Utility of [68Ga]Gallium Citrate PET/CT Imaging in the Diagnosis of Active Spinal Tuberculosis and Response Assessment in Comparison with [18F]FDG PET/CT – A Prospective Study

Utility of [68Ga]Gallium Citrate PET/CT Imaging in the Diagnosis of Active Spinal Tuberculosis and Response Assessment in Comparison with [18F]FDG PET/CT – A Prospective Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Utility of [68Ga]Gallium Citrate PET/CT Imaging in the Diagnosis of Active Spinal Tuberculosis and Response Assessment in Comparison with [18F]FDG PET/CT – A Prospective Study Justin K Varghese, Saumya Sara Sunny, Justin Arockiaraj. S. V, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9384366/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Objective: Spinal tuberculosis (STB) remains a major clinical challenge in high-burden countries. Infection imaging agents such as [18F]FDG and [67Ga]Gallium citrate have limitations in specificity and interpretation. [68Ga]Gallium citrate, produced via a [68Ge/67Ga] generator, offers logistical and economic advantages. This prospective study evaluated the utility of [68Ga]Gallium citrate PET/CT for diagnosing active spinal TB and for treatment response assessment in comparison with [18F]FDG PET/CT. Methods: Thirty-two patients with suspected spinal TB underwent baseline [68Ga]Gallium citrate PET/CT and those with uptake in disease more than or equivalent to the uptake in the abdominal aorta were considered positive. All patients then received the standard anti-tubercular therapy (ATT). Follow-up imaging at 9–12 months included repeat [68Ga]Gallium citrate PET/CT (n = 21), of which 17 patients were also underwent [18F]FDG PET/CT. Lesions with SUVmax > 2.5 were considered metabolically active. Imaging findings were correlated with clinical outcomes. The uptake on functional imaging was correlated with other clinical, radiological, microbiological and histopathological data for each patient. Results: At baseline, 22/32 patients (68.8%) demonstrated increased [68Ga]Gallium uptake consistent with infective spondylodiscitis, while 10 (31.2%) showed no abnormal uptake. There was no statistically significant correlation between tracer uptake and clinical, radiological, or laboratory parameters. Follow-up imaging in 21 patients demonstrated complete resolution of increased [68Ga]Gallium uptake in all 12 baseline-positive cases and remained negative in 9 initially negative cases, correlating with symptomatic improvement. In contrast, [18F]FDG PET/CT performed in 17 patients showed persistent [18F]FDG avidity in 13 patients despite clinical remission, while 4 showed no abnormal uptake. Conclusion: Although [68Ga]Gallium citrate PET/CT does not appear to be a reliable diagnostic modality, it is useful in identifying active spinal TB and may serve as a reliable marker for therapeutic response in patients with baseline tracer uptake. Persistent [18F]FDG uptake despite clinical recovery indicates the limited specificity of [18F]FDG PET/CT for response assessment, likely reflecting residual inflammatory activity rather than active disease. Given its generator-based production and lower infrastructural requirements, [68Ga]Gallium citrate PET/CT may represent a cost-effective and accessible functional imaging modality for spinal TB, particularly in resource-limited settings with a high disease burden. Figures Figure 1 Figure 2 Figure 3 Figure 4 INTRODUCTION Globally, tuberculosis (TB) continues to pose a significant public-health threat, with sustained endemicity in numerous low- and middle-income regions and a re-emergence being observed in parts of the developed world ( 1 ). India carries 26% of the world’s TB burden, and the management of spinal TB (STB) remains a challenge ( 2 ). Among all forms of infectious spondylitis, STB shows the most extensive and diverse structural and functional alterations. Prompt recognition and comprehensive therapy are essential to ensure complete recovery and healing in affected patients ( 3 ). Delays in diagnosis and treatment are associated with an increase in the frequency of complications such as deformities and paraparesis ( 4 ). Plain radiographs have limited utility in the early detection of STB, as they can reveal only initial anatomical changes, which are often not apparent during the early stages of the disease ( 5 ). MRI is the preferred imaging modality for STB, offering greater sensitivity than X-ray and higher specificity than CT, with rapid evaluation of neurological involvement ( 6 ). CT-guided fine needle aspiration cytology is useful for obtaining specimens for culture and histopathological examination. However, it cannot differentiate between active and inactive tuberculosis ( 5 ). Hence, an optimal functional imaging modality to identify active STB lesions is warranted. [18F]FDG PET/CT appears to be a highly effective modality for detecting active disease, staging extraspinal involvement, guiding biopsy, assessing disease extent, predicting multidrug resistance, and monitoring treatment response in tuberculosis patients ( 7 ). [18F]FDG PET/CT is an accurate and sensitive marker for the assessment of early treatment response in tuberculosis ( 8 ). However, [18F]FDG PET/CT has certain drawbacks. False high uptake can occur due to a good host immune response system, and false negative imaging can occur in an immunocompromised state. Moreover, [18F]FDG PET may be falsely positive in patients with uninfected or loosened bone implants ( 9 ). Therefore, treatment decisions cannot solely rely on uptake in [18F]FDG PET/CT ( 10 ). For many years, [67Ga]Gallium citrate was widely used in nuclear medicine for imaging infectious and inflammatory diseases ( 11 ). However, its clinical application has declined due to several limitations. Being a cyclotron-produced tracer with a long physical half-life of about 78 hours, it emits high-energy gamma photons (92–300 keV), leading to suboptimal image quality and higher radiation exposure. Recent advances in positron emission tomography have renewed interest in gallium-based radiopharmaceuticals, particularly [68Ga]Gallium citrate. Produced from a generator system, [68Ga]Gallium offers favourable imaging characteristics, including a shorter half-life (68 minutes), positron emission for high-resolution PET/CT imaging, and reduced radiation burden ( 12 ). In addition, [68Ga]Gallium citrate demonstrates a strong affinity for transferrin and lactoferrin at infection sites, enabling early and accurate detection of active inflammatory and infectious processes ( 13 ). The advent of [68Ga]Gallium citrate, owing to its favourable physical properties, has revolutionised molecular imaging. It provides imaging opportunities for almost all the key factors involved in inflammation, with recent growing attention on macrophage differentiation, different types of receptor expression, and the release of chemokines and vascular adhesion molecules ( 14 ). [68Ga]Gallium citrate is a tracer that localises to inflammatory foci by specific transferrin-dependent mechanisms ( 15 ). Studies have shown that [68Ga]Gallium citrate accumulates in both pulmonary and extrapulmonary tuberculosis and hence may be useful in distinguishing active from inactive cases ( 16 ). Gallium is selectively absorbed by infectious and inflammatory tissues, which can be attributed to increased capillary permeability, as well as its ability to bind to ferritin in leukocytes ( 9 ). And also Gallium binds to transferrin and enters cells through transferrin channels, accumulates at infection sites due to increased vascular permeability, direct uptake by pathogens via lactoferrin in leukocytes targeting activated macrophages, and the formation of gallium–siderophore complexes in iron-deficient environments that promote its intracellular retention ( 13 ). The simple and low-cost production of [68Ga]Gallium citrate, along with its lower radiation dose and faster scan time, makes it a practical and useful choice for routine Nuclear Medicine imaging. The aim of the study is to assess the ability of [68Ga]Gallium citrate PET/CT to differentiate active from inactive spinal tuberculosis and to compare its effectiveness with [18F]FDG PET/CT in evaluating treatment response in these patients. MATERIAL AND METHODS Study Protocol This prospective observational study was conducted over a 36-months period (February 2022 to January 2025) at a 3,500-bed, university-affiliated private teaching hospital located in a high tuberculosis–burden country in South Asia. The study protocol was approved by the Institutional Review Board (IRB No. 14977). Baseline and follow-up [68Ga]Gallium citrate PET/CT scans were performed and independently interpreted by two experienced Nuclear Medicine physicians. At follow-up, [18F]FDG PET/CT imaging was also obtained. Sites demonstrating radiotracer avidity were correlated with corresponding MRI findings (if available), which were reviewed by an experienced radiologist. Study subjects The study included adult patients (> 18 years of age) presenting to the Spinal Disorders Surgery Outpatient department with suspected or confirmed spinal tuberculosis. The diagnosis was established using a composite reference standard that integrated clinical assessment with supportive imaging findings, microbiological confirmation, and/or histopathological evidence. Eligible participants were either treatment-naïve or had received antitubercular therapy for less