Abstract
Introduction
Bacterial infection and Modic changes (MCs) as causes of low back pain (LBP) are debated. Results diverged between two randomised controlled trials examining the effect of amoxicillin with and without clavulanic acid versus placebo on patients with chronic LBP (cLBP) and MCs. Previous biopsy studies have been criticised with regard to methods, few patients and controls, and insufficient measures to minimise perioperative contamination. In this study, we minimise contamination risk, include a control group and optimise statistical power. The main aim is to compare bacterial growth between patients with and without MCs.
Methods and analysis
This multicentre, case–control study examines disc and vertebral body biopsies of patients with cLBP. Cases have MCs at the level of tissue sampling, controls do not. Previously operated patients are included as a subgroup. Tissue is sampled before antibiotic prophylaxis with separate instruments. We will apply microbiological methods and histology on biopsies, and predefine criteria for significant bacterial growth, possible contamination and no growth. Microbiologists, surgeons and pathologist are blinded to allocation of case or control. Primary analysis assesses significant growth in MC1 versus controls and MC2 versus controls separately. Bacterial disc growth in previously operated patients, patients with large MCs and growth from the vertebral body in the fusion group are all considered exploratory analyses.
Ethics and dissemination
The Regional Committees for Medical and Health Research Ethics in Norway (REC South East, reference number 2015/697) has approved the study. Study participation requires written informed consent. The study is registered at ClinicalTrials.gov (NCT03406624). Results will be disseminated in peer-reviewed journals, scientific conferences and patient fora.
Trial registration number
Keywords: ORTHOPAEDIC & TRAUMA SURGERY, Spine, Back pain, Diagnostic microbiology, MICROBIOLOGY
STRENGTHS AND LIMITATIONS OF THIS STUDY.
Large multicentre biopsy study of adult patients with and without Modic changes (cases and controls) who undergo spinal surgery.
Standardised surgical protocol designed to reduce the risk of contamination.
Biopsies are analysed by established clinical methods and blinded microbiologists.
Several research laboratories are involved in processing samples.
Some subgroup analyses may be underpowered.
Introduction
Non-specific low back pain (LBP) constitutes a major socioeconomic challenge worldwide due to pain and disability and is a cost-driving phenomenon to society.1 However, surgical and non-surgical treatments offer uncertain or only modest improvement in outcome.2
Modic changes (MCs) are signal changes on MRI that extend from the vertebral endplate into the bone marrow of the vertebral body. There is some evidence for an association between MCs and the presence of LBP3–5 and that MCs increase the likelihood of the disc being a nociceptive source of LBP.6 The aetiology of MCs is unknown, but there are three main theories: mechanical wear, autoimmune response to an injured disc and low-grade bacterial infection. MCs can be subdivided into three types: MC1 (oedema), MC2 (fatty infiltration) and MC3 (sclerosis).7 It is suggested that patients with MCs constitute a subgroup of non-specific LBP,8 although MCs are also found in populations without LBP.
The infection theory of MCs suggests that a mechanical injury to the disc may allow bacteria into the disc space, causing a low-grade bacterial infection.9 Cutibacterium acnes, a common skin commensal, has been suggested as a possible agent. Cytokine and propionic acid production may cause local inflammation and, consequently, MCs.10 Introducing C. acnes to rat tail discs and rabbit discs led to lesions on MRI similar to MC1 in two studies using type 2 or a wild-type C. acnes 11 12 and did not lead to any lesions in one study using type 1a C. acnes.13
In 2015, a systematic review including 11 studies examining bacterial presence in disc material in patients with LBP, estimated 34% positive samples. Only 4 of the 11 studies examined the relationship between presence of bacteria and MCs.14
A later study using fluorescence in situ hybridisation found bacteria embedded within disc tissue with inflammatory cells in seven (13%) of 51 patients with lumbar disc herniation and none of 14 controls without herniation (p=0.33). Bacteria were not related to MCs.15
The microbiological method used in this study is not universally accepted for disc material, has known pitfalls like autofluorescence (that could occur due to, ie, elastin and collagen present in the disc) and can suffer from lack of specificity16 and bacteria was only confirmed by PCR in one out of the seven patients with positive bacterial findings.
