Periodontology 2000, Vol. 75, 2017, 24–44 © 2017 John Wiley & Sons A/S.
y & Sons A/S. Published by John Wiley & Sons Ltd
Printed in Singapore. All rights reserved
What exactly distinguishes
aggressive from chronic
periodontitis: is it mainly a
difference in the degree of
bacterial invasiveness?
UBELE VAN DER VELDEN
For centuries, two distinct forms of destructive peri-
odontal disease have been recognized: one with a
‘systemic’ etiology; and the other with a ‘local’ etiol-
ogy. This presumably started with Fouchard & Hunter
in the 18th century and received additional attention
in the 20th century (113). Gottlieb (69–71) was proba-
bly the first to distinguish a form of periodontitis that
was frequently found in young individuals and he
called it ‘alveolar atrophy or diffuse atrophy’. He
described this condition as a noninflammatory dis-
ease causing loosening, elongation and wandering of
teeth in individuals who were generally free of carious
lesions and dental deposits. He attributed this disease
to physiological deficiencies of alveolar bone or root
cementum. This was in contrast to Schmutz–Pyor-
rhea, which was thought to be caused by the accumu-
lation of deposits on the teeth and was characterized
by inflammation, shallow pockets and resorption of
the alveolar crest. Over time, various names have
been given to the so-called noninflammatory peri-
odontal disease: genuine paradentosis by Becks (20)
in 1931; periodontosis by Orban & Weinmann (139) in
1942; and, finally (because of a lack of proof of any
degenerative process), juvenile periodontitis by Butler
(30) in 1969. Gradually, this term was accepted by the
scientific community and the common term peri-
odontosis became replaced with juvenile periodonti-
tis. However, it took more than 20 years for the term
periodontosis to become obsolete.
In the same decade when Gottlieb introduced the
term Schmutz–Pyorrhea, McCall & Box (121)
24
PERIODONTOLOGY 2000
suggested the term periodontitis simplex, and Imrie
suggested the term chronic general periodontitis (87).
Since that time, several other names have been sug-
gested for this condition, such as paradentitis margin-
alis superfacilis (82) and paradentitis (20). Even in the
textbook of Glickman (67), in 1972, the terms simple
periodontitis or marginal periodontitis were used,
whereas in the textbook of Manson (117), from 1970,
the term chronic periodontitis was employed. The
American Academy of Periodontology (6) adopted
the term chronic marginal periodontitis in 1977.
Screening PubMed using the search term ‘adult
periodontitis’ showed that in the 1960s the term
chronic periodontitis became more popular than it
was pre-1960. The first time that a paper with adult
periodontitis in the title emerged was in PubMed
in 1981 (188). Schluger et al. (160), in their textbook
of 1977, concluded in an extensive discussion on
the terminology and classification of periodontal
diseases: ‘The data now available appear to support
subclassification of marginal periodontitis into juve-
nile and adult types’.
Almost 10 years later, this nomenclature was
adopted by the American Academy of Periodontology
in the 1986 classification that recognized adult peri-
odontitis and juvenile periodontitis, which was subdi-
vided into prepubertal periodontitis, localized
juvenile periodontitis and generalized juvenile peri-
odontitis (7). Three years later, the 1989 World Work-
shop in Periodontics recommended modifying the
classification of juvenile periodontitis into early-onset

periodontitis as an umbrella designation. This was
followed by subdivision into prepubertal periodonti-
tis (localized and generalized), juvenile periodontitis
(localized and generalized) and rapidly progressive
periodontitis (5). However, in 1999, during the Inter-
national Workshop for Classification of Periodontal
Diseases and Conditions, it was decided that ‘it was
wise to discard classification terminologies that were
age-dependent or required knowledge of rates of
progression’. Accordingly, highly destructive forms
of periodontitis, formerly considered under the
umbrella term of early-onset periodontitis, were
renamed aggressive periodontitis (12). According to
the working group, distinguishing features were rapid
attachment loss, bone destruction and familial aggre-
gation. A secondary clinical feature that is frequently,
but not universally, present is inconsistency between
the amounts of microbial deposits and the severity of
periodontal tissue destruction. In addition, localized
aggressive periodontitis has a circumpubertal onset,
whereas generalized aggressive periodontitis usually
affects persons under 30 years of age, although
patients may be older (105).
Regarding adult periodontitis, the term chronic
periodontitis was eventually adopted by the work-
shop participants because it is less restrictive than the
age-dependent designation of adult periodontitis.
The group agreed upon the following simple classifi-
cation for this most common form of periodontitis:
chronic periodontitis, localized and generalized. Sec-
ondary clinical features included: (i) most prevalent
in adults, but can occur in children and adolescents;
(ii) the amount of destruction is consistent with the
presence of local factors; (iii) subgingival calculus is a
frequent finding; and (iv) slow-to-moderate rates of
progression, but may have periods of rapid tissue
destruction (110).
Thus, for a proper diagnosis a clinician needs infor-
mation on: (i) the onset and rate of progression of
periodontal tissue destruction; (ii) familial aggrega-
tion; and (iii) assessment of whether or not the
amount of destruction is consistent with the presence
of local factors. Obviously, all three items suffer from
inherent problems. It is also impossible to assess the
onset of periodontal destruction, and previous clini-
cal measurements and/or radiographs are needed for
assessing the progression of periodontal destruction.
Therefore, rapid progression is mostly estimated on
the basis of the age of the patient in relation to the
amount of periodontal breakdown at that age. The
assessment of a possible familial aggregation is also
problematic because family members may have undi-
agnosed disease, tooth loss from caries, etc.
Aggressive and chronic periodontitis
Regarding the lack of consistency between the
amounts of microbial deposits and the severity of
periodontal tissue destruction, no objective criteria
exist and this analysis therefore suffers from subjec-
tive interpretation of clinical evaluation. Therefore,
research on the etiology and treatment of periodontal
diseases is challenging, being dependent on those
rather vague patient selection criteria.
Historical review of changing diagnostic
terms from 1967 to 2015
In order to place the changing diagnostic terms that
have been used in studies over the last few decades
into a historical perspective, the PubMed database
was searched (as of July 2016) for studies published in
1967, 1977, 1987, 1997, 2007 and 2015 (the most
recent full year at the time of preparation of the
manuscript) using the search terms periodontitis,
periodontosis, juvenile periodontitis, rapidly progres-
sive periodontitis, adult periodontitis, aggressive
periodontitis, chronic periodontitis, refractory peri-
odontitis and necrotizing/ulcerative periodontitis.
The time period chosen, starting in 1967 with data
obtained at decade intervals subsequently, was based
on the following factors: (i) in 1966 the first World
Workshop in Periodontics was held; (ii) the first glos-
sary of periodontal terms was published in 1977, and
Schluger et al., in their textbook of 1977, proposed
the subclassification of marginal periodontitis into
juvenile and adult types; (iii) the American Academy
of Periodontology, 1986 classification, recognized
adult periodontitis and juvenile periodontitis (subdi-
vided into prepubertal periodontitis, localized juve-
nile periodontitis and generalized juvenile
periodontitis); (iv) to have a time point of evaluation
just before the major changes of the 1999 Interna-
tional Workshop for Classification of Periodontal Dis-
eases and Conditions; and (v) to have two evaluation
time points after the major changes of the 1999 Inter-
national Workshop for Classification of Periodontal
Diseases and Conditions. The results are presented in
Table 1. Over the time period of the study, the num-
ber of publications with a diagnostic term in the title
increased by more than 14-fold, from 35 in 1967 to
498 in 2015. The term periodontitis appeared to be
used throughout the time period of the study, of
almost 50 years. Regarding chronic periodontitis, it
can be seen that this term was already present in
1967 and that its use increased over time, culminating
in almost 50% of publications in 2015. In 1967, more
than 50% of papers had periodontosis in the title.
This decreased to 6.3% in 1987 and to 0.9% in 1997. It
25
Van der Velden