than one month prior to enrolment. Pregnant or lactating women and individuals younger than 18 years of age were excluded from the study. Study protocol Patients who provided written informed consent were prospectively enrolled and underwent a baseline [68Ga]Gallium citrate PET/CT scan according to standardized imaging protocol. The flow chart of study protocol is shown in Fig. 1. The acquired images were visually interpreted and correlated with relevant clinical findings. Following imaging, patients received appropriate management in the form of antitubercular therapy or surgical intervention, as clinically indicated. A follow-up evaluation was performed after 9–12 months, which included repeat [68Ga]Gallium citrate and [18F]FDG PET/CT imaging. Representative findings are illustrated in Figs. 2–4. Treatment response as assessed on both PET/CT modalities was correlated with clinical outcomes. Radiotracer uptake patterns were further analysed in relation to demographic characteristics, clinical presentation, CT and MRI findings, biochemical parameters (total leukocyte count [TLC], erythrocyte sedimentation rate [ESR], and C-reactive protein [CRP]), microbiological results (mycobacterial culture and XPERT MTB/RIF assay), and histopathological findings where available (Table 1). In this study, the effective radiation dose for a regional spine PET/CT examination was estimated to range from 4–6 mSv for [68Ga]Gallium citrate PET/CT and 5–7 mSv for [18F]FDG PET/CT. These values represent the combined radiation exposure from the administered radiotracer and the low-dose, non-contrast CT acquisition performed for attenuation correction and anatomical localisation. [68Ga]Gallium citrate imaging protocol: [68Ga]Gallium citrate preparation: [68Ga]Gallium citrate was eluted from a Germanium generator with HCL after labelling with buffer citrate solution for 10 minutes and passing through a water cartridge; the cartridge was washed with 30% ethanol. Imaging : Non–contrast CT imaging followed by a [68Ga]Gallium citrate PET (regional) scan for the area of interest was performed 30 minutes to 1 hour post-IV administration of [68Ga]Gallium citrate (dose: 111–185 MBq). [18F]FDG PET/CT (regional) imaging protocol: [18F]FDG PET/CT imaging was performed according to standard patient preparation protocols. After fasting for 4–6 hours, [18F]FDG was administered intravenously at a dose of 185–250 MBq through a peripheral vein. Following tracer injection, patients were instructed to drink water and remain seated to minimize physiologic skeletal muscle uptake of [18F]FDG. Image Acquisition: Emission imaging was done 45–60 minutes after tracer administration. Data were acquired for 2–5 minutes per bed position, with acquisition time adjusted based on patient habitus and count statistics to ensure optimal image quality. Image Processing and Reconstruction: Images were acquired in three-dimensional mode and reconstructed with CT-based attenuation correction using an ordered subset expectation maximization (OSEM) algorithm. Reconstructed datasets were generated in axial, sagittal, and coronal planes for comprehensive evaluation. Image Display The integrated PET/CT workstation enabled precise co-registration and alignment of PET and CT datasets, allowing multiplanar reconstruction and three-dimensional cine-mode review for detailed anatomical and metabolic assessment. Image Interpretation Baseline [68Ga]Gallium citrate PET/CT images were visually assessed. Tracer uptake at suspected disease sites was considered positive when it was equal to or greater than the uptake in the abdominal aorta, and these findings were correlated with the corresponding CT features. Patients were re-evaluated 9–12 months after completing antitubercular therapy with repeat [68Ga]Gallium citrate and [18F]FDG PET/CT scans, performed 1–2 days apart. Presence or absence of uptake was documented on [68Ga]Gallium citrate PET CT at follow-up. On follow up [18F]FDG PET/CT scans, maximum standardized uptake value (SUVmax) was calculated using software-generated regions of interest over the involved spinal segments. SUVmax was determined by normalizing tissue radioactivity to the injected dose and patient body weight. An SUVmax greater than 2.5 indicated persistent metabolic activity. Abnormal [18F]FDG accumulation was considered positive if SUVmax, normalized to injected dose and body weight, exceeded this threshold. Post-treatment [68Ga]Gallium citrate and [18F]FDG PET/CT findings were compared and correlated with clinical outcomes and MRI reports (if available). Based on these data, the utility of [68Ga]Gallium citrate PET/CT was evaluated for baseline disease assessment and as a marker of treatment response in spinal tuberculosis. The role of [18F]FDG PET/CT in assessing therapeutic response was also systematically analysed. Statistical analysis: Descriptive statistics like mean, standard deviation (SD), median, interquartile range (IQR), frequencies, and percentages were used to present the socio-demographic and clinical variables. The Fisher’s exact test was used. All tests were two-sided at α : 0.05 level of significance. All statistical analyses were performed using Stata/BE software, version 18.0. RESULTS The study cohort consisted of 32 patients, including 14 males (43.7%) and 18 females (56.3%), with a mean age of 42.13 years (range: 21–67 years). 21 patients underwent [68Ga]Gallium citrate PET/CT at baseline, within 1 week of initiating antitubercular therapy, while the remaining 11 patients were scanned within 1 month of treatment commencement. All patients presented with low backache as the primary symptom, and 12 patients (37.5%) exhibited neurological deficits at presentation. The lumbar spine was the most involved region (50%), followed by the thoraco-lumbar (32%) and the thoracic spine region (18%). Among the total cohort of 32 patients, CT imaging demonstrated paravertebral or soft tissue collections in 9 patients (28.1%), narrowing of disc space in 8 patients (25%), and vertebral body involvement in 10 patients (31.3%). MRI showed abscess formation in 11 patients (34.4%), vertebral destruction in 6 patients (18.8%), and intervertebral disc involvement in 6 patients (18.8%). Inflammatory markers were elevated in a subset of patients, with erythrocyte sedimentation rate (ESR) raised in 6 patients (18.8%) and C-reactive protein (CRP) elevated in 8 patients (25%). Biopsy specimens were obtained from 20 of the 32 enrolled patients. Histopathological examination revealed features of chronic spondylitis in 9 patients (28.1%), necrotising granulation spondylitis in 5 patients (15.6%), and focal histiocytic aggregates in 6 patients (18.8%). Microbiological analysis showed Mycobacteria Growth Indicator Tube (MGIT) culture was positive in 10 patients (31.3%), while Xpert MTB/RIF assay was positive in 19 patients (59.4%) - Table 1. A baseline [68Ga]Gallium citrate PET/CT scan was performed in 32 patients, out of which 22 (68.8%) had positive scans with increased uptake in the spinal region, consistent with infective spondylodiscitis. 10 patients (31.2%) had negative scans with no uptake in the spinal lesions; among these, 2 patients exhibited avid uptake in the lung and mediastinal lymph nodes, another 2 showed muscle uptake in the iliacus and psoas muscles, while the remaining 6 patients had no abnormal uptake in either spinal or extra-osseous regions. Among the 21 patients who completed follow-up evaluation (Table 2), 15 were managed exclusively with antitubercular therapy for a duration of 9–12 months, while 6 patients required additional surgical intervention. All 21 patients experienced significant symptomatic improvement in back pain and neurological deficits. This was statistically significant, with resolution of uptake in patients with a baseline-positive scan (p-value = 0.05). Correlation of [68Ga]Gallium citrate PET/CT with MRI and CT findings CT findings- including paravertebral or other soft-tissue collections (p=0.64), vertebral body involvement, and intervertebral disc involvement (p=0.68), showed no statistically significant association with baseline [68Ga]Gallium citrate uptake. MRI features- such as marrow oedema (p=0.63), vertebral or disc involvement (p=0.52), and the presence of paravertebral (p=0.44), epidural (p=0.17), intraosseous, or soft tissue abscesses (p=1), showed no significant correlation with baseline tracer uptake (Table 1). On follow-up imaging, all patients demonstrated either complete or partial resolution of radiological abnormalities on repeat CT and follow-up MRI of the spine. Correlation of [68Ga]Gallium citrate PET/CT with laboratory parameters Elevated inflammatory markers- including erythrocyte sedimentation rate (ESR) (p=0.66), C-reactive protein (CRP) (p=0.64), and total leukocyte count (TLC) (p=1), were not significantly associated with positive baseline [68Ga]Gallium citrate PET/CT findings. However, on follow up, absence of [68Ga] Gallium citrate uptake was statistically significant, with decrease in the previously elevated baseline ESR (p value of 0.006) and CRP (p value of 0.0003) in all 21 patients (Table 4). This was not noted in the total leukocyte counts, possibly due to the non-specific nature of the test. Correlation of [68Ga]Gallium citrate with microbiological findings Baseline [68Ga]Gallium citrate PET/CT imaging did not correlate significantly with positive MGIT culture (p=1) or XPERT TB PCR (p=0.18). [68Ga]Gallium