It has been suggested that selected patients with chronic LBP (cLBP) and MCs may benefit from antibiotic treatment. A randomised controlled trial (RCT) from Denmark in 2013 concluded that 100 days of amoxicillin/clavulanic acid provided a substantially larger improvement in patient-reported function and pain compared with placebo in patients with cLBP, MC1 and a former disc herniation.10
A similar RCT from Norway, the AIM (Antibiotics In Modic changes) study, did not show a clinically important effect of amoxicillin over placebo in patients with cLBP, MC1 or MC2, and a previous disc herniation, neither in analyses of MC1 and MC2 together, nor in MC1 separately.17 A small subgroup with abundant MC-related bone oedema reported an effect on disability, but the effect varied widely, there was no effect on LBP intensity, unblinding may have contributed to reduced effect in the placebo group, and the results need to be confirmed.18
Physical evidence of an infective agent was not demonstrated in the aforementioned RCTs. Yet, treatment of patients with cLBP and MCs with antibiotics remains commercially available.
Bacterial disc findings in patients with cLBP and MCs differed in previous studies and may partly be due to contamination rather than infection. Few studies included a control group,9 10 19 several had small samples,20 21 some used percutaneous biopsy techniques, with a high risk of contamination, and others did not specify if separate instruments were used for biopsy and surgery.8 Prophylactic antibiotics/steroids were administered before biopsy in some studies or not specified. The qualitative and quantitative microbiological methods used have limitations, including the risk of contamination during tissue handling22 and difficulties in differentiating contamination from true positive bacteria.23 24 For example, autofluorescence in disc tissue may reduce the specificity of detecting bacteria by fluorescence in situ hybridisation.16 Finally, bacterial findings are less likely with anterior (retroperitoneal) versus traditional posterior surgical approaches (used in our study).25
In this study, we have designed methods specifically to reduce the risk of preoperative bacterial contamination of the tissue samples, we have included a control group, we will use complementary semiquantitative and quantitative microbiological methods, and we will assess bacterial growth in subgroups.
Planned analyses
Primary analyses
MC1 versus control (significant growth from disc, yes/no).
MC2 versus control (significant growth from disc, yes/no).
Exploratory subgroup analyses
MC1 and MC2 in previously operated versus control (significant growth from disc, yes/no).
Large MCs versus control (significant growth from disc, yes/no). Large MCs are defined as MCs with volume ≥25% of vertebral body volume or height >50% of vertebral body height.
MC1 and MC2 versus control in fusion group (significant growth from vertebral body biopsy, yes/no). Vertebral body biopsies are not performed in the disc herniation group.
Methods and analysis
Study design
This multicentre, case–control study examines disc material and vertebral body biopsies of patients with cLBP undergoing lumbar fusion or lumbar disc herniation surgery. We include patients with degenerative changes/spondylolisthesis (fusion group) or disc herniation in line with the proposed infection theory. Cases have MCs at the level of tissue sampling and controls do not. Previously operated patients will be included as a subgroup. Tissue will be sampled before routine antibiotic prophylaxis with separate instruments and operating tables, and after all personnel have changed gloves. We will apply microbiological methods and histology on all tissue samples and prespecify criteria for significant bacterial growth, possible contamination and no growth. We will compare significant growth from the disc (yes/no) between patients with MC1 versus controls and MC2 versus controls separately (primary analyses). Exploratory subgroup analyses will assess bacterial disc growth in previously operated patients, in those with large MCs, and bacterial growth from the MC/vertebral body in the lumbar fusion group.
In this study, the microbiologists and pathologist are blinded regarding MC status. The clinicians are blinded to bacterial cultivation, PCR and histological report results.
Patient and public involvement
A user representative has been involved in interdisciplinary meetings, planning the study and securing patient involvement.
