DOI: 10.1111/prd.
12241
REVIEW ARTICLE
Periodontal herpesvirus morbidity and treatment
Jørgen Slots1 | Henrik Slots2,3,4
1
School of Dentistry, University of Southern California, Los Angeles, California
2
University of Nevada at Reno School of Medicine, Reno, Nevada
3
St. George's School of Medicine, St. George, Grenada
4
Renown Medical Center, Reno, Nevada
Correspondence: Jørgen Slots, School of Dentistry, University of Southern California, MC-0641, 925 W 34th St, Los Angeles, CA 90089-0641 (jslots@usc.edu).
KEYWORDS
Cytomegalovirus, Epstein-Barr virus, herpes simplex virus, periodontal treatment, valacyclovir
1 | BACKGROUND
Inflammatory periodontal disease includes gingivitis and periodontitis.
Gingivitis ranges from a mild chronic inflammation to the life‐threaten-
1
ing noma infection. Simple gingivitis is a bacterial biofilm infection
that affects virtually all dentate individuals throughout the world. Sev-
ere gingivitis, such as pregnancy gingivitis,2,3 diabetic gingivitis,4,5
6 7
acute necrotizing ulcerative gingivitis, HIV gingivitis, and periodontal
8,9
abscesses, may involve both bacteria and herpesviruses. Treatment
of all types of gingivitis entails removal of the causative bacterial bio-
film, but bleeding gingivitis, which is a risk factor for periodontitis10
11-15
and is frequently associated with herpesviruses, may benefit from
antiherpesviral treatment as well.
Periodontitis is characterized by break down of the periodontal
ligament and alveolar bone and complex interactions among active
herpesviruses, specific bacterial pathogens, and destructive immune
responses.16 Most periodontitis starts in the third decade of life but
can begin at any age.17 Four billion individuals worldwide have a his-
tory of periodontitis, and the global prevalence of severe periodonti-
tis is estimated to be 11%.18 Severe periodontitis occurs in 8.9% of
the US adult population and is particularly prevalent in impoverished
19
and marginalized communities. Periodontitis has also been associ-
ated with at least 57 medical diseases and disabilities.20,21 The asso-
ciation between periodontitis and systemic morbidity may be the
result of periodontal herpesviruses entering the systemic circulation
and infecting distant body sites.22
Dental and calculus biofilms were traditionally thought to be
the cause of periodontitis, but an etiology based on biofilm accu-
22-24
mulation has been deemphasized. Biofilm formation alone is
unable to explain the low occurrence of periodontitis in some
patients with considerable biofilm buildup and, conversely, the initi-
ation and rapid progression of classic localized juvenile (aggressive)
periodontitis exhibiting virtually no detectable biofilm. Also, peri-
odontal treatments that focus on the removal of dental plaque and
210 | © 2019 John Wiley & Sons A/S. wileyonlinelibrary.com/journal/prd
Published by John Wiley & Sons Ltd
calculus have produced varying outcomes.25 In the late 1970s,
these clinical realities led to a reappraisal of the etiology of peri-
odontitis, from being a microbiologically nonspecific disease to a
specific infection involving unique anaerobic bacteria.26-28 Her-
pesviruses were added to the etiology of periodontitis in the late
1990s, further underscoring the microbial specificity of the dis-
ease.16 Coinfection of periodontal herpesviruses and bacterial
pathogens is not coincidental or benign.29 Herpesvirus‐bacteria
interaction is implicated in the onset of rapidly advancing periodon-
titis, and the absence of either herpesviruses or bacterial pathogens
may preclude the development of severe periodontitis. Hence, pre-
ventive and curative treatments that target both herpesviruses and
pathogenic bacteria, rather than bacteria alone, may be more profi-
cient in preempting periodontal breakdown or arresting disease‐
active periodontitis.
Similarly to herpesvirus systemic diseases, herpesvirus peri-
odontitis begins with rapid tissue break down followed by disease
stability that may last for several years or even a lifetime, possibly
interrupted with minor relapses.22 Localized juvenile periodontitis
starts at the onset of puberty, probably because of a hormone‐
induced reactivation of periodontal herpesviruses,30 and is a classic
example of a short‐lived, highly destructive periodontal disease
that burns out spontaneously.31 Shifts in the balance between the
intrinsic virulence of the herpesvirus infection and the prevailing
effectiveness of the anti‐herpesvirus host defense may determine
the on‐off pattern of periodontal disease progression. Cell‐
mediated immunity limits the local spread of herpesviruses more
effectively during reactivation events than during the primary
infection, and thus tissue destruction tends to be less severe dur-
ing recurrence of the disease. Immunocompetent people may
experience herpesvirus reactivation and periodontitis relapse fol-
lowing substantial immunosuppressive events or after new infec-
tions with immunologically unrelated herpesviruses. Individuals
with genetically or acquired compromised cellular immunity are at
Periodontology 2000. 2019;79:210–220.
SLOTS AND SLOTS | 211