Table 1. Papers with diagnostic terms in the title found in PubMed in 1967, 1977, 1987, 1997, 2007 and 2015*

Diagnostic terms 1967 1977 1987 1997 2007 2015

used n (%) n (%) n (%) n (%) n (%) n (%)

Periodontitis 10 (28.6) 9 (25.7) 26 (20.5) 59 (53.2) 82 (41.8) 179 (35.9)

Marginal 4 (11.4) 1 (2.8) 7 (5.5) – – –

periodontitis

Adult periodontitis – – 10 (7.9) 20 (18.0) 1 (0.5) 2 (0.4)

Chronic periodontitis 1 (2.8) 5 (14.3) 12 (9.4) – 64 (32.7) 234 (47.0)

Chronic adult – – 3 (2.4) 6 (5.4) 2 (1.0) 3 (0.6)

periodontitis

Chronic marginal – 2 (5.7) 4 (3.1) – 1 (0.5) 1 (0.2)

periodontitis

Periodontosis 19 (54.3) 12 (34.3) 8 (6.3) 1 (0.9) – –

Prepubertal – – 6 (4.7) 4 (0.4) 1 (0.5) –

periodontitis

Juvenile 1 (2.8) 6 (14.1) 25 (19.7) 2 (1.8) 2 (1.0) –

periodontitis

Localized juvenile – – 7 (5.5) 5 (4.5) 1 (0.5) –

periodontitis

Generalized juvenile – – 1 (0.8) – – –

periodontitis

Rapidly progressive – – 7 (5.5) 4 (0.4) 1 (0.5) –

periodontitis

Early-onset – – 7 (5.5) 8 (7.2) 1 (0.5) –

periodontitis

Aggressive – – – – 24 (12.2) 51 (11.2)

periodontitis

Localized aggressive – – – – 2 (1.0) 4 (0.8)

periodontitis

Generalized – – – – 13 (6.6) 22 (4.4)

aggressive
periodontitis

Refractory – – 3 (2.4) 2 (1.8) 1 (0.5) 1 (0.2)

periodontitis

Necrotizing/ – 1 (2.8) 1 (0.8) – – 1 (0.2)

ulcerative
periodontitis

Total number of 35 36 127 111 196 498

publications with
diagnostic terms
in the title

Total number of 984 1,008 1,482 1,480 2,157 2,357

publications in
periodontology/
periodontal disease
*The search terms periodontitis, periodontosis, juvenile periodontitis, rapidly progressive periodontitis, adult periodontitis, aggressive periodontitis, chronic peri-
odontitis and necrotizing/ulcerative periodontitis were used.