citrate PET CT and [18F]FDG PET CT after completion of ATT Of the 32 patients who underwent baseline [68Ga]Gallium citrate PET/CT, 21 (65.6%) returned for follow-up imaging. Among these, 17 patients also underwent [18F]FDG PET/CT. All 21 patients demonstrated negative findings on follow-up [68Ga]Gallium citrate PET/CT, irrespective of their baseline scan status. Among the 17 patients who additionally underwent follow up [18F]FDG PET/CT, 13 (76.5%) had [18F]FDG avidity within the spinal lesions, with SUV values ranging from 3.19 to 20.29. Of these 13 [18F]FDG -positive patients, only 6 (46.2%) had shown avidity on baseline [68Ga]Gallium citrate PET/CT (Table 3). DISCUSSION Tuberculosis continues to present as a significant global health challenge, especially when delays in diagnosis and treatment lead to substantial morbidity and mortality ( 15 ). History, clinical examination, and blood tests such as CRP and ESR, as well as spinal X-ray and CT, have limited value in the early diagnosis of spinal TB. Magnetic resonance imaging (MRI) offers detailed anatomical information and is highly sensitive for evaluating patients who have not undergone surgery. However, its utility is reduced in the presence of metal implants ( 17 ). [68Ga]Gallium citrate PET/CT identifies both pulmonary and extrapulmonary tuberculous lesions, helping distinguish active from inactive disease and supporting treatment assessment. It is also more sensitive than CT for detecting extrapulmonary involvement ( 18 ). In this study, 32 patients underwent baseline [68Ga]Gallium citrate PET/CT and received standard antitubercular therapy. After 9 to 12 months, 21 patients (8 males, 13 females; mean age 49 years, range 26–64) underwent follow-up [68Ga]Gallium citrate and [18F]FDG PET/CT to assess treatment response. Of the 21 patients who initially had positive [68Ga]Gallium citrate scans, all (100%) showed negative findings on follow-up scans after antitubercular therapy, accompanied by symptomatic resolution. At baseline evaluation, 22 of 32 patients (69%) demonstrated increased tracer uptake on [68Ga]Gallium citrate PET/CT. Calabria et al. suggested that [68Ga]Gallium Citrate has exhibited the capability to identify bacterial infections by accumulating in infectious foci and surrounding tissues, and its interaction with transferrin aids in the distribution to infected areas, which are characterized by heightened vascular permeability and chemotactic factors produced by human leukocytes ( 19 ). Ankrah et al. suggested that [68Ga]Gallium citrate is less likely to accumulate in inflammatory lesions with no active infection ( 20 ). In our follow-up, it was observed that 21 out of 21 (100%) patients had negative [68Ga]Gallium citrate scans. This outcome is likely attributed to the absence of active infection foci, as these patients demonstrated clinical and radiological improvement. Among patients with positive [68Ga]Gallium citrate uptake at baseline, 14 of 18 (77.8%) were confirmed positive by Xpert MTB testing, while 4 (22.2%) were negative. Variability in tracer avidity across patients may reflect differences in viable bacterial load within lesions. In a subset of cases, the baseline [68Ga]Gallium citrate scans did not demonstrate significant tracer avidity, suggesting potential limitations in the diagnostic capability of [68Ga]Gallium citrate PET/CT as a baseline imaging modality. Furthermore, out of the twenty-one patients, seventeen had [18F]FDG PET CT scan on the follow-up. Among these seventeen cases, thirteen showed [18F]FDG avidity in spinal disease, with SUVmax ranging from 3.19 to 20.29. Four cases were negative and in symptomatic remission. Of the thirteen [18F]FDG-positive cases, all the patients showed symptomatic clinical improvement. [18F]FDG PET/CT enables non-invasive, semi-quantitative assessment of metabolic activity within lesions. Active tubercular sites typically contain lymphocytes, epithelioid cells, and Langerhans-type giant cells, all of which exhibit high glucose metabolism, resulting in increased [18F]FDG uptake. A reduction in [18F]FDG uptake over time may reflect a favourable response to anti-tubercular therapy and help guide the appropriate duration of treatment ( 21 ). The accumulation of [18F]FDG can also be occurred in healing bones that were free from infections ( 22 ). Promising Indicator of Clinical Response: On follow-up, the absence of tracer uptake in lesions that showed avidity at baseline was strongly associated with positive clinical outcomes following completion of antitubercular therapy. This observation correlated with radiological improvements, including evidence of sclerosis or bone fusion on X-ray and CT, and reductions in abscess size, oedema, discitis, and hyperintensity on T1-weighted MRI images. High [18F]FDG uptake on PET/CT may reflect either ongoing active disease or heightened host immune activity that is ultimately self-resolving, making interpretation challenging ( 23 ) and also tuberculous granulomatous inflammation appears as [18F]FDG avid lesions on PET/CT imaging ( 24 ). On follow-up with [18F]FDG PET/CT scans, 13 of 17 patients demonstrated significant tracer avidity. However, there is a possibility that a healed site may appeared as falsely positive. The observed [18F]FDG avidity in the study could be attributed to ongoing inflammatory cellular processes rather than active infection. Scherer et al. suggest that elevated [18F]FDG uptake may not solely be attributed to increased metabolic activity resulting from active infection, but rather it may also serve as an indicator of tissue regeneration ( 25 ). This observation could potentially elucidate the heightened [18F]FDG uptake seen in our patients following 9–12 months of ATT treatment. Calabria et al. proposed that in cases of chronic inflammation, other immune cells, such as fibroblasts, may show uptake of [18F]FDG, potentially leading to a resemblance of an infectious process ( 19 ). Vorster et al. suggested that [68Ga]Gallium Citrate is less likely to accumulate in post-infective inflammation, making it a potentially important clinical tool, particularly as [18F]FDG often remains present in TB lesions even after treatment ( 15 ). [18F]FDG does not differentiate between bone infection and early normal bone healing, which presents a high level of cellular metabolism and glucose consumption, thereby mimicking the uptake of [18F]FDG during infection ( 9 ) . Given that most patients in our study showed symptomatic improvement at follow-up, the utility of [18F]FDG PET/CT as a definitive tool for response assessment in this context may be limited. Challenges in Understanding Non-Avid Disease on [68Ga]Gallium Citrate scan: Due to the small sample size, it remains challenging to definitively explain why some patients presented with non-avid disease in the baseline [68Ga]Gallium Citrate PET/CT scan. This phenomenon may be influenced by variations in bacterial load or microcellular changes that occur in affected tissues. CONCLUSION The use of [68Ga]Gallium citrate PET CT in assessing Tuberculosis of the spine to demonstrate disease activity is valuable, although it should not be relied upon solely as a baseline diagnostic imaging modality. Nevertheless, it can serve as a potential marker to gauge treatment response in patients with uptake on the initial scan, and it can assist in making informed decisions regarding the continuation or cessation of treatment. Despite symptomatic remission and disease resolution, the infection site may still show false-positive [18F]FDG avidity because of ongoing cellular inflammation. Therefore, [18F]FDG PET/CT may not reliably indicate therapeutic response. The [68Ga]Gallium Citrate PET/CT scan proves to be a valuable functional imaging modality for clinicians in the assessment of spinal tuberculosis, especially in low-income and developing countries with a high disease burden. Its generator-based production, as opposed to reliance on cyclotron facilities, significantly reduces costs and technical barriers, thus enhancing accessibility in regions equipped with PET/CT technology. This cost-effective approach can greatly improve diagnostic capabilities and patient care in resource-constrained settings. LIMITATIONS OF THE STUDY - The acquisition of delayed images with [68Ga]Gallium citrate is challenging due to the tracer's short half-life. - The sample size of the study, particularly those who had follow up assessment is small. - The findings are based on a single-centre experience, which may affect the broader applicability of the results. - Not all patients had the complete panel of relevant biochemical, microbiological tests and biopsy reports available. MRI scans were not done in all patients at both baseline and at follow-up. Declarations Conflicts of Interest: The authors have no conflicts of interest to disclose. Declarations of interest: None Acknowledgments: This study was made possible through the support of the Department of Biotechnology (DBT) and was funded by the Department of Health Research (DHR), ICMR- Government of India. AUTHOR CONTRIBUTIONS Study conceptualization: Justin K Varghese, Saumya Sara Sunny, Julie Hephzibah Methodology : Justin K Varghese, Saumya Sara Sunny, Julie Hephzibah Data collection: Justin K Varghese, Saumya Sara Sunny Literature search and resources: Justin K Varghese, Saumya Sara Sunny, Julie Hephzibah, Justin Arockiaraj, Venkatesh K, Abi Manesh S Data analysis and interpretation: Justin K Varghese, Saumya Sara Sunny, Julie Hephzibah, Mahasampath Gowri S Drafting the manuscript and resource people: Justin K Varghese, Saumya Sara Sunny, Julie Hephzibah, Justin Arockiaraj, Venkatesh K, Abi Manesh S Project administration : Justin K Varghese, Saumya Sara Sunny, Julie Hephzibah Review of final manuscript and approval for publication: Justin K Varghese, Saumya Sara Sunny, Julie Hephzibah, Justin Arockiaraj, Venkatesh K, Abi Manesh S, Mahasampath Gowri S References Garg B, Mehta N, Mukherjee RN, Swamy AM, Siamwala BS, Malik G. 