domingo, 29 de octubre de 2017

Could low grade bacterial infection contribute to low back pain? A systematic review

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Abstract

Background

Recently, there has been both immense interest and controversy regarding a randomised, controlled trial which showed antibiotics to be effective in the treatment of chronic low back pain (disc herniation with Modic Type 1 change). While this research has the potential to result in a paradigm shift in the treatment of low back pain, several questions remain unanswered. This systematic review aims to address these questions by examining the role of bacteria in low back pain and the relationship between bacteria and Modic change.

Methods

We conducted electronic searches of MEDLINE and EMBASE and included studies that examined the relationship between bacteria and back pain or Modic change. Studies were rated based on their methodological quality, a best-evidence synthesis was used to summarise the results, and Bradford Hill’s criteria were used to assess the evidence for causation.

Results

Eleven studies were identified. The median (range) age and percentage of female participants was 44.7 (41–46.4) years and 41.5% (27–59%), respectively, and in 7 of the 11 studies participants were diagnosed with disc herniation. Nine studies examined the presence of bacteria in spinal disc material and all identified bacteria, with the pooled estimate of the proportion with positive samples being 34%. Propionibacterium acnes was the most prevalent bacteria, being present in 7 of the 9 studies, with median (minimum, maximum) 45.0% (0–86.0) of samples positive. The best evidence synthesis found moderate evidence for a relationship between the presence of bacteria and both low back pain with disc herniation and Modic Type 1 change with disc herniation. There was modest evidence for a cause-effect relationship.

Conclusions

We found that bacteria were common in the spinal disc material of people undergoing spinal surgery. There was moderate evidence for a relationship between the presence of bacteria and both low back pain with disc herniation and Modic Type 1 change associated with disc herniation and modest evidence for causation. However, further work is needed to determine whether these organisms are a result of contamination or represent low grade infection of the spine which contributes to chronic low back pain.

Keywords

BacteriaDiscInfectionLow back painModic changeSystematic review

Background

There has been both immense interest and controversy regarding a recent randomised, controlled trial (RCT) which showed antibiotic treatment to be effective in the treatment of chronic low back pain in individuals with herniated discs and associated Modic Type 1 changes (bone oedema) on magnetic resonance imaging (MRI) [1]. The RCT was based on the hypothesis that some individuals with a disc herniation develop chronic low back pain due to a secondary infection that occurs in the disc. While this research has the potential to result in a paradigm shift in the treatment of low back pain, it has not currently been translated into clinical practice. These findings have some similarities to the discovery of Helicobacter pylori and the shift it led to in the way peptic ulcers are treated. However, a greater understanding of the evidence underlying this RCT is required before a change in practice can be justified. Moreover, although the potential for good is high, the potential for harm in selecting for antimicrobial resistance with the prolonged use of broad spectrum antibiotics is also significant.
This recent RCT by Albert et al. [1] was based on the findings of their previous biopsy study which suggested that those who developed early Modic Type 1 changes were more likely to have infection with Propionibacterium acnes (P. acnes) [2]. However, there are several questions that remain unanswered; have other studies investigated the presence of bacteria in people with low back pain, and if so, what bacteria were identified, what were the associated participant and clinical characteristics, what evidence is there that bacteria are associated with low back pain, and are Modic changes markers for bacterial infection. This systematic review aims to address these questions by examining the evidence for the presence of bacteria in spinal structures of patients undergoing lumbar spine surgery and investigating the relationship between bacterial infection and Modic change. This work has the potential to provide a greater understanding of the evidence behind a potentially effective and safe treatment approach for individuals with chronic low back pain and disc herniation, thus significantly reducing the individual suffering and societal burden associated with this condition.

Methods

This systematic review was conducted according to the 2009 PRISMA statement [3,4].

Search strategy

A computerised search strategy was performed using MEDLINE and EMBASE from January 1946 until March 2014. We used the following MeSH headings and key words; ‘bacteria’, ‘infection’, ‘propionibacterium acnes’, ‘microbial’, ‘low back pain’, ‘Modic change’, and ‘lumbar surgery’. The search was limited to human studies of adults published in the English language. We also searched the reference lists of studies included in this review.
We included studies which examined i) the role of bacteria in low back pain and ii) the relationship between the presence of bacteria and Modic changes. Studies where participants had low back pain secondary to a previous bacterial exposure or current systemic infection were excluded.
Information was extracted and tabulated on the characteristics of the identified studies and their cohorts, the prevalence and type of bacteria identified, the methods used for bacterial identification and to minimize contamination, the results of studies examining the relationship between bacteria and Modic change, and evidence for a causal relationship.