26

is interesting that in 1987 about the same number of
publications dealt with research on these types of
patients; however, apart from periodontosis, it is now
referred to as prepubertal periodontitis, localized
juvenile periodontitis, generalized juvenile periodon-
titis, rapidly progressive periodontitis and early-onset
periodontitis. Studies with these diagnostic terms
were not found in 2015. In that year, only 77 (16.4%)
of publications dealt with the research topic of early-
onset forms of periodontitis as patients were now
being referred to as having localized and generalized
aggressive periodontitis.
Diagnostic criteria of aggressive
periodontitis in publications from 2015
Regarding aggressive periodontitis, a further analysis
was carried out on the 77 publications from 2015 to
evaluate the diagnostic criteria described in the sec-
tion ‘material and methods’ of experimental clinical
studies. Consequently, 33 papers had to be excluded:
12 reviews; 14 case reports; four papers with abstracts
in English but with the main text in Chinese; one let-
ter to the editor; and one author response; a further
one paper was not accessible. Thus, 44 papers were
available for evaluating the diagnostic criteria used
for selection of patients in these studies. The results
of the evaluations are presented in Table 2 and show
that Armitage (12) was the most frequently used refer-
ence (N = 31). Adding the reference American Acad-
emy of Periodontology (2000) (9) (N = 3) and
International workshop (1999) (8) (N = 3) implies that
84% of the studies refer to the diagnostic criteria
established at the International Workshop for Classi-
fication of Periodontal Diseases and Conditions in
1999. However, five studies had no reference at all,
and four studies did not include the referred refer-
ence in the reference list. Eight studies used Armitage
(12) as a reference but provided no additional infor-
mation. The 27 studies with additional information
presented data on age and pocket depth or attach-
ment loss and, to a lesser extent, on bone loss
(N = 12). It is interesting that 20 studies selected sub-
jects of ≤ 35 years of age, whereas seven included
subjects up to 55 years of age. However, none of
these 27 studies provided additional information
regarding familial aggregation or rapid periodontal
breakdown. A total of six studies reported docu-
mented familial aggregation according to interview
and six studies mentioned rapid destruction. How-
ever, rapid destruction was documented by previous
radiographs in only one study and in the other stud-
ies was based on the relationship between the
Aggressive and chronic periodontitis
amount of attachment/bone loss and patient age.
The aspect of inconsistency between the amounts of
microbial deposits and the severity of periodontal tis-
sue destruction was mentioned in four studies. How-
ever, only one of these documented the inconsistency
by stating: ‘Only those participants who presented
with deep pockets with a minimal subgingival plaque
and healthy tissue response, free of inflammation
were selected for aggressive periodontitis category’
(182).
The above analysis of publications in 2015 that
used aggressive periodontitis in the title shows clearly
the difficulties faced when interpreting the outcome
of the studies. First, one may wonder whether the
studies that cite Armitage (12) without providing
additional information, as reference for patient selec-
tion, really applied all the criteria of Armitage cor-
rectly. The same is probably applicable to the studies
that present additional information but only for a few
items (mostly pocket depth, attachment/bone loss
and age). The rapidity of destruction is presumably
almost never assessed, which implies that at the time
of the study, the patient may be in a quiescent stable
situation, as most of the periodontal breakdown had
occurred before the start of the study. Familial aggre-
gation, although easy to evaluate by interview, is sub-
ject to the inherent problem of lack of objectivity and
was recorded only in a few studies. Lastly, no criteria
have been developed to measure objectively the
inconsistency between the amounts of microbial
deposits and the severity of periodontal tissue
destruction. Such an inconsistency is present com-
monly, but not always, in patients with localized juve-
nile periodontitis and those with generalized severe
periodontitis (29).
Differences between aggressive
periodontitis and chronic
periodontitis
Individual differences exist regarding the degree of
susceptibility to destructive periodontal disease.
The most disease-prone persons may develop sev-
ere periodontitis at an early age, whereas others
experience little periodontal breakdown up to old
age. A recent retrospective study, based on a radio-
graphic evaluation spanning 6.6 years on average,
showed that patients with aggressive periodontitis
have a significantly faster linear pattern of progres-
sion than do patients with chronic periodontitis:
0.31 mm/year vs. 0.20 mm/year, respectively (138).
Nevertheless, severe periodontal breakdown at
27
 Table 2. Diagnostic criteria and referred references in papers with aggressive periodontitis in the title, published in 2015 and found in PubMed using the search term

28
aggressive periodontitis

Study number in reference list 1 2 10 11 13 17 18 27 37 41 42 56 57 59 65

No reference X X
Van der Velden

Referred reference not included in reference list

American Academy of Periodontology (9)

International workshop (8)

A: Armitage (12), C: Casarin et al. (35), H: Hodge et al. A A A A A A A A A A A A A

(84), L: Lang et al. (106)

Except for the reference no additional information X X X X

Age ≤ 35 years (x), range or mean  standard X X X X 14–45 X X X

deviation

Pocket depth ≥ 4 mm X

Pocket depth ≥ 5 mm X X X X X X

Pocket depth ≥ 6 mm

Attachment loss X X

Attachment loss ≥ 2 mm

Attachment loss ≥ 3 mm X X X

Attachment loss ≥ 4 mm

Attachment loss ≥ 5 mm X X X X X

Attachment loss ≥ 6 mm

Evidence of bone loss X X X

Severe bone loss X X

Familial aggregation mentioned: documented or no – – – Documented Documented – – Documented – – Documented – – – –

data

Rapid progression mentioned: documented or no data – – – – – – – Documented – – – – – No data –

Amount of microbial deposits not consistent with – – – – – – – – – – – – – – –

severity breakdown mentioned: documented or no
data

Study number in reference list 74 76 81 88 91 92 94 102 109 114 127 128 135 138 140
 Table 2. (Continued)

Study number in reference list 74 76 81 88 91 92 94 102 109 114 127 128 135 138 140

No reference X X X

Referred reference not included in reference list X X

American Academy of Periodontology (9)

International workshop (8) X X X

A: Armitage (12), C: Casarin et al. (35), H: Hodge et al. H A, L A A A C A A A

(84), L: Lang et al. (106)

Except for the reference no additional information

Age ≤ 35 years (x), range or mean  standard X X X X X 25–55 18–50 X 18–39 X X 16–40 ≤ 45
deviation

Pocket depth ≥ 4 mm

Pocket depth ≥ 5 mm X X X X X X

Pocket depth ≥ 6 mm X X X

Attachment loss

Attachment loss ≥ 2 mm X

Attachment loss ≥ 3 mm X

Attachment loss ≥ 4 mm X

Attachment loss ≥ 5 mm X X X

Attachment loss ≥ 6 mm X X

Evidence of bone loss X X

Severe bone loss X

Familial aggregation mentioned: documented or no – – – – – – – – – – – Documented – – –

data

Rapid progression mentioned: documented or no data – – – – – – – – No data – – – – – Documented

Amount of microbial deposits not consistent with – – – – – – – – – – – No data – – –

severity of breakdown mentioned: documented or no
data

Study number in reference list 142 146 148 150 157 164 166 167 168 179 182 184 185 192
Aggressive and chronic periodontitis

29
 Table 2. (Continued)

30
Study number in reference list 142 146 148 150 157 164 166 167 168 179 182 184 185 192

No reference
Van der Velden

Referred reference not included in reference list X X

American Academy of Periodontology (9) X X

International workshop (8) X

A: Armitage (12), C: Casarin et al. (35), H: Hodge et al. A A A A A A A A A A A

(84), L: Lang et al. (106)

