• Tuberculosis
• Respiratory Infection
• Imaging/CT MRI etc

Tuberculosis (TB) is a pressing global human health problem that resulted in over 10 million cases and 1.3 million deaths in 2022.1 The WHO proposes to end this global epidemic by 2035, which would necessitate reducing TB deaths by 95%, TB incidence by 90%, and eliminating catastrophic costs for TB-affected households compared with the 2015 levels. There is doubt this can be achieved.

An established means to attempt these reductions would be greater yet more targeted use of preventive antibiotic therapy for clinically asymptomatic (referred to as latent) early or limited infection. A recent systematic review estimated the overall effectiveness of preventive treatment (TPT) is 49%.2 The risk reduction conferred by TPT was found greater in high-burden (0.31) versus low-burden (0.58) settings. Most studies covered by the analysis deployed established TPT regimens of 6–9 months isoniazid (H), 4 months of rifampicin (R) or 3 months of combined RH therapy. Shorter or less intensive rifapentine (P) containing regimens of equivalent efficacy (1HP and 3HP) are now available.3 The review concluded the number needed to treat with TPT to prevent one case of ‘active’ TB was between 29 and 43 in high-burden settings and between 213 and 455 in low-burden settings. These numbers reflect the low overall risk of TB even following infectious contact (5–10% mainly over the first 2 years). In the review, those with a positive tuberculin-skin-test (TST) or IFN gamma release assay (IGRA) result at baseline benefitted from greater protection by TPT (≥80%), regardless of age. However, the specificity of these tests to predict progression is modest, and thus, their widespread use and implementation of TPT in high-burden settings is therefore low.

The modest specificity of IGRA and TST to predict progression has prompted the search for tests of greater positive predictive value, of which the most prominent are based on transcriptomic analysis of peripheral blood.4 The same problem of relatively low rates of progression and thus a need for large and prolonged studies if a clinical benchmark is deployed also inhibits development and validation of such markers. Recognising latent TB to be heterogeneous,5 higher resolution anatomical and functional imaging of humans and non-human primates in the form of combined 18-Fluorodeoxyglucose positron emission and computed tomographic scanning (PET/CT) has been proposed as a means to both stratify risk and thereby reduce sample size in experimental medicine studies.6 In 35 asymptomatic, antiretroviral-therapy-naive, HIV-1-infected adults with latent TB, Esmail et al identified 10 individuals with pulmonary abnormalities suggestive of subclinical, active disease who were substantially more likely to progress to clinical disease.7 In environments of high TB incidence, reinfection may account for a proportion of radiographic changes. More recently, and in a low incidence environment, Kim et al investigated 20 household contacts of TB by PET/CT, reporting that four of eight PET-CT-positive contacts sampled had Mycobacterium tuberculosis identified (three through culture, one via nucleic acid amplification) from intrathoracic lymph nodes or bronchial wash. Very interestingly, a mycobacteriophage-based technique to lyse M. tuberculosis and thus render its DNA accessible to PCR amplification was positive in six ultimately treated PET/CT-positive contacts, but negative in three of the four remaining PET/CT-positive contacts who had stable or resolving changes at follow-up. The test was also negative in three of the four contacts with a negative baseline PET/CT scan.8 PET/CT cannot be a routine diagnostic, but a validated accurate microbiological test of this nature would be very important.

In this issue of the journal, the same authors reporting the same study incrementally add to their prior findings by proposing four radiographic feature patterns that associate with distinct clinical and microbiological outcomes, further supporting the utility of PET/CT for objective classification of TB infection phenotypes.9 The classifications were (1) positive PET and positive CT; (2) positive PET and negative or indeterminate CT; (3) indeterminate PET and negative CT; (4) negative PET and negative CT. Limitations of power, follow-up restricted to 12 months, and that 7 out of 20 contacts were treated thus modifying the natural history are acknowledged.

A much larger prospective study of PET/CT in untreated TB contacts followed for up to 5 years is not cited, although in the public domain.10 A total of 250 HIV-uninfected, adult household contacts of rifampicin-resistant TB with a negative symptom screen underwent baseline PET/CT, repeated in 112 after 5–15 months. Following guidelines, participants did not receive preventive therapy. All participants had intensive baseline screening with spontaneous, followed by induced, sputum sampling and were then observed for an average of 4.7 years for culture-positive disease. Baseline PET/CT abnormalities were evaluated in relation to culture-positive disease. At baseline, 59 (23.6%) participants had lung PET/CT findings consistent with TB, of which 29 (11.6%) were defined as subclinical TB with active features. A further 83 (34.2%) had other lung parenchymal abnormalities and 108 (43.2%) had normal lungs. During 1107 person-years of follow-up, 14 cases of culture-positive TB were diagnosed. Six cases were detected by intensive baseline screening, all would have been missed by symptom-based screening strategy and only one was detected by a WHO-recommended chest X-ray screening strategy. Those with baseline subclinical TB lesions on PET/CT were significantly more likely to be diagnosed with culture-positive TB over the study period, compared with those with normal lung parenchyma (10/29 (34.5%) vs 2/108 (1.9%), HR 22.37, p<0.001). These findings challenge the latent/active TB paradigm demonstrating that subclinical disease exists up to 4 years prior to microbiological detection and/or symptom onset. There are important implications for screening and management of TB. A review of data from TB prevalence population surveys to estimate the proportion of TB that is subclinical concluded a median of 50.4% of prevalent bacteriologically confirmed TB was subclinical and thus liable to contribute significantly to transmission.11

Another aspect to the reports of Kim et al is the interchangeable use of the terms ‘incipient’ and subclinical TB. The latter has a clinical case definition, whereas the former is inferential, making benchmarking of a study more difficult. Renewed appreciation of the spectrum of asymptomatic TB states has contributed to this problem of inconsistent terminology. Inconsistency in definitions, terminology and diagnostic criteria for different TB states may limit progress in research and product development that are needed to achieve TB elimination. A new consensus framework to classify TB that accommodates key disease states but at the same time sufficiently simple to support pragmatic research and implementation has recently been proposed.12 Through an international Delphi exercise that involved 71 participants representing a wide range of disciplines, sectors, income settings and geographies, consensus was reached on a set of conceptual states, related terminology and research gaps. The International Consensus for Early TB (ICE-TB) framework distinguishes disease from infection by the presence of macroscopic pathology and defines two subclinical and two clinical TB states based on reported symptoms or signs of TB, further differentiated by likely infectiousness (figure 1). The presence of viable M. tuberculosis and an associated host response are prerequisites for all states of infection and disease.

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Figure 1

Conceptual Mycobacterium tuberculosis infection and tuberculosis (TB) states identified with consideration of benefit resulting from diagnosis and treatment (A) and pathways across infection and disease states (B). Pathology=macroscopic pathology; infectious=ability to cause new Mtb infections; symptoms and signs=TB symptoms and signs; self-cleared=absence of viable Mtb after Mtb infection, never crossed disease threshold and not received treatment; infected=persistence of Mtb infection, including after microbiological or self-cure from disease, remains at risk of developing disease. Full recovery=disease resolved in absence of post-TB impairment, with or without treatment; post-TB=disease or disability due to damage caused by TB pathology after microbiological or self-cure. Reproduced from Coussens AK, Zaidi SMA, Allwood BW, et al. Classification of early tuberculosis states to guide research for improved care and prevention: an international Delphi consensus exercise. Lancet Respir Med 2024;12(6):484-98. doi: 10.1016/S2213-2600(24)00028-6 with permission from Elsevier.