T A B L E 1 Human herpesvirus (HHV) characteristics and classification

Genome Herpesviridae Replication
HHV family size (kbp)a subfamilyb cyclea Host rangea Latency site(s)a,b
HHV‐1 (HSV) 150 Alpha Short Broad Sensory ganglia
HHV‐2 (HSV) 150 Alpha Short Broad Sensory ganglia
HHV‐3 (VZV) 125 Alpha Short Broad Sensory ganglia
HHV‐4 (EBV) 172 Gamma Intermediate Highly restricted B‐lymphocytes
HHV‐5 (HCMV) 240 Beta Long Restricted Secretory glands,
lymphoreticular cells,
kidneys, and other tissues
HHV‐6 144 Beta Long Restricted T‐lymphocytes,
monocytes, macrophages
HHV‐7 145 Beta Long Restricted CD4+ T‐cells
HHV‐8 (KSHV) 165 Gamma Intermediate Highly restricted B‐lymphocytes

EBV, Epstein‐Barr virus; HCMV, human cytomegalovirus; HSV, herpes simplex virus; kbp, kilobase pair; KSHV, Kaposi sarcoma‐associated human her-
pesvirus; VZV, varicella‐zoster virus.
a
Ahmad et al99.
b
Kukhanova et al100.

increased risk of frequent and long‐lasting herpesvirus reactivation
and extensive periodontal tissue destruction.32 Periodontitis is also
associated with elevated antibody levels against infecting her-
pesviruses which, however, appear to be unable to halt disease
16
progression. Once infected, an individual harbors the herpesvirus
for life.
This article reviews herpesvirus occurrence in periodontitis and
proposes a pharmacotherapeutic approach to the treatment of her-
pesvirus‐associated periodontitis. Severe/active periodontitis tends to
contain high copy counts of reactivated herpesviruses and is the
main focus of this article. Longstanding mild‐to‐moderate
periodontitis typically harbors latent (if any) herpesviruses, rarely
causes serious damage to a dentition, responds well to a variety of
therapies, and is not a topic of this review.
2 | HERPESVIRUS CHARACTERISTICS AND
CLASSIFICATION
Herpesvirus virions have a diameter of approximately 0.25 μm and
consist of a double‐stranded, linear DNA molecule of 125‐240 kb in
length, an icosahedral capsid containing 162 capsomers, a proteina-
ceous tegument, and a host cell membrane‐derived envelope con-
taining virally induced glycoproteins.33 Reflecting their large genomic
size, herpesviruses possess a high protein coding capacity, with esti-
mates ranging from 160 to more than 200 open reading frames.
Herpesviruses infect most animal species, and more than 100 differ-
ent types of herpesvirus have been identified.
Table 1 shows the key characteristics and classification of
human herpesviruses. Eight human herpesvirus genera with distinct
biological and clinical characteristics have been described: Human
herpesvirus 1 (herpes simplex virus type 1), Human herpesvirus 2
(herpes simplex virus type 2), Human herpesvirus 3 (varicella‐zoster
virus), Human herpesvirus 4 (Epstein‐Barr virus), Human herpesvirus
5 (cytomegalovirus), Human herpesvirus 6 (human herpesvirus 6),
Human herpesvirus 7 (herpesvirus 7), and Human herpesvirus 8
(Kaposi sarcoma‐associated herpesvirus 8). The Herpesviridae family
is divided into the alpha subfamily (herpes simplex virus type 1
[oral‐facial type], herpes simplex virus type 2 [genital type], and
varicella‐zoster virus), the beta subfamily (cytomegalovirus, human
herpesvirus 6, and herpesvirus 7), and the gamma subfamily
(Epstein‐Barr virus types 1 and 2, and Kaposi sarcoma‐associated
herpesvirus 8). Alpha herpesviruses exhibit a relatively short repro-
ductive cycle, rapid lysis of infected cells, and latency in sensory
ganglia. Beta herpesviruses demonstrate a long reproductive cycle,
slowly progressing infection, occasional enlargement of infected
cells, and tropism for a large range of cells. Gamma herpesviruses
are specific for B‐lymphocytes and viral latency is typically found
in lymphoid tissue.
Herpesviruses have developed strategies to downregulate
antiviral host defenses.16 The viruses encode immunoevasive gly-
coproteins that interfere with antigen presentation, T‐cell immune
surveillance, and natural killer cell function. Viral proteins seek to
alter or mimic the function of major histocompatibility complex
proteins, leukocyte activation and migration, induction and activity
of cytokines and interferons, antibody‐based defense mechanisms,
and host cell susceptibility to apoptosis. Despite elaborate
immune‐evasion efforts by herpesviruses, the host immune system
generally prevails in immunocompetent subjects. However, her-
pesvirus disease incidence and severity is elevated in immunologi-
cally immature and genetically compromised (medical syndromes)
patients and in individuals who are immunosuppressed as a result
of advanced age (immunosenescence), disease (eg, HIV infection
sequelae⁄AIDS) or treatment (eg, chemotherapy, radiotherapy,
pharmacological immunosuppression with organ transplantation,
and/or high‐dose corticosteroids).
212 | SLOTS
3 | HERPESVIRUSES IN MEDICAL
DISEASES
The eight members of the human herpesvirus family infect parenchy-
mal cells, connective tissue cells, epithelial cells, hematopoietic cells,
and other cell types which can cause disease by mechanisms that
are direct, indirect, or immunoregulatory.29 Herpesviral diseases are
the result of direct cell lysis or host immune reactions against viral
proteins, and the clinical outcomes of herpesvirus infections range
from subclinical or mild disease to encephalitis, pneumonia, cancer,
33
and various other lethal infections. Herpesviruses have been linked
to morbidity in virtually every organ of the body, including kidney,
liver, pancreas, heart, brain, lungs, stomach, adrenal glands, genitalia,
eye, blood vessels, intestines, joints, skin, and salivary glands.34 The