Except for the reference no additional information X X X X

Age ≤ 35 years (x), range or mean  standard X X X X X 27  4.5

deviation

Pocket depth ≥ 4 mm X

Pocket depth ≥ 5 mm X

Pocket depth ≥ 6 mm X X

Attachment loss

Attachment loss ≥ 2 mm X

Attachment loss ≥ 3 mm

Attachment loss ≥ 4 mm X

Attachment loss ≥ 5 mm X X

Attachment loss ≥ 6 mm

Evidence of bone loss X X X X

Severe bone loss

Familial aggregation mentioned: documented or no – – – – – – No data – – – – – – Documented

data

Rapid progression mentioned: documented or no data – – – – – No data No data – – – – – – –

Amount of microbial deposits not consistent with – – – – – No data No data – – – Documented – – –

severity of breakdown mentioned: documented or no
data

In total, 77 papers published in 2015 with aggressive periodontitis in the title were found in PubMed. Thirty-three papers were excluded: 12 reviews; 14 case reports; four papers with the abstract in English but the main text in Chi-
nese; one letter to the editor; and one author response; in addition, a further one paper was not accessible. Thus, 44 papers were available for evaluation of the diagnostic criteria described in the section ‘material & methods’.
 Aggressive and chronic periodontitis

20 years of age is much more striking and has Bacterial and viral aspects
received much more attention than severe peri-
By the end of the 1970s, the search for a specific bac-
odontal breakdown at age 60, although at a subject
terium as a possible causative agent for periodontitis
level, the rate of breakdown may be comparable
in young individuals had received a large boost with
over a short period of time. Owing to lack of infor-
the isolation of Actinobacillus (Aggregatibacter) acti-
mation about the onset of periodontal breakdown
in older subjects, it is generally assumed that the nomycetemcomitans from deep pockets of patients
with localized juvenile periodontitis (170). Subse-
amount of breakdown is the result of a slowly pro-
quent studies in the early 1980s showed that the
gressing disease. Rapid development of severe peri-
occurrence of A. actinomycetemcomitans in these
odontal breakdown at a young age is rare (3) but a
patients was extremely high, varying from 89% to
comparable rapid development of severe periodon-
tal breakdown at an older age may be just as rare, 100% (55, 115, 171). The bacterium was present in
20% of juveniles and 36% of adults with no or mini-
although this has never been properly investigated.
mal gingivitis and shallow pockets; and in 50% of
Thus, as suggested by Armitage (12), the diagnostic
patients with adult periodontitis (177). A more exten-
term of the disease should be age independent and
sive study, a few years later, showed that 96.5% of
accordingly the term aggressive periodontitis was
patients with juvenile periodontitis harbored A. acti-
born. The problem that remains is that it is almost
nomycetemcomitans, whereas only 20.8% of the adult
impossible to use the term aggressive periodontitis
patients with periodontitis and 16.9% of the peri-
as long as there is no proper way of diagnosing the
odontally healthy subjects had the organism (190).
disease. This may be illustrated by the manner in
Over the years this seemingly clear picture has
which the definitions aggressive periodontitis and
become more complicated. At present, some strains
chronic periodontitis were used in a recent paper
(100). Subjects showing ≥ 5 mm loss of attachment of A. actinomycetemcomitans are viewed only as
opportunistic pathogens whereas the specific JP2
at the proximal sites of molars and/or incisors in at
clone has properties of a true exogenous pathogen
least two quadrants were classified as having
(101). Ko€ no
€ nen & Mu € ller (101) also suggested that
aggressive periodontitis (100). The classification of
generalized aggressive periodontitis is likely to be an
chronic periodontitis was assigned to subjects who
extension of localized aggressive periodontitis rather
did not have aggressive periodontitis, and had two
than a different entity. This supposition is supported
or more teeth with attachment loss of ≥ 4 mm and
by findings from a study of families with juvenile peri-
probing depth of ≥ 4 mm, and at least one tooth
odontitis, which showed that 26 patients had general-
with bleeding on probing (100). This implies that
ized juvenile periodontitis and earlier records of these
the only difference between aggressive periodontitis
patients were consistent with localized juvenile peri-
and chronic periodontitis was 1 mm of attachment
loss. odontitis (118).
The progression of periodontal lesions from a local-
Periodontitis is a complex disease, being the
ized to a more generalized form may coincide with
result of a combination of factors, including: (i)
the introduction of a more complex microbiota which
the subgingival biofilm on both the tooth-root sur-
resembles that of generalized chronic periodontitis
face and on the pocket lining epithelium; (ii)
genetic factors and epigenetic modifications; (iii) (101). This view is supported by a recent study in
which 267 consecutive patients with periodontitis,
lifestyle-related risk factors, such as smoking, stress
which was diagnosed as either chronic periodontitis
and poor diet; and (iv) systemic diseases, notably
(n = 183) or aggressive periodontitis (n = 84), were
diabetes (112). These disease determinants interact
screened for the presence of A. actinomycetemcomi-
in a delicate and changing equilibrium. It is likely
tans and Porphyromonas gingivalis (133). Aggregati-
that genetic factors, in combination with microor-
bacter actinomycetemcomitans was detected in 54% of
ganisms, play a dominant role in the development
subjects with aggressive periodontitis and in 48% of
of periodontitis in young individuals, whereas life-
subjects with chronic periodontitis. A slightly higher
style-related factors become more important later
detection rate of P. gingivalis was found in chronic
in life (112). The topics of bacterial/viral, host
periodontitis (67%) compared with aggressive
response and genetic aspects of chronic periodon-
titis and aggressive periodontitis are only briefly periodontitis (52%) (133). Nevertheless, the above
findings were based on traditional bacterial
reviewed here and the reader is referred to several
identification, and more advanced open-ended
recent reviews to gain further insight into those
molecular techniques might have been able to relate
particular subject matters.