Study population and recruitment
Orthopaedic surgeons will recruit patients scheduled for spinal fusion or lumbar disc herniation surgery at four Norwegian university hospitals. The fusion group consists of patients with cLBP and degenerative disc disease, or spondylolisthesis (isthmic or degenerative). If there are MCs at the level of biopsy, the patient is defined as a case. If there are no MCs at the level of biopsy, the patient is defined as a control. We will also record the presence of MCs at neighbouring levels in the lumbar spine.
The study started recruiting patients in 29 January 2018 and end of inclusion is estimated in spring 2024.
Further details are included in online supplemental appendix S1.
bmjopen-2023-082244supp001.pdf (743.2KB, pdf)
Eligibility criteria and outcome variables
Outcome variables are described in online supplemental appendix S2.
Inclusion and exclusion criteria are described in online supplemental appendix S3.
Tissue sampling methods
Dedicated surgeons with specific knowledge of the study will include and operate on the patients at each study centre.
A written protocol for sampling will ensure uniformity. In addition, the principal investigator will visit each hospital, provide lectures on collecting biopsies and attend the first procedures at each centre. The principal investigator will perform follow-up visits after inclusion begins.
Surgical approach, overview of samples collected, biopsy sizes and test kits are described in online supplemental appendix S4.
The surgeon must specify the location of the bony biopsies according to figure 1.26
Figure 1.
To ensure that vertebral body biopsies correspond with the location of Modic changes, surgeons will record the anatomic location of the biopsies according to figure 1.
This ensures that the vertebral body biopsy is harvested from an MC region (or a region without MCs in controls), and that MC type in the biopsy region can be verified.
To avoid inflicting unnecessary postoperative pain to the disc herniation group, we will not perform biopsies of the vertebral body or annulus. In the fusion group, these biopsies represent negligible additional surgical trauma.
We include biopsies from the dermis as ‘positive control samples’ since we expect to find bacterial growth from the normal skin flora, especially C. acnes. In contrast, the subfascial tissue is a ‘negative control’ as it is not part of the affected MC area and is well beneath the dermis, where no normal flora is expected.
Both populations receive open surgeries, and samples are harvested through a surgical incision, reducing the risk of skin contamination.
Our primary prophylactic antibiotic is cefazoline. In instances of penicillin allergy, clindamycin will be administered.
Routine antibiotic prophylaxis will be delayed up to 1 hour after the incision. If biopsies are not obtained within 1 hour, prophylactic antibiotics will be administered regardless. In some cases (reoperations, obese patients), the biopsies may be harvested later than 1 hour after skin incision. Any protocol violation will be recorded.
Our target population of elective immune-competent patients (with few comorbidities) is expected to have a low risk of postoperative infection.
The tissue samples will be harvested with study-specific instruments not utilised for intervertebral disc access, and each biopsy will be taken with a new instrument (figure 2).
Figure 2.
Setup of dedicated surgical biopsy instruments.
The instrument kit includes nerve root retractors, Kerrison rongeurs, surgical drainage, bipolar cauterisation forceps, chisel, hammer, scissors, scalpels for incision of the annulus, scalpel for dermis biopsy, surgical and anatomical forceps. The vertebral body biopsy will be obtained with an 8G biopsy needle.
The two operating surgeons and the sterile scrub nurse will change their gloves between the surgical approach and tissue sampling. Samples will be processed on a separate operating table in individual zones for each layer of tissue. The non-sterile operating room nurse aiding in transferring the samples to sterile containers wears gloves to reduce risk of contamination with bacterial DNA.
Microbiological methods
Four microbiological departments have participated in the planning of this study and codeveloped a stringent protocol to ensure that the biopsies are handled, analysed and stored uniformly at the participating centres.
The microbiologists and laboratory technicians analysing the samples are blinded as to whether the samples are from the case or control group. The statistician and orthopaedic surgeons are blinded for the laboratory results, and these results are not recorded in the electronic hospital patient records. Unblinding will be performed at the end of the study after all microbiological analyses are performed and documented.
Processing of tissue samples is described in online supplemental appendix S5,S6.