herpes simplex virus type 1 is associated with atherosclerosis and
various types of neuropathology. Epstein‐Barr virus and cytomegalo-
virus have been implicated in multiple chronic autoimmune diseases,
including systemic lupus erythematosus, rheumatoid arthritis, multi-
ple sclerosis, pemphigus vulgaris, Sjögren's syndrome, and giant cell
arteritis. The Epstein‐Barr virus is also a direct carcinogen in
nasopharyngeal carcinoma, gastric carcinoma, and various lym-
phomas. Cytomegalovirus can cause serious infections in immunolog-
ically immature hosts (eg, newborns with congenital infections) and
in immune‐compromised hosts (eg, HIV‐infected patients and organ
transplant recipients) and may contribute to atherosclerosis.
Atherosclerotic lesions can be produced in chickens by Gallid alpha-
herpesvirus 2 (Marek's disease herpesvirus),35 and in mice by Murid
herpervirus 1 (mouse cytomegalovirus).36 Table 2 provides an over-
view of medical diseases that are verified to have, or strongly sus-
pected of having, a herpesvirus etiology.
4 | HERPESVIRUSES IN PERIODONTAL
DISEASE
The role of herpesviruses in periodontal disease has been an impor-
16,22
tant research topic for the past 20 y. Table 3 shows the summa-
rized prevalence of periodontal herpesviruses from 50 worldwide
studies. Recent publications have corroborated a high prevalence of
5,8,37-51 52
herpesviruses in periodontitis and peri‐implantitis.
Herpesviruses can reach high copy counts in periodontitis
53
lesions. Kubar et al found that subgingival cytomegalovirus copy
counts in viral‐positive sites ranged from 5 × 102
7.4 × 103 copies/mL. Hamdi et al5 detected 7.0 × 105‐ 1.5 × 106
subgingival copy counts of cytomegalovirus in children with type 1
diabetes. Saygun et al 54
found that median copy counts in deep
pockets reached 6.4 × 104/mL (range: 2.1 × 103 ‐ 4.6 × 105/mL) for
cytomegalovirus and 7.1 × 105/mL (range: 2.1 × 103 ‐ 8.3 × 108/mL)
for Epstein‐Barr virus. Sunde et al55 identified Epstein‐Barr virus
copy counts of 3.53 × 10 /mL and 9.26 × 10 /mL in two refractory
5 5
periodontitis lesions. Kato et al56 showed Epstein‐Barr virus in
infected deep periodontal pockets to comprise copy counts of
between 3.74 × 103/mL and 2.83 × 109/mL. Gingival tissue of
AND SLOTS
aggressive periodontitis may contain even higher herpesvirus copy
counts.57,58 In addition, aggressive periodontitis is frequently
infected with 2 or 3 different herpesviruses,42 and tends to harbor
reactivated herpesviruses, whereas nonprogressive chronic periodon-
titis typically contains latent herpesviruses.59 The periodontium of a
single individual can show productive and latent herpesvirus infec-
tions simultaneously.60 Periodontitis patients also exhibit high serum
levels of herpesvirus antibodies and inflammatory mediators.61-63
Comorbidity between periodontitis and various medical20,64,65
and oral66 diseases constitutes one of the most intriguing research
topics of recent years. As argued elsewhere,22 periodontal her-
pesviruses may represent the main link between periodontitis and
systemic diseases. Marginal and apical periodontitis may be the only
body sites in generally healthy individuals that display longstanding
inflammation containing a substantial accretion of reactivated her-
pesviruses capable of entering the systemic circulation and infecting
a variety of organs.67 The close relationship between periodontitis
and several herpesvirus‐related medical diseases is consistent with a
systemic impact of periodontal herpesviruses.64,65
5 | PERIODONTAL TREATMENT
The concept of a herpesvirus‐bacterial etiology of periodontitis
ought to be the foundation for periodontal treatment. Pure mechani-
cal surgical and nonsurgical therapies of the past that targeted bio-
film and calculus yielded an average gain of 1‐2 mm in clinical
attachment, mostly as a result of decreased gingival inflammation
and not of true periodontal regeneration, but generally failed to
arrest disease‐active periodontitis.22 Ramfjord et al25 treated peri-
odontitis patients with (i) scaling and root planing only, (ii) scaling
and root planing + subgingival curettage, (iii) scaling and root planing
+ modified Widman flap surgery, and (iv) scaling and root plan-
ing + pocket reduction surgery; and, after 5 y, in sites with initial
pocket depth > 6 mm, found average clinical attachment gains of (i)
0.59, (ii) 1.04, (iii) 0.63, and (iv) 0.43 mm. In that order, 29.5%,
32.7%, 22.6%, and 18.5% of periodontal sites gained clinical attach-
ment but as many as 14.8%, 10.9%, 8.1%, and 10.8% of sites lost
clinical attachment. Ramfjord et al25 also found that in pockets of
depth 4‐6 mm, 9% of sites gained, but as many as 25% of sites lost,
clinical attachment, mainly as a result of trauma from mechanical
treatment.
to A chemotherapy that has an inadequate spectrum of activity or
fails to reach all pathogens may not halt active periodontitis either.
In a 1‐y study, Haffajee et al68 treated periodontitis patients with (i)
scaling and root planing only, (ii) scaling and root planing + 500 mg
of azithromycin once daily for 3 d, (iii) scaling and root plan-
ing + 250 mg of metronidazole three times daily for 2 wk, and (iv)
scaling and root planing + 20 mg of doxycycline twice daily for
12 wk. In pockets > 6 mm they found average depth reductions of
(i) 1.6, (ii) 2.3, (iii) 3.0, and (iv) 1.6 mm, but also pocket depth
increases in 22%, 12%, 17%, and 15% of the study patients, respec-
tively, and average clinical attachment gains of (i) 1.1, (ii) 1.5, (iii) 2.3,
SLOTS AND SLOTS | 213

