My colleague Professor Eija Könönen at Turku University had asked me some time ago whether I wanted to contribute to an invited review on the microbiology of aggressive periodontitis. Not being a microbiologist (in contrast to Eija) I was a bit hesitant. But the topic was interesting and research into the matter promised to end, once and forever, persisting myths about Aggregatibacter, something which I found tempting. So, I agreed. Meanwhile, the issue had been dealt with from different perspectives, including necessarily large portions of narrative review of the literature beginning with the 1970s, and systematic searches for the role of Aggregatibacter actinomycetemcomitans and recent studies on the microbiota/microbiome of aggressive periodontitis using whole genomic DNA probes and, in particular, 16S ribosomal RNA genomic analyses. It will be published later this year in Periodontology 2000.
One of the few longitudinal studies identified by our systematic search  for a possible role of A. actinomycetemcomitans in the etiology of aggressive periodontitis was the study by Fine et al. (2007) , who
“… screened 1075 students clinically and microbiologically, and subgingival plaque, saliva and buccal epithelial-cell samples were examined for A. actinomycetemcomitans. Of those who carried the organism, 38 were followed for at least 1 year after the initial examination (test group); at the screening visit, 36 students had been diagnosed as periodontally healthy (up to one 5-mm pocket without attachment loss) or as ‘borderline’ healthy (two or more 5-mm pockets with <2 mm of attachment loss), and two were ‘potentially diseased’ (pocket depth 6 mm with attachment loss of >2 mm in one or two teeth). In addition, 58 age- and gender-matched students, confirmed negative for A. actinomycetemcomitans, formed the control group; 55 were periodontally healthy and the others were ‘borderline’ healthy at the outset of the study (see Fig. 2 in the original article). Among all 1075 students, 13 (1.2%) had already developed localized aggressive periodontitis and 13.7% were culture positive for A. actinomycetemcomitans. The majority of students were African-American or Hispanic, and the former had a slightly higher carrier rate than the latter (16.6% and 11.5%, respectively). At recall, eight students presented with bone loss, which was visible on bitewing radiographs taken yearly. All were A. actinomycetemcomitans-positive and two harbored the JP2 clone. Four had been classified at baseline as healthy, two as ‘borderline’ and two as ‘potentially diseased’. No subject in the A. actinomycetemcomitans-negative control group presented with bone loss at any recall. Survival analysis indicated a higher likelihood for carriers of A. actinomycetemcomitans to develop pockets and attachment loss over time compared with control subjects who were negative for A. actinomycetemcomitans. The authors concluded that the detection of A. actinomycetemcomitans in periodontally healthy children can serve as a risk marker for the initiation of localized aggressive periodontitis; however, given the sparseness and heterogeneity of the data (i.e. the groups seemed to differ clinically at the outset, so some carriers of A. actinomycetemcomitans might have already developed periodontitis), the evidence may be considered weak.”
Well, there is in fact evidence that the two groups, i.e. those being either positive (1) or negative (0) for A. actinomycetemcomitans (AA), differed at the outset. In the table below, frequencies for the two groups are given for different disease states (DIA), where (2) means “potential periodontal disease” (according to the authors, 6 mm or greater pocket depth with 2 mm or greater attachment loss at 1 or 2 teeth) and (1) “borderline disease” (2 or more 5 mm pockets with less than 2 mm attachment loss). A (0) score (assumed “periodontal health”) then means anything else.
DIA (rows) by AA (columns)
The two groups indeed statistically differ with a p value of less than 0.001. When periodontitis is by definition progressing if left untreated, any periodontal pathogen would be associated with the progression of already established disease, including A. actinomycetemcomitans. Albeit Hujoel et al. (2013) report, in their original Table 1, a high relative risk of 19.5 (95% confidence interval 1.12-338.7) for alveolar bone loss 1 mm or more, they caution their readers in a footnote to the table that,
“[r]elative risk was calculated based on six of 36 onsets of destructive periodontal disease among A. actinomycetemcomitans-infected individuals and on 0.5/58.5 onsets [note addition of 0.5 to cell count for continuity correction] of destructive periodontal disease among individuals not infected with A. actinomycetemcomitans. When the relative risk is calculated excluding individuals with 5-mm pockets and <2 mm attachment loss, the resulting relative risk is non-significant.” (Emphasis added.)
I was pleased to read meanwhile the recent systematic review  by Hujoel et al. (2013) who tried to find longitudinal cohort studies that identified significant associations between exposure to specific microorganisms and the subsequent onset of destructive periodontal disease. Since the classic studies on smoking and lung cancer and the event of evidence-based medicine, “cohort studies have become considered as key evidence when it comes to establishing the etiology of chronic diseases. The aim of this study was to conduct a systematic review on the specific infection hypothesis.”