Assessment of bacterial growth:
For each tissue sample, bacterial growth is recorded and identified at species level. Initially, the microbiologist grades the plates as ‘no growth’, ‘possible contamination’ and ‘significant growth’.
The growth can be difficult to categorise since much of the normal flora, for example, coagulase negative staphylococci, can be considered as contamination. C. acnes is known to be a contaminant from staff, in the environment, and also in PCR reagents.27 At the same time, this microbe is increasingly considered clinically relevant in orthopaedic infections. In contrast, Micrococcus spp is rarely considered clinically relevant.
The term ‘no growth’ means the absence of growth to the level of detection of the methods used in this study.
Possible contamination means that the bacteria may be derived from the environment and can be introduced at any step from the sample is taken to the analyses in the laboratory. Such bacteria are probably not from the patient. In addition, contamination from the patient’s dermis/subdermis cannot be ruled out.
We plan to do 16S rDNA PCR analyses of all samples. Based on initial assessment and PCR results, samples will be finally categorised as explained in table 1.
Table 1.
Categorisation of bacterial growth for each tissue sample
| Initial categorisation | Description | Final categorisation with positive PCR* | Final categorisation with negative PCR† |
| No growth | No growth, single colonies outside the streak or clinically irrelevant species (ie, Micrococcus spp). | No growth | No growth |
| Possible contamination | <5 single colonies on primary plate and no growth from enrichment broth | ‘Possible significant growth’ | ‘No growth’ |
| No growth on primary plate but growth from enrichment broth | ‘Possible significant growth’ | ‘No growth’ | |
| Significant growth | Growth on primary plate and from enrichment broth, or growth ≥5 single colonies on primary plate regardless of growth or not in enrichment broth | ‘Significant growth’ | ‘Significant growth’ |
*PCR analysis (16S rDNA sequencing) positive for the same species as the cultivated possible contaminant. The sample may still be considered contamination, but we cannot rule out that the growth is significant.
†PCR analyses (16S rDNA sequencing) negative for the cultivated possible contaminant. The sample is considered a true ‘no growth’.
The main endpoint for bacteriology is significant growth or no growth. As 16S rDNA PCR sequencing can be vulnerable to contamination, we are more certain about negative than positive results being correct. Thus, we have yet not prespecified whether positive PCR results and an initial categorisation of possible contamination should be considered as positive bacteriology in the primary analysis (see the ‘Statistics’ section).
Based on cultivation alone, many samples will be clearly graded as ‘significant growth’ or ‘no growth’. Classification of growth will be less clear when there are fewer than five single colonies on the primary plate and no growth from the enrichment broth, or no growth on the primary plate but growth from the enrichment broth (table 1). Before unblinding, sensitivity analyses (see below) will be done after such ‘possible contamination’ has been recategorised as ‘significant growth’ or ‘no growth’ based on PCR and ‘histological findings’.
The dermis is included as a ‘positive control sample’ since we expect to find bacterial growth from the normal flora, especially C. acnes. In contrast, the subfascial tissue is considered a ‘negative control’ as the tissue is well beneath the dermis, where no normal flora is expected, and it is not part of the affected MC region. In addition, air samples from the operating theatre are included as negative control.
The microbiologist will be blinded for the case versus control status of biopsies until the evaluation of bacterial growth and all PCR analyses are completed.
Molecular methods
We will perform direct 16S rDNA Sanger sequencing on all frozen tissue samples to confirm culture findings or find any other bacteria present in the biopsies.28
Other broad metagenomic methods will also be considered, for example, nanopore or Illumina sequencing.29
Since C. acnes is considered the main pathogen in this setting, we will also use a specific quantitative PCR on all samples. This may be a more sensitive method than culturing. Thus, by dividing samples into categories of ‘high’ or ‘low’ C. acnes genome copy number,30 more of the samples may end up as positive, regardless of culture findings.
