The definition of tuberculosis infection based on the spectrum of TB disease [TB0112]

Tuberculosis (TB) is an airborne disease transmitted by inhaling droplet nuclei, ranging from 1 to 5 µm, released when contagious individuals cough, speak, sing, or sneeze. After exposure to Mycobacterium tuberculosis (Mtb), around 20–25% of individuals become infected. Of these, 5–10% may develop active TB within the first five years. In the remaining 90%, the immune system—via innate and adaptive responses—controls the pathogen's replication. About 10% of infected individuals may develop active TB at some point in their lifetime. The risk is significantly higher for those co-infected with HIV, with a 10% annual risk and up to a 50% lifetime risk of developing active TB. The term "latent tuberculosis infection" (LTBI) refers to a state of persistent immune response to Mtb antigens, as detected by tests like the tuberculin skin test (TST) or interferon-gamma (IFN-γ) release assay (IGRA), without clinical signs of active TB.

Historically, a dualistic approach—classifying cases as either latent TB infection (LTBI) or active TB disease—was used for research, prevention, diagnosis, and treatment. While this simplified TB pathogenesis, recent evidence reveals a more complex continuum from LTBI to active TB disease. This continuum is shaped by the metabolic state of Mycobacterium tuberculosis (Mtb) (ranging from dormancy to intermittent and active replication) and the host's immune responses (innate and adaptive), which work to control infection.

The World Health Organization (WHO) has proposed removing the term "latent," using simply "TB infection" to reflect the broader range of Mtb states, including dormancy. This article discusses the evolving definition of TB infection, the tools recommended for its diagnosis and treatment, and new perspectives on prevention and public health.

To better capture this continuum and support future clinical differentiation, two additional stages—"incipient" and "subclinical" TB—have been introduced. The entire TB infection-to-disease spectrum can now be described in six stages: uninfected individual, TB infection, incipient TB, subclinical TB without symptoms, subclinical TB with unrecognized symptoms, and symptomatic TB disease.

The term "incipient TB," which falls between TB infection and subclinical TB, is challenging to define due to limited evidence. In this stage, bacilli are viable, likely alternating between dormancy (typical of TB infection) and periods of low metabolic activity and replication. Patients with incipient TB are probably not infectious. Currently, no validated tools exist to specifically diagnose incipient TB. Infection diagnostic tests like the tuberculin skin test (TST) and interferon-gamma release assays (IGRAs) are positive and remain so as the disease progresses toward active TB. Due to the minimal bacterial replication and limited lesions at this stage, it is difficult to recommend an “ideal” drug regimen for treating incipient TB.

Subclinical TB is classified as "disease" because of the presence of viable Mycobacterium tuberculosis (Mtb) bacteria, which, despite not causing clinical symptoms, produce detectable abnormalities through radiological or microbiological tests. In this stage, the bacilli are metabolically active and replicating, making subclinical TB potentially infectious. Diagnosis relies on microbiological and radiological tools, as traditional clinical symptoms are often absent or unrecognized by patients.

Subclinical TB poses significant risks for Mtb transmission in communities, as it may be more prevalent than commonly recognized. Based on a prevalence-to-notification ratio of roughly 2:1, there may be approximately 7 million subclinical TB cases within a global total of 14 million TB cases. Evidence from prevalence surveys indicates that the gap between existing and diagnosed TB cases often consists of culture-positive (frequently sputum smear-negative), symptom-free patients showing radiological abnormalities. Even among sputum smear-positive individuals with high bacterial loads, between 34% and 68% may be asymptomatic. The diagnostic tools for subclinical TB are the same as those for active TB, although clinical criteria may be less reliable, as many individuals do not report symptoms.

To effectively monitor and evaluate the success of TB infection management policies, both at individual clinics and on a national level, assessing the "cascade of care" is essential. The cascade of care outlines each step from TB infection diagnosis through to treatment completion, highlighting critical stages such as screening, initial testing, receiving test results, referral if positive, medical examination, treatment recommendation, treatment initiation, and treatment completion. Tracking the proportion of individuals at each stage is crucial for understanding program effectiveness. Additionally, adverse events from any drug regimen should be actively monitored.

For significant public health impact, it is ideal that most individuals diagnosed and recommended for TB infection treatment complete their treatment. Maintaining a TB infection registry, similar to those for active TB cases, is essential.

The World Health Organization (WHO) identifies three key research areas for TB infection management: assessing progression risks from TB infection to active disease in high-risk groups, developing optimal algorithms to exclude active TB, and improving the performance of TB infection tests in at-risk populations. Enhanced diagnostic methods for at-risk populations needing preventive therapy and establishing effective treatment strategies for recent contacts of multidrug-resistant TB patients are also high research priorities.

Source: Migliori GB, Ong CWM, Petrone L, et al. The definition of tuberculosis infection based on the spectrum of tuberculosis disease. Breathe 2021; 17: 210079.