Skip to main content
Download PDF

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)

Journal of Orthopaedic Surgery and Research volume 19, Article number: 376 (2024) Cite this article

Abstract

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).

Background

Epidemiology

In 2022, an estimated 10.6 million people fell ill with tuberculosis (TB) and 6.4 million patients received TB treatment [1]. TB and HIV are the two leading infectious diseases causes of death worldwide, with TB ranking number one cause of death in people living with HIV (PLWH) and responsible for the burden of multimorbidity in low-and-middle-income countries [2,3,4]. South Africa has the most devastating TB/HIV epidemic with an HIV prevalence of 19% in adult TB cases and a TB incidence of 615/100,000 in some regions [5,6,7,8]. In 2019, 7.1% of the previously treated TB cases and 3.4% of the new TB cases in South Africa were resistant to rifampicin and/or isoniazid [9]. TB vaccine development has recently been successful, but not in PLWH who are more likely to develop extrapulmonary TB (EPTB) [10,11,12]. Musculoskeletal TB accounts for approximately 20% of EPTB cases, with spinal involvement in up to 50 percent of these cases (Fig. 1) [13, 14]. It is believed that spinal tuberculosis (STB) arises from the hematogenous spread of Mycobacterium tuberculosis (Mtb) from a primary pulmonary infection into the well perfused cancellous bone of the vertebral bodies. [15] STB is a spondylitis or spondylodiscitis caused by Mtb, historically called Pott's disease or Pott`s spine. It commonly manifests as localised backpain, pain, spinal deformity with/without instability, neurological deficit, and constitutional symptoms. The time from initial symptoms to diagnosis can take several years [16,17,18]. Diagnosis relies on clinical presentation, spinal imaging, and microbiological testing from lesion biopsy [19].Therapy includes TB treatment, immobilization, and spinal surgery in selected patients [20].

Fig. 1
figure 1

Pie chart depicting the proportions of different manifestations of tuberculosis (TB)

Full size image

Clinical and radiological phenotypes of spinal TB

Little is known about the extent of disease in STB, and isolated STB, which is confined to the vertebra and surrounding anatomical structures, as well as disseminated forms of STB have been described (Fig. 2, 3) [21, 22]. The latter presents with spinal lesion(s) plus additional TB lesion(s) in other parts of the body such as the lungs, pleura, lymph nodes, meninges, urogenital, gastrointestinal tract, and other musculoskeletal involvement such as peripheral joints [23]. The diagnosis of disseminated STB requires whole body imaging and/or microbiological evidence of additional sites of infection, e.g., a positive GeneXpert from a lymph node aspirate or a positive urine culture for Mtb [24]. With this, the question arises, whether isolated spinal TB without any other active focus can be a stand-alone entity and whether the disseminated form of STB is a dual Mtb infection with potentially different strain types at the different sites of disease [25].

Fig. 2
figure 2

Definition of isolated spinal tuberculosis (TB) and disseminated spinal TB in the Spinal TB X cohort

Full size image
Fig. 3
figure 3

Example 18FDG-PET/CTs of two patients with spinal tuberculosis (TB). Patient 1 with sagittal (A) and coronal plane (B) with disseminated spinal tuberculosis. Spinal TB [white arrow] with a pulmonary TB lesion [green arrow] and mediastinal lymph node with FDG uptake [blue arrow]. Patient 2 with sagittal (C) and coronal plane (D) with isolated spinal tuberculosis. Spinal TB [white arrow] with no other lesion in the body in 18FDG-PET/CT

Full size image

Imaging in tuberculosis

Magnetic resonance imaging (MRI) is the imaging gold standard for STB and has a reported sensitivity of 94% and specificity of 93% in detecting spondylodiscitis [26]. MRI can accurately detect spinal cord compression, intrinsic changes of the cord, bony changes of the vertebral body as well as the extent of disc destruction, and psoas abscess formations [27]. If possible, MRI of the whole spine should be performed to detect non-continuous lesions, occurring in up to 20% of patients [28]. 2-Deoxy-2-[18F]fluoro-d-glucose positron emission tomography/computed tomography (PET/CT) has been shown to be able to detect sites of infection and monitor treatment response in tuberculosis [29]. 18FDG accumulates in tissue with increased glucose metabolism (e.g., infections, inflammatory conditions, malignant conditions, ischemia). It has been found that 18FDG uptake values are higher in patients with STB compared to patients with pyogenic spondylitis [30]. A small study has shown that 18FDG-PET/CT is potentially superior to MRI in accuracy to diagnosing STB [31]. Semi-automatic technique to quantify complex tuberculous lesions on 18FDG-PET/CT and allows for standardised assessment [32].