T A B L E 2 Herpesviruses in medical diseases and disabilities

Method of Site of initial Treatment (FDA‐approved)
HHV family transmissiona infectiona,b Clinical diseasesb Diagnostic testinga,b a,b

HSV‐1 Close contact Mucoepithelial Gingivostomatitis, herpetic Tzanck smear, cell culture, Acyclovir, valacyclovir,
cells whitlow, herpes gladiatorum, ELISA, immunofluorescent famciclovir, penciclovir,
herpetic keratitis, eczema staining, in situ DNA probe trifluridine
herpeticum, herpes analysis, PCR
encephalitis, genital herpes
HSV‐2 Close contact Mucoepithelial Genital, neonatal herpes virus Tzanck smear, cell culture, Acyclovir, valacyclovir,
cells infection, gingivostomatitis ELISA, immunofluorescent famciclovir, penciclovir,
staining, in situ DNA probe trifluridine
analysis, PCR
VZV Close contact and Mucoepithelial Varicella (chickenpox), herpes Tzanck smear, direct Acyclovir, valacyclovir,
respiratory cells, T‐cells zoster (shingles), interstitial fluorescent antibody to famciclovir, varicella‐zoster
pneumonia membrane antigen test, immune globulin, zoster
PCR, antigen detection immune plasma, live
vaccine
EBV Saliva B‐cells, epithelial Infectious mononucleosis, hairy Heterophile antibody, None
cells oral leukoplakia, Burkitt serologic tests (VCA‐IgM,
lymphoma, Hodgkin lymphoma, VCA‐IgG, EA, EBNA)
nasopharyngeal carcinoma
HCMV Close contact, Monocytes, Heterophile‐negative Hematoxylin‐eosin staining, Ganciclovir, valganciclovir,
body granulocytes, mononucleosis syndrome, PCR, serology, culture foscarnet, trigluridine,
secretions, lymphocytes, congenital infection, (immunocom‐promised) cidofovir
transfusions, and epithelial cytomegalic inclusion body
tissue transplant cells disease, immunocompromised
diseases (pneumonia,
pneumonitis, retinitis, colitis,
esophagitis, transplant failure)
HHV‐6 Saliva T‐lymphocytes Roseola, multiple sclerosis, Serology, PCR, antigen test, Not well established,
chronic fatigue syndrome, culture possibly ganciclovir and
cofactor in pathogenesis of foscarnet
AIDS, transplant failure
HHV‐7 Saliva T‐lymphocytes Roseola Serology None
KSHV Close contact B‐lymphocytes, Kaposi sarcoma, primary Immunofluorescence Culture studies show
oral epithelium, effusion lymphoma, (standard technique), PCR replication inhibition with
peripheral blood multicentric Castleman disease foscarnet being the most
mononuclear effective followed by
cells ganciclovir

EA, Early Antigen; EBNA, Epstein–Barr nuclear antigen; EBV, Epstein‐Barr virus; FDA, The US Food and Drug Administration; HCMV, human cytomegalovirus;
HHV, human herpes virus; HSV, herpes simplex virus; KSHV, Kaposi sarcoma‐associated human herpesvirus; VCA, viral capsid antigen; VZV, Varicella‐Zoster
virus.
a
Murray et al101.
b
Ahmad et al99.

