Evolution of the Serotypes of Aggregatibacter Actinomycetemcomitans In Relation to Aggressive Periodontitis and Geographic Origin of Individuals – A Review of the Literature

Aggressive periodontitis is a severe and rapidly progressing form of periodontitis [1,2] that affecting supporting tissues of the teeth induced by microbial deposits [3]. Aggregatibacter actinimycetemcomitans is an important pathogen related to aggressively progressive periodontal breakdown in adolescents and adults [4,5]. A. actinomycetemcomitans (A.a.) can be grouped into seven serotypes (a-g) [6,7]. Several studies have examined the relationship of A.a. serotype, ethnical status and geographic populations, periodontal disease status [8,9,10]. Individuals are usually colonized by a single serotype that can exist for life [8,11,12]. The frequency distribution of A.a. serotypes differs among various populations [13]. The available literature suggests that serotypes a, b. and c occur much more often among oral isolates than d, e, f and g [14,15,16]. The serotype distributions have been shown to be different among various geographic populations including African, Asian, Europeans, and North and South American [15,16,17,18,19]. The purpose of the present study was to review the studies that have investigated the prevalence and the distribution of A.a. serotypes in subgingival samples Crimson Publishers Wings to the Research Review Article


Study selection
Studies involving the distribution of A.a. serotypes in subgingival samples of periodontitis patients and periodontally healthy subjects by employing culture, indirect immunofluorescence and/ or immunodiffusion assays, and polymerase chain reaction (PCR) were eligible for inclusion in this review. Data were extracted from each study: (a) the first author and year of publication; (b) the country where the study was investigated; (c) searched serotypes and (d) possible association between periodontal conditions and serotypes.

Result
Forty-two articles were identified. The full text/abstract of each of the 42 papers was reviewed. The study selections are presented in Table 1. The publication dates ranged from 1983 to 2018. Clinical isolates from diverse geographic populations with different periodontal conditions were evaluated. The samples were obtained of the subjects from Brazil, Germany, Greece, Indonesia, Japan, Korea, Taiwan, Thailand and United States (US) etc. Table 1 shows the prevalence and distribution of A.a. serotypes a, b and c were largely found, and serotype c was the most prevalent. These serotypes were isolated from various periodontal conditions, including aggressive periodontitis. Serotypes d, e, f and g were either not detected or were relatively infrequent. Some A.a. isolates were non-typed.  Serotypes d and f were not detected. Serotype c showed the highest prevalence (52.9%), followed by a (31.8%).
The prevalence of serotype c in severe periodontitis was significantly greater than that of serotypes of a and b. Serotype c (57%) was the most prevalent, followed by a (33%) and b (7%).