Transcriptomic profiling in tuberculosis

Host transcriptomics have identified RNA signatures for tuberculosis diagnosis and monitoring treatment response as well as understanding the immunological mechanisms of pulmonary TB [33, 34]. Several RNA signatures have been identified for risk of disease stratification, screening for TB, tracking treatment response and prediction of treatment failure [35,36,37,38]. Lately, an RNA signature which predicts recent exposure to Mtb in humans has been identified [39]. The description of these RNA signatures is opening the possibility for developing large-scale point of care screening tests as well as targeted (personalized) intervention to prevent the disease and, in patients with active tuberculosis, create customized treatment plans [36]. However, the diagnosis of EPTB and particularly STB remains challenging simply because sample collection requires invasive procedures in the absence of a blood-based diagnostic test. Host transcriptomics may be the key for a blood-based test for STB.

Treatment of spinal TB

Treatment combination and duration of treatment of STB has not been systemically studied in randomised controlled trials for various reasons. According to WHO, adults with extrapulmonary TB can safely be treated with a 6-month regimen except for patients with TB of the central nervous system and musculoskeletal TB, including patients with STB. These subgroups require 9–12 months of treatment duration.

Treatment for STB consists primarily of chemotherapy (antituberculosis treatment; ATT) and in case of a “spine at risk”, surgery is required additionally [40, 41]. Drug-sensitive TB can be treated using the standard combined 4-drug regimen medication according to body weight. The WHO suggests an intensive phase using with rifampicin, isoniazid, pyrazinamide, and ethambutol for two months, followed by continuation phase using rifampicin and isoniazid for seven to ten months [42] Guidelines for the treatment of multi-drug resistant (MDR) STB are lacking. According to WHO, patients with severe forms of extrapulmonary MDR TB including TB meningitis, brain abscesses, osteomyelitis and arthritis (which includes STB) should not be treated with the new 9-month all-oral regimen for MDR-TB and longer regimens apply for patients with severe forms of extrapulmonary diseases such as STB [43]. However, treatment durations of STB as well as dosing of TB drugs differ significantly between different countries and an infectious diseases expert with experience in extrapulmonary TB disease should always be consulted [44].

Methods and design

Aims and objectives

The aims of this project are to (1) describe the clinical phenotype of STB (isolated versus disseminated STB), (2) explore different imaging modalities using MRI of the spine and whole-body PET/CT, (3) identify RNA signatures for the two different clinical phenotypes of STB: the isolated and disseminated form of STB, and (4) to analyse the genomes of Mtb isolates extracted from different specimens from different sites of the body, hence identifying dual infection. Objectives are listed in Box 1.

Box 1 Spinal TB X objectives
Full size table

Study design, setting, and eligibility

This is a prospective cohort study of HIV-infected and -uninfected patients with STB who live in the Cape Town metropole, South Africa. Patients with suspected STB will be referred from Groote Schuur Hospital and its affiliated teaching hospitals (Mitchell`s Plain Hospital, New Somerset Hospital, Victoria Hospital Wynberg) to the study team at the University of Cape Town. Eligibility criteria are listed in Box 2. We aim to recruit 100 participants over a timeframe of three years.

Box 2 Eligibility criteria
Full size table

Patient and public involvement

Patients or the public are not involved in the design, or conduct, or reporting, or dissemination plans of this prospective cohort study.

Case definition

Only cases with clinical signs and symptoms and suspicion of STB on MRI will be included in the Spinal TB X cohort study (Fig. 4). Definite STB is defined as microbiological evidence of Mtb infection in tissue of spinal lesions or psoas abscess drainage.