T A B L E 3 Prevalence of subgingival herpesvirusesa

Periodontal status Cytomegalovirus (%) Epstein‐Barr virus (%) Herpes simplex virus‐1 (%)
Aggressive periodontitis 46 52 71
Chronic periodontitis 46 39 36
Healthy periodontium 6 8 6
a 16
Data were combined from Tables 1 and 2 in Slots. The prevalence values represent the median of herpesvirus‐positive subgingival sites in 50 world-
wide studies.

and (iv) 1.1 mm, but also clinical attachment loss in 39%, 32%, 17%, 11.6% of periodontitis sites that had not received any initial or sup-
and 15% of the study patients, respectively. The loss of clinical portive therapy for 6 y.
attachment in the studies by Ramfjord et al25 and Haffajee et al68 Because the overarching goal of periodontitis treatment and the
resembles the findings by Lindhe et al69 of clinical attachment loss in expectation of patients is arrest of periodontal breakdown, the
214 | SLOTS AND SLOTS

T A B L E 4 Treatment of periodontal herpesviruses

Study (authors,
reference Periodontal Periodontal Viral
numbers) diagnosis treatment identification Outcome and comments
Yapar et al 102
Aggressive Widman flap Basic PCR 11 HCMV‐positive sites pretreatment → 0
periodontitis surgery + doxycycline, positive at 3 mo post treatment. 12 EBV‐
100 mg daily for positive sites pretreatment → 1 positive at 3
14 d + SRP mo post treatment. Significant improvement in
all clinical variables.
Jadav et al103 Generalized Widman flap Nested PCR Number of HCMV‐positive sites reduced from
aggressive surgery + doxycycline, 70% to 0%, and number of EBV‐positive sites
periodontitis 100 mg daily for reduced from 50% to 10% at 3 mo post
7 d + 0.2% chlorhexidine treatment
oral rinse twice daily for
2 wk + SRP
Wu et al104 Chronic periodontitis Initial periodontal therapy Nested PCR 21 EBV‐positive sites pretreatment → 9 positive
after initial therapy
Shah and Chronic periodontitis Ultrasonic scaling Multiplex PCR 4 HSV‐1‐positive sites pretreatment →1
Mehta 105 positive at 6 wk post treatment. 7 HCMV‐
positive sites pretreatment → 0 positive at 6
wk post treatment. 1 EBV‐positive site
pretreatment → 0 positive at 6 wk post
treatment.
Grenier et al106 Chronic periodontitis SRP Nested PCR 37 HSV‐1‐positive sites pretreatment → 28
positive at 6 wk post treatment. 6 HCMV‐
positive sites pretreatment → 1 positive at 6
wk post treatment. 25 EBV‐positive sites
pretreatment → 6 positive at 6 wk post
treatment.
Idesawa et al12 Chronic periodontitis SRP Real‐time PCR 11 EBV salivary‐positive sites pretreatment → 5
positive at 6 wk post treatment.
9.46 ± 5.40 × 105/mL salivary EBV counts
pretreatment → 9.01 ± 4.80 × 103/mL salivary
EBV counts post treatment. No reduction in
total bacterial counts. Significant clinical
improvement.
Ding et al107 Chronic periodontitis SRP Nested PCR 14 HCMV‐positive deep lesions pretreatment →
2 positive at 2 mo post treatment. 11 EBV‐
positive deep lesions pretreatment → 0
positive at 2 mo post treatment. Similar results
at 2 wk post treatment.
Kshitish and Chronic periodontitis 0.2% chlorhexidine Multiplex PCR HCMV‐positive subgingival sites reduced from
Laxman 108 subgingival rinse 50% to 0% at 7 d post treatment (small sample
size)
Saygun et al109 Aggressive Widman flap TaqMan® HCMV counts decreased 37.5‐fold in
periodontitis + chronic surgery + SRP real‐time PCR subgingival sites and 64.6‐fold in saliva at 3
periodontitis mo post treatment. EBV counts decreased 5.7‐
fold in subgingival sites and 12.9‐fold in saliva
at 3 mo post treatment.
Saygun et al9 Periodontal abscess Incision and drainage + Basic PCR 12 HCMV‐positive abscesses pretreatment → 0
Widman flap surgery + positive at 4 mo post treatment. 13 EBV‐
doxycycline, 100 mg positive abscesses pretreatment → 0 positive
daily for 14 d at 4 mo post treatment.
Prato et al110 26‐y‐old man, acute Acyclovir for 1 wk Histology + direct Acyclovir treatment cleared an HSV‐acute
gingival recession immunofluorescence gingival infection, and the lesion healed with
no residual gingival recession