31
Van der Velden
specific microbiomes to distinct types of periodontal
disease.
Viruses, as well as bacteria, have been implicated
in the etiology of periodontitis. An active herpesvirus
infection capable of impairing periodontal host
defenses may actually mediate the entry of bacterial
pathogens into gingiva (169). The initial study inves-
tigated the presence of human cytomegalovirus,
Epstein–Barr virus, herpes simplex virus, human
papillomavirus and HIV in crevicular fluid samples
from 30 patients with advanced periodontitis (143).
Human cytomegalovirus was detected in 60% of the
patients with periodontitis, Epstein–Barr virus in
30%, herpes simplex virus in 20%, human papillo-
mavirus in 17% and HIV in 7% (143). Numerous
studies on periodontal herpesviruses have since been
carried out. The results of a recent review (169)
showed median values of 49%, 45% and 63% for the
subgingival prevalence of human cytomegalovirus,
Epstein–Barr virus and herpes simplex virus type I,
respectively, in aggressive periodontitis. In chronic
periodontitis, these values were 40%, 32% and 45%,
respectively. However, the cited studies differed
markedly in herpesvirus presence. Such differences
could be caused by mischaracterization of the peri-
odontal disease activity status, disparity in viral reac-
tivation states, inefficient molecular detection
methods and patients being of different ethnic/geo-
graphical backgrounds (169). Aggressive and chronic
periodontitis may be distinguished by in-depth her-
pesvirus analyses, but not according to the mere
subgingival presence or absence of herpesvirus gen-
omes (169).
Host-response aspects
Already in 1902, Znamensky (191) had described the
histopathological changes of periodontal disease in
terms of infiltration of connective tissue with white
blood cells and concluded that this reflected chronic
inflammation. Subsequently, equally detailed
descriptions of the periodontal lesions were pub-
lished by James & Counsel in 1927 (89) and Wein-
mann in 1941 (186), but added local bacteria to the
disease pathogenesis. However, the host immune
response in periodontal diseases was not studied in
detail for several decades. Based on recent compre-
hensive reviews by Ford et al. (60) and Cekici et al.
(36), it is unlikely that there are major immunological
differences between aggressive periodontitis and
chronic periodontitis. However, neutrophilic poly-
morphonuclear leukocytes may play a special role in
periodontal disease pathogenesis.
32
Early studies on neutrophils in periodontal crevices
showed that they were present in both healthy and
inflamed gingiva (54, 165). It was also shown that
neutrophils could be sampled from crevices of clini-
cally healthy gingiva, even when histological sections
failed to show any inflammatory infiltrates in the gin-
gival connective tissue (15). By labeling blood neu-
trophils it was shown that the neutrophils migrate
from the blood vessels into the crevices and that they
migrate at a higher rate to inflamed sites than to
healthy sites (16). In a full dentition with a healthy
periodontium, about 30,000 neutrophils enter the
oral cavity per minute (159). Since 1970, a vast
amount of literature has been published on the func-
tion and dysfunction of neutrophils, and readers are
referred to the previously mentioned reviews. Individ-
uals with manifest impairment of neutrophil func-
tions are predisposed to severe periodontitis, as
observed in subjects with leukocyte adhesion defi-
ciency, Kostmann syndrome, Chediak–Higashi syn-
drome, Papillon–Lefe vre syndrome and Down
syndrome (95, 136, 152).
Studies in the 1970s found an association between
juvenile periodontitis and decreased neutrophil
chemotaxis, as assessed on peripheral blood neu-
trophils (31, 43, 106). Subsequent studies showed that
72–86% of patients with juvenile periodontitis exhibit
decreased neutrophil chemotaxis (153), but not all
studies were able to identify this neutrophil defect
(24, 99, 129, 176). In chronic periodontitis, studies
showed either normal (173, 176) or depressed (103)
chemotaxis. A recent study suggested that neutrophils
from the peripheral blood of patients with chronic
periodontitis exhibit reduced chemotactic accuracy
(151). It is likely that decreased chemotaxis will result
in increased tissue transit times, which may be more
pronounced in juvenile/aggressive periodontitis com-
pared with chronic periodontitis. Juvenile/aggressive
periodontitis has also been related to decreased
phagocytosis of peripheral neutrophils in many (14,
32, 34, 97, 174, 181), but not in all (176), studies. In
adult/chronic periodontitis, studies showed either
normal (14, 176) or reduced (32) phagocytic activity,
suggesting a more frequent reduction of neutrophil
phagocytosis in juvenile/aggressive periodontitis than
in chronic periodontitis.
Peripheral neutrophils of patients with juvenile/
generalized early-onset periodontitis contain and
release abnormally high levels of oxygen radicals in
response to stimuli (98, 108, 168), suggesting hyperac-
tivity of such neutrophils, but other studies found
normal or even reduced production of oxygen radi-
cals from peripheral neutrophils after stimulation