We will also use whole genome sequencing on C. acnes isolates for phylogenetic analyses to compare isolates found in samples from the same patient.31 Phylogenetic analyses may aid in discriminating between relevant bacterial growth and contamination. In addition, we will examine the typing profiles of C. acnes isolates to see whether strains are of the typical implant-associated types (Ib or Ic) or other phylotypes.
Histology
The following tissue samples for histopathological analysis will be obtained and stored in formaldehyde:
Fusion group: nucleus pulposus, annulus fibrosus, vertebral body endplate/marrow.
Disc herniation group: nucleus pulposus.
An experienced senior pathologist analyses all samples in block sections according to the classification presented in online supplemental appendix S7.
The aforementioned classification is not a validated score in itself but can be applied as part of an overall assessment.32 The presence of a C. acnes infection may include a variety of inflammatory cells and/or neutrophils, as opposed to an acute response.32
We will consider doing ROC analyses to find an optimal cut-off for this score. In order to classify histology as either positive or negative we will dichotomise the final classification into ‘significant growth’ and ‘no growth’.
The pathologist analysing the samples will be blinded to case or control group status and microbiological results.
Radiology
Standardised lumbar spine MRI will be performed at baseline in both surgical populations and at 1 year in the lumbar disc herniation group. As in the AIM study, sagittal T1-weighted and T2-weighted fast spin echo images (to assess the presence, type and size of MCs), axial T2-weighted fast spin echo images, and sagittal short tau inversion recovery images will be included.33
MCs are defined by T1 and T2 images alone as signal changes in the vertebral bone marrow. They extend from but are not separated from, the endplate, are not ‘round shaped and abutting the endplate with a smaller base than height (more likely focal fatty marrow or haemangiomas), and do not extend through the endplate (Schmorl’s nodes)’.33
The three MC types are defined as follows: MC1: hypointense on T1 images, hyperintense on T2 images; MC2: hyperintense on T1, isointense or hyperintense on T2; MC3: hypointense on T1 and T2 images. Borderline MC1 versus MC2 (near isointense on T1) will be rated as MC2.33
Patients are grouped by MC type at the disc level where tissue samples are taken (index level). Those with primary (most extensive) or secondary MC1 at the superior and/or inferior endplate at the index level will be graded as MC1, regardless of whether other MC types exist at the index level or any other level. Patients with MC2, but not MC1, at the index level, are included in an MC2 group. Patients without MCs at the index level are controls, regardless of whether other levels contain MCs. Patients with MC3, but not MC1 or MC2, at the index level are not eligible for our study.
Two radiologists with at least 7 years of spine MRI experience will independently assess MRI findings. In cases of disagreement, the conclusive MC findings will be determined in consensus, their mean value will be used, or a third experienced MRI evaluator will decide. Interobserver agreement will be examined using kappa statistics.
Additional radiological details are described in online supplemental appendix S8.
MCs slowly interconvert over time,34 and an MC may take time to develop secondary to a possible low-grade disc infection following a disc herniation. Controls with a disc herniation may, therefore, theoretically have bacteria in the disc and an MC may develop later. Vice versa, patients with MCs may have had a disc infection that has resolved at the time of MRI examination.
Data collection
Collection of data is described in online supplemental appendix S9.
Statistics, sample size and power calculations
The main aim of this study is to investigate if the proportions of patients with significant bacterial growth from perioperative disc biopsies differ between cases (MC1 patients or MC2 patients) versus controls without MCs. The null hypothesis is that there is no difference between cases and controls. The alternative hypothesis is that there is a difference.
Our sample size calculation is based on previously published data and a prespecified relevant difference in proportions of bacterial growth among cases versus controls. A recent Swedish biopsy study reported bacterial disc growth in 5% of 20 controls without disc herniation (one had MC).35 A systematic review reported a pooled incidence of 34% bacterial findings in biopsies of the intervertebral disc in patients with LBP or MCs (not all studies reported presence of MCs).14 A systematic review and meta-analysis from 2019 reported a pooled prevalence of discs with bacteria of 25%.36
We calculated the sample size using a two-sided Pearson’s χ2 test. For the primary analysis, with two primary endpoints, we aim to achieve 80% power to detect a difference in bacterial growth in 25% of cases with MC1 or MC2 vs 5% of controls. Due to multiple testing, we use Bonferroni correction (alfa 0.025). We, therefore, plan to analyse at least 60 cases with MC1, 60 cases with MC2 and 60 controls.