(Continues)
SLOTS AND SLOTS | 215

TABLE 4 (Continued)
Study (authors,
reference Periodontal Periodontal Viral
numbers) diagnosis treatment identification Outcome and comments
Hanookai et al111 Trisomy 21 SRP Basic PCR 3 HSV‐1‐positive sites pretreatment → 4
periodontitis positive at 4 wk post treatment. 5 HCMV‐
positive sites pretreatment → 6 positive at 4
wk post treatment. 6 EBV‐positive sites
pretreatment → 4 positive at 4 wk post
treatment.
Yildirim et al112 3‐y‐old and 6‐y‐old SRP + long‐term Real‐time PCR 1 HCMV‐positive (2.7 × 104 counts/mL of
siblings with antibiotic therapy saliva) persons pretreatment → 0 positive at 2
Kostmann syndrome (trimethoprim‐ y post treatment. 2 EBV‐positive
and periodontitis sulfamethoxazole) (2.5 × 106 counts/mL of saliva) persons
pretreatment → 2 positive (2.0 × 104 counts/
mL of saliva) at 2 y post treatment.
Jaramillo et al113 Preeclampsia with SRP Basic PCR 4 HCMV‐positive sites pretreatment → 2
mild‐to‐moderate positive at post partum. 7 EBV‐positive sites
periodontitis pretreatment → 7 positive at post partum.
Pacheco et al114 11‐y‐old girl with SRP + amoxicillin‐ Basic PCR HCMV and EBV were detected pretreatment,
Papillon‐Lefèvre metronidazole therapy but not at 16 mo post treatment. Treatment
syndrome (250 mg of each/3 arrested rapid disease progression.
periodontitis times daily/10 d)
Martelli et al115 Chronic periodontitis Nd:YAG laser Real‐time PCR 11 HCMV‐positive sites pretreatment → 1
positive post treatment. 87 EBV‐positive sites
pretreatment → 19 positive post treatment.
Miller et al88 Recurrent oral HSV Valacyclovir, 2 g twice on Real‐time PCR 29 EBV‐positive salivary samples pretreatment
infections day 1 and 1 g twice the (saliva study) → 18 positive on day 3 post treatment. No
following day change in the placebo group.
Fu et al116 Chronic periodontitis SRP + valacyclovir Clinical Valacyclovir improved clinical outcome
parameters
Sunde et al55 63‐y‐old male, type 2 Valacyclovir, 500 mg, Real‐time PCR EBV in 2 deep pockets (pretreatment copy
diabetes, refractory twice daily for 10 d counts 9.26 × 105/mL and 3.53 × 105/mL)
periodontitis showed no EBV at 1 y post treatment.
‘Dramatically’ improved clinical status.
Hamdi et al5 9‐ to 13‐y‐old children, SRP Real‐time PCR 20 HCMV‐positive sites (average copy counts:
type 1 diabetes, 1.1 × 106/mL) pre‐treatment → 13 positive
gingivitis, and (average copy counts: 867) at 9 mo post
periodontitis treatment. Improvement in periodontal clinical
status and glycosylated hemoglobin level.

EBV, Epstein‐Barr virus; HCMV, human cytomegalovirus; HSV, herpes simplex virus; Nd:YAG, neodymium‐doped yttrium aluminum garnet; SRP, scaling
and root planing.

