A structural and metabolic framework for classifying pre-clinical tuberculosis infection phenotypes using 18F-FDG PET-CT: a prospective cohort analysis following M. tuberculosis exposure.

Tuberculosis (TB) control efforts are limited by ineffective characterisation of tuberculosis infection (TBI) -a heterogeneous spectrum of pre-clinical infection states, invisible to tools of routine clinical screening, that are associated with variable risk of progression to TB disease. In this prospective study, we use positron emission tomography-CT (PET-CT) as a high-resolution imaging modality to characterise and classify structural and metabolic features observed in 16 asymptomatic household TB contacts with normal chest radiographs. We identify four feature patterns that associate with distinct clinical and microbiological outcomes, supporting potential utility of PET-CT for objective classification of TBI phenotypes.

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.

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. FUNDING: MRC Confidence in Concept.

PET-CT for characterising TB infection (TBI) in immunocompetent subjects: a systematic review.

Introduction. There is emerging evidence of a potential role for PET-CT scan as an imaging biomarker to characterise the spectrum of tuberculosis infection (TBI) in humans and animal models.Gap Statement. Synthesis of available evidence from current literature is needed to understand the utility of PET-CT for characterising TBI and how this may inform application of PET-CT in future TBI research.Aim. The aims of this review are to summarise the evidence of PET-CT scan use in immunocompetent hosts with TBI, and compare PET-CT features observed in humans and animal models.Methodology. MEDLINE, Embase and PubMed Central were searched to identify relevant publications. Studies were selected if they reported PET-CT features in human or animals with TBI. Studies were excluded if immune deficiency was present at the time of the initial PET-CT scan.Results. Six studies - four in humans and two in non-human primates (NHP) were included for analysis. All six studies used 2-deoxy-2-[18F]fluoro-d-glucose (2-[18F]FDG) PET-CT. Features of TBI were comparable between NHP and humans, with 2-[18F]FDG avid intrathoracic lymph nodes observed during early infection. Progressive TBI was characterised in NHP by increasing 2-[18F]FDG avidity and size of lesions. Two human studies suggested that PET-CT can discriminate between active TB and inactive TBI. However, data synthesis was generally limited by human studies including inconsistent and poorly characterised cohorts and the small number of eligible studies for review.Conclusion. Our review provides some evidence, limited primarily to non-human primate models, of PET-CT utility as a highly sensitive imaging modality to reveal and characterise meaningful metabolic and structural change in early TBI. The few human studies identified exhibit considerable heterogeneity. Larger prospective studies are needed recruiting well characterised cohorts with TBI and adopting a standardized PET-CT protocol, to better understand utility of this imaging biomarker to support future research.