Multi-level tuberculosis of the spine identified by 18 F-FDG-PET/CT and concomitant urogenital tuberculosis: a case report from the spinal TB X cohort.

BACKGROUND: Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb) and typically infects the lungs. However, extrapulmonary forms of TB can be found in approximately 20% of cases. It is suggested, that up to 10% of extrapulmonary TB affects the musculoskeletal system, in which spinal elements (spinal tuberculosis, STB) are involved in approximately 50% of the cases. STB is a debilitating disease with nonspecific symptoms and diagnosis is often delayed for months to years. In our Spinal TB X Cohort, we aim to describe the clinical phenotype of STB using whole-body 18 F-fluorodeoxyglucose positron emission tomography computed tomography (PET/CT) and to identify a specific gene expression profile for the different stages of dissemination on PET/CT. Here we report on the first patient recruited into our cohort who underwent PET/CT before treatment initiation, at 6-months and at 12-months - time of TB treatment completion. CASE PRESENTATION: A 27-year-old immunocompetent male presented with severe thoracolumbar back pain for 9 months with severe antalgic gait and night sweats. Magnetic resonance imaging (MRI) of the whole spine revealed multilevel spinal disease (T5/6, T11/12, L3/4) in keeping with STB. After informed consent and recruitment into the Spinal TB X Cohort, the patient underwent PET/CT as per protocol, which revealed isolated multilevel STB (T4-7, T11/12, L3/4) with no concomitant lung or urogenital lesion. However, sputum and urine were Xpert MTB/RIF Ultra positive and Mtb was cultured from the urine sample. CT-guided biopsy of the T11/12 lesion confirmed drug-sensitive Mtb on Xpert MTB/RIF Ultra and the patient was started on TB treatment according to local guidelines for 12 months. The 6-month follow-up PET/CT revealed new and existing spinal lesions with increased FDG-uptake despite significant improvement of clinical features and laboratory markers. After 9 months of treatment, the patient developed an acute urethral stricture, most likely due to urogenital TB, and a suprapubic catheter was inserted. The 12-month PET/CT showed significantly decreased PET/CT values of all lesions, however, significant persistent spinal inflammation was present at the end of TB treatment. Clinically, the patient was considered cured by the TB control program and currently awaits urethroplasty. CONCLUSIONS: In our case, PET/CT emerged as a valuable imaging modality for the initial assessment, surpassing MRI by revealing more comprehensive extensive disease. Subsequent PET/CT scans at 6-month uncovered new lesions and increased inflammation in existing ones, while by the end of TB treatment, all lesions exhibited improvement. However, the interpretation of FDG avidity remains ambiguous, whether it correlates with active infection and viable Mtb. or fibro- and osteoblast activity indicative of the healing process. Additionally, the absence of extraspinal TB lesions on PET/CT despite positive microbiology from sputum and urine maybe explained by paucibacillary, subclinical infection of extraspinal organs. The Spinal TB X Cohort endeavours to shed light on whole-body imaging patterns at diagnosis, their evolution midway through TB treatment, and upon treatment completion. Ultimately, this study aims to advance our understanding of the biology of this complex disease.

Comparing gene expression profiles of adults with isolated spinal tuberculosis to disseminated spinal tuberculosis identified by 18FDG-PET/CT at time of diagnosis, 6- and 12-months follow-up: classifying clinical stages of spinal tuberculosis and monitoring treatment response (Spinal TB X cohort study).

BACKGROUND: Tuberculosis (TB) is one of the top ten causes of death worldwide, with approximately 10 million cases annually. Focus has been on pulmonary TB, while extrapulmonary TB (EPTB) has received little attention. Diagnosis of EPTB remains challenging due to the invasive procedures required for sample collection. Spinal TB (STB) accounts for 10% of EPTB and often leads to lifelong debilitating disease due to devastating spinal deformation and compression of neural structures. Little is known about the extent of disease, although both isolated STB and a disseminated form of STB have been described. In our Spinal TB X cohort study, we aim to describe the clinical phenotype of STB using whole-body 18FDG-PET/CT, identify a specific gene expression profile for different stages of dissemination and compare findings to previously described gene expression signatures for latent and active pulmonary TB. METHODS: A single-centre, prospective cohort study will be established to describe the distributional pattern of STB detected by whole-body 18FDG-PET/CT and gene expression profile of patients with suspected STB on magnetic resonance imaging (MRI) at point of diagnosis, six months, and 12 months. Blood biobanking will be performed at these time points. Specimens for microbiology will be obtained from sputum/urine, from easily accessible sites of disease (e.g., lymph nodes, abscess) identified in the first 18FDG-PET/CT, from CT-guided biopsy and/or surgery. Clinical parameters and functional scores will be collected at every physical visit. Data will be entered into RedCap® database; data cleaning, validation and analysis will be performed by the study team. The University of Cape Town Ethics Committee approved the protocol (243/2022). DISCUSSION: The Spinal TB X cohort study is the first prospective cohort study using whole-body 18FDG-PET/CT scans in patients with microbiologically confirmed spinal tuberculosis. Dual imaging techniques of the spine using 18FDG-PET/CT and magnetic resonance imaging as well as tissue diagnosis (microbiology and histopathology) will allow us to develop a virtual biopsy model. If successful, a distinct gene-expression profile will aid in blood-based diagnosis (point of care testing) as well as treatment monitoring and would lead to earlier diagnosis of this devastating disease. TRIAL REGISTRATION: The study has been registered on ClinicalTrials.gov (NCT05610098).

Identifying quantitative sncRNAs signature using global sequencing as a potential biomarker for tuberculosis diagnosis and their role in regulating host response.

OBJECTIVES: The study aimed to identify a quantitative signature of circulating small non-coding RNAs (sncRNAs) as a biomarker for pulmonary tuberculosis disease (active-TB/ATB) and explore their regulatory roles in host-pathogen interactions and disease progression. METHODS: We conducted a cross-sectional study recruiting subjects diagnosed with active-TB (drug-sensitive and drug-resistant) and healthy controls. Sera samples were collected and utilized for preparing small RNA libraries. Quantitative patterns of circulating sncRNAs (miRNAs, piRNAs and tRFs) were identified via high-throughput sequencing and DeSeq2 analysis and validated in independent active-TB cohorts. Functional knockdown for two selected miRNAs were also performed. RESULTS: A diagnostic signature of four sncRNAs for both drug-sensitive and drug-resistant active-TB cases was validated, exhibiting an AUC of 0.96 (95% CI: 0.937-0.996, p < 0.001) with 86.7% sensitivity (95% CI: 0.775-0.932) and 91.7% specificity (95% CI: 0.730-0.990) in ROC analysis. Functional knockdown demonstrated regulatory roles of hsa-miR-223-5p and hsa-miR-10b-5p in Mycobacterium tuberculosis (Mtb) growth and pro-inflammatory cytokine expression (IL-6 and IL-8). CONCLUSION: The study identified a diagnostic tool utilizing a signature of four sncRNAs with high specificity and sensitivity, enhancing our understanding of sncRNAs as ATB diagnostic biomarker. Additionally, hsa-miR-223-5p and hsa-miR-10b-5p demonstrated potential roles in Mtb pathogenesis and host-response to infection.