While the search by Hujoel et al. (2013) revealed the same three studies with a positive association or, in case of Fine et al. (2007) claimed positive association, of onset of periodontitis and A. actinomycetemcomitans as our search, it was amazing to read that no further study could be found although the search terms included Eubacterium nodatum, Fusobacterium nodatum, Fusobacterium periodonticum, Tannerella forsythensis [sic], Prevotella melaninogenica, Porphyromonas gingivalis, Treponema denticola, Treponema pallidum [sic], Prevotella intermedia, and Campylobacter rectus .
So, after 30 years or so of a specific plaque hypothesis which sparked the industry to develop heavily marketed diagnostic tests, first based on culture, then DNA-probes, and finally real-time PCR; one has to conclude that little evidence had been accumulated. Hujoel et al. (2013) write,
“These three studies [reporting a positive association between A. actinomycetemcomitans colonization and onset of periodontitis] were conducted in predominantly non-Caucasian pediatric populations living in geographic areas with an elevated child-mortality rate. These studies did not obtain physical or laboratory markers of health, making it possible that A. actinomycetemcomitans was not a cause but a marker for poor environmental or systemic health. No cohort studies were identified supporting the infection hypothesis in adults, Caucasians or in a population residing in areas with child-mortality rates reflective of healthy population goals.
My own group had luckily the opportunity to follow a cohort of conscripts of the German Armed Forces for one year of their service as regards their periodontal condition and presence and absence of oral A. actinomycetemcomitans . In a few soldiers (6.7%), periodontal situation deteriorated but that was not related to presence of A. actinomycetemcomitans. On the other hand, heavy smokers (>20 cigarettes per day) had a 14-fold increased risk (p<0.05) for becoming “periodontally active” as compared to light or non-smokers.
Hujoel et al. (2013), referring to our “negative” paper, writes,
“Given the absence of evidence [of an association between specific infection and destructive periodontal disease etiology], it is unclear why it became ‘virtually sacrilegious’ to question why destructive periodontal disease became defined as an infectious disease. Multi-billion-dollar tobacco and food industries probably did not object to the labeling of destructive periodontal disease and dental caries as infectious diseases caused by specific microorganisms. Patients however may have suffered as the persistent emphasis on infection successfully obfuscated some of the more likely and preventable drivers of the worldwide destructive periodontal-disease epidemic.”
 (“actinobacillus actinomycetemcomitans”[MeSH Terms] OR (“actinobacillus”[All Fields] AND “actinomycetemcomitans”[All Fields] OR “actinobacillus actinomycetemcomitans”[All Fields] OR (“aggregatibacter”[All Fields] AND “actinomycetemcomitans”[All Fields] OR “aggregatibacter actinomycetemcomitans”[All Fields]) AND (“aggressive periodontitis[MeSH Terms] OR (“aggressive”[All Fields] AND “periodontitis”[All Fields] OR “aggressive periodontitis”[All Fields] AND (“longitudinal studies”[MeSH Terms] OR (“longitudinal[All Fields] AND “studies”[All Fields] OR “longitudinal studies”[All Fields] OR “prospective”[All Fields])
 Fine DH, Markowitz K, Furgang D, Fairlie K, Ferrandiz J, Nasri C, McKiernan M, Gunsolley J. Aggregatibacter actinomycetemcomitans and its relationship to initiation of localized aggressive periodontitis: longitudinal cohort study of initially healthy adolescents. J Clin Microbiol 2007; 45: 3859–3869. Haubek D, Ennibi OK, Poulsen K, Vaeth M, Poulsen S, Kilian M. Risk of aggressive periodontitis in adolescent carriers of the JP2 clone of Aggregatibacter (Actinobacillus) actinomycetemcomitans in Morocco: a prospective longitudinal cohort study. Lancet 2008; 371: 237–242. Höglund Åberg C, Sjödin B, Lakio L, Pussinen PJ, Johansson A, Claesson R. Presence of Aggregatibacter actinomycetemcomitans in young individuals: a 16-year clinical and microbiological follow-up study. J Clin Periodontol 2009; 36: 815–822. Müller HP, Eger T, Lobinsky D, Hoffmann S, Zöller L. A longitudinal study of Actinobacillus actinomycetemcomitans
in army recruits. J Periodontal Res 1997; 32: 69–78. Erratum in J Periodontal Res 1997; 32: 408. Van der Velden U, Abbas F, Armand S, Loos BG, Timmerman MF, van der Weijden GA, van Winkelhoff AJ, Winkel EG. Java project on periodontal diseases. The natural development of periodontitis: risk factors, risk predictors and risk determinants. J Clin Periodontol 2006; 33: 540–548.
19 February 2013 @ 1:36 pm.
Last modified October 30, 2014.