proclivity for clinical averages to hide great variability and critical
outcomes can create a false perception of therapeutic success, as
demonstrated above. The problem is that a large number of peri-
odontal sites with probing gains (of uncertain clinical significance)
overwhelm the clinical scores of relatively few deteriorating sites.
Rather than relying on averages of mainly surrogate variables, peri-
odontal therapy ought to be evaluated based on the ability to stop
or avoid disease progression in each and every site of a dentition.
Reversal or prevention of disease‐active periodontitis is contingent
upon a marked suppression of periodontal pathogens.
Treatment of severe periodontitis starts logically with her-
pesviruses, as they are initiators of upgrowth of periodontopathic
bacteria.22 Because herpesviruses reside in periodontal inflammatory
cells,70 a mere reduction of gingival inflammation decreases
herpesvirus copy counts. However, localized juvenile periodontitis
and other types of aggressive periodontitis may demonstrate high
levels of herpesviruses but barely detectable inflammation,30 proba-
bly as a result of leukotoxin production by coinfecting Aggregatibac-
ter actinomycetemcomitans,71 suggesting that severe periodontitis
may warrant a more comprehensive treatment than just gingivitis
management. Table 4 shows the efficacy of various treatments
against periodontal herpesviruses. Encouragingly, herpesviral infec-
tions of the periodontium respond to scaling and root planing, anti-
septic treatments and antiviral systemic medication.
A self‐evident truth is that even a perfectly effective therapy
saves no teeth if the treatment is unaffordable or unavailable. To
treat billions of periodontitis patients worldwide, many of whom are
poor, periodontal care must be based on minimal professional
216 | SLOTS
T A B L E 5 Affordable, time‐saving, safe, and effective treatment of severe/disease‐active periodontitis
Time Treatment
Day 0 10% povidone‐iodine subgingival irrigation for 5 min
Day 0 Gross scaling with ultrasonic instrument
Day 0 10% povidone‐iodine subgingival irrigation for 5 min
Day 0 Systemic valacyclovir, 500 mg, twice daily for 10 d
Day 0 0.1%‐0.25% sodium hypochlorite (dilute regular household bleach)
oral rinse for 30 s twice weekly (patient self‐care)
Day 10 10% povidone‐iodine subgingival irrigation for 5 min
Day 10 Definitive scaling and root planing
Day 10 Amoxicillin+metronidazole or ciprofloxacin+metronidazole
Day 10 Patient self‐care: instruction in oral hygiene, including oral rinsing
with 0.1%‐0.25% sodium hypochlorite (dilute regular household
bleach) for 30 s twice weekly
intervention and rely heavily on patient self‐care. Such therapy for
severe periodontitis, which is outlined in Table 5, would specifically
target herpesviruses (valacyclovir/acyclovir) and periodontopathic
bacteria (amoxicillin+metronidazole, ciprofloxacin+metronidazole),
and apply common antiseptics (povidone‐iodine, sodium hypochlo-
rite) plus ultrasonic scaling. The proposed therapy employs inexpen-
sive antimicrobial agents and is readily implemented in clinical
practice and patient self‐care. The 2‐visit treatment described below
can be performed in approximately 2 h. The entire therapy may even
be carried out in 1 session, rather than in 2, by administering valacy-
clovir and bacterial antibiotics concomitantly, but initial heavy gingi-
val bleeding may complicate calculus identification and removal.
The suggested therapy targets periodontal pathogens in subgingi-
val sites, within gingiva, and in major ecosystems of the mouth, and
includes overlapping and duplicating treatments, each of which
shows effectiveness against herpesviruses and/or pathogenic bacte-
ria.72 Irrigation of periodontal pockets with povidone‐iodine helps to
73,74
reduce the number of subgingival pathogens. Povidone‐iodine is
applied to the base of periodontal pockets of both scaled and non-
scaled sites, using, for example, a 3‐mL endodontic syringe with a
23‐gauge cannula having a blunt end and side ports. A single course
of subgingival iodine irrigation of the entire dentition takes about
1.5 min and is performed 3 times for a total application time of
5 min. Systemic valacyclovir (500 mg twice daily for 10 d) has the
potential to eliminate high loads of herpesviruses in deep periodontal
55 57,58,75-77
pockets and within inflamed gingiva. Herpesviral
chemotherapeutics are effective against viruses in the lytic phase
but presumably not in the latent phase, which basically limits the use
AND SLOTS
Purpose/Comments
To reduce introduction of viruses and bacteria into the
bloodstream during scaling
To reduce subgingival calculus and biofilm to diminish gingival
bleeding in order to facilitate detection and thorough removal of
calculus on day 10 (see below)
To reduce remaining viruses and bacteria post scaling
Antiviral drug for treatment of herpesvirus infections. May be
substituted by less expensive acyclovir. As herpesviruses trigger
bacterial upgrowth, antiviral therapy is carried out first.
Sodium hypochlorite is highly effective in removing and preventing
dental biofilm and gingival inflammation (bleeding)
To reduce introduction of viruses and bacteria into the
bloodstream during scaling
Scaling and root planing only in sites with verified calculus or
suspicion of calculus (antiseptics and antibiotics are used to
remove periodontal pathogens in nonscaled sites)
Amoxicillin+metronidazole (250 mg of each, 3 times daily for 8 d)
for young and middle‐aged patients. Ciprofloxacin+metronidazole
(500 mg of each, twice daily for 8 d) for older patients and for
patients in developing countries.
Oral rinsing with sodium hypochlorite (used long term) to reduce
dental biofilm buildup and prevent gingival inflammation
of valacyclovir to disease‐active periodontitis. Antibiotic therapies for
bacterial pathogens consist of the combinations amoxicillin+metron-