(24, 34, 176). Increased release of oxygen radicals after
stimulation of peripheral neutrophils has also been
reported in untreated patients with adult/chronic
periodontitis, but also in treated patients (64, 119)
and in patients post-treatment (75); these results are
suggestive of constitutionally hyperreactive neu-
trophils. Another study showed that therapy reduced
total oxygen radical production, but not extracellular
radical release, by unstimulated neutrophils (hyper-
activity) (120). A distinction may be warranted
between neutrophil hyperactivity (in which excess
oxygen radicals are produced in the absence of a
stimulus) and hyperreactivity (in which excess radical
production follows stimulation of neutrophil surface
receptors) (38). Neutrophil hyperreactivity is not
entirely a constitutional feature of patients with
chronic periodontitis but can occur secondarily to
periodontal inflammation (111). Certain proinflam-
matory mediators are able to activate peripheral
neutrophils (50), and oxidatively stressed neutrophils
in chronic periodontitis may release extracellular
superoxide, which can be reversed by therapy (48).
No studies have compared hyperactivity or hyperre-
activity of neutrophils in juvenile/aggressive peri-
odontitis vs. chronic periodontitis and thus no
conclusion can be made regarding the relative magni-
tude of oxidative stress in these two diseases.
It should be realized that most neutrophil studies
include rather a small number of patients, which
temper the conclusions of such studies. For example,
a Japanese study (176) from 2001 evaluated the neu-
trophil function in a group of 162 subjects distributed
over four relatively large well-defined subgroups,
according to the Page & Schroeder classification
(141). No significant differences were found in neu-
trophil function in terms of chemotaxis, phagocytosis,
superoxide production and adhesion (176). A recent
systematic review examined the profile of cytokines/
chemokines in the gingival crevicular fluid and con-
cluded that the current weight of evidence is not suf-
ficient to prove a difference between aggressive and
chronic periodontitis (53).
Genetic aspects
In general, the role of genetics is considered as more
important in younger patients with aggressive peri-
odontitis than in older subjects with chronic peri-
odontitis. Evidence for a hereditary aspect of
paradentosise had already been suggested in
Germany by Boenheim (25), in 1928, and was sub-
stantiated in the 1930s by Belser (22) and Dickman
(51). Their results showed that 57.7% of the family
Aggressive and chronic periodontitis
members of paradentose probands also had the dis-
ease, which was much higher than the reported
prevalence of 14.2% in the general population at that
time. A more recent American study, which included
77 siblings of 39 probands with localized or genera-
lized juvenile periodontitis, found that almost 50% of
the siblings also had juvenile periodontitis (26). The
largest family study of juvenile periodontitis, to date,
includes 227 probands and 527 family members (60
with localized juvenile periodontitis, 72 with genera-
lized juvenile periodontitis, 254 unaffected and 141
with an unknown periodontal condition) (118). The
majority of the families were of African-American ori-
gin. The authors concluded that the most likely mode
of inheritance was autosomal dominant in both
African–American and Caucasian kindreds, with a
penetrance of 70% in African–American people and
73% in Caucasian people.
Few epidemiological studies have evaluated the
family relationship in chronic/adult periodontitis.
Several studies have failed to show a familial cluster-
ing of the disease (19, 40, 52); however, a study of
5,375 patients with chronic (adult) periodontitis, and
with a mean age of 50 years, showed that 37% of the
subjects had at least one parent or sibling with peri-
odontitis (194). A study of 24 families, selected on the
basis of having a proband with chronic adult peri-
odontitis plus a spouse and one to three children,
showed that 45% of the children in the age group 10–
15 years had at least one pocket of ≥ 5 mm in con-
junction with loss of attachment (145). The general
prevalence of periodontitis in that age group in the
same city was 5% (180). Twin studies, in which sub-
jects were selected on having a twin brother/sister
and not on the basis of a proband with periodontitis,
all reported a heritable component for chronic peri-
odontitis (44, 125, 126). These studies suggest that
chronic/adult periodontitis may aggregate in families.
As reviewed by Loos et al. (112), genome-wide
association studies followed by replication studies in
large case–control populations have identified several
single-nucleotide polymorphisms in a number of
gene loci as risk factors for aggressive periodontitis.
Those include: (i) PTGS2, a gene on chromosome 1
that encodes the enzyme prostaglandin-endoperox-
ide synthase-2 (also known as cyclooxygenase-2),
which converts arachidonic acid to prostaglandin H2;
(ii) IL10, a gene that encodes the anti-inflammatory
cytokine, interleukin-10, on chromosome 1; (iii)
DEFB1, a gene on chromosome 8 that encodes defen-
sin beta 1, an antimicrobial peptide; (iv) ANRIL (an-
tisense noncoding RNA in the INK4 locus) a gene on
chromosome 9 that is involved in transcriptional
33
Van der Velden
repression; and (v) GLT6D1 (glycosyltransferase 6
domain containing 1), a gene for glycosyltransferase
located on chromosome 9. Polymorphisms within
ANRIL and PTGS2 gene loci tended to be associated
also with chronic periodontitis. The genetic risk vari-
ant identified in GLT6D1 was located within an
intron, while the genetic risk variants for the other
genes (ANRIL, PTGS2, IL10 and DEFB1) were located
in regulatory regions. It is unknown whether the
genetic variants in intronic and regulatory regions
may, by themselves, be truly causative or simply be
genetic markers of other genetic variations; regard-
less, they may lead to subtle changes in the expres-
sion of associated coding regions and may affect the
quantity of the transcription and subsequent protein
products (112). These associations confirm that
genetics play a more important role in aggressive
periodontitis than in chronic periodontitis. Neverthe-
less, as suggested by Nibali et al. (134), the influence
of genetics in chronic periodontitis should not be dis-
regarded as negligible. Two recent genome-wide
association studies found genetic variants related to
chronic periodontitis (137, 158).
Bacterial invasion of the
periodontal tissues
The phagocytosis and killing of microorganisms by
neutrophils, together with the release of antimicrobial
peptides by epithelial cells and neutrophils function-
ing as endogenous antibiotics, form the first line of
the innate immune defense against viruses, bacteria
and fungi (149). The major antimicrobial peptides
include alpha-defensins and cathelicidin LL-37
released from neutrophils, and beta-defensins
expressed by oral epithelial cells (47). To maintain a
healthy periodontium, neutrophils form a ‘wall’
between the bacteria colonizing the tooth surface and
the underlying epithelium to attempt to phagocytoze
bacteria attached to the tooth surface. During this
process of ‘frustrated phagocytosis’, neutrophil lyso-
somal enzymes (products of the oxidative burst) and
other proinflammatory substances are released into
the pocket and/or the underlying tissue, where they
may exert destructive effects (153).
It is interesting to note how thoughts come and go
in periodontal research. In the glossary of periodontal
terms published in 1986, periodontitis is described
merely as an inflammatory destructive disease.
However, Goady (68) had already described, in 1907,
bacterial invasion of periodontal tissues, pointing to
the infectious nature of the disease. Later
34
publications also reported on the presence of bacteria
in the periodontal membrane (178) and within the
epithelium and the underlying tissues (21). Decades
later, Sussman et al. (175) concluded (based on a ser-
ies of publications from the 1950s and 1960s) that the
ability of bacteria to penetrate intact tissue was still a
matter of considerable controversy and that the pres-
ence of bacteria in the connective tissue of the inter-
dental col had not been investigated. Their
subsequent study employed lamina propria biopsies
from adult periodontitis sites and showed bacterial
invasion in 20% of interdental cols, in 14% of sites
with gingivitis sites, in 2% of sites with ulceration and
in 3% of sites with intact epithelium (175). As chronic
inflammation was present also in tissue specimens
with no evidence of bacterial penetration, they con-
cluded that gingival inflammation may well be the
response to bacterial products rather than to frank
microbial penetration (175). In subsequent years,
convincing evidence has been presented showing
that in the case of juvenile periodontitis, bacterial
invasion can indeed occur (33, 66), and that viable
A. actinomycetemcomitans can be demonstrated
within periodontal tissues (45). In Fig. 1A, a case of
juvenile periodontitis is presented, showing radio-
graphically cup-shaped interdental bone loss in
which the most apical part of the radiolucency is
mid-interdental and not at the tooth site, consistent
with bacterial invasion deep in the tissues. Treatment
of this A. actinomycetemcomitans-positive patient
with a 7-day course of metronidazole plus amoxi-
cillin, scaling and root planing and oral hygiene
A
B
Fig. 1. (A) Baseline; patient at 15 years of age. (B) Patient
at 24 years of age, 9 years after treatment.