Methodological quality

To assess the methodological quality of the included studies, two reviewers (DU and SMH) independently scored them using the adapted scoring system of Lievense et al. [5,6] (Table 1). Each of the items was scored as positive (1), negative (0), or unclear (?), with a maximum possible score of 100%. Where the reviewers disagreed and could not achieve consensus, a third reviewer (FC) gave a final judgement. High quality was defined as achieving a score above the mean of all quality scores.
Table 1
Criteria used to assess the methodological quality of selected cohort and cross-sectional studies (Lievense et al. [5,6])
Item
Criterion
Study type
Study population
  
1
Selection before disease was present or at uniform point
CH/CC/CS
2
Cases and controls were drawn from the same population
CC
3
Participation rate ≥80% for cases/cohort
CH/CC/CS
4
Participation rate ≥80% for controls
CC
5
Sufficient description of baseline characteristics
CH/CC/CS
Assessment of risk factor
  
6
Presence of bacteria was blinded
CH/CC/CS
7
Presence of bacteria were measured identical for cases and controls
CC
8
Presence of bacteria were assessed prior to the outcome
CH/CC/CS
Assessment of outcome
  
9
Low back pain/ Modic change was assessed identical in studied population
CH/CC/CS
10
Low back pain/ Modic change was assessed reproducibly
CH/CC/CS
11
Low back pain/ Modic change was assessed according to standard definitions
CH/CC/CS
Study design
  
12
Prospective design was used
CH/CC/CS
13
Follow-up time ≥2 years
CH
14
Withdrawals ≤20%
CH
Analysis and data presentation
  
15
Appropriate analysis techniques were used
CH/CC/CS
16
Adjusted for at least age and sex
CH/CC/CS
CH, Applicable to cohort studies; CC, Applicable to case–control studies; CS, Applicable to cross-sectional studies; OA, Osteoarthritis.
As the criteria specific to the methodological assessment of RCTs is not included in the study by Lievense et al. [5,6], the PEDro scale [7] was used. The PEDro scale rates 11 aspects of the methodological quality of RCTs as being absent or present (Table 2). The total score ranges from 0 to 10, as the first item (eligibility criteria) is not included in the scoring. Studies that obtain a score of less than 6 points are considered to be of low quality, while those with a score of greater than 6 points are of high quality.
Table 2
The PEDro Scale [7– criteria used to assess the methodological quality of selected randomised control trials
 
Yes
No
Where/comments
1. Eligibility criteria were specified
   
2. Subjects were randomly allocated to groups (in a crossover study, subjects were randomly allocated an order in which treatments were received)
   
3. Allocation was concealed
   
4. The groups were similar at baseline regarding the most important prognostic indicators
   
5. There was blinding of all subjects
   
6. There was blinding of all therapists who administered the therapy
   
7. There was blinding of all assessors who measured at least one key outcome
   
8. Measures of at least one key outcome were obtained from more than 85% of the subjects initially allocated to groups
   
9. All subjects for whom outcome measures were available received the treatment or control condition as allocated or, where this was not the case, data for at least one key outcome was analysed by “intention to treat”
   
10. The results of between-group statistical comparisons are reported for at least one key outcome
   
11. The study provides both point measures and measures of variability for at least one key outcome
   
TOTAL (checked excluding eligibility criteria specified):
   

Best evidence synthesis

A best evidence synthesis was used to summarise the data (Table 3). It was not possible to perform a meta-analysis due to the heterogeneity between the studies. The studies were ranked according to their design, with cohort studies considered to be a higher level of evidence than case control and cross-sectional studies. The level of evidence of studies was determined in conjunction with the quality score calculated for each study.
Table 3
Criteria list for determining the level of evidence for best evidence synthesis, adapted from Lievense et al. [6,7]
Level of evidence
Criteria for inclusion in best evidence synthesis
Strong evidence
Generally consistent findings in multiple high quality cohort studies
Moderate evidence
Generally consistent findings in 1 high quality cohort study, >2 high quality case–control studies, or >3 high quality case–control studies
Limited evidence
Generally consistent findings in a single cohort study, 1 or 2 case–control studies, or multiple cross-sectional studies
Conflicting evidence
Inconsistent findings in <75% of the trials
No evidence
No studies could be found