idazole (250 mg of each, 3 times daily for 8 d) for young to middle‐
aged patients, and ciprofloxacin+metronidazole (500 mg of each,
twice daily for 8 d) for patients allergic to penicillin or for older
patients and patients in developing countries who frequently harbor
subgingival enteric rods.72,78,79 Patient self‐care includes oral rinsing,
twice weekly for 30 s, with freshly prepared sodium hypochlorite.
Sodium hypochlorite is readily available as household bleach, and
0.165% sodium hypochlorite can be obtained by adding 1 teaspoon
(5 mL) of 8.25% Regular Clorox Bleach© to a large glass (250 mL =
8.5 oz) of water. Sodium hypochlorite exerts strong antimicrobial,
antibiofilm, and anti‐inflammatory effects80-84 and, because of its
nondiscriminative action of killing, does not induce pathogenic super-
infections and may even promote a healthier oral microbiota because
of rapid post‐treatment repopulation of indigenous/low virulence
bacteria relative to pathogenic species. Overuse or a high concentra-
tion of sodium hypochlorite may produce brownish/black extrinsic
tooth staining in some individuals.
Valacyclovir and acyclovir are acyclic nucleoside analogues that
inhibit herpesviral DNA polymerase and thus replication of the viral
genome. Valacyclovir is an orally administered acyclovir prodrug pro-
viding greater oral bioavailability than acyclovir, and is particularly
effective against herpes simplex viruses, varicella‐zoster virus, and
Epstein‐Barr virus.85 Prolonged treatment with valacyclovir at
dosages of 500‐1000 mg/d is well tolerated in immunocompetent
individuals, and adverse events are infrequent and generally mild,
with headache reported most often.86 Resistance to valacyclovir is
SLOTS AND SLOTS
not yet of major clinical significance.87 Valacyclovir treatment, in
addition to eliminating periodontal herpesviruses55 can also decrease
the salivary herpesviral load and potentially prevent herpesvirus
transmission to other individuals. A short course of valacyclovir, of
2 g twice on the day of treatment and 1 g twice the following day,
resulted in a significant decrease in salivary Epstein‐Barr virus level
compared with controls.88 Valacyclovir, 500 mg orally twice daily for
1 mo, reduced the salivary load of Epstein‐Barr virus by 82% com-
pared with placebo.89 Valacyclovir therapy, 3 g/d for 14 d, resulted
in >100‐fold reduction of Epstein‐Barr virus genome copies in the
oral wash fluid of patients with acute infectious mononucleosis.90
6 | CONCLUDING REMARKS
Herpesviruses in periodontal disease has been a research topic in
more than 30 countries since the first publications appeared in the
mid‐1990s.91,92 Disease‐active periodontitis is associated with, and
probably caused by, reactivated herpesviruses, specific bacteria, and
destructive immune reactions. Periodontal therapy that does not tar-
get the specific etiology of periodontitis may produce little or no
clinical improvement. Herpesviruses may persist in periodontal sites
for extended periods of time and pose an ongoing risk for disease
progression, making prevention the key. Preemptive and curative
treatments of periodontal herpesviruses are surprisingly simple.
Effective antigingivitis treatment averts herpesviruses, residing in
inflammatory cells70, from entering the periodontium, and a number
of anti‐infective therapies can reduce or eradicate herpesviruses in
periodontitis lesions (Table 4).
Current periodontal treatments differ in cost and effectiveness.
Traditional periodontal surgery for curative purpose is a high‐cost
mode of treatment of dubious effectiveness. Inappropriate surgery is
not inconsequential; besides failing to resolve active periodontitis, it
consumes limited healthcare funds, and concerns about cost and the
discomfort of surgery may lead patients to forgo professional peri-
odontal care. Scaling and root planing can reduce gingivitis and is more
justifiable, but its ability to halt active periodontitis is in serious
doubt.68 While pure mechanical treatment cannot be relied upon to
arrest active periodontitis,93 mechanical depuration combined with
antiseptics and systemic antibiotics,94-96 and even treatments using
only dilute bleach oral rinse80,81,97 or systemic amoxicillin + metron-
idazole,98 have shown promising effectiveness. A combined mechani-
cal‐chemotherapeutic treatment, or perhaps chemotherapy alone, may
suffice to arrest progressive periodontal disease. Complete removal of
subgingival calculus is not always attainable and may not be essential
to stop active periodontitis. Randomized controlled clinical trials in
pertinent patient populations are obviously needed to assess the effi-
cacy of various types of periodontal antimicrobial treatment. Text-
books and professional organizations rarely include effectiveness,
affordability, and quality of life in guidelines on periodontal therapy,
but new inexpensive treatments have made cost‐benefit comparisons
among therapies increasingly useful and necessary.
| 217
To sum up, the failure of purely mechanical treatment to halt
active periodontitis is a therapeutic issue too important to ignore.
However, a relatively simple ‘cure’ may be available for progressive
periodontal disease. Select subgingival scaling and the use of inex-
pensive antiseptics and systemic chemotherapy against periodontal
herpesviruses and bacterial pathogens may suffice to arrest active
periodontitis. The notion of a periodontopathic role of herpesviruses
is poised to provide a new guideway for controlling periodontitis
and perhaps certain medical diseases. Knowledge of periodontal her-
pesviruses may constitute an inflection point in the science and
practice of periodontology.
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How to cite this article: Slots J, Slots H. Periodontal
herpesvirus morbidity and treatment. Periodontol 2000.
2019;79:210–220. https://doi.org/10.1111/prd.12241