traditionally, tuberculosis was divided into susceptible individuals that, upon exposure, contract Mycobacterium tuberculosis (MTB). The bacteria can either be successfully contained or progress to active disease. In 90% of individuals infected with the MTB, host's innate and adaptive immune responses manage to contain the infection and maintain an asymptomatic state. Individuals can harbour MTB as a latent infection that can reactivate–most commonly within the first two years after the acquisition and if or when a person becomes immune compromised due to comorbid conditions or therapies that modulate the immune response.

Understanding of the states of TB infection is evolving, and not surprisingly, the dichotomous separation is a simplification of the biological processes that govern the transition from infection to tuberculous disease.

The categories that define the tuberculosis spectrum can be understood by looking at the regulation of MBT metabolic activity and the host's innate and acquired immunity to TB (4). The classical latent TB infection and TB disease stages have been reclassified with the addition of two main groups: incipient and subclinical TB, that overall characterizes to what is known as the TB spectrum (5).

Incipient TB

MTB is viable but not cultivable with alternating periods of dormant metabolic activity and replication (4,5). Also, it has been described as an “asymptomatic, early pre-clinical disease during which pathology (bacteria replication and immune response) evolves. Radiological abnormalities or positive microbiological tests may or may not be present. This state may either evolve and lead to symptomatic clinical TB or regress and remain asymptomatic. Altered immune mediators such as interferon (IFN) signalling signatures, along with others, may provide biomarkers for this stage (6).

Subclinical TB

MTB is viable and can be grown in sputum culture, however, it does not cause the traditional TB symptoms found in clinical TB disease (5). Some authors have defined it as an asymptomatic state (7) or non-recognizable symptoms (5). This stage emphasizes the evolution from TB infection to TB disease. Antibodies to MTB antigens have shown to be potential biomarkers for distinguishing subclinical TB (5). Progression from incipient and subclinical TB can be speculated through detection of low levels of MTB-specific IgG antibodies (5).

The classic concept of TB progression is depicted alongside the evolving dynamic model (see Figure 1).

Figure 1:

Model representations of the natural history of M. tuberculosis infection and tuberculosis disease.

Diagnostic approach to tuberculosis states

The World Health Organization (WHO) and United Nations High-Level Meeting on TB in 2018, highlighted the need for new tests for TB infection, which can improve the differentiation between LTBI states and TB and stratify the risk of progression to TB among those infected (8,9). Several signals based on host RNA gene expression have been identified, and this avenue has been explored for potential biomarkers (10,11). One of these RNA signatures is being tested as a diagnostic prototype and is named Xpert-MTB-HR (12). It uses 3-genes (GBP5, DUSP3, and KLF2) and has been shown to distinguish individuals with TB from those with other pulmonary diseases in several settings (13). On the other hand, in a temporally well-defined cohort of TB household contacts, Tabone et al identified the 30 top differentially expressed genes (DEGs) perturbed in each TB state (incipient, subclinical, and clinical TB) compared to controls (14). Interestingly, they also analyzed other published signatures in their population, and they found very few genes overlapped with other previously published signatures. Given MTB's low virulence and metabolic activity in the incipient stage, it is challenging to determine the optimal treatment duration or regimen (2). Future treatment options could include therapeutic vaccines and TB antibiotics with immunosuppressive agents.

Individuals with subclinical stages do not have symptoms or present with atypical clinical symptoms; however, they have radiologic or microbiologic evidence of TB disease (5). A recent study from Zambia reported that people with confirmed tuberculosis meeting the definition of subclinical tuberculosis (no cough persisting for ≥2 weeks) frequently had a nonspecific or shorter duration of cough (for <2 weeks or other symptoms) (15). While it is likely that subclinical TB contributes to transmission, the proportion of MTB transmission attributed to subclinical TB is difficult to ascertain. However, a paper by Kendall et al has estimated that 7 to 10 million people are currently living with subclinical TB (16).

The current consensus for treating subclinical TB is similar to TB pulmonary disease (17); however, the role of short-course anti-tuberculous therapy remains to be defined.

LTBI is a mixed bag of heterogenous states that encompasses 25% of the global population, most of whom reside in low- and middle-income countries or within specific populations in high-income countries. The risk of progression to subclinical and full-blown TB is variable. To prevent one TB disease, the number needed to treat with preventive therapy is estimated to be between 67 and 157 persons (18). Refining the risk of “activation” and identifying a subset that should be prioritized because of the higher risk of transition to tuberculosis disease will have major implications for TB programs.

The emerging understanding that incipient TB is a subset of LTBI that is more likely to progress to TB disease and that subclinical TB can be responsible for transmitting MTB infection in communities suggests that current screening programs are insufficient to prevent the spread of infection as only symptomatic individuals undergo testing. For Canada to make progress towards meeting the goal of ending TB, active screening programs for populations with a higher prevalence of MTB infection with ability for detection and treatment early in the course of illness are needed to prevent the further spread of infection.

Contributors:

Writing – Original Draft, M Herrera, E Taguiam, KB Laupland, ZV Rueda, Y Keynan; Writing – Review & Editing, M Herrera, E Taguiam, KB Laupland, ZV Rueda, Y Keynan.

Ethics Approval:

All research meets the ethical guidelines, including adherence to the legal requirements of the study country.

Informed Consent:

N/A

Registry and the Registration No. of the Study/Trial:

N/A

Data Accessibility:

N/A

Funding:

No funding was received for this work.

Disclosures:

The authors have nothing to disclose.

Peer Review:

This manuscript has been peer reviewed.

Animal Studies:

N/A