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Available from: https://www.frontiersin.org/articles/ 10.3389/fmed.2021.758636 Rivas-Garcia A, Sarria-Estrada S, Torrents-Odin C, Casas-Gomila L, Franquet E. Imaging findings of Pott’s disease. Eur Spine J. 2013 June;22(Suppl 4):567–78. van de W MVAMC. M S. 68Ga-citrate PET/CT in tuberculosis: a pilot study. The quarterly journal of nuclear medicine and molecular imaging: official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of. [Internet]. 2019 Mar [cited 2024 Oct 16];63(1). Available from: https://pubmed.ncbi.nlm.nih.gov/24651268/ Calabria FF, Guadagnino G, Cimini A, Leporace M. PET/CT Imaging of Infectious Diseases: Overview of Novel Radiopharmaceuticals. Diagnostics. 2024;14(10):1043. Ankrah AO, van der Werf TS, de Vries EFJ, Dierckx RAJO, Sathekge MM, Glaudemans AWJM. PET/CT imaging of Mycobacterium tuberculosis infection. Clin Transl Imaging. 2016;4:131–44. Kubihal V, Sharma R, Krishna Kumar RG, Chandrashekhara SH, Garg R. Imaging update in spinal tuberculosis. J Clin Orthop Trauma. 2021;25:101742. Comparison of 18F-FDG. and 68Ga PET imaging in the assessment of experimental osteomyelitis due to Staphylococcus aureus | European Journal of Nuclear Medicine and Molecular Imaging [Internet]. [cited 2025 Aug 17]. Available from: https://link.springer.com/article/ 10.1007/s00259-005-1841-9 Yu WY, Lu PX, Assadi M, Huang XL, Skrahin A, Rosenthal A, et al. Updates on 18F-FDG-PET/CT as a clinical tool for tuberculosis evaluation and therapeutic monitoring. Quant Imaging Med Surg. 2019 June;9(6):1132–46. Kung BT, Seraj SM, Zadeh MZ, Rojulpote C, Kothekar E, Ayubcha C, et al. An update on the role of 18F-FDG-PET/CT in major infectious and inflammatory diseases. Am J Nucl Med Mol Imaging. 2019;9(6):255–73. Scherer J, Mukasa SL, Wolmarans K, Guler R, Kotze T, Song T et al. 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. Infection [Internet]. 2024 June 19 [cited 2024 Oct 16]; Available from: https://doi.org/10.1007/s15010-024-02327-5 Tables Table 1 to 4 are available in the Supplementary Files section. Supplementary Files Table1.docx Table2.docx Table3.docx Table4.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 24 Apr, 2026 Reviewers invited by journal 17 Apr, 2026 Editor assigned by journal 12 Apr, 2026 First submitted to journal 10 Apr, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9384366","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":624663436,"identity":"55c28cc2-6534-4370-af97-8a12681afb0f","order_by":0,"name":"Justin K Varghese","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0003-3850-0433","institution":"Christian Medical College, Vellore","correspondingAuthor":true,"prefix":"","firstName":"Justin","middleName":"K","lastName":"Varghese","suffix":""},{"id":624663437,"identity":"9c9be133-5b6c-4dfc-9bcc-174dede7f932","order_by":1,"name":"Saumya Sara Sunny","email":"","orcid":"","institution":"Christian Medical College, Vellore","correspondingAuthor":false,"prefix":"","firstName":"Saumya","middleName":"Sara","lastName":"Sunny","suffix":""},{"id":624663438,"identity":"4fb29504-2989-4402-b943-9c92b03845a6","order_by":2,"name":"Justin Arockiaraj. S. V","email":"","orcid":"","institution":"Christian Medical College, Vellore","correspondingAuthor":false,"prefix":"","firstName":"Justin","middleName":"Arockiaraj. S.","lastName":"V","suffix":""},{"id":624663439,"identity":"2d1f6c7e-a896-45b0-aeed-4ed0aeb6585f","order_by":3,"name":"Venkatesh Krishnan","email":"","orcid":"","institution":"Christian Medical College, Vellore","correspondingAuthor":false,"prefix":"","firstName":"Venkatesh","middleName":"","lastName":"Krishnan","suffix":""},{"id":624663440,"identity":"bb46d13c-1245-4fb5-829e-229fb41781fa","order_by":4,"name":"Abi Manesh S","email":"","orcid":"","institution":"Christian Medical College, Vellore","correspondingAuthor":false,"prefix":"","firstName":"Abi","middleName":"Manesh","lastName":"S","suffix":""},{"id":624663441,"identity":"7b0dc374-adb3-4b46-ad2d-542396440857","order_by":5,"name":"Mahasampath Gowri","email":"","orcid":"","institution":"Christian Medical College, Vellore","correspondingAuthor":false,"prefix":"","firstName":"Mahasampath","middleName":"","lastName":"Gowri","suffix":""},{"id":624663442,"identity":"f2e6de4d-d823-4609-9978-56d1ddcdeec5","order_by":6,"name":"Julie Hephzibah","email":"","orcid":"https://orcid.org/0000-0002-9917-3926","institution":"Christian Medical College, Vellore","correspondingAuthor":false,"prefix":"","firstName":"Julie","middleName":"","lastName":"Hephzibah","suffix":""}],"badges":[],"createdAt":"2026-04-11 04:19:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9384366/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9384366/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107834959,"identity":"1d67ba2e-4bd8-43c0-bc27-4dcdbd4b6373","added_by":"auto","created_at":"2026-04-26 15:50:38","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":259232,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart of study protocol\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9384366/v1/b044f6a4f1beb0707eebe8a8.jpg"},{"id":107869578,"identity":"ea2d8890-b823-4c36-8c50-508cac341927","added_by":"auto","created_at":"2026-04-27 07:37:27","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":275319,"visible":true,"origin":"","legend":"\u003cp\u003e34-year-old lady diagnosed with L4-L5 spine TB (XPERT positive). Baseline [68Ga]Gallium Citrate PET/CT scan (Image a) shows intense uptake consistent with infective spondylodiscitis at the L4-L5 level. Follow-up scan (Image b) after antitubercular therapy (ATT) shows disease regression with no residual tracer avidity.\u003c/p\u003e\n\u003cp\u003eBaseline MRI of lumbar spine (T2W) shows inflammatory changes with loss of disc height is noted at L4-L5 level with intravertebral intraosseous abscess (Image c \u0026amp; d)\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-9384366/v1/db2afa91fe74d92fcc58ed75.png"},{"id":107869405,"identity":"3e8cf16d-70eb-4466-8e4c-3e4d3c826201","added_by":"auto","created_at":"2026-04-27 07:37:00","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1457383,"visible":true,"origin":"","legend":"\u003cp\u003eA 40-year-old gentleman with history of L1-L2 spinal Tuberculosis with XPERT TB positive. CT findings suggestive of features of paravertebral abscess and infective discitis at L1-L2 levels. [68Ga]Gallium Citrate images shows no avidity.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImage- a\u0026amp;b: Baseline: \u003c/strong\u003e[68Ga]Gallium Citrate PET/CT images - no avidity\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImage- c\u0026amp;d: Post ATT - follow-up: \u003c/strong\u003e[68Ga]Gallium Citrate PET/CT images - no avidity\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImage- e\u0026amp;f: Post ATT - follow-up: \u003c/strong\u003e[18F]FDG PET/CT images shows uptake in the L1-L2 vertebral levels (SUV 12.78), suggestive of a positive scan.\u003c/p\u003e","description":"","filename":"Figure44.png","url":"https://assets-eu.researchsquare.com/files/rs-9384366/v1/b809bede036210d74237f21c.png"},{"id":107834962,"identity":"31afcbc3-c04e-4dd7-b71a-f975641420a3","added_by":"auto","created_at":"2026-04-26 15:50:38","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":582672,"visible":true,"origin":"","legend":"\u003cp\u003eA 30-year-old gentleman diagnosed with L2-L3 spine TB (Xpert TB positive). Baseline (Image a) imaging features are suggestive of infective spondylodiscitis. [68Ga]Gallium Citrate PET/CT scan shows absence of uptake at the L2-L3 level. Follow-up scan (Image b) after ATT shows disease regression with no tracer avidity.