Bradford Hill’s criteria for causation

We used Bradford Hill’s criteria to examine the evidence for causation [8]. These criteria, along with a description of each, are included in Table 4. The Bradford Hill’s criteria are commonly used to determine whether there is adequate evidence of a causal relationship between an incidence and a consequence.
Table 4
Evidence for a causal relationship between low virulent bacteria and low back pain according to Bradford Hill’s criteria
Bradford Hill’s criteria
Description of criterion
Evidence for a causal relationship between bacteria and low back pain
Temporal relationship
This is an essential criterion. For a possible risk factor to be the cause of a disease it has to come before the disease. This is generally easier to establish from cohort studies but rather difficult to establish from cross-sectional or case–control studies when measurements of the possible cause and the effect are made at the same time.
There is one longitudinal study available [2]. However, this only examined the development of Modic changes in participants with disc herniation (with and without positive cultures).
Plausibility
The association of a risk factor with a disease is more likely to be the cause of the disease if the association found is consistent with knowledge obtained from other sources such as animal experiments, experiments on biological mechanisms, etc. However, this criterion must be used with care because, often, the lack of plausibility may simply reflect a lack of scientific knowledge.
It is plausible for low virulent bacteria to cause chronic infection and symptoms such as low back pain. However, the bacteria isolated are also known potential contaminants.
Consistency
If similar results have been found in different populations using different study designs, then the association is more likely to be causal since it is unlikely that all studies were subject to the same type of errors (chance, bias, or confounding). However, a lack of consistency does not exclude a causal association since different exposure levels and other conditions may reduce the impact of the causal factor in certain studies.
There is consistency in the results across a number of studies; however, these studies were largely all cross-sectional in design and in similar populations (i.e., those having spinal surgery for disc herniation). A study that examined a control group (consisting of patients with trauma, myeloma, scoliosis, and degenerative disc disease) found patients with low back pain (sciatica) to have more positive tissue cultures (53% [19/36]) as compared with controls (0% [0/14] P = 0.0003) (Stirling et al. [17]).
Strength of an association
The strength of an association is measured by the size of the relative risk. A strong association is more likely to be causal than is a weak association, which could more easily be the result of confounding or bias.
In most of the identified studies there were a significant proportion of bacteria but few compared this to control groups.
Dose–response relationship
Further evidence of a causal relationship is provided if increasing levels of exposure lead to increasing risks of disease.
There is limited evidence to support a dose–response relationship.
Specificity
If a particular exposure increases the risk of a certain disease but not the risk of other diseases, then this is strong evidence in favour of a cause-effect relationship. However, one-to-one relationships between exposure and disease are rare and lack of specificity should not be used to say that a relationship is causal.
Similar bacterial species have been isolated in all studies, but few examined control groups.
Reversibility
When the removal of a possible risk factor results in a reduced risk of disease, then the likelihood that this association is causal is increased. Ideally, this should be assessed by conducting a RCT. Unfortunately, for many exposures/diseases such RCTs are just not possible in practice.
A single randomised controlled trial by Albert et al. [1] demonstrated that antibiotic treatment was effective in the treatment of chronic low back pain of greater than 6 month’s duration occurring after a previous disc herniation (in conjunction with Modic type 1 changes).
Coherence
The suggested cause-effect relationship should essentially be consistent with the natural history and biology of the disease.
The relationship is consistent with the natural history and biology of an infective process.
Analogy
The causal relationship will be further supported if there are similarities with other (well-established) cause-effect relationships.
Low grade infection in other sites (albeit involving prosthetic joints) may present with subacute or chronic pain and swelling.
RCT, Randomised controlled trial.

Results

Eleven studies were included in this systematic review (Figure 1; Table 5). Of these, one was a RCT, one had a cross-sectional and a longitudinal component, and nine were cross-sectional. Ten studies examined the presence of bacteria in people undergoing spinal surgery (Table 6) and four studies investigated the relationship between the presence of bacteria and Modic changes (Table 7).
Figure 1
PRISMA flow diagram showing the flow of information through the different phases of the systematic review.
Table 5
Characteristics of the 11 identified studies
Studies
Study design
Demographics, n (% Female)
Clinical features and surgery performed
Study inclusions/exclusions (includes previous interventions)
Modic changes examined
Control group
Quality score
Mean age (years)
Disc studies
     
Albert [2]
Cross-sectional/ cohort
61 (27% F)
Disc herniation
Inclusions:
Yes – Type, size, and volume were graded according to the Nordic Modic Protocol
No
78/75
Age: 46.4
Primary surgery at a single spinal level
18 to 65 years old
MRI-confirmed lumbar disc herniation
 