Discussion
It is convinced that the differences in serotypes distribution related to geography and/or ethnic group. The current presented data indicate that the geographic distribution of serotypes is not uniform [4,40,43,49]. The distribution pattern of A.a. serotypes varies greatly depending on the periodontal status of the allocated population and the country where the study takes place [30,32,35 ,40,43,45,47,49,52,53,58]. Some studies suggest that different A.a. serotypes are associated with periodontal health, periodontitis [6,10,15,18,31,34,39,49,52,57]. It is suggested that patients are usually infected by one serotype and colonization is stable over time [8,36,37], however occasional individuals are infected with two or three serotypes [34,37,39,40,44,47,52,545,57,59]. Most investigators found relatively low frequencies of multiple-serotype infection, except a study in Japan that shows 2 or 3 serotypes of A.a. with a frequency of 33% of the sites tested [31]. In general, the serotypes a-c occurred much more frequently among oral isolates than serotypes d-g. In African-Americans, a, b, and c serotypes seem to be distributed in equal frequencies, whereas in Hispanic subjects, a strong association with serotype c was reported [34]. In Greece [43], serotype a, b, and c were largely found to be equally distributed. In Brazilian population, the serotypes are in majority of a, b and c (up to 98%), with the serotype c most prevalent. Serotypes d, e, and f were either rare or not-detected [16,40,46]. In 2010 Chen et al. [41] reported that the serotype c is the dominant serotype followed by serotypes of a, and b, the d, e, and f were either not detected or relatively rare in the United States [41]. This is greatly different from the previous reported.
In Taiwan, two studies demonstrated that the c serotype was the predominant [21,58], other studies found that serotype b was more than c or other serotypes [15,32]. In contrast, serotype b was commonly observed in Caucasian populations [37] and in German patients [37]. The serotype distribution pattern of A.a. within a local population may change over time, as seen in Indonesian periodontitis patients between 1994 to 2002 [36]. Serotypes d-f were rarely detected in most populations worldwide [40,42,45], however, a high prevalence of serotype e (19-47%) was noted in Indonesian [36] and Japanese [31]. JP2 (serotype b) strain with super-leukotoxicity was discovered in 1979 by the authors of Tsai et al. [61]. In Japan, serotype c was predominantly identified in the gingival tissues of LAgP patients [31], and the distribution of serotypes was influenced by the presence of P. gingivalis (P.g.). The longitudinal follow-up study in Indonesia demonstrated that the mean increase in probing pocket depth between 1994 and 2002 was significantly greater in subjects' culture positive in 2002 in comparison to subjects without detectable A. actinomycetemcomitans (A.a.) in 2002 [36]. The shifts of the predominant serotype b to a more prevalence as evidenced by the studies in Indonesia and in the United States [41] might be explained to some extent, associated with the periodontal treatment including the use of antibiotics, and the high titer of antibody levels to predominant infected serotypes of A.a. The high levels of anti-A.a. antibody together with viable polymorphonuclear neutrophils (PMNs) and complement could more efficiently kill the infecting A.a. [62]. Thirdly, some previous studies classified serotype f as serotype b due to the serological cross-reactivity with anti-serotype b-specific antiserum [29]. Fourthly, study has shown that the recombination between strains of the same A.a. serotype appears to take place in nature, suggesting that non-serotypeable strains are serotype antigen-deficient variants originating from strains of the known serotypes [63]. In Brazil, AgP subjects were not exclusively associated with A.a. serotype b [40,46]. Isolates from healthy subjects belong to serotype c or a [46]. Serotype c was the most A.a., and was isolated from various periodontal conditions, including AgP [45]. In Greek population, A.a. was more prevalent in untreated periodontitis subjects, but no clear predominance of a specific A.a. serotype and absence of the JP2 clone were observed [43]. In Sweden, the findings indicate that periodontitis affecting the primary dentition does not necessary leads to the presence of periodontal attachment loss in the permanent dentition [39].
The JP2 clone shows a limited geographical and ethnic host range, predisposing in subjects with an African lineage, but absent from non-African population from Northern Europe [14,65]. However, Claesson et al. [44] found that Caucasians can carry the JP2 clone of A. actinomycetemcomitans. The studies cited in this review have varied widely in periodontal disease diagnosis and status, sampling protocols, study design and microbial detection methods and serotype analysis techniques. The periodontal therapy aims to the elimination of A.a. from periodontal pockets has been shown to be correlated with the outcomes of therapy. Akrivopoulou et al. [59] studied the prevalence of A.a. serotypes and reported
In the study of the antibiotic resistance in human periimplantitis microbiota, Ramus et al. [64] reported that all six A.a. subject strains exhibited in vitro resistance to clindamycin, and five to doxycycline, whereas none were resistant in vitro to either amoxicillin, metronidazole or amoxicillin plus metronidazole [65]. However, adjunctive systemic amoxicillin plus metronidazole medication to scaling and root planing (SRP) significantly improved the clinical outcomes with respect to mean probing pocket depth, clinical attachment loss compared to SRP alone [66]. In contrast, Aggregatibacter actinomycetemcomitans JP2 homotypic biofilms were more susceptible in vitro to doxycycline than amoxicillin plus metronidazole [66]. Such results highlight the need for culture and antibiotic susceptibility tests in patients with aggressive periodontitis (AgP) and patients with peri-implantitis prior to systemic use of antibiotics concomitantly to periodontal therapy. In conclusion, this review indicates that different ethnic groups are preferentially colonized by different A. actinimycetemcomitans serotypes and the relationship between different A.a. serotypes and periodontal conditions remains to be investigated in the future.