The MC2 sample is likely to become larger than n=60 since we recruit MC1 and MC2 patients consecutively and MC2 is more common than MC1.
The microbiologists will decide whether samples with ‘possible significant growth’ (see above) can be regarded as positive microbiological tests for bacterial growth or not in the primary analyses after they see how the 16S PCR performs on our tissue samples with the initial categorisation ‘significant growth’ and ‘no growth’, but before the microbiologist will be unblinded (cases vs controls). Before unblinding, we will also consider categorisation of patients (positive/negative bacterial growth) depending on the results of endplate, dermis and subfascia.
We will consider performing statistical sensitivity analysis where samples with possible contamination and positive PCR (‘possible significant growth’) are recategorised as positive bacterial growth.
We will also consider sensitivity analyses with categorisation of patients (positive/negative bacterial growth) depending on results from endplate, dermis and subfascia.
The primary endpoint will be analysed with a logistic regression model with bacterial growth (positive/negative) as the outcome and group (MC1 or MC2 vs control) as the main explanatory variable. The following covariates will be included in the model to adjust for possible confounding: gender, age, HIZ (high-intensity zone representing an annular tear) and disc contour. The selection of covariates was based on biological plausibility, a recent review37 and their reported associations with MC (eg, disc herniation/degeneration)34 and presence of C. acnes in disc material (eg, bulging disc, HIZ).38
After fitting the model, the model-predicted marginal probabilities of positive bacterial findings will be estimated for both groups. The effect measure will be the difference between the two probabilities and will be reported with a 95% CI and a p value for the null hypothesis of a zero difference. The SE of the difference will be estimated using the delta method.
The exploratory and sensitivity analyses will be carried out with the same model, after replacing outcome and main explanatory variable as appropriate. The subgroup analysis of previously operated will be carried out by adding previously operated as an interaction term between groups, and previously operated as covariates in the logistic model. A significant coefficient for the interaction term will indicate a subgroup effect.
Ethics and dissemination
The Regional Committees for Medical and Health Research Ethics in Norway (REC South East, reference number 2015/697) has approved the study. Study participation requires a written informed consent. The study is registered at ClinicalTrials.gov (NCT03406624). Results are planned to be published in peer-reviewed international medical journals.
Supplementary Material
Acknowledgments
The authors give thanks to the Departments of Microbiology, Radiology and Orthopedic surgery at the respective University hospitals including patients. A special thanks to prof. Finn Reinholt at Department of Pathology at Rikshospitalet, for examining all histological samples, to Hege Haugen, study coordinator in Hagavik, and Fredrik Müller at the Department of Microbiology at Oslo University Hospital. Furthermore, special thanks to all bioengineers and operating nurses involved in the processing and procurement of the biopsies.
Footnotes
@LarsChrBraten
Contributors: KS, CH, MPR, AE, KWG, LCB and J-AZ were involved in conception and trial design. MPR prepared the first draft of the manuscript. KS, CH, AE, KWG, J-AZ, LCB, FCD, IA, SBM, MBÅ, MKT, MH-P and IEO were involved in revision of the article. SBM, MBÅ, IA, FCD and MPR were responsible for recruitment of patients and data collection. MF provided statistical expertise. All the authors critically revised the manuscript and approved the submitted version.
Funding: The South East Norway regional Health Authority supported this work (Helse Sør-Øst RHF (grant number 2018032). The non-profit foundation Sophies Minde Ortopedi supported this work (grant number 14/2015).
Disclaimer: The funding authorities were not involved in trial design, collection or analysis of data, or drafting of the manuscript.
Competing interests: None declared.
Patient and public involvement: Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.
Ethics statements
Patient consent for publication
Not applicable.
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