instructions resulted in mineralization of the dem-
ineralized bone (Fig. 1B).
Regarding chronic/adult periodontitis, an early
electron microscopy study found that bacteria were
occasionally present in superficial epithelial cells and,
in one of 13 patients, in the periodontal lamina pro-
pria (177). In contrast, Frank (61) confirmed, in a
study of 14 patients, 35–56 years of age, with
advanced periodontitis, an earlier observation (62)
that bacteria infiltrate the junctional epithelium and
the underlying connective tissue in more than half of
cases. In a study of eight patients with advanced peri-
odontal disease only one showed bacteria in the con-
nective tissue, while bacteria were found in the
pocket epithelium in five (155). In another study of
two patients with advanced chronic periodontitis,
bacteria were found deep in the connective tissue in
both (4), whereas in a study of seven patients with
chronic generalized advanced periodontitis, four
showed bacterial invasion into the epithelium as well
as into the connective tissue, while in the other three
bacterial invasion was limited to the epithelium (116).
Subsequent studies using immunofluorescence and
immunohistochemical staining for identification of
bacteria showed the presence of A. actinomycetem-
comitans, P. gingivalis, Prevotella intermedia and
Actinomyces naeslundii in periodontal tissues (114,
154, 156). More recently it was shown in vitro that
A. actinomycetemcomitans and P. gingivalis are able
to survive within and spread to neighboring epithelial
cells (123, 189). An in vivo study demonstrated the
presence of P. gingivalis in inflamed regions of gingi-
val biopsies from periodontitis lesions as well as from
clinically healthy sites of subjects previously treated
for periodontitis but not in biopsies from periodon-
tally healthy subjects (96). Gingipains from P. gingi-
valis have the ability to splice the chemokine,
interleukin-8, into a version capable of increasing
neutrophil chemotaxis and priming the respiratory
burst (49), providing a mechanism for neutrophil-
mediated tissue destruction induced by tissue-invad-
ing P. gingivalis.
An interesting study investigated the intra-connec-
tive tissue localization of A. actinomycetemcomitans
and P. gingivalis in six patients with untreated peri-
odontitis who exhibited ongoing periodontal destruc-
tion (154). Periodontal disease progression was
determined using the ‘tolerance’ method (77), mea-
suring loss of attachment at 1-week intervals in order
to identify short episodes of disease activity. The
results showed that all subjects were positive for
A. actinomycetemcomitans and P. gingivalis, and that
P. gingivalis counts were significantly elevated in the
Aggressive and chronic periodontitis
connective tissue of disease-active sites when com-
pared with nonactive sites. Invasion of periodontal
connective tissue with A. actinomycetemcomitans
also occurred significantly more frequently in dis-
ease-active sites than in nonactive sites (77). It has
been suggested, on the basis of data from longitudi-
nal monitoring of periodontal attachment level and
alveolar bone in humans and animals, that periodon-
tal disease progresses by recurrent acute episodes
(72, 172). If invasion of bacteria into the connective
tissue occurs mainly at brief episodes of disease pro-
gression, it is not unexpected to find discrepancies in
studies on the presence of bacteria in periodontal
connective tissue. For detailed information on the
mechanisms of how microbial, environmental and
genetic factors contribute to bacterial invasion of
periodontal tissues, the reader is referred to the
recent excellent review by Ji et al. (90).
The term pathobiont was recently introduced in
the periodontal literature (46). A pathobiont is a
symbiont – a natural member of the human
microbiota – that is able to promote pathology
only when specific genetic or environmental con-
ditions are altered in the host (39). The phe-
nomenon that juvenile periodontitis/early-onset
periodontitis and most cases of aggressive peri-
odontitis start early in life and that the classical
periodontopathic bacteria are now regarded as
pathobionts (80), implies that the host response
involving neutrophils and antimicrobial peptides is
less efficient at destroying pathogens in those indi-
viduals than in the general population. However,
an unhealthy lifestyle in terms of smoking, stress
and poor nutrition of adults may also weaken host
resistance and result in the development of peri-
odontitis. It is hypothesized that bacteria invade
and survive more readily within the periodontal
connective tissue of patients with juvenile peri-
odontitis/early-onset periodontitis than of patients
with chronic periodontitis.
Figure 2A presents a case of aggressive periodonti-
tis in a 37-year-old nonsmoking woman. Clinical
inspection showed intensely red and swollen papillae
and a full-mouth bleeding score of 100%. Pockets up
to 12 mm were found at the second premolars and at
all molars, and through-and-through furcation
involvement was observed in the maxilla. Radio-
graphs showed advanced bone loss (Fig. 2C). Treat-
ment included prescription of metronidazole (500 mg
three times daily for 7 days) and rinsing twice daily
with chlorhexidine without any further instruction or
treatment. Evaluation after 4 weeks showed a major
gingival improvement (Fig. 2B), a full-mouth bleeding
35
Van der Velden
score of 19% and substantial pocket-depth reduc-
tions. Subsequent conventional treatment resulted in
a full-mouth bleeding score of 8%, pocket depths
below 5 mm, almost closed furcations and extensive
alveolar bone gain (Fig. 2D). This striking healing
response may be a result of the antibiotic treatment
given at the time of bacterial invasion into the con-
nective tissue, when the bone was demineralized but
connective fiber attachment to the root was still
intact. Immediate scaling and root planing to the dis-
tance of the tip of the probe, which often penetrates
deep into connective tissue (28), was avoided to pre-
vent removal of attached connective tissue fibers,
36
Fig. 2. (A) Baseline. (B) Four-week
follow-up. (C) Radiographs at base-
line. (D) Radiographs at 8-month fol-
low-up.
which could cause down-growth of pocket epithelium
and prevent connective tissue reattachment (147).
Diagnosis of invasive periodontitis
The problem we currently face is how to identify peri-
odontitis in the disease-active state. Infections, in
general, cause a rise in body temperature, and it is
conceivable that periodontal inflammation is also
associated with elevated gingival temperature. Early
studies on oral temperature reported that the gingival
papilla is cooler than the corresponding position in

