Many studies over the past several decades have found a correlation between periodontal disease and a host of systemic morbidities, including atherosclerotic cardiovascular disease, diabetes, pneumonia, adverse pregnancy outcomes and chronic obstructive pulmonary diseases; one study found a possible link between marginal periodontitis and Parkinson disease. The connection appears to be inflammatory mediators in the bloodstream.

Although apical periodontitis may present with such clinical signs as inflammation, pain, swelling, redness and loss of function, it can also be asymptomatic for years, undiscovered unless spotted by the practitioner on a radiograph. But even asymptomatic apical periodontitis can affect the level of systemic inflammatory mediators and thereby have a negative impact on overall health. To better understand this relationship, Georgiou et al from the University of Amsterdam and Vrije Universiteit, the Netherlands, undertook a systematic review of the available evidence and conducted a meta-analysis of the results.

After a thorough search of the relevant published research, the authors found 20 studies (with a total of >800 patients) that matched the inclusion criteria for their systematic review, including 9 studies that had not been included in  the only previous systematic review, conducted in 2013, on this topic. Of the qualifying studies, 12 were case-control studies. The remaining 8 were interventional studies, which assessed inflammatory markers before and after treatment that included pus drainage, antibiotic administration, endodontic treatment, extraction or a combination of these. Some studies were limited to patients with either asymptomatic or symptomatic apical periodontitis; others included both.

The studies tested for a wide range of inflammatory markers in the bloodstream; sufficient data were

collected from the case-control studies to conduct 6 meta-analyses. In the largest comparisons, the authors found a significant relationship between elevated levels of C-reactive protein, an inflammatory marker directly linked to atherosclerotic vascular disease and increased risk of acute cardiovascular events, and patients with apical periodontitis accompanied by either a severe or moderate periapical index (PAI). They also found a significant relationship between elevated levels of asymmetrical dimethylarginine and interleukin-6 (Table 1).

A further meta-analysis showed that treatment for apical periodontitis significantly reduced the levels of C3 complement, a protein network associated with metabolic syndrome, diabetes and cardiovascular risk. A further meta-analysis failed to prove that treat-ment reduced C-reactive protein levels. However, both meta-analyses were based on small, older studies, which calls into question their reliability.


The sum of our current knowledge indicates that untreated apical periodontitis contributes to systemic inflammation, known to negatively affect human health. Because of the wide variation among the published data in inclusion criteria, sample size, follow-up times and controlling for confounding factors such as smoking and depression, further study is warranted to find the pathway through which apical periodontitis has an impact on systemic inflammation and how this can be most effectively treated.

Georgiou AC, Crielaard W, Armenis I, et al. Apical periodontitis is associated with elevated concentrations of inflammatory mediators in peripheral blood: a systematic review and meta-analysis. J Endod 2019;1279-1295.