Exclusions:
Received antibiotic treatment within previous 2 weeks
Stirling [14]
Cross-sectional
36 (NA)
Discogenic radiculitis
Not specified
No
No
78
Age: NA
Microdiscectomy
Stirling [17]
Cross-sectional
207 (NA)
Discogenic radiculitis
Not specified
No
Yes – patients with trauma, tumour, or scoliosis
56
Age: NA
Microdisectomy
Agarwal [16]
Cross-sectional
52 (42% F)
Radiculopathy
Inclusions:
No
No
78
Age: 43.9
Disc herniation
Sensory or motor symptoms in a single lumbar nerve distribution
Lumbar microdiscectomy
Positive physical examination findings (positive straight leg raise test, distributional weakness, diminished deep tendon reflexes)
MRI lumbar spine positive for HNP
Exclusions:
Diabetes mellitus, oral steroid use in the month before surgery, other immunosuppressive medications
Plain radiography demonstrating severe loss of disc height
High grade degenerative disc disease, spondylolisthesis > grade 1
History of prior lumbar surgery, multilevel symptomatic HNP or trauma
Red flags (progressive weakness, bowel/bladder complaints, radiographic unknown mass, unexpected weight loss)
Diagnosis of inflammatory arthritides, crystalline arthropathies, or other rheumatologic diseases
Arndt [9]
Cross-sectional
83 (59% F)
Disc degeneration
Not specified
Yes – Type 1 and 2 according to the Modic classification
No
67
Age: 41
Lumbar disc replacement at L3-4, L4-5, or L5-S1
Coscia [11]
Cross-sectional
165 (NA)
Disc herniation
Not specified
No
Yes – Five groups, including cervical disc herniations, lumbar disc herniations, lumbar discogenic pain, deformity, and control
78
Age: NA
Surgery not specified
Ben-Galim [10]
Cross-sectional
30 (40% F)
Disc herniation
Exclusions:
No
No
67
Age: 46.4 (NA)
Lumbar discectomy
Individuals who had been treated with antibiotics in the 2 months preceding the study
Those who had undergone back surgery
History of intradiscal injections
Fritzell [12]
Cross-sectional
10 (40% F)
Disc herniation
Not stated
No
No
67
Age (range): 20–47
Surgery not specified
Carricajo [13]
Cross-sectional
54 (41%)
Disc herniation
Not stated
No
No
67
Age: 44.8 (NA)
Surgery not specified
Albert [1]
Randomised controlled trial
Intervention group:
Chronic LBP (>6 months) occurring after a previous disc herniation and who also had Modic type 1 changes in the vertebrae adjacent to the previous herniation
Inclusions:
Yes – Modic Type 1 only; size and volume of Modic changes were graded according to the Nordic Modic Protocol
Yes
100
Aged between 18 and 65 years
90 (58.2% F)
MRI-confirmed disc herniation L3/L4 or L4/L5 or L5/S1 within the preceding 6–24 months
Age: 44.7 (10.3)
Placebo group:
Lower back pain of >6 months duration
72 (58.2% F)
Nil surgery
Modic type 1 changes adjacent to the previously herniated disc on repeat MRI
Age: 45.5 (9.2)
Exclusions:
Allergy to antibiotics
Current pregnancy or lactation
Any kidney disease
Pending litigation
Bone studies
Wedderkopp [15]
Cross-sectional
24 (58% F)
‘Persistent LBP’ Modic type I changes in at least 1 vertebra
Inclusion: Type 1 Modic changes on MRI
Yes – Modic Type 1 only
No
67
Age: 43 (NA)
No surgery performed
HNP, Herniated nucleus pulposus; LBP, Low back pain.
Table 6
Methods used for bacteria identification and to minimize contamination and prevalence, and type of bacteria identified
Studies and design
Biopsy: Method, site and no. of specimens
Methods to minimize contamination
Duration of culturing biopsy material
Bacteria identification methods
Culture-positive samples (n, %)
Organisms identified in positive cultures (%)
Subsequently made generic analysis of P. acnes species
Quality score
Albert [2] Cross-sectional
Open
All scalpels flamed before use as extra precaution
7 days with subsequent 1 day of subculture
Culture, PCR
28/61 (46%)
P. acnes : 86%
Analytical profile index biochemical analysis using Rapid ID 32A kit (bioMerieux) and PCR amplification of 16S rDNA
78
Disc material
Gram-positive cocci: 14%
Five specimens
Coagulase-negative (CN) staphylococci: 7%
Stirling [14] Cross-sectional
Open
Stringent aseptic precautions taken to minimise risk of contamination
7 days
Culture, serology
19/36 (53%)
P. acnes : 84%
Microscopy of Gram-stained smears of tissue samples
78
Disc material
CN staphylococci: 11%
Not stated
Corynebacterium propinquum: 5%
Stirling [17] Cross-sectional
Open
Not stated
7 days
Culture, serology
76/207 (37%)
P. acnes : 64%
