Cytokine Profiles and suPAR in Spondylodiscitis
Condition: Spondylodiscitis
MeSH terms: Discitis
Study type: Observational

Summary: 
      Spondylodiscitis is an infectious disease of the intervertebral discs and adjacent vertebral
      bodies, which often has a protracted progression. Diagnosis is frequently delayed because of
      the unspecific pathology and a lack of specific infection markers. However, an early
      diagnosis is fundamental to prevent long periods with symptoms including extensive back pain
      and progressive and destructive changes of the spine.

      Cytokines can be helpful to extend the knowledge about diverse biological processes.
      Furthermore, they are a promising category of biomarkers that are already present in the
      early phases of developing diseases. Currently, little is known about the participation of
      cytokines in Spondylodiscitis. The aim of this study is to establish a non-invasive method to
      improve the diagnosis of spondylodiscitis. Therefore, blood and tissue samples will be
      analyzed at different time points for the concentration of specific cytokines to select
      potential marker cytokines via a Multiplex Assay and suPAR (soluble urokinase-type
      plasminogen activator receptor) via ELISA. After successful identification of the biomarkers
      cytokines and suPAR, verification of the results will be done by expression analysis of
      cytokine-producing cells.

      The potential of such a diagnostic method lies in reducing medical costs and preventing
      extensive pain and structural changes of the spine.

      Experimental research will be performed with the approval of the ethic committee of the
      medical faculty of the University of Cologne.
    

Detailed description: 
      Spondylodiscitis is a primary infection of the intervertebral discs with secondary infection
      of the adjacent end-plates and vertebral bodies. It is relatively rare with an incidence of
      2.4:100.000 and three times more common among men. The process of infection, which is
      commonly creeping, leads to a destruction of the vertebral bodies and production of
      abscesses, which can cause neurological deficits.

      Clinical symptoms, especially in the early stages, are uncommon. Patients suffer from
      unspecific back pain and fever occurs only in 50% of all cases. Currently, markers used
      including leucocyte count, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)
      are also unspecific.For this reason of that several weeks may elapse between the first signs
      of symptoms and the final diagnosis of spondylodiscitis. Therefore, the identification of the
      pathogen is indispensable for an effective antibiotic therapy.

      Spinal infections are generally monomicrobial, frequently with a haematogenous source.
      Therefore, blood cultures can be used for identifying the pathogens. In case of negative
      blood cultures, the pathogens can be identified by invasive methods such as percutaneous
      punch biopsy or CT-guided fine needle aspiration. Despite biopsies, the pathogen can only be
      identified in two out of three patients. Failures of pathogen identification are mainly due
      to previous systemic antibiotic treatment. As a consequence, diagnosis is often based on
      medical imaging methods (CT, MRT, PET, radiograph, skeletal scintigraphy). The disadvantage
      of these methods is that structural changes of the spine must occur to become visible.

      Treatment of an advanced spondylodiscitis consists of removal of the necrotic tissue,
      stabilization of the affected vertebral bodies and concomitant antibiotic therapy. Randomized
      studies for the duration of antibiotic treatments have not been published as yet. Current
      recommendations are between 6 to 12 weeks. For evaluating the therapy response only the
      clinical improvement and the CRP value are used. The mean period of stay in the hospital is
      about 49 days.

      The goal is to establish a non-invasive method which allows discrimination of infectious and
      non-infectious diseases to improve the diagnosis of spondylodiscitis. For that purpose, blood
      and tissue samples from patients with spondylodiscitis and erosive osteochondrosis will be
      collected and analyzed for their cytokine and suPAR concentration. Erosive osteochondrosis is
      a non-infectious, degenerative disease of the spine with similar surgical treatment. Thus, it
      is an optimal reference group. Nevertheless, erosive osteochondrosis includes special types,
      called modic type I-III. Because modic type I is associated with an immune response caused by
      repeated traumata of the spine this modic type will be excluded from the study.

      Cytokines are messengers, which are present in blood and all tissues, regulating the immune
      response. In this study, the goal is to assess if cytokine profiles and suPAR contribute to
      the discrimination of infectious and non-infectious spondylodiscitis and if this could be
      verified by the characterization of the cytokine-producing cells. Furthermore, the
      investigators want to analyze the therapy response by measuring the cytokine and suPAR
      profiles.

      Routine blood collection will be carried out directly before surgery and also during the
      stationary hospitalization on day 4 and day 10. Additional blood collection will be done
      after 6 weeks and 3 months during the follow-up. At each time point serum and plasma will be
      used for the study to determine the cytokine and suPAR concentration and expression of the
      cytokine-producing cells. Necrotic tissue, which is removed during the surgery, will be
      analyzed microbiologically as well as pathologically. Parts of this tissue will also be used
      for the determination of cytokines. Further blood samples will be collected when a patient
      appears again in the Department of Orthopaedic Surgery and Traumatology because of treatment
      and therapy of a re-infection. A minimum of 15 patients per group - control group (erosive
      osteochondrosis modic type II-III) and spondylodiscitis - will be included in this study.
      Both groups should be homogeneous in sex and age distribution.

      There will be no additional pain or complications for the patients participating in this
      study. All samples will be collected for a period of about one year and stored at -80°C.
      Afterwards, the blood and tissue samples will be analyzed for potential marker suPAR via
      ELISA and cytokines by using a Multiplex Assay. Furthermore, results will be linked to
      anamnesis to detect potential correlations. Specific correlations can indicate a diagnostic
      and perhaps a prognostic value of the measured cytokines and suPAR.
    

Intervention name(s): Cytokine Profile and suPAR
Intervention type(s): Other
Intervention description(s): Routine blood collection will be carried out directly before surgery and also during the stationary hospitalization on day 4 and day 10. Additional blood collection will be done after 6 weeks and 3 months during the follow-up.
Observational model: Other
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Patients with spondylodiscitis, erosive osteochondrosis
      
Biospecimen description: 
      Bio-Plex Pro Human Cytokine Group I 27-plex Assay (IL-1β, IL-1ra, IL-2, IL-4, IL-5, IL-6,
      IL-7, IL-8, IL-9, IL-10, IL-12 (p70), IL-13, IL-15, IL-17, FGF basic, Eotaxin, G-CSF, GM-CSF,
      IFN-γ, IP-10, MCP-1, MIP-1α, MIP-1β, PDGF-BB, RANTES, TNF-α, VEGF), suPAR (soluble
      urokinase-type plasminogen activator receptor)
    
Keywords: Spondylodiscitis; erosive osteochondrosis; infection; cytokine profiles; lumbar, thoracic spine; suPAR