Received: 15 October 2023 | Revised: 21 December 2023 | Accepted: 14 January 2024

DOI: 10.1111/prd.12553

REVIEW ARTICLE

The role of viruses in oral mucosal lesions

Henrik Dommisch | Andrea Maria Schmidt-­Westhausen

Department of Periodontology, Oral

Medicine and Oral Surgery, Charité –
Universitätsmedizin Berlin, Corporate
Member of Freie Universität Berlin and
Humboldt Universität zu Berlin, Berlin,
Germany
Correspondence
Henrik Dommisch, Department of
Periodontology, Oral Medicine and Oral
Surgery, Charité – Universitätsmedizin
Berlin, Corporate Member of Freie
Universität Berlin and Humboldt
Universität zu Berlin, Berlin, Germany.
Email: henrik.dommisch@charite.de
Abstract
The mucosa of the oral cavity is exposed to a large number of different microorgan-
isms such as archaea, bacteria, fungi, parasites, and viruses. Among those, viruses
cause specific infections, which can easily be transmitted from one person to another.
The infectious route may not only include patients and their relatives but also the
dental professional team. Thus, a wide knowledge regarding specific viral infections
is crucial for the daily routine. Signs and symptoms of oral viral infections can be
completely absent or develop into a pronounced clinical picture, so that early detec-
tion and information determine the further course of the infection and its influence
on other inflammatory diseases, such as periodontitis, as well as the safety of family
members and the social environment. As the clinical manifestation of viral infections
may be highly variable leading to heterogenous mucosal lesions it is, in most cases,
mandatory to differentiate them by specific microbiological tests in addition to clini-
cal examination procedures. This article will give an overview of the role of viruses
infecting the oral mucosa, and in addition, describe their clinical manifestation and
management.

KEYWORDS
condyloma acuminatum, COVID-­19, cytomegalovirus, Epstein–Barr virus, focal epithelial
hyperplasia, herpes simplex virus, human herpes virus, human papillomavirus, Monkeypox, oral
mucosa, Sars-­COV-­2, varicella zoster virus, virus

1 | I NTRO D U C TI O N
Various viruses, such as the well-­known human herpes viruses (HHV),
but also recently discovered viruses, such as Sars CoV-­2, can infect the
oral mucosa resulting either in disease manifestation or in the spread of
viruses through, for example, saliva.1 The clinical manifestation of viral
infections of the oral mucosal tissues ranges from small inconspicuous
spots, redness, swelling, blistering, and ulcerations to hyperkeratotic
changes which may complicate the clinical diagnosis by sole clinical ex-
amination. Thus, an accurate diagnosis of viral diseases is usually only
possible with the aid of additional laboratory tests, and therewith, the
actual validation of the causative microorganism.2
For the affected patients, clinical signs and symptoms can vary
tremendously. Similar to the clinical appearance, some patients
perceive no symptoms directing to an infectious disease, whereas
others may experience severe pain and physical disabilities. In
this context, patients may be extremely worried, and hence, an
adapted medical-­psychological advice could be necessary. While
some viral infections may even disappear spontaneously, others
are recurrent, and therewith, affect the patient lifelong. Those
patients require a specific education regarding potential compli-
cations and risks associated with the virus infection as well as with
the potential viral tissue damage. In some cases, patients need ad-
ditional advice regarding their nutritional behavior. In the same

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2 DOMMISCH and SCHMIDT-­WESTHAUSEN

context, it is also important to address further influencing envi-
ronmental factors, such as smoking, alcohol, and stress, that foster
inflammatory reactions and simultaneously hinder wound healing
processes in the oral cavity. 3
In addition, it has been shown that intraoral viral infections
can be associated with periodontitis, a common complex inflam-
matory disease of the oral cavity, which is also considered a con-
dition belonging to the chronic noncommunicable diseases.4-­14
The affected patients require not only profound management
of the viral infection but also a systematic stepwise periodon-
tal therapy following the recently implemented clinical practice
guidelines.15,16
In this article, types, epidemiology, clinical manifestations, and
management of common and new orofacial infections of viral origin
will be presented.
2.1.2 | Clinical features—oral manifestations
The herpes virus is mainly located in structures of the ectoderm,
such as skin mucosa, eyes, and the central nervous system (CNS).
Experimental studies have shown that latent HSV infection can also
be present in epithelial cells.18 Any epithelial cell, including oral epi-
thelial cells, may be infected by HSV-­1. The virus enters epithelial
cells by binding to heparan sulfate proteoglycans (HSPGs) on the
cell surface due to the viral glycoproteins B, C, and D (gB, gC, and
gD). Glycoprotein D than binds to the epithelial receptors nectin-
­1 or nectin-­2, which leads to mechanisms allowing for entrance of
the viral capsid and tegument into the cytoplasm. 21 If the epithelial
structure is not intact (due to injuries or even other viral infections,
such as HIV) and adherens junctions are disrupted, nectin-­1 may
be widely exposed leading to increased binding of HSV-­1 and even
wide-­spread to cells showing intact adherens junctions. 22