Microscopy of Gram-stained smears of tissue samples
56
Disc material
CN staphylococci: 14%
Not stated
Propionibacteria: 10.5%
Agarwal [16] Cross-sectional
Open
Disc material retained in a closed sterile sample cup
5 days
Culture
10/52 (19.2%)
P. acnes : 70%
Not stated
78
Disc material
Peptostreptococci: 10%
Not stated
Staphylococci aureus: 10%
CN staphylococci: 10%
Arndt [9] Cross-sectional
Open
Disc structures stored in sterile syringes filled with physiological saline solution, care was taken to avoid contamination during conditioning process of biopsy
Blood agar, Drigalski agar: 24 h
Culture
40/83 (48.2%)
P. acnes : 45%
Not stated
67
Disc material
Polyvitex chocolate agar: 4 days
CN staphylococci: 40%
1 in 1st 25 disk replacements; 3 in following 58
Blood agar supplemented with hemin: 5 days
CN bacilli: 7.5%
Peptone glucose yeast broth: 10 days
Bactec Peds Plue bottle with fructooligosaccharide nutritional supplement: 7 days
Coscia [11] Cross-sectional
Open
Specimens were obtained sterilely immediately at the time of surgical excision
Cultured using extended duration incubation techniques (repeated subcultures up to several weeks duration)
Culture
16/30 (53.3%)
Staphylococcus: 36%
Not stated
78
Disc material
P. acnes : 18%
Not stated
Ben-Galim [10] Cross-sectional
Open
Samples are processed and cultured intraoperatively under stringent, sterile operating theatre conditions, culture mediums were warmed to room temperature before each operation
2 weeks
Culture
2/30 (6.7%)
CN staphylococci: 100%
Not stated
67
Disc material
Four pieces (disc material dissected into four pieces)
Fritzell [12] Cross-sectional
Open
Samples taken openly (no needle), all operations except for one were performed through a microscope with use of bipolar diathermy, assuring a very ‘dry’ operation field
Not applicable
PCR
(PCR)
(PCR)
Not stated
67
Disc material
2/10 (20%)
Bacillus cereus: 50%
Two – one from annulus fibrosus and one from nucleus pulposus
Citrobacterbraaki/freundi: 50%
Carricajo [13] Cross-sectional
Open
Obtained under aseptic conditions
One horse-blood agar, two chocolate PolyVitex agar: 10 days
Culture
12/54 (22%)
P. acnes : 17%
Not stated
67
One Schaedler medium: 20 days
Disc material, muscle, ligamentum flavum
Anaerobic streptococci: 8%
Three – muscle, ligamentum flavum, herniated intervertebral discs
Wedderkopp [15] Cross-sectional
Needle
Obtained with sterile technique
2 weeks
Culture
2/24 (8.3%)
Staph epidermidis: 50%
Not stated
67
CN staphylococci: 50%
Vertebral body
One – at site of Modic Type 1 change
Table 7
Studies examining the relationship between the presence of low virulent bacteria and modic changes
Studies
Study design
Demographics N (% Female) Mean age (years)
Clinical features
Measure of modic change
Results
Quality score
Albert [1]
Randomised controlled trial
Treatment group:
Chronic LBP (>6 months) occurring after a previous disc herniation and who also had Modic type 1 changes in the vertebrae adjacent to the previous herniation
Type, size, and volume graded according to the Nordic Modic Protocol
Modic changes: Treatment group: 142 (92.2%)
100
90 (58.2% F)
Placebo group: 130 (97%)
Grade 1 Modic changes: Treatment group: 10.4%; Placebo group: 28.8%
Age: 44.7 (10.3)
P = 0.006
Placebo group:
At 1-year follow-up, 10 patients in both groups demonstrated no Modic changes
72 (58.2% F)
Treatment group: Significant decrease in volume; volume 2–4 were reduced to volume 1 (P = 0.05)
Age: 45.5 (9.2)
Placebo group: Not observed
Albert [2]
Cohort
61 (27% F)
Disc herniation
Type, size, and volume graded according to the Nordic Modic Protocol
Discs (anaerobic bacteria): 80% developed new Modic changes in the vertebrae adjacent to the previous disc herniation. Discs (Aerobic): No new; MC discs (negative cultures): 44% new MC
78
Age: 46.4
The association between an anaerobic culture and new MCs was significant
5.60 (95% CI 1.51–21.95), (P = 0.004)
Arndt [9]
Cross-sectional
83 (59% F)
Disc degeneration
Modic changes (Type 1 and 2)
There was no significant association between Modic changes and positive cultures (P = 0.2)
67
Age: 41
Wedderkopp [15]
Cross-sectional
24 (58% F)
No clinical symptoms; Modic type I changes in at least 1 vertebra
Type 1 Modic changes only
There was no evidence of bacteria in vertebrae with Modic type 1 changes, with only 2/24 patients yielding bacteria.
67
Age: 43 (NA)

