Mycobacterium tuberculosis (MTB)

Discovered over 140 years ago, tuberculosis (TB) remains one of the biggest public health challenges worldwide, causing substantial morbidity and mortality. Despite being preventable and curable,¹ the global burden of TB remains daunting. According to the World Health Organization (WHO), TB is one of the top ten causes of death and the leading cause of death from a single infectious agent.¹ The availability of the right diagnostics solutions for TB is a key component of the recommended interventions to achieve global elimination goals.

According to the latest WHO TB report, in 2023, an estimated 10.8 million people fell ill with TB, and >1.25 million people died of TB disease, of which 161,000 were HIV positive.¹ 400,000 people were estimated to have developed drug-resistant TB.¹ The burden of TB is disproportionately high in low- and middle-income countries, where most of TB cases and deaths occur. Vulnerable populations, including those with HIV, malnourished individuals, and the economically disadvantaged, are at particularly high risk.^2,3 The disease not only affects individuals' health but also impinges on their economic well-being and that of their families.⁴

The transmission dynamics of TB make its control both a challenge and a necessity. TB is caused by Mycobacterium tuberculosis and spreads through the air when people with active TB in their lungs cough, sneeze, or talk.³ Without proper treatment, TB can become a severe and often fatal disease, emphasizing the need for accurate and early diagnosis.

Human tuberculosis exists on a continuous spectrum from latent TB infection (LTBI, or TB infection) to active TB disease.⁵ After initial exposure, M. tuberculosis may be eliminated by the host immune response, persist as a latent infection, or progress to primary active disease.⁵ Diagnostics and treatment interventions are different for managing TB infection or disease.

Individuals with latent TB infection (LTBI) have been infected with M. tuberculosis but do not show symptoms and are not contagious since the bacteria is viable but not actively replicating at the site of infection. The immune system keeps the bacteria in a dormant state. Approximately one-quarter of the world's population is estimated to have LTBI.⁶ Immunocompetent individuals with LTBI have a 5-10% lifetime risk of developing symptoms and progressing to active TB disease.⁷ Those with compromised immune systems, such as people living with HIV, have a higher risk of falling ill.

Diagnosing and treating LTBI is recommended in high-risk populations, including individuals with high risk of exposure to TB infection, or high risk of progression from latent to active TB.^7,8 Effectively targeting LTBI can significantly reduce the incidence of future TB cases, and it is also an essential part of the global TB elimination program of the WHO. Skin tests (e.g. TST and TBST) or blood-based tests (e.g. interferon-gamma release assays, IGRAs) are recommended to diagnose TB infection and inform preventive treatment decisions.^7,8

Incipient TB infection and subclinical TB disease are characterized by viable and replicating M. tuberculosis bacteria at the site of infection without or with tissue damage, respectively, but the patient lacks clinical TB symptoms. In turn, radiographic abnormalities or microbiologic evidence are absent during incipient TB but can be detected during subclinical disease.⁵

Active TB disease occurs when the immune system fails to contain the dormant bacteria, leading to an active infection. Individuals gradually develop less and less controlled abnormalities at the site of the infection by their immune systems that eventually lead to symptoms such as prolonged cough, fever, night sweats, and weight loss.³ Active TB is contagious when it affects the lungs or airways, spreading through airborne droplets when an infected person coughs, sneezes, or speaks. Timely diagnosis is critical to prevent further transmission, reduce disease severity by initiating adequate treatment, and improve patient outcomes. Delayed diagnosis can lead to prolonged infectiousness and transmission, increased complications, and higher mortality rates, especially in vulnerable populations.

Diagnosing active tuberculosis involves multiple steps, including a review of patient symptoms, chest X-ray, rapid molecular diagnostics, culture testing, and drug susceptibility testing. Molecular tests have a central role because they provide faster results. M. tuberculosis is a slow-growing bacterium, replicating only once every 18 to 24 hours. This slow replication makes culture-based diagnosis less timely, often taking weeks to yield results, which would delay appropriate therapy initiation.^1,9

Drug-resistant tuberculosis (DR-TB) further exacerbates the challenge due to its complexity, prolonged treatment, and poorer patient outcomes compared to drug-susceptible TB. Multidrug-resistant TB (MDR-TB) and extensively drug-resistant (XDR-TB) forms require prolonged treatment with second-line drugs that are often less effective, more toxic, and more expensive. Within the broader context of antimicrobial resistance (AMR), DR-TB serves as a prominent example of how resistance mechanisms can emerge, spread, and threaten public health efforts.

Successfully diagnosing and treating DR-TB improves patient outcomes and contributes to global AMR mitigation strategies, emphasizing stewardship, improved diagnostic infrastructure, and surveillance to contain and reduce the spread of resistant infections. DR-TB in most instances, is man-made primarily due to the lack of access to rapid and adequate diagnostic tools for drug susceptibility testing.

Nontuberculous mycobacteria (NTM) infections differ from tuberculosis (TB) in several ways, primarily in their epidemiology, pathogenicity, clinical significance, and treatment. Unlike M. tuberculosis, which is a human-adapted and obligate pathogen transmitted person-to-person, NTM species are environmental organisms found in soil, water, and biofilms.¹⁰ Infections with these facultative pathogens are typically acquired through inhalation or direct inoculation rather than human transmission.¹¹

NTM infections present with variable clinical significance and manifestations, ranging from pulmonary disease (often in patients with underlying lung conditions) to skin, soft tissue, and disseminated infections, particularly in immunocompromised individuals.11 Diagnosing NTM infections is crucial because they can mimic TB but require different management strategies. Further, NTMs often exhibit intrinsic antibiotic resistance and necessitate prolonged, species-specific multidrug regimens.¹¹

Without proper diagnosis and tailored treatment, NTM infections can lead to severe acute or chronic disease, tissue destruction, declining lung function, and poor outcomes, particularly in vulnerable populations such as individuals with cystic fibrosis or other conditions with bronchiectasis.¹¹ Accurate identification through molecular diagnostics and culture-based methods is essential to ensure appropriate therapy and prevent unnecessary TB treatment or delays in effective management.

Given the complexity between LTBI and active TB, drug-susceptible TB and DR-TB, and tuberculosis and nontuberculous infections, timely and accurate diagnostics are crucial for initiating appropriate treatment and informing decisions related to adequate public health and transmission control measures.

The WHO End TB strategy aims for a 95% reduction in TB deaths and a 90% cut in new cases by 2035.¹² Attaining these targets requires concerted efforts and investments in prevention, diagnostics, treatments, and healthcare infrastructure. Yet, there is much to do.

In 2023, there was still a sizable gap between the estimated number of people who develop TB each year (incident cases, 10.8 million) and the number of people newly diagnosed with TB and officially reported as a TB case (8.2 million).¹ Additionally, only 48% of patients received a WHO-recommended rapid diagnostic tests (WRDs) as the initial diagnostics in 2023.¹ This accounts for 3.9 million of the 8.2 million people newly diagnosed with TB in 2023.¹ The goal is for all notified patients to be tested initially with a WRD by 2027.¹

Tuberculosis remains a significant global health challenge in part due to its bacterial properties. Strengthening diagnostic capabilities in resource-limited settings is crucial for achieving global TB elimination. This includes investments in laboratory infrastructure and implementation of diagnostics for both latent and active forms of tuberculosis.

Enhanced access to advanced diagnostics will ensure underserved populations receive timely and accurate TB diagnoses, facilitating better prevention steps and health outcomes and reducing transmission.