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Table 4 Evidence for a causal relationship between low virulent bacteria and low back pain according to Bradford Hill’s criteria

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

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.
  1. RCT, Randomised controlled trial.