What were the characteristics of people with low back pain that have bacterial infection?

Table 5 presents the characteristics of the study cohorts in the 11 identified studies. The average number of participants in the 11 studies was 74, with samples ranging from 10 to 207. The median (minimum, maximum) age and percentage of female patients was 44.7 (41, 46.4) years and 41.5% (27, 59), respectively. In five of the 11 studies, the participants were diagnosed with disc herniation alone [2,9-13], with the remaining six studies recruiting participants with discogenic radiculitis [14,15], radiculopathy and disc herniation [14,16,17], disc degeneration [10], disc herniation and Modic changes [1], and Modic changes only [15].
Three studies reported the use of a control group; Albert’s RCT included an intervention group receiving antibiotic treatment and a placebo group [1], Stirling et al. [17] recruited patients with trauma, tumours, or scoliosis for their controls, and, similarly, Coscia et al. [11] included patients with trauma or neuromuscular deformity. Four of the 11 studies specified the inclusion and exclusion criteria they used [2,10,16]; with previous use of antibiotics [2,10], allergy to antibiotics [1], and previous surgery [10,16] reported to be exclusions. None of the studies specified osteomyelitis or discitis as exclusion criteria.

What was the prevalence and type of bacteria identified in studies examining participants undergoing spinal surgery?

Table 6 presents the prevalence and type of bacteria identified in 10 studies examining participants undergoing spinal surgery. Nine studies investigated the presence of bacteria in spinal disc material, with one study examining the vertebral body with Modic Type 1 change. Of the nine studies that examined disc material, the median (minimum, maximum) percentage of culture positive samples was found to be 22.0% (6.7, 53.3). The data are presented as a forest plot (Figure 2) with the pooled estimate of the proportion with positive cultures being 34%. Eight of these nine studies identified more than one bacteria, with the study by Ben-Galim et al. [10] only reporting the presence of coagulase-negative staphylococci. While a variety of bacteria were identified, P. acnes was the most prevalent, being present in seven of the nine studies and the most common bacteria in six of the nine studies. A median (minimum, maximum) of 45% (0, 86.0) of samples were positive for P. acnes, followed by coagulase-negative staphylococci, which was present in 14% (0, 100) of cases. The study by Wedderkopp et al. [15], which investigated the presence of bacteria in the vertebral body, reported 8.3% of cultures to be positive, with staphylococcus epidermis and coagulase-negative staphylococci each being present in 50% of cultures.
Figure 2
Forest plot showing the proportion of positive cultures in the nine studies examining the presence of bacteria in disc material in patients undergoing spinal surgery.
There were a variety of methods used to identify bacteria and minimize contamination. Nine of the 10 studies used an open procedure to obtain biopsies, with one study by Wedderkopp et al. [15] using a closed, needle approach. Six studies used cultures to identify bacteria [9-11,13,15,16], two studies used culture and serology [14,17], and the remaining two used PCR with [2] or without culture [12]. Studies obtained between one and five specimens for assessment. The duration of culturing varied considerably between the studies, ranging from 5 to 7 days [4,10,14,15,17] to 2 to 3 weeks [11,12,16,18]. Moreover, only three of the 10 studies performed genetic analysis to determine the species of P. acnes identified [4,14,15]. With respect to minimizing contamination, five of the studies simply stated that aseptic or sterile techniques were used [10,11,13,15,17], while the others reported a wide variety of techniques including flaming scalpels [2], using bipolar diathermy [12], and collecting specimens in sterile cups and syringes [9,16].

Are Modic changes markers of bacterial infection in low back pain?