Fig. 4
figure 4

Case definition for "definite" spinal tuberculosis (TB) in the Spinal TB X cohort. MRI magnetic resonance imaging, Mtb Mycobacterium tuberculosis, AFB acid-fast bacilli (Ziehl–Neelsen or auramine-rhodamine stain), CT computed tomography

Full size image

Study procedures

Detailed study procedures and timelines are displayed in Table 1 and Fig. 5. At the pre-screening visit, patients will be assessed regarding their eligibility to join the study. Routine clinical work-up includes blood tests, MRI and work-up for tuberculosis. Patients with suspected spinal tuberculosis on MRI will be approached to join the Spinal TB X cohort study. Informed consent will be obtained by study nurses in the native language of the patient. After inclusion in the study, the screening visit will be performed. At baseline, clinical examination as well as blood collection [creatinine, Alanine transaminase (ALT), full blood count (FBC) including differential count (DIFF), C-reactive protein (CRP) and Haemoglobin A1C (HbA1c)] will be performed. CD4-count, and HIV viral load will be tested in PLWH. Every patient with no history of HIV infection will undergo HIV testing according to national guidelines. Sputum and urine will be collected for GeneXpert Ultra test and Mtb culture including drug sensitivity testing, and screening for diabetes and pregnancy will be completed. Whole-body PET/CTs will be performed within ten days after the screening visit. At the PET/CT visit, serum, heparin blood (for Peripheral Blood Mononuclear Cells) and whole blood (in PAXgene tubes) will be collected for biobanking. After the PET/CT, patients will undergo spinal biopsies, or surgery where applicable and specimen will be collected for GeneXpert Ultra test and Mtb culture including drug sensitivity testing. Within ten days of the PET/CT visit, patients will be reviewed and examined by the study team and PET/CT findings will be discussed. Where applicable, patients will be referred to medical specialties for further biopsies of sites of infection detected by PET/CT. Patients with microbiologically confirmed "definite" STB on the collected specimen will be started on TB treatment according to local guidelines. Patients with other diagnoses confirmed by culture or histology will be excluded from the study. In the following one to five months, every patient will be contacted by the study team on a regular basis and undergo a standardized questionnaire regarding their clinical course of disease and tuberculosis and HIV (if applicable) drug adherence monitoring. Six months after the first PET/CT, patients will undergo the second PET/CT. At the second PET/CT visit, serum, heparin blood (for Peripheral Blood Mononuclear Cells) and whole blood (in PAXgene tubes) will be collected for biobanking. Additionally, FBC including DIFF and CRP will be collected to determine inflammatory trends. Furthermore, a random-glucose test and in female participants, a beta-HCG-urine test, will be performed. At months seven to eleven, telephonic follow-up will be continued and at month 12, PET/CT 3 will be performed. At the third PET/CT visit, serum, heparin blood (for Peripheral Blood Mononuclear Cells) and whole blood (in PAXgene tubes) will be collected for biobanking. Additionally, FBC including DIFF and CRP will be collected to determine inflammatory trends. Furthermore, a random-glucose test and in female participants, a beta-HCG-urine test, will be performed.

Table 1 Spinal TB X study timelines
Full size table
Fig. 5
figure 5

Spinal TB X study flow. TB tuberculosis, MRI magnetic resonance imaging, PET/CT 18F-fluorodeoxyglucose positron emission tomography/computed tomography

Full size image

Data collection, data cleaning, and statistical analysis

All study source data will be collected on paper case report forms and entered and stored in RedCap® on a dedicated secure central database at the University of Cape Town. Data will be reviewed by at least two investigators (JS, FT, SM, KW) for completeness and data cleaning, validation and analysis performed by the academic study team. All data will be transferred to R, Version 4.2.2 for all analysis. Normally distributed continuous data will be presented as mean ± SD and non-Gaussian distributed variables as median + IQR. Categorical data will be presented as percentages with 95% CI where appropriate. For patient group comparisons, we will use χ2 analysis with calculation of ORs and 95% CI (where appropriate) for discrete variables and student t-test and analysis of variance for normally distributed continuous variables. Multiple logistic regression analyses (entry model) will be performed on age, sex, and baseline characteristics where applicable. Significance will be accepted at the two-sided level of 0.05. Whole-genome and RNA-sequencing will be performed through third parties. Measurement of semi-quantitative PET/CT values will be performed using MIM® Version 7.2.8 (MIM Software Inc., Cleveland, Ohio, USA) according to a standardized reading protocol which allows to compare values between patients with isolated and disseminated STB. Patients which underwent the initial PET/CT but had no confirmed STB diagnosis will serve as control group for the gene-expression profile analysis.