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-9384366/v1/16a9952a9a452e1021b77875.png"},{"id":107872443,"identity":"9dc1bbdd-e6b8-4117-a96b-23ffdf187782","added_by":"auto","created_at":"2026-04-27 07:57:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4240639,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9384366/v1/89b4dd63-e540-4ce9-ba05-bfcdfa6e4faa.pdf"},{"id":107834961,"identity":"0d793c05-c285-4b3d-b7c5-d00b55e742fb","added_by":"auto","created_at":"2026-04-26 15:50:38","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":30037,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-9384366/v1/b58292b8040571dc521ed59e.docx"},{"id":107834963,"identity":"d3c15257-5910-4450-bf0a-ec5124543e62","added_by":"auto","created_at":"2026-04-26 15:50:38","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":24616,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-9384366/v1/527a5c1cc953fe10bcc2d7ec.docx"},{"id":107870690,"identity":"2bdc4ec0-1221-4676-9229-9ba511245c37","added_by":"auto","created_at":"2026-04-27 07:40:24","extension":"docx","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":24735,"visible":true,"origin":"","legend":"","description":"","filename":"Table3.docx","url":"https://assets-eu.researchsquare.com/files/rs-9384366/v1/ce079dfa138c1764b63c2df6.docx"},{"id":107834965,"identity":"c4833f34-bb33-467c-9225-dafc15e3c974","added_by":"auto","created_at":"2026-04-26 15:50:38","extension":"docx","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":19763,"visible":true,"origin":"","legend":"","description":"","filename":"Table4.docx","url":"https://assets-eu.researchsquare.com/files/rs-9384366/v1/3f927a09ec880312aab9e80f.docx"}],"financialInterests":"","formattedTitle":"\u003cp\u003eUtility of [68Ga]Gallium Citrate PET/CT Imaging in the Diagnosis of Active Spinal Tuberculosis and Response Assessment in Comparison with [18F]FDG PET/CT – A Prospective Study\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eGlobally, tuberculosis (TB) continues to pose a significant public-health threat, with sustained endemicity in numerous low- and middle-income regions and a re-emergence being observed in parts of the developed world (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). India carries 26% of the world\u0026rsquo;s TB burden, and the management of spinal TB (STB) remains a challenge (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Among all forms of infectious spondylitis, STB shows the most extensive and diverse structural and functional alterations. Prompt recognition and comprehensive therapy are essential to ensure complete recovery and healing in affected patients (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Delays in diagnosis and treatment are associated with an increase in the frequency of complications such as deformities and paraparesis (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Plain radiographs have limited utility in the early detection of STB, as they can reveal only initial anatomical changes, which are often not apparent during the early stages of the disease (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). MRI is the preferred imaging modality for STB, offering greater sensitivity than X-ray and higher specificity than CT, with rapid evaluation of neurological involvement (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). CT-guided fine needle aspiration cytology is useful for obtaining specimens for culture and histopathological examination. However, it cannot differentiate between active and inactive tuberculosis (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Hence, an optimal functional imaging modality to identify active STB lesions is warranted.\u003c/p\u003e \u003cp\u003e[18F]FDG PET/CT appears to be a highly effective modality for detecting active disease, staging extraspinal involvement, guiding biopsy, assessing disease extent, predicting multidrug resistance, and monitoring treatment response in tuberculosis patients (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). [18F]FDG PET/CT is an accurate and sensitive marker for the assessment of early treatment response in tuberculosis (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). However, [18F]FDG PET/CT has certain drawbacks. False high uptake can occur due to a good host immune response system, and false negative imaging can occur in an immunocompromised state. Moreover, [18F]FDG PET may be falsely positive in patients with uninfected or loosened bone implants (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Therefore, treatment decisions cannot solely rely on uptake in [18F]FDG PET/CT (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eFor many years, [67Ga]Gallium citrate was widely used in nuclear medicine for imaging infectious and inflammatory diseases (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). However, its clinical application has declined due to several limitations. Being a cyclotron-produced tracer with a long physical half-life of about 78 hours, it emits high-energy gamma photons (92\u0026ndash;300 keV), leading to suboptimal image quality and higher radiation exposure. Recent advances in positron emission tomography have renewed interest in gallium-based radiopharmaceuticals, particularly [68Ga]Gallium citrate. Produced from a generator system, [68Ga]Gallium offers favourable imaging characteristics, including a shorter half-life (68 minutes), positron emission for high-resolution PET/CT imaging, and reduced radiation burden (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). In addition, [68Ga]Gallium citrate demonstrates a strong affinity for transferrin and lactoferrin at infection sites, enabling early and accurate detection of active inflammatory and infectious processes (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe advent of [68Ga]Gallium citrate, owing to its favourable physical properties, has revolutionised molecular imaging. It provides imaging opportunities for almost all the key factors involved in inflammation, with recent growing attention on macrophage differentiation, different types of receptor expression, and the release of chemokines and vascular adhesion molecules (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). [68Ga]Gallium citrate is a tracer that localises to inflammatory foci by specific transferrin-dependent mechanisms (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Studies have shown that [68Ga]Gallium citrate accumulates in both pulmonary and extrapulmonary tuberculosis and hence may be useful in distinguishing active from inactive cases (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Gallium is selectively absorbed by infectious and inflammatory tissues, which can be attributed to increased capillary permeability, as well as its ability to bind to ferritin in leukocytes (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). And also Gallium binds to transferrin and enters cells through transferrin channels, accumulates at infection sites due to increased vascular permeability, direct uptake by pathogens via lactoferrin in leukocytes targeting activated macrophages, and the formation of gallium\u0026ndash;siderophore complexes in iron-deficient environments that promote its intracellular retention (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). The simple and low-cost production of [68Ga]Gallium citrate, along with its lower radiation dose and faster scan time, makes it a practical and useful choice for routine Nuclear Medicine imaging.\u003c/p\u003e \u003cp\u003eThe aim of the study is to assess the ability of [68Ga]Gallium citrate PET/CT to differentiate active from inactive spinal tuberculosis and to compare its effectiveness with [18F]FDG PET/CT in evaluating treatment response in these patients.\u003c/p\u003e"},{"header":"MATERIAL AND METHODS","content":"\u003cp\u003eStudy Protocol\u003c/p\u003e \u003cp\u003eThis prospective observational study was conducted over a 36-months period (February 2022 to January 2025) at a 3,500-bed, university-affiliated private teaching hospital located in a high tuberculosis\u0026ndash;burden country in South Asia. The study protocol was approved by the Institutional Review Board (IRB No. 14977).\u003c/p\u003e \u003cp\u003eBaseline and follow-up [68Ga]Gallium citrate PET/CT scans were performed and independently interpreted by two experienced Nuclear Medicine physicians. At follow-up, [18F]FDG PET/CT imaging was also obtained. Sites demonstrating radiotracer avidity were correlated with corresponding MRI findings (if available), which were reviewed by an experienced radiologist.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eStudy subjects\u003c/strong\u003e \u003cp\u003eThe study included adult patients (\u0026gt;\u0026thinsp;18 years of age) presenting to the Spinal Disorders Surgery Outpatient department with suspected or confirmed spinal tuberculosis. The diagnosis was established using a composite reference standard that integrated clinical assessment with supportive imaging findings, microbiological confirmation, and/or histopathological evidence.\u003c/p\u003e \u003c/p\u003e \u003cp\u003eEligible participants were either treatment-na\u0026iuml;ve or had received antitubercular therapy for less than one month prior to enrolment. Pregnant or lactating women and individuals younger than 18 years of age were excluded from the study.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eStudy protocol\u003c/strong\u003e \u003cp\u003ePatients who provided written informed consent were prospectively enrolled and underwent a baseline [68Ga]Gallium citrate PET/CT scan according to standardized imaging protocol. The flow chart of study protocol is shown in Fig.\u0026nbsp;1. The acquired images were visually interpreted and correlated with relevant clinical findings. Following imaging, patients received appropriate management in the form of antitubercular therapy or surgical intervention, as clinically indicated. A follow-up evaluation was performed after 9\u0026ndash;12 months, which included repeat [68Ga]Gallium citrate and [18F]FDG PET/CT imaging. Representative findings are illustrated in Figs.\u0026nbsp;2\u0026ndash;4.\u003c/p\u003e \u003c/p\u003e \u003cp\u003eTreatment response as assessed on both PET/CT modalities was correlated with clinical outcomes. Radiotracer uptake patterns were further analysed in relation to demographic characteristics, clinical presentation, CT and MRI findings, biochemical parameters (total leukocyte count [TLC], erythrocyte sedimentation rate [ESR], and C-reactive protein [CRP]), microbiological results (mycobacterial culture and XPERT MTB/RIF assay), and histopathological findings where available (Table\u0026nbsp;1).