Only four of the 11 studies we identified examined Modic changes. The RCT by Albert et al. [1] examined differences in Modic Type 1 changes after antibiotic treatment and found a reduction in their volume in the treatment group compared to the placebo group (P = 0.05). In Albert et al.’s biopsy study [2], low virulent bacteria were identified in participants who did and did not develop new Modic Type 1 changes, and conversely, those that had no bacteria present also developed Modic Type 1 changes. However, overall, a significant association between anaerobic bacteria and Modic Type 1 change was reported (5.60; 95% CI, 1.51–21.95; P = 0.004). The study by Arndt et al. [9] reported no significant association between the presence of bacteria and Modic Type 1 and 2 changes on MRI, and Wedderkopp et al. [15] reported that there was no evidence of bacteria in vertebrae with Modic Type 1 changes.

What did the best evidence synthesis show with regards to the role of bacteria in low back pain and the relationship between bacteria and Modic changes?

Eleven studies examined the role of bacteria in low back pain (Table 5). This included one RCT and 10 cross-sectional studies. The mean methodological quality score of the 10 cross-sectional studies was 70%, with scores ranging from 56% to 78%. Four of the 10 observational studies were considered to be of high quality (according to the Lievense criteria), as they were given a quality score above the mean [2,11,14,16]. The RCT by Albert et al. [1] was also considered high quality as it scored greater than six on the PEDro scale. Overall, the best evidence synthesis indicated moderate evidence for a role of bacteria in low back pain with disc herniation.
Four studies examined the relationship between the presence of bacteria and Modic changes (Table 7). This included one RCT, one cohort study, and two cross-sectional studies. The RCT and cohort study were of high quality and the cross-sectional studies were of low quality. Overall, the best-evidence synthesis indicated moderate evidence for a relationship between the presence of bacteria and Modic Type 1 changes with disc herniation.

What evidence is there for causation according to Bradford Hill’s criteria?

Table 4 presents Bradford Hill’s criteria, an explanation of each criterion, and evidence for a causal relationship between low virulent bacteria and chronic back pain in relation to each criterion. While there was evidence for causation with respect to five of Bradford Hill’s criteria (plausibility, strength of the association, specificity, reversibility, and coherence), there was no or limited evidence for the remaining four criteria (temporal relationship, consistency, dose–response relationship, and analogy). Overall, this approach suggests that there is modest evidence for a cause-effect relationship, with a major criteria (reversibility) being present between low virulent bacteria and chronic low back pain. However, further work is needed to clarify the role of bacterial infection in the development of low back pain with disc herniation.