Discussion

The purpose of this study is to describe the clinical phenotype of spinal TB using whole body PET/CT and to identify a mRNA gene expression profile of isolated spinal TB versus disseminated spinal TB stratified by HIV status. Due to the long follow-up period of the participants, loss to follow-up is anticipated in some of the patients. To counteract this, participants can agree to house visits for such case in the informed consent and provide next of kin details. Further, we follow up participants monthly with telephone calls to keep close contact to the participants and to be aware of any other issues. Participants with significant incidental findings on PET/CT that require immediate diagnostic procedures or treatment may be withdrawn from the study if the investigator deems that continuing participation may not be in the participant’s best interests. At each contact with the participant, information regarding adverse events (AE) will be elicited by appropriate questioning and examinations. All events, both expected/unexpected and related/unrelated will be recorded on a source document. Source documents will include progress notes, laboratory reports, consult notes, phone call summaries, survey tools, and data collection tools. Source documents will be reviewed in a timely manner by the research team. All reportable adverse events that are identified will be recorded on the appropriate case report form (CRF) and in the study chart. The start date, stop date, severity of each reportable event, and the investigator’s judgment of the AE’s relationship and expectedness to the study will also be recorded on the CRF. In the event of a participants` withdrawal from the study due to an AE, it must be recorded on the CRF as such. Adverse events associated with standard of care (TB treatment, biopsies, surgery) will be reported to the Human Research Ethics Committee and marked as study unrelated.

If successful, new diagnostic modalities and treatment plans can be developed, enhancing personalized medicine. Persons with previously undiagnosed medical, surgical, or other conditions identified at screening, including but not limited to PET/CT imaging, HIV infection diagnosis, will benefit from early diagnosis, referral, and rapid access to treatment systems. Similarly, participants who develop new conditions during follow-up will also benefit from early diagnosis and linkage to care. In addition, spinal TB patients will be monitored closely by the study team throughout the study period.

Availability of data and materials

Not applicable.

Abbreviations

AE:

Adverse event

TB:

Tuberculosis

Mtb:

Mycobacterium tuberculosis

EPTB:

Extrapulmonary tuberculosis

STB:

Spinal tuberculosis

MRI:

Magnetic resonance imaging

PET/CT:

2-Deoxy-2-[18F]fluoro-d-glucose positron emission tomography/computed tomography

CRF:

Case report form

References

  1. World Health Organization. Global tuberculosis report 2022. Geneva: World Health Organization; 2022.

    Google Scholar 

  2. World Health Organization. Global tuberculosis report 2013: World Health Organization; 2014.

  3. Diedrich CR, O’Hern J, Wilkinson RJ. HIV-1 and the Mycobacterium tuberculosis granuloma: a systematic review and meta-analysis. Tuberculosis (Edinb). 2016;98:62–76.

    Article  CAS  PubMed  Google Scholar 

  4. Thienemann F, Ntusi NAB, Battegay E, Mueller BU, Cheetham M. Multimorbidity and cardiovascular disease: a perspective on low- and middle-income countries. Cardiovasc Diagn Therapy. 2019;10:376–85.

    Article  Google Scholar 

  5. World Health Organization. Fact sheets: HIV/AIDS. 2019.

  6. UNAIDS. HIV/AIDS South Africa. Geneva2020.

  7. Naidoo P, Theron G, Rangaka MX, Chihota VN, Vaughan L, Brey ZO, et al. The South African tuberculosis care cascade: estimated losses and methodological challenges. J Infect Dis. 2017;216:S702–13.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Global burden of chronic respiratory diseases and risk factors, 1990–2019: an update from the Global Burden of Disease Study 2019. EClinicalMedicine. 2023; 59:101936.