\u003c/p\u003e \u003cp\u003eIn this study, the effective radiation dose for a regional spine PET/CT examination was estimated to range from 4\u0026ndash;6 mSv for [68Ga]Gallium citrate PET/CT and 5\u0026ndash;7 mSv for [18F]FDG PET/CT. These values represent the combined radiation exposure from the administered radiotracer and the low-dose, non-contrast CT acquisition performed for attenuation correction and anatomical localisation.\u003c/p\u003e \u003cp\u003e[68Ga]Gallium citrate imaging protocol: [68Ga]Gallium citrate preparation: [68Ga]Gallium citrate was eluted from a Germanium generator with HCL after labelling with buffer citrate solution for 10 minutes and passing through a water cartridge; the cartridge was washed with 30% ethanol.\u003c/p\u003e \u003cp\u003e \u003cem\u003eImaging\u003c/em\u003e: Non\u0026ndash;contrast CT imaging followed by a [68Ga]Gallium citrate PET (regional) scan for the area of interest was performed 30 minutes to 1 hour post-IV administration of [68Ga]Gallium citrate (dose: 111\u0026ndash;185 MBq).\u003c/p\u003e \u003cp\u003e[18F]FDG PET/CT (regional) imaging protocol: [18F]FDG PET/CT imaging was performed according to standard patient preparation protocols. After fasting for 4\u0026ndash;6 hours, [18F]FDG was administered intravenously at a dose of 185\u0026ndash;250 MBq through a peripheral vein. Following tracer injection, patients were instructed to drink water and remain seated to minimize physiologic skeletal muscle uptake of [18F]FDG.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eImage Acquisition:\u003c/h2\u003e \u003cp\u003eEmission imaging was done 45\u0026ndash;60 minutes after tracer administration. Data were acquired for 2\u0026ndash;5 minutes per bed position, with acquisition time adjusted based on patient habitus and count statistics to ensure optimal image quality.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eImage Processing and Reconstruction:\u003c/h3\u003e\n\u003cp\u003eImages were acquired in three-dimensional mode and reconstructed with CT-based attenuation correction using an ordered subset expectation maximization (OSEM) algorithm. Reconstructed datasets were generated in axial, sagittal, and coronal planes for comprehensive evaluation.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eImage Display\u003c/strong\u003e \u003cp\u003eThe integrated PET/CT workstation enabled precise co-registration and alignment of PET and CT datasets, allowing multiplanar reconstruction and three-dimensional cine-mode review for detailed anatomical and metabolic assessment.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eImage Interpretation\u003c/strong\u003e \u003cp\u003eBaseline [68Ga]Gallium citrate PET/CT images were visually assessed. Tracer uptake at suspected disease sites was considered positive when it was equal to or greater than the uptake in the abdominal aorta, and these findings were correlated with the corresponding CT features.\u003c/p\u003e \u003c/p\u003e \u003cp\u003ePatients were re-evaluated 9\u0026ndash;12 months after completing antitubercular therapy with repeat [68Ga]Gallium citrate and [18F]FDG PET/CT scans, performed 1\u0026ndash;2 days apart.\u003c/p\u003e \u003cp\u003ePresence or absence of uptake was documented on [68Ga]Gallium citrate PET CT at follow-up. On follow up [18F]FDG PET/CT scans, maximum standardized uptake value (SUVmax) was calculated using software-generated regions of interest over the involved spinal segments. SUVmax was determined by normalizing tissue radioactivity to the injected dose and patient body weight. An SUVmax greater than 2.5 indicated persistent metabolic activity. Abnormal [18F]FDG accumulation was considered positive if SUVmax, normalized to injected dose and body weight, exceeded this threshold.\u003c/p\u003e \u003cp\u003ePost-treatment [68Ga]Gallium citrate and [18F]FDG PET/CT findings were compared and correlated with clinical outcomes and MRI reports (if available). Based on these data, the utility of [68Ga]Gallium citrate PET/CT was evaluated for baseline disease assessment and as a marker of treatment response in spinal tuberculosis. The role of [18F]FDG PET/CT in assessing therapeutic response was also systematically analysed.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis:\u003c/h2\u003e \u003cp\u003eDescriptive statistics like mean, standard deviation (SD), median, interquartile range (IQR), frequencies, and percentages were used to present the socio-demographic and clinical variables. The Fisher\u0026rsquo;s exact test was used. All tests were two-sided at α : 0.05 level of significance. All statistical analyses were performed using Stata/BE software, version 18.0.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eThe study cohort consisted of 32 patients, including 14 males (43.7%) and 18 females (56.3%), with a mean age of 42.13 years (range: 21\u0026ndash;67 years). 21 patients underwent [68Ga]Gallium citrate PET/CT \u0026nbsp; at baseline, within 1 week of initiating antitubercular therapy, while the remaining 11 patients were scanned within 1 month of treatment commencement.\u003c/p\u003e\n\u003cp\u003eAll patients presented with low backache as the primary symptom, and 12 patients (37.5%) exhibited neurological deficits at presentation. The lumbar spine was the most involved region (50%), followed by the thoraco-lumbar (32%) and the thoracic spine region (18%). Among the total cohort of 32 patients, CT imaging demonstrated paravertebral or soft tissue collections in 9 patients (28.1%), narrowing of disc space in 8 patients (25%), and vertebral body involvement in 10 patients (31.3%).\u003c/p\u003e\n\u003cp\u003eMRI showed abscess formation in 11 patients (34.4%), vertebral destruction in 6 patients (18.8%), and intervertebral disc involvement in 6 patients (18.8%). Inflammatory markers were elevated in a subset of patients, with erythrocyte sedimentation rate (ESR) raised in 6 patients (18.8%) and C-reactive protein (CRP) elevated in 8 patients (25%). Biopsy specimens were obtained from 20 of the 32 enrolled patients. Histopathological examination revealed features of chronic spondylitis in 9 patients (28.1%), necrotising granulation spondylitis in 5 patients (15.6%), and focal histiocytic aggregates in 6 patients (18.8%). Microbiological analysis showed Mycobacteria Growth Indicator Tube (MGIT) culture was positive in 10 patients (31.3%), while Xpert MTB/RIF assay was positive in 19 patients (59.4%) - Table 1.\u003c/p\u003e\n\u003cp\u003eA baseline [68Ga]Gallium citrate PET/CT scan was performed in 32 patients, out of which 22 (68.8%) had positive scans with increased uptake in the spinal region, consistent with infective spondylodiscitis. 10 patients (31.2%) had negative scans with no uptake in the spinal lesions; among these, 2 patients exhibited avid uptake in the lung and mediastinal lymph nodes, another 2 showed muscle uptake in the iliacus and psoas muscles, while the remaining 6 patients had no abnormal uptake in either spinal or extra-osseous regions.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Among the 21 patients who completed follow-up evaluation (Table 2), 15 were managed exclusively with antitubercular therapy for a duration of 9\u0026ndash;12 months, while 6 patients required additional surgical intervention. All 21 patients experienced significant symptomatic improvement in back pain and neurological deficits. This was statistically significant, with resolution of uptake in patients with a baseline-positive scan (p-value = 0.05).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCorrelation of\u0026nbsp;\u003c/em\u003e\u003cem\u003e[68Ga]Gallium citrate PET/CT with MRI\u0026nbsp;\u003c/em\u003e\u003cem\u003e\u0026nbsp;and CT findings\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eCT findings- including paravertebral or other soft-tissue collections (p=0.64), vertebral body involvement, and intervertebral disc involvement (p=0.68), showed no statistically significant association with baseline [68Ga]Gallium citrate uptake.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMRI features- such as marrow oedema (p=0.63), vertebral or disc involvement (p=0.52), and the presence of paravertebral (p=0.44), epidural (p=0.17), intraosseous, or soft tissue abscesses (p=1), showed no significant correlation with baseline tracer uptake (Table 1).\u003c/p\u003e\n\u003cp\u003eOn follow-up imaging,\u0026nbsp;all patients demonstrated either complete or partial resolution of radiological abnormalities on repeat CT and follow-up MRI of the spine.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCorrelation of\u0026nbsp;\u003c/em\u003e\u003cem\u003e[68Ga]Gallium citrate PET/CT with laboratory parameters\u003c/em\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eElevated inflammatory markers- including erythrocyte sedimentation rate (ESR) (p=0.66), C-reactive protein (CRP) (p=0.64), and total leukocyte count (TLC) (p=1), were not significantly associated with positive baseline [68Ga]Gallium citrate PET/CT findings.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHowever, on follow up, absence of [68Ga] Gallium citrate uptake was statistically significant, with decrease in the previously elevated baseline ESR (p value of 0.006) and CRP (p value of 0.0003) in all 21 patients (Table 4). This was not noted in the total leukocyte counts, possibly due to the non-specific nature of the test.