the vestibular sulcus (63) as well as the sublingual
area (23, 187). The temperature of the papilla
increases with increases in both gingival redness and
pocket depth (63), reflecting local inflammatory
events. Subgingival temperature increases from ante-
rior to posterior regions of the mouth, and the tem-
perature of the mandible is higher than that of the
maxilla (130, 132). Sublingual temperature appears to
be rather constant (130) and is higher in female sub-
jects than in male subjects (36.7 and 36.5°C, respec-
tively). The mean vestibular sulcus temperature is
about 34°C (131, 132).
Direct comparison of shallow healthy and dis-
eased pockets showed that bleeding pockets have a
higher temperature than do nonbleeding sites (86).
The higher temperature of bleeding shallow pockets
was confirmed on the basis of differences between
sublingual temperature and pocket temperature
(85). A tendency for increasing temperature with
increasing pocket depth has also been reported (58,
78, 104, 124, 183). Haffajee et al. (79) carried out a
prospective study on patients with untreated peri-
odontitis and found that elevated mean subgingival
temperature was related to subsequent attachment
loss, particularly in individuals who exhibited more
than one progressing site. The odds ratios of a sub-
ject exhibiting new attachment loss at one or more
or two or more sites were 14.5 and 64.0, respec-
tively, if the subject’s mean subgingival temperature
exceeded 35.5°C as assessed at six sites per tooth
(79).
It has been suggested that the raised temperatures
in the presence of inflammation are caused by
increased circulation. However, it is more likely that
increased blood flow has a cooling effect on the
inflammatory process. Therefore, the raised temper-
ature of an inflamed area is the result of an increase
in local heat production caused by an increased
local metabolism (107). The elevated subgingival
temperature of 35.5°C at the sites with subsequent
attachment loss may be related to an increased local
inflammatory infiltrate as such, but it is tempting to
speculate that the elevated subgingival temperature
reflects bacterial invasion of the periodontal connec-
tive tissue. Mestnik et al. (122) showed that adjunc-
tive use of amoxicillin with metronidazole in
patients with aggressive periodontitis produced a
gain of clinical attachment, but five of the subjects
in the antibiotic group gained less than the median
gain of attachment of the total group. It may be sug-
gested that the reason why these five subjects did
not benefit from the antibiotic treatment is because
of the presence of a microflora that is resistant to
Aggressive and chronic periodontitis
the prescribed antibiotics. However, another possi-
bility is absence of bacterial invasion in the connec-
tive tissue at the time point when the antibiotics
were given. A few years ago, two systematic reviews
were published on the effectiveness of systemic
amoxicillin plus metronidazole as adjunctive therapy
to scaling and root planing: one examined the effec-
tiveness of antibiotic on aggressive periodontitis;
and the other examined the effectiveness of antibi-
otic on chronic periodontitis (161, 162). The
weighted mean difference in attachment gain was
0.42 mm for aggressive periodontitis and 0.21 mm
for chronic periodontitis. This implies that the addi-
tion of amoxicillin plus metronidazole was more
effective in aggressive periodontitis than in chronic
periodontitis, a result that could be explained by a
difference in bacterial invasiveness between the two
disease types. However, it has been argued that the
distinction between the two disease types in these
two systematic reviews was not clear, and a recent
systematic review was unable to confirm the addi-
tional effect of amoxicillin plus metronidazole in
aggressive periodontitis (193).
Two studies on aggressive periodontitis showed
that the administration of amoxicillin plus metron-
idazole, together with mechanical treatment, in the
initial phase of therapy provides greater reduction of
pocket depth and a larger gain of clinical attachment
at initially deep sites than does antibiotic adminis-
tration 3 or 6 months after the initial active phase of
treatment (73, 93). There is strong evidence that
antibiotics are more effective when given to a dis-
rupted biofilm than to an undisrupted biofilm (82).
Kaner et al. (93) explained the difference in clinical
results between immediate and late administration
of antibiotic by hypothesizing that the immediate
administration of antibiotics results in a higher drug
concentration in situ compared with late adminis-
tration. This difference could be the result of
increased blood flow and capillary permeability dur-
ing the initial inflammatory state, which is decreased
after the initial active therapy. However, the differ-
ence in treatment outcome may also be explained
on the basis of bacterial gingival invasion at the time
of active treatment, which may be resolved post-
treatment. In the light of the discussion above, it
could be hypothesized that elevated subgingival
temperature may help to distinguish between inva-
sive and noninvasive periodontitis. Such a distinc-
tion may aid the clinician in the decision of whether
to prescribe systemic antibiotics; however, research
is needed to show the proof of principle of the
above concepts.
37
Van der Velden
Concluding remarks
Periodontitis is a multifactorial disease for which an
etiologically based classification is elusive. It is likely
that periodontitis proceeds with bursts of disease
activity caused by an imbalance between the patho-
biont and the host immune response. Bacterial inva-
sion of the periodontal connective tissue may be an
important trigger of disease activity bursts. After
clearance of invading bacteria by the host defense or
by treatment, periodontitis is expected to return to a
nonprogressive disease state. Scaling and root plan-
ing during periods of disease burst may remove con-
nective tissue fiber attachment and give rise to
epithelial down-growth, thereby preventing connec-
tive tissue reattachment. Treatment with systemic
antibiotics, on the other hand, may not damage the
periodontal ligament. Because elevated subgingival
temperature is associated with disease activity, an
assessment of the pocket temperature may help to
identify patients suitable for treatment with systemic
antibiotics. The importance of diagnosing disease-
active periodontitis is indisputable, and it is suggested
that the concept of bacterial invasive periodontitis
should be included in future classifications of peri-
odontal disease.
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