  9. Kwan CK, Ernst JD. HIV and tuberculosis: a deadly human syndemic. Clin Microbiol Rev. 2011;24:351–76.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Barnes PF, Bloch AB, Davidson PT, Snider DE Jr. Tuberculosis in patients with human immunodeficiency virus infection. N Engl J Med. 1991;324:1644–50.

    Article  CAS  PubMed  Google Scholar 

  11. Tait DR, Hatherill M, Van Der Meeren O, Ginsberg AM, Van Brakel E, Salaun B, et al. Final analysis of a trial of M72/AS01E vaccine to prevent tuberculosis. N Engl J Med. 2019;381:2429–39.

    Article  CAS  PubMed  Google Scholar 

  12. Ndiaye BP, Thienemann F, Ota M, Landry BS, Camara M, Dièye S, et al. Safety, immunogenicity, and efficacy of the candidate tuberculosis vaccine MVA85A in healthy adults infected with HIV-1: a randomised, placebo-controlled, phase 2 trial. Lancet Respir Med. 2015;3:190–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kaya A, Topu Z, Fitoz S, Numanoglu N. Pulmonary tuberculosis with multifocal skeletal involvement. Monaldi Arch Chest Dis. 2004;61:133–5.

    Article  CAS  PubMed  Google Scholar 

  14. Turgut M. Spinal tuberculosis (Pott’s disease): its clinical presentation, surgical management, and outcome. A survey study on 694 patients. Neurosurg Rev. 2001;24:8–13.

    Article  CAS  PubMed  Google Scholar 

  15. Sankaran B. Tuberculosis of bones and joints. Ind J Tub. 1993;40:109–18.

    Google Scholar 

  16. Flamm ES. Percivall Pott: an 18th century neurosurgeon. J Neurosurg. 1992;76:319–26.

    Article  CAS  PubMed  Google Scholar 

  17. Batirel A, Erdem H, Sengoz G, Pehlivanoglu F, Ramosaco E, Gulsun S, et al. The course of spinal tuberculosis (Pott disease): results of the multinational, multicentre Backbone-2 study. Clin Microbiol Infect. 2015;21(1008):e9–18.

    Google Scholar 

  18. Dunn R, Zondagh I, Candy S. Spinal tuberculosis: magnetic resonance imaging and neurological impairment. Spine. 2011;36:469–73.

    Article  PubMed  Google Scholar 

  19. Garg RK, Somvanshi DS. Spinal tuberculosis: a review. J Spinal Cord Med. 2011;34:440–54.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Jutte PC, Van Loenhout-Rooyackers JH. Routine surgery in addition to chemotherapy for treating spinal tuberculosis. Cochrane Database Syst Rev. 2006:1004532.

  21. Schirmer P, Renault CA, Holodniy M. Is spinal tuberculosis contagious? Int J Infect Dis. 2010;14:e659–66.

    Article  PubMed  Google Scholar 

  22. Al-Khudairi N, Meir A. Isolated tuberculosis of the posterior spinal elements: case report and discussion of management. JRSM Open. 2014;5:2054270414543396.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Batirel A, Erdem H, Sengoz G, Pehlivanoglu F, Ramosaco E, Gülsün S, et al. The course of spinal tuberculosis (Pott disease): results of the multinational, multicentre Backbone-2 study. Clin Microbiol Infect. 2015;21:1008e9-e18.

    Article  Google Scholar 

  24. Harkirat S, Anana S, Indrajit L, Dash AK. Pictorial essay: PET/CT in tuberculosis. Indian J Radiol Imaging. 2008;18:141–7.

    Article  PubMed Central  Google Scholar 

  25. Manabe YC, Dannenberg AM Jr, Tyagi SK, Hatem CL, Yoder M, Woolwine SC, et al. Different strains of Mycobacterium tuberculosis cause various spectrums of disease in the rabbit model of tuberculosis. Infect Immun. 2003;71:6004–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Modic M, Feiglin D, Piraino D, Boumphrey F, Weinstein M, Duchesneau P, et al. Vertebral osteomyelitis: assessment using MR. Radiology. 1985;157:157–66.

