Effect of Infection, Modic and Inflammation on Clinical Outcomes in Radiculopathy

Recent findings have suggested that a bacterial infection of the herniated disc aggravates pain symptoms. This bacterial infection is often associated with the presence of Modic changes (MC). Besides, evidence indicates that inflammation is also involved in resorption of herniated tissue.
The objective of this prospective cohort study is to explore the contribution of infection and inflammation in lumbar and cervical radiculopathy. We hypothesize that patients with MC, infection and inflammation will suffer the most and that surgical intervention will have a disappointing outcome. Antibiotic therapy may be more effective in these patients. Inflammation is thus believed to work in two ways, dependent on the type of inflammatory cells: combined with a bacterial infection the inflammation will be accompanied by pro-inflammatory cytokines that worsen the outcome. In patients without such an infection, the inflammation will be accompanied by cytokines that induce a resorption process that accelerates recovery.
Study population: 320 patients between 18 and 75 years old with either a lumbar (n=160) or cervical (n=160) herniated disc that will be subjected to discectomy.
The present study investigates the effects and interactions of bacterial infection (bacterial cultures), disc inflammation (histological analysis of macrophages, M1 and M2 type), MC and blood biomarkers indicating inflammation or infection on the clinical outcome of patients with cervical or lumbar disc herniation. A mean difference of 2-points on a 10 point NRS scale will be regarded as clinically relevant. Pain reduction over the course of one-year follow-up will be scored.

Primary Objective(s):
In a group of sciatica and cervical radiculopathy patients undergoing disc surgery, this study will determine the effects of bacterial infiltration of the disc on patient reported pain scores, in the presence or absence of Modic changes on MRI and histological defined disc inflammation.

Secondary Objective(s):
1. A secondary aim of this study is to assess whether patients that suffer from disc inflammation benefit more from anti-inflammatory drugs than those without inflammation.
2. Another secondary aim of this study is to further explore the inflammation process by characterizing different types of macrophages (M1 and M2) and B and T cells.
3. Furthermore, this study aims to associate the presence of bacterial infection to the presence and type of Modic Changes.
4. At last, the present study assess the general inflammation (BSE, leukocyte differentiation) and vascular status (Cholesterol) in a group of sciatica and cervical radiculopathy patients, during surgery (from 01-07-2021).

Hypothesis of al sub objectives:
- Does the presence and degree of bacterial infection differ between patients with and without Modic changes?
Dudli (2017) revealed that 60% of P. acne infected discs showed a pathological inflammatory response. All of these discs were accompanied by Modic changes in the adjacent endplate. This insinuates that Modic changes are a pathological response to a bacterial infection. Hence, we expect that it is more likely to find a bacterial infection in patients with Modic changes, than in patients without Modic changes.

- Does the presence of infection influence the clinical baseline and outcome data, and does this differ between patients with and without Modic changes?
Because of excreted bacterial products combined with the pro inflammatory cytokines excreted due to the inflammatory response that may occur we expect to find that the presence of infection has a negative effect on the clinical outcomes. However, because Dudli (2017) has shown that only patients with Modic changes show a pathological inflammatory response, we expect that this effect is stronger in patients with Modic changes than in patients without Modic changes.

- Does the presence of Modic changes influence the clinical baseline and outcome data, and does this differ between patients with and without a bacterial infection?
Dudli (2017) found an upregulation of Tropomyosin receptor kinase (Trk) A,B and C, which have been associated with nerve pain, in patients with Modic changes. Based on these findings we would expect a negative of Modic changes on pain symptoms. However, El Barzouhi (2014) found no effect of the presence of Modic changes on back pain. Hence we expect to see no or a small negative effect of Modic changes on the clinical outcomes. In addition, El Barzouhi’s findings might be explained by the possibility that Modic changes are still visible on MRI even if the infection is gone. Therefore, we believe that the co-presence of Modic changes and an infection may have a big effect on the clinical outcomes but that Modic changes alone have a small influence the clinical symptoms.

- Does the presence of Modic changes influence the type of macrophage (M1 or M2) infiltration?
Djuric (2018) et al showed that in patients without Modic changes, macrophage infiltration has a beneficial effect on the clinical outcomes, and that in patients with Modic changes, macrophage infiltration had the opposite effect. We therefore expect to find more pro inflammatory (M1) macrophages in patients with, and more pro resorption (M2) macrophages in patients without Modic changes.

- Does the presence of infection influence the type of macrophage (M1 or M2) infiltration?
P. Acne has been shown to recruit macrophages and induce an inflammatory reaction, which makes it more likely to find M1 macrophages in patients with a bacterial infection. Djuric et al (2018) showed that the presence of Modic changes determined whether patients suffered or benefited from macrophage infiltration, and probably whether their type is M1 or M2. As mentioned before, we hypothesized that Modic changes are a consequence of infection, thus we expect that in patients without an infection we will find a higher degree of M2 macrophages. Taken together, we expect infection to direct the type of macrophages towards M1.

- Is there an interaction between the effect of the presence of Modic change and infection on the type of macrophage (M1 or M2) infiltration?
Based on the findings of Dudli (2017) et al, We expect that an infection without the pro inflammatory response accompanied by Modic changes will lead to less M1 infiltration. We also expect that patients with Modic changes that do not have an active infection will have a lower degree of M1 infiltration and probably a higher degree of M2 infiltration due to the reconsolidation process that is stimulated in the disc. Taken together, we expect to find an interaction effect of infection and Modic changes

- Does the type of macrophage (M1 or M2) influence the clinical outcomes?
M1 macrophages are pro inflammatory and their cytokines are associated with aggravation of the clinical symptoms. M2 macrophages on the contrary, are associated with resorption of waste material and are thought to help with disc resorption, therefore we expect that M1 has a negative effect on the clinical outcomes and M2 has a beneficial effect on the clinical outcomes.

All participants will be asked to co-operate during the entire follow-up. During follow-up patients will be asked to fill in questionnaires regarding clinical outcome (NRS, ODI/NDI & GPE) and medication status at 8 weeks, 16 weeks, 26 weeks and 52 weeks post-surgery. Patients will receive emails with a
link to the follow up questionnaires around the above mentioned time points.