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCorrelation of\u0026nbsp;\u003c/em\u003e\u003cem\u003e[68Ga]Gallium citrate with microbiological findings\u003c/em\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eBaseline [68Ga]Gallium citrate PET/CT imaging did not correlate significantly with positive MGIT culture (p=1) or XPERT TB PCR (p=0.18).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003cem\u003e[68Ga]Gallium citrate\u0026nbsp;\u003c/em\u003e\u003cem\u003ePET CT and\u0026nbsp;\u003c/em\u003e\u003cem\u003e[18F]FDG PET CT\u0026nbsp;\u003c/em\u003e\u003cem\u003e\u0026nbsp;after completion of ATT\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eOf the 32 patients who underwent baseline [68Ga]Gallium citrate PET/CT, 21 (65.6%) returned for follow-up imaging. Among these, 17 patients also underwent [18F]FDG PET/CT.\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAll 21 patients demonstrated negative findings on follow-up [68Ga]Gallium citrate PET/CT, irrespective of their baseline scan status. Among the 17 patients who additionally underwent follow up [18F]FDG PET/CT, 13 (76.5%) had [18F]FDG avidity within the spinal lesions, with SUV values ranging from 3.19 to 20.29. \u0026nbsp;Of these 13 [18F]FDG -positive patients, only 6 (46.2%) had shown avidity on baseline [68Ga]Gallium citrate PET/CT (Table 3).\u0026nbsp;\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eTuberculosis continues to present as a significant global health challenge, especially when delays in diagnosis and treatment lead to substantial morbidity and mortality (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). History, clinical examination, and blood tests such as CRP and ESR, as well as spinal X-ray and CT, have limited value in the early diagnosis of spinal TB. Magnetic resonance imaging (MRI) offers detailed anatomical information and is highly sensitive for evaluating patients who have not undergone surgery. However, its utility is reduced in the presence of metal implants (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). [68Ga]Gallium citrate PET/CT identifies both pulmonary and extrapulmonary tuberculous lesions, helping distinguish active from inactive disease and supporting treatment assessment. It is also more sensitive than CT for detecting extrapulmonary involvement (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn this study, 32 patients underwent baseline [68Ga]Gallium citrate PET/CT and received standard antitubercular therapy. After 9 to 12 months, 21 patients (8 males, 13 females; mean age 49 years, range 26\u0026ndash;64) underwent follow-up [68Ga]Gallium citrate and [18F]FDG PET/CT to assess treatment response. Of the 21 patients who initially had positive [68Ga]Gallium citrate scans, all (100%) showed negative findings on follow-up scans after antitubercular therapy, accompanied by symptomatic resolution.\u003c/p\u003e \u003cp\u003eAt baseline evaluation, 22 of 32 patients (69%) demonstrated increased tracer uptake on [68Ga]Gallium citrate PET/CT. Calabria et al. suggested that [68Ga]Gallium Citrate has exhibited the capability to identify bacterial infections by accumulating in infectious foci and surrounding tissues, and its interaction with transferrin aids in the distribution to infected areas, which are characterized by heightened vascular permeability and chemotactic factors produced by human leukocytes (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Ankrah et al. suggested that [68Ga]Gallium citrate is less likely to accumulate in inflammatory lesions with no active infection (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). In our follow-up, it was observed that 21 out of 21 (100%) patients had negative [68Ga]Gallium citrate scans. This outcome is likely attributed to the absence of active infection foci, as these patients demonstrated clinical and radiological improvement.\u003c/p\u003e \u003cp\u003eAmong patients with positive [68Ga]Gallium citrate uptake at baseline, 14 of 18 (77.8%) were confirmed positive by Xpert MTB testing, while 4 (22.2%) were negative. Variability in tracer avidity across patients may reflect differences in viable bacterial load within lesions. In a subset of cases, the baseline [68Ga]Gallium citrate scans did not demonstrate significant tracer avidity, suggesting potential limitations in the diagnostic capability of [68Ga]Gallium citrate PET/CT as a baseline imaging modality.\u003c/p\u003e \u003cp\u003eFurthermore, out of the twenty-one patients, seventeen had [18F]FDG PET CT scan on the follow-up. Among these seventeen cases, thirteen showed [18F]FDG avidity in spinal disease, with SUVmax ranging from 3.19 to 20.29. Four cases were negative and in symptomatic remission. Of the thirteen [18F]FDG-positive cases, all the patients showed symptomatic clinical improvement.\u003c/p\u003e \u003cp\u003e[18F]FDG PET/CT enables non-invasive, semi-quantitative assessment of metabolic activity within lesions. Active tubercular sites typically contain lymphocytes, epithelioid cells, and Langerhans-type giant cells, all of which exhibit high glucose metabolism, resulting in increased [18F]FDG uptake. A reduction in [18F]FDG uptake over time may reflect a favourable response to anti-tubercular therapy and help guide the appropriate duration of treatment (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). The accumulation of [18F]FDG can also be occurred in healing bones that were free from infections (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003ePromising Indicator of Clinical Response:\u003c/h2\u003e \u003cp\u003eOn follow-up, the absence of tracer uptake in lesions that showed avidity at baseline was strongly associated with positive clinical outcomes following completion of antitubercular therapy. This observation correlated with radiological improvements, including evidence of sclerosis or bone fusion on X-ray and CT, and reductions in abscess size, oedema, discitis, and hyperintensity on T1-weighted MRI images.\u003c/p\u003e \u003cp\u003eHigh [18F]FDG uptake on PET/CT may reflect either ongoing active disease or heightened host immune activity that is ultimately self-resolving, making interpretation challenging (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e) and also tuberculous granulomatous inflammation appears as [18F]FDG avid lesions on PET/CT imaging (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOn follow-up with [18F]FDG PET/CT scans, 13 of 17 patients demonstrated significant tracer avidity. However, there is a possibility that a healed site may appeared as falsely positive. The observed [18F]FDG avidity in the study could be attributed to ongoing inflammatory cellular processes rather than active infection. Scherer et al. suggest that elevated [18F]FDG uptake may not solely be attributed to increased metabolic activity resulting from active infection, but rather it may also serve as an indicator of tissue regeneration (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). This observation could potentially elucidate the heightened [18F]FDG uptake seen in our patients following 9\u0026ndash;12 months of ATT treatment. Calabria et al. proposed that in cases of chronic inflammation, other immune cells, such as fibroblasts, may show uptake of [18F]FDG, potentially leading to a resemblance of an infectious process (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Vorster et al. suggested that [68Ga]Gallium Citrate is less likely to accumulate in post-infective inflammation, making it a potentially important clinical tool, particularly as [18F]FDG often remains present in TB lesions even after treatment (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). [18F]FDG does not differentiate between bone infection and early normal bone healing, which presents a high level of cellular metabolism and glucose consumption, thereby mimicking the uptake of [18F]FDG during infection (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) .\u003c/p\u003e \u003cp\u003eGiven that most patients in our study showed symptomatic improvement at follow-up, the utility of [18F]FDG PET/CT as a definitive tool for response assessment in this context may be limited.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eChallenges in Understanding Non-Avid Disease on [68Ga]Gallium Citrate scan:\u003c/h2\u003e \u003cp\u003eDue to the small sample size, it remains challenging to definitively explain why some patients presented with non-avid disease in the baseline [68Ga]Gallium Citrate PET/CT scan. This phenomenon may be influenced by variations in bacterial load or microcellular changes that occur in affected tissues.\u003c/p\u003e \u003c/div\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eThe use of [68Ga]Gallium citrate PET CT in assessing Tuberculosis of the spine to demonstrate disease activity is valuable, although it should not be relied upon solely as a baseline diagnostic imaging modality. Nevertheless, it can serve as a potential marker to gauge treatment response in patients with uptake on the initial scan, and it can assist in making informed decisions regarding the continuation or cessation of treatment.\u003c/p\u003e \u003cp\u003eDespite symptomatic remission and disease resolution, the infection site may still show false-positive [18F]FDG avidity because of ongoing cellular inflammation. Therefore, [18F]FDG PET/CT may not reliably indicate therapeutic response.