    Article  CAS  PubMed  Google Scholar 

  27. Moorthy S, Prabhu NK. Spectrum of MR imaging findings in spinal tuberculosis. Am J Roentgenol. 2002;179:979–83.

    Article  Google Scholar 

  28. Shetty A, Kanna RM, Rajasekaran S. TB spine—Current aspects on clinical presentation, diagnosis, and management options. Seminars in Spine Surgery 2016. p. 150–62.

  29. Chen RY, Via LE, Dodd LE, Walzl G, Malherbe ST, Loxton AG, et al. Using biomarkers to predict TB treatment duration (Predict TB): a prospective, randomized, noninferiority, treatment shortening clinical trial. Gates Open Res. 2017;1:9.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Bassetti M, Merelli M, Di Gregorio F, Della Siega P, Screm M, Scarparo C, et al. Higher fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) uptake in tuberculous compared to bacterial spondylodiscitis. Skeletal Radiol. 2017;46:777–83.

    Article  PubMed  Google Scholar 

  31. Altini C, Lavelli V, Niccoli-Asabella A, Sardaro A, Branca A, Santo G, et al. Comparison of the diagnostic value of MRI and whole body (18)F-FDG PET/CT in diagnosis of spondylodiscitis. J Clin Med. 2020;9.

  32. Malherbe ST, Dupont P, Kant I, Ahlers P, Kriel M, Loxton AG, et al. A semi-automatic technique to quantify complex tuberculous lung lesions on 18F-fluorodeoxyglucose positron emission tomography/computerised tomography images. EJNMMI Res. 2018;8:55.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Burel JG, Babor M, Pomaznoy M, Lindestam Arlehamn CS, Khan N, Sette A, et al. Host transcriptomics as a tool to identify diagnostic and mechanistic immune signatures of tuberculosis. Front Immunol. 2019;10.

  34. Odia T, Malherbe ST, Meier S, Maasdorp E, Kleynhans L, du Plessis N, et al. The peripheral blood transcriptome is correlated with PET measures of lung inflammation during successful tuberculosis treatment. Front Immunol. 2021;11.

  35. Penn-Nicholson A, Mbandi SK, Thompson E, Mendelsohn SC, Suliman S, Chegou NN, et al. RISK6, a 6-gene transcriptomic signature of TB disease risk, diagnosis and treatment response. Sci Rep. 2020;10:8629.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zak DE, Penn-Nicholson A, Scriba TJ, Thompson E, Suliman S, Amon LM, et al. A blood RNA signature for tuberculosis disease risk: a prospective cohort study. Lancet. 2016;387:2312–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Suliman S, Thompson EG, Sutherland J, Weiner J 3rd, Ota MOC, Shankar S, et al. Four-gene pan-African blood signature predicts progression to tuberculosis. Am J Respir Crit Care Med. 2018;197:1198–208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Thompson EG, Du Y, Malherbe ST, Shankar S, Braun J, Valvo J, et al. Host blood RNA signatures predict the outcome of tuberculosis treatment. Tuberculosis. 2017;107:48–58.

    Article  CAS  PubMed  Google Scholar 

  39. Ault RC, Headley CA, Hare AE, Carruthers BJ, Mejias A, Turner J. Blood RNA signatures predict recent tuberculosis exposure in mice, macaques and humans. Sci Rep. 2020;10:16873.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Rajasekaran S. Kyphotic deformity in spinal tuberculosis and its management. Int Orthop. 2012;36:359–65.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Rajasekaran S, Soundararajan DCR, Reddy GJ, Shetty AP, Kanna RM. A validated score for evaluating spinal instability to assess surgical candidacy in active spinal tuberculosis-an evidence based approach and multinational expert consensus study. Global Spine J. 2023;13:2296–309.

    Article  PubMed  Google Scholar 

  42. World Health Organization. WHO consolidated guidelines on tuberculosis. Module 4: treatment-drug-susceptible tuberculosis treatment: World Health Organization; 2022.

  43. World Health Organization. WHO operational handbook on tuberculosis. Module 4: treatment-drug-resistant tuberculosis treatment, 2022 update: World Health Organization; 2022.

