PET-CT-guided characterisation of progressive, preclinical tuberculosis infection and its association with low-level circulating Mycobacterium tuberculosis DNA in household contacts in Leicester, UK: a prospective cohort study

Kim, Jee Whang; Bowman, Karen; Nazareth, Joshua; Lee, Joanne; Woltmann, Gerrit; Verma, Raman; Sharifpour, Meedya; Shield, Christopher; Rees, Catherine; Kamil, Anver; Swift, Benjamin; Haldar, Pranabashis

Abstract

Background
Incipient tuberculosis, a progressive state of Mycobacterium tuberculosis infection with an increased risk of developing into tuberculosis disease, remains poorly characterised. Animal models suggest an association of progressive infection with bacteraemia. Circulating M tuberculosis DNA has previously been detected in pulmonary tuberculosis by use of Actiphage, a bacteriophage-based real-time PCR assay. We aimed to investigate whether serial [18F]fluorodeoxyglucose ([18F]FDG)-PET-CT could be used to characterise the state and progressive trajectory of incipient tuberculosis, and examine whether these PET-CT findings are associated with Actiphage-based detection of circulating M tuberculosis DNA.

Methods
We did a prospective 12-month cohort study in healthy, asymptomatic adults (aged ≥16 years) who were household contacts of patients with pulmonary tuberculosis, and who had a clinical phenotype of latent tuberculosis infection, in Leicester, UK. Actiphage testing of participants’ blood samples was done at baseline, and [18F]FDG PET-CT at baseline and after 3 months. Baseline PET-CT features were classified as positive, indeterminate, or negative, on the basis of the quantitation (maximum standardised uptake value [SUVmax]) and distribution of [18F]FDG uptake. Microbiological sampling was done at amenable sites of [18F]FDG uptake. Changes in [18F]FDG uptake after 3 months were quantitatively categorised as progressive, stable, or resolving. Participants received treatment if features of incipient tuberculosis, defined as microbiological detection of M tuberculosis or progressive PET-CT change, were identified.

Findings
20 contacts were recruited between Aug 5 and Nov 5, 2020; 16 of these participants had a positive result on IFNγ release assay (QuantiFERON-TB Gold Plus [QFT]) indicating tuberculosis infection. Baseline PET-CT scans were positive in ten contacts (all QFT positive), indeterminate in six contacts (three QFT positive), and negative in four contacts (three QFT positive). Four of eight PET-CT-positive contacts sampled had M tuberculosis identified (three through culture, one through Xpert MTB/RIF Ultra test) from intrathoracic lymph nodes or bronchial wash and received full antituberculosis treatment. Two further unsampled PET-CT-positive contacts were also treated: one with [18F]FDG uptake in the lung (SUVmax 9·4) received empirical antituberculosis treatment and one who showed progressive [18F]FDG uptake received preventive treatment. The ten untreated contacts with [18F]FDG uptake at baseline (seven QFT positive) had stable or resolving changes at follow-up and remained free of tuberculosis disease after 12 months. A positive baseline Actiphage test was associated with the presence of features of incipient tuberculosis requiring treatment (p=0·018).

Interpretation
Microbiological and inflammatory features of incipient tuberculosis can be visualised on PET-CT and are associated with M tuberculosis detection in the blood, supporting the development of pathogen-directed blood biomarkers of tuberculosis risk.

Citation

Kim, J. W., Bowman, K., Nazareth, J., Lee, J., Woltmann, G., Verma, R., Sharifpour, M., Shield, C., Rees, C., Kamil, A., Swift, B., & Haldar, P. (2024). PET-CT-guided characterisation of progressive, preclinical tuberculosis infection and its association with low-level circulating Mycobacterium tuberculosis DNA in household contacts in Leicester, UK: a prospective cohort study. The Lancet Microbe, 5(2), e119-e130. https://doi.org/10.1016/s2666-5247%2823%2900289-6

• Journal Article Type: Article
• Acceptance Date: Jan 3, 2024
• Online Publication Date: Jan 17, 2024
• Publication Date: 2024
• Deposit Date: Mar 12, 2024
• Publicly Available Date: Mar 12, 2024
• Journal: The Lancet Microbe
• Print ISSN: 2666-5247
• Electronic ISSN: 2666-5247
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 5
• Issue: 2
• Pages: e119-e130
• DOI: https://doi.org/10.1016/s2666-5247%2823%2900289-6
• Keywords: Virology; Infectious Diseases; Microbiology (medical); Microbiology
• Additional Information: This article is maintained by: Elsevier; Article Title: PET-CT-guided characterisation of progressive, preclinical tuberculosis infection and its association with low-level circulating Mycobacterium tuberculosis DNA in household contacts in Leicester, UK: a prospective cohort study; Journal Title: The Lancet Microbe; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/S2666-5247(23)00289-6; Content Type: article; Copyright: © 2023 The Author(s). Published by Elsevier Ltd.