\u003c/p\u003e \u003cp\u003eThe [68Ga]Gallium Citrate PET/CT scan proves to be a valuable functional imaging modality for clinicians in the assessment of spinal tuberculosis, especially in low-income and developing countries with a high disease burden. Its generator-based production, as opposed to reliance on cyclotron facilities, significantly reduces costs and technical barriers, thus enhancing accessibility in regions equipped with PET/CT technology. This cost-effective approach can greatly improve diagnostic capabilities and patient care in resource-constrained settings.\u003c/p\u003e \u003cp\u003e \u003cem\u003eLIMITATIONS OF THE STUDY\u003c/em\u003e \u003c/p\u003e \u003cp\u003e- The acquisition of delayed images with [68Ga]Gallium citrate is challenging due to the tracer's short half-life.\u003c/p\u003e \u003cp\u003e- The sample size of the study, particularly those who had follow up assessment is small.\u003c/p\u003e \u003cp\u003e- The findings are based on a single-centre experience, which may affect the broader applicability of the results.\u003c/p\u003e \u003cp\u003e- Not all patients had the complete panel of relevant biochemical, microbiological tests and biopsy reports available. MRI scans were not done in all patients at both baseline and at follow-up.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cem\u003eConflicts of Interest:\u003c/em\u003e The authors have no conflicts of interest to disclose.\u003c/p\u003e\n\u003cp\u003eDeclarations of interest: None\u003c/p\u003e\n\u003cp\u003eAcknowledgments:\u003c/p\u003e\n\u003cp\u003eThis study was made possible through the support of the Department of Biotechnology (DBT) and was funded by the Department of Health Research (DHR), ICMR- Government of India.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAUTHOR CONTRIBUTIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStudy conceptualization:\u003c/em\u003e Justin K Varghese, Saumya Sara Sunny, Julie Hephzibah\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eMethodology\u003c/em\u003e: Justin K Varghese, Saumya Sara Sunny, Julie Hephzibah\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eData collection:\u003c/em\u003e Justin K Varghese, Saumya Sara Sunny\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eLiterature search and resources:\u003c/em\u003e Justin K Varghese, Saumya Sara Sunny, Julie Hephzibah, Justin Arockiaraj, Venkatesh K, Abi Manesh\u0026nbsp;S\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eData analysis and interpretation:\u003c/em\u003e Justin K Varghese, Saumya Sara Sunny, Julie Hephzibah, Mahasampath Gowri S\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eDrafting the manuscript and resource people:\u003c/em\u003e Justin K Varghese, Saumya Sara Sunny, Julie Hephzibah, Justin Arockiaraj, Venkatesh K, Abi Manesh\u0026nbsp;S\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eProject administration\u003c/em\u003e:\u0026nbsp;Justin K Varghese, Saumya Sara Sunny, Julie Hephzibah\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eReview of final manuscript and approval for publication:\u003c/em\u003e Justin K Varghese, Saumya Sara Sunny, Julie Hephzibah, Justin Arockiaraj, Venkatesh K, Abi Manesh S, Mahasampath Gowri S\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGarg B, Mehta N, Mukherjee RN, Swamy AM, Siamwala BS, Malik G. 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Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://link.springer.com/article/\u003c/span\u003e\u003cspan address=\"https://link.springer.com/article/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00259-005-1841-9\u003c/span\u003e\u003cspan address=\"10.1007/s00259-005-1841-9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYu WY, Lu PX, Assadi M, Huang XL, Skrahin A, Rosenthal A, et al. Updates on 18F-FDG-PET/CT as a clinical tool for tuberculosis evaluation and therapeutic monitoring. Quant Imaging Med Surg. 2019 June;9(6):1132\u0026ndash;46.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKung BT, Seraj SM, Zadeh MZ, Rojulpote C, Kothekar E, Ayubcha C, et al. An update on the role of 18F-FDG-PET/CT in major infectious and inflammatory diseases. Am J Nucl Med Mol Imaging. 2019;9(6):255\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eScherer J, Mukasa SL, Wolmarans K, Guler R, Kotze T, Song T et al. 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. Infection [Internet]. 2024 June 19 [cited 2024 Oct 16]; Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s15010-024-02327-5\u003c/span\u003e\u003cspan address=\"10.1007/s15010-024-02327-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 to 4 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"annals-of-nuclear-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"anme","sideBox":"Learn more about [Annals of Nuclear Medicine](http://link.springer.com/journal/12149)","snPcode":"12149","submissionUrl":"https://www.editorialmanager.com/anme/default2.aspx","title":"Annals of Nuclear Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-9384366/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9384366/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective:\u003c/h2\u003e \u003cp\u003eSpinal tuberculosis (STB) remains a major clinical challenge in high-burden countries. Infection imaging agents such as [18F]FDG and [67Ga]Gallium citrate have limitations in specificity and interpretation. [68Ga]Gallium citrate, produced via a [68Ge/67Ga] generator, offers logistical and economic advantages. This prospective study evaluated the utility of [68Ga]Gallium citrate PET/CT for diagnosing active spinal TB and for treatment response assessment in comparison with [18F]FDG PET/CT.\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e \u003cp\u003eThirty-two patients with suspected spinal TB underwent baseline [68Ga]Gallium citrate PET/CT and those with uptake in disease more than or equivalent to the uptake in the abdominal aorta were considered positive. All patients then received the standard anti-tubercular therapy (ATT). Follow-up imaging at 9\u0026ndash;12 months included repeat [68Ga]Gallium citrate PET/CT (n\u0026thinsp;=\u0026thinsp;21), of which 17 patients were also underwent [18F]FDG PET/CT. Lesions with SUVmax\u0026thinsp;\u0026gt;\u0026thinsp;2.5 were considered metabolically active. Imaging findings were correlated with clinical outcomes. The uptake on functional imaging was correlated with other clinical, radiological, microbiological and histopathological data for each patient.\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e \u003cp\u003eAt baseline, 22/32 patients (68.8%) demonstrated increased [68Ga]Gallium uptake consistent with infective spondylodiscitis, while 10 (31.2%) showed no abnormal uptake. There was no statistically significant correlation between tracer uptake and clinical, radiological, or laboratory parameters. Follow-up imaging in 21 patients demonstrated complete resolution of increased [68Ga]Gallium uptake in all 12 baseline-positive cases and remained negative in 9 initially negative cases, correlating with symptomatic improvement. In contrast, [18F]FDG PET/CT performed in 17 patients showed persistent [18F]FDG avidity in 13 patients despite clinical remission, while 4 showed no abnormal uptake.\u003c/p\u003e\u003ch2\u003eConclusion:\u003c/h2\u003e \u003cp\u003eAlthough [68Ga]Gallium citrate PET/CT does not appear to be a reliable diagnostic modality, it is useful in identifying active spinal TB and may serve as a reliable marker for therapeutic response in patients with baseline tracer uptake. Persistent [18F]FDG uptake despite clinical recovery indicates the limited specificity of [18F]FDG PET/CT for response assessment, likely reflecting residual inflammatory activity rather than active disease. Given its generator-based production and lower infrastructural requirements, [68Ga]Gallium citrate PET/CT may represent a cost-effective and accessible functional imaging modality for spinal TB, particularly in resource-limited settings with a high disease burden.\u003c/p\u003e","manuscriptTitle":"Utility of [68Ga]Gallium Citrate PET/CT Imaging in the Diagnosis of Active Spinal Tuberculosis and Response Assessment in Comparison with [18F]FDG PET/CT – A Prospective Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-26 15:50:33","doi":"10.21203/rs.3.rs-9384366/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2026-04-24T15:52:40+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-17T04:36:50+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-13T02:11:02+00:00","index":"","fulltext":""},{"type":"submitted","content":"Annals of Nuclear Medicine","date":"2026-04-11T00:19:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"annals-of-nuclear-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"anme","sideBox":"Learn more about [Annals of Nuclear Medicine](http://link.springer.com/journal/12149)","snPcode":"12149","submissionUrl":"https://www.editorialmanager.com/anme/default2.aspx","title":"Annals of Nuclear Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"06a255be-2693-48bb-b7a6-9f23c6a14bb1","owner":[],"postedDate":"April 26th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-26T15:50:33+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-26 15:50:33","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9384366","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9384366","identity":"rs-9384366","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}