  44. Garg D, Goyal V. Spinal tuberculosis treatment: an enduring bone of contention. Ann Indian Acad Neurol. 2020;23:441–8.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Vanino E, Granozzi B, Akkerman OW, Munoz-Torrico M, Palmieri F, Seaworth B, et al. Update of drug-resistant tuberculosis treatment guidelines: a turning point. Int J Infect Dis. 2023;130(Suppl 1):S12–5.

    Article  CAS  PubMed  Google Scholar 

  46. von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP, et al. The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. Int J Surg. 2014;12:1495–9.

    Article  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

The Spinal TB X project is supported by AO Foundation, AO Spine (AOS-DIA-22–029-TRA). AO Spine is a clinical division of the AO Foundation –an independent medically-guided not-for-profit organization based in Davos, Switzerland. Prof. Friedrich Thienemann, Dr Sandra Mukasa, Prof. Reto Guler and Dr Karen Wolmarans receive support from the EDCTP2 programme supported by the European Union (grant number RIA2017T- 2004-StatinTB). The General Medicine & Global Health (GMGH) Research Unit (www.gmgh.africa) of the University of Cape Town provided institutional support. Julian Scherer received further personal financial support from the Postgraduate Funding Office of the University of Cape Town for his PhD-project.

Author information

Authors and Affiliations

  1. General Medicine & Global Health (GMGH), Department of Medicine and Orthopaedic Research Unit (ORU), Division of Orthopaedic Surgery, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa

    Julian Scherer

  2. Department of Traumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland

    Julian Scherer & Hans-Christoph Pape

  3. Department of Medicine, Faculty of Health Science, General Medicine and Global Health (GMGH), University of Cape Town, 4Th Floor, Chris Barnard Building, Anzio Road, Observatory, Cape Town, 7925, South Africa

    Sandra L. Mukasa, Karen Wolmarans & Friedrich Thienemann

  4. Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Division of Immunology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa

    Reto Guler

  5. International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa

    Reto Guler

  6. Department of Medicine, CUBIC, PETCT, University of Cape Town, Cape Town, South Africa

    Tessa Kotze

  7. Division of Medical Microbiology, Department of Pathology, Faculty of Health Sciences, Institute of Infectious Diseases and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa

    Taeksun Song

  8. Orthopaedic Research Unit (ORU), Division of Orthopaedic Surgery, Faculty of Health Science, University of Cape Town, Cape Town, South Africa

    Robert Dunn, Maritz Laubscher & Michael Held

  9. Department of Internal Medicine, University Hospital Zurich, University of Zurich, Zurich, Switzerland

    Friedrich Thienemann

Authors
  1. Julian Scherer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sandra L. Mukasa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Karen Wolmarans
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Reto Guler
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tessa Kotze
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Taeksun Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Robert Dunn
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Maritz Laubscher
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hans-Christoph Pape
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Michael Held
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Friedrich Thienemann
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

FT was responsible for the initial idea of this study. FT and JS conducted an extensive literature review, study design and planning. All authors have contributed not only to the set-up of the Spinal TB X study, but also to various aspects of the study design with input relating to their specific expertise in the field. FT, JS, SM, KW, HCP, RD, ML, RG, PK, TK, TS and MH have developed the study protocol. FT and JS wrote the study protocol. JS developed CRFs and the database. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Friedrich Thienemann.

Ethics declarations

Ethics and consent to participate

The present study was approved by the University of Cape Town, Faculty of Health Science, Human Research Ethics Committee (REF: 243/2022). Written informed consent must be obtained from every patient participating in this study. We aim to adhere to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for this type of study wherever possible. [46]

Consent for publication

Not applicable.

Competing interest

None of the authors has a relationship with industry or financial disclosure related to the content of this manuscript.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Scherer, J., Mukasa, S.L., Wolmarans, K. et al. 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). J Orthop Surg Res 19, 376 (2024). https://doi.org/10.1186/s13018-024-04840-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13018-024-04840-7

Keywords

Journal of Orthopaedic Surgery and Research

ISSN: 1749-799X