Discussion

This review identified 11 studies which examined the role of bacteria in individuals with low back pain. Ten studies reported the presence of bacteria in people undergoing spinal surgery, with P. acnes being the most commonly identified. Participants with bacterial infection were aged in their 40’s, were of both genders, and were most commonly diagnosed with lumbar disc herniation. The best evidence syntheses showed moderate evidence for low virulent bacteria having a role in low back pain with disc herniation and moderate evidence for a relationship between bacterial infection and Modic Type 1 change with disc herniation. There was also modest evidence for a causal relationship between the presence of bacteria and low back pain with disc herniation according to the Bradford Hill criteria.
All nine studies which examined the spinal disc material of individuals undergoing spinal surgery, found bacteria to be present in the disc, with pooled estimate of the proportion of positive cultures found to be 34%. P. acnes was the most common bacterium identified, being reported in seven of the nine studies, with a median (range) of 45.0% (0–86.0) of positive cultures. In contrast, the study by Wedderkopp et al. [15], which examined the presence of bacteria in the lumbar vertebrae, did not identify P. acnes in Modic Type 1 changes. While P. acnes is part of the normal human microbiota and has even been shown to stimulate protective responses against various cancers, there is growing evidence to suggest that it can have a pathological role in the human body, including being a cause of infections in injured structures and indwelling medical devices [18]. It is believed that the predominance of P. acnes, which is an anaerobic bacterium, may reflect the unusual environment in the disc where the lack of vascularity results in a very low oxygen tension and a low pH which provides ideal conditions for low virulent anaerobic bacteria to grow.
While each of the 10 studies identified bacteria in excised spinal tissue, there were inconsistencies between studies with respect to the prevalence of positive cultures and the types of bacteria identified. These inconsistencies may have been due to differences in study methodology, including the use of varying methods and time frames for detecting bacteria (cultures, PCR, and serology), culturing the biopsy material, and administering the antibiotic treatment. For instance, the two studies by Fritzell et al. [12] and Ben-Galim et al. [10], which did not report the presence of the P. acnes, used stringent methodology, including PCR to detect bacterial DNA and stringent aseptic biopsy methods, respectively, as well as longer time periods to culture the biopsies. Moreover, only six of the 10 studies reported on the administration of antibiotics, with three studies providing the dose before spinal tissue was excised [9,10,16] and three studies after tissue was removed [2,12,15].
Participants with positive cultures were of both genders, primarily in their 40’s, and most commonly presented for spinal surgery due to lumbar disc herniation. This clinical profile may be explained by the reduction in water content of the disc during the fifth decade and the greater susceptibility of the disc to injury, allowing influx of bacteria into the damaged disc and subsequent colonisation and chronic infection.
There was moderate evidence for a relationship between the presence of bacteria and Modic Type 1 changes with disc herniation. This evidence was based on the cohort study [2] and RCT [1] by Albert et al. that recruited low back pain participants with disc herniation and Type 1 Modic changes [2]. In contrast, the cross-sectional studies by Arndt [10] and Wedderkopp [15] found no association between bacteria and Type 1 and 2 Modic changes in people with disc degeneration and Type 1 Modic changes in those with ‘persistent’ low back pain, respectively. It is important to note that Modic Type 1 change and disc herniation are prevalent in 14 to 16% [19,20] and 30% (at the L5/S1 level) of individuals with low back pain, respectively [21]. Moreover, while the prevalence of disc pathology occurring concurrently with Modic Type 1 change has been reported to range from 11.5 to 17.5% [21], these data are not specific to disc herniation, and include other disc pathologies such as disc bulge and disc degeneration. However, overall, these results suggest that the concurrent prevalence of Modic Type 1 change and disc herniation is low and thus individuals with these pathologies, who may respond to treatments such as antibiotics, only represent a select subgroup of the low back pain population. Moreover, although we have focussed on the relationship between bacteria and Modic change, it has been hypothesised that Modic changes may also result from mechanical forces acting on the vertebral endplate. It is clear that further study is required to determine which clinical characteristics clearly identify the presence of bacteria in lumbar discs and the pathological processes involved with the development of Modic change.
The mechanism by which bacteria may enter the lumbar spinal tissue is unclear. There are several hypotheses presented in the literature. It has been suggested that injury to the disc which breaches the disc’s integrity allows low virulent organisms that are commonly present on human skin to travel via the blood stream to the disc [1,2]. The presence of the bacteria in the disc subsequently sets up an inflammatory response in the adjacent bone due to the release of cytokines and propionic acid, which enter the vertebrae through normal disc nutrition. It has also been suggested that the presence of bacteria may be the result of primary disc degeneration which allows pathogenic organisms to enter the disc and/or hinders their elimination [12]. Moreover, Arndt et al. [9] postulated that bacteria may be the result of haematogenous spread from a distant septic location, contiguous spread from an adjacent infection, or transvenous retrograde pathway from the pelvis. It is clear that further investigation is needed to understand the mechanisms underlying the presence of bacteria in spinal disc and bone material.
There is considerable debate in the literature about whether the presence of the bacteria in spinal discs is actually due to infection or a result of contamination during study procedures. While a number of studies in this review reported that the presence of bacteria might be due to low grade infection in the disc [2,11,12,14,16,17], several studies also suggested that contamination may play a role [10,13,15]. The inclusion of control cultures and control groups in future studies may assist in determining whether the low virulent bacteria identified are due to true infection or contamination.
There are several limitations and strengths to this study. There were a small number of studies identified and these were mainly cross-sectional and of modest quality. Only one RCT and one longitudinal study were identified. Studies varied considerably in their methodology, particularly in methods used to identify bacteria and minimize contamination and only three studies included a control group. A meta-analysis was not able to be performed due to the heterogeneity of the studies identified. However, the key strength of this study is that it is the first systematic review on this topic. We have performed a systematic search of the literature, tabulated the key features of the identified studies, performed a best evidence synthesis to summarise the data, and examined causation using the Bradford Hill criteria.

Conclusions

This systematic review found moderate evidence to indicate low virulent bacteria have a role in low back pain with disc herniation and moderate evidence for a relationship between bacteria and Modic Type 1 change associated with disc herniation. While there was also modest evidence for causation, further work is needed to determine whether these low virulent organisms are a result of contamination or represent low grade infection of the lumbar spine which contributes to chronic low back pain associated with type 1 Modic changes in people with disc herniation.

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