2 | H E R PE S S I M PLE X V I RU S

2.1 | HSV primary infection

2.1.1 | Epidemiology

HSV-­1 is more persistently present in humans than any other virus.

Primary infection with HSV 1 occurs in early childhood is often
asymptomatic or manifests as acute gingivostomatitis (gingivosto-
matitis herpetica), it is most commonly seen in children between
the ages of 2 and 4 years. Epidemiological studies have shown that
the median age of patients has exceeded 10 years.17 Antibodies
are activated, but definitive elimination of the virus after primary
infection is not achieved. As for viral persistence, 20%–40% of
the population suffer from recurrent clinical infection, and HSV-­1
antibodies are detectable in 70%–90% of adults.18 Since the virus
is not completely eliminated by the host's immune response, re-
activation, and thus, recurrent clinical symptoms are possible.
However, the latency is dependent on the individual CD8 + T cell
response as those cells is critical for regulation of HSV latency by
inhibiting viral reactivation, and therewith, promoting total anti-
genic shutdown.19,20
The age distribution of primary HSV-­2 infection reflects the
onset of sexual activity. HSV-­2 causes oral changes in addition
to genital efflorescences in 10%–20% of the population. On the
other hand, 15%–30% of primary genital infections are caused
by HSV 1. Oral and genital infections with one or both herpes
simplex viruses (HSV) may occur simultaneously, although a pre-
vious HSV-­1 infection appears to be protective against genital
infection.1
Transmission of HSV occurs through direct contact with saliva
or through objects contaminated with the saliva of a virus shedder.
The cause of infection in children is usually a parent with an active
F I G U R E 1 Clinical manifestation of recurrent Herpes simplex
herpetic lesion. Replication-­competent HSV is detectable in saliva in
infection. Redness, swelling, and fibrin coating at (A) the lower lip
1%–10% of all adults. The herpes virus is mainly located in structures and (B) the posterior hard palatum as clinical signs of recurrent
derived from the ectoderm (Figure 1A). However, an intact epithe- H. simplex infection in the region of (A) a branch of the Nervus
lium provides an effective barrier to HSV infection. mentalis and (B) the Nervus palatinus major.

DOMMISCH and SCHMIDT-­WESTHAUSEN
Many infections with HSV are subclinical. The most common
clinical manifestations of primary HSV-­1 infection are stomatitis and
pharyngitis, yet HSV 2 may also play a role in some cases. Primary
herpetic gingivostomatitis manifests both locally and systemically.
Patients (usually children or young adults) present with fever, ca-
tarrh, and malaise; symptoms may resemble the prodromal stages
of influenza; radiculo-­meningoencephalic involvement is possible.
Usually, the lymph nodes are swollen and painful. After 1–2 days,
small vesicles between one and several millimeters in diameter may
appear on the gingiva, hard palate (Figure 1B) and the entire oral
mucosa as well as within the vermillion border of the lips. The vesi-
cles burst and become irregular painful ulcers. Increased salivation,
foetor ex ore, bleeding tendency, and inability to eat are symptoms
of the infection. In otherwise healthy individuals, healing without
scarring occurs in the period between 10 and 14 days. Recurrence of
an acute gingivostomatitis does not occur.
HSV 1 has been detected in 72%–78% of patients with rapidly
progressive periodontitis (juvenile periodontitis, aggressive peri-
odontitis), whereas HSV 2 was found in 17% of those patients.12,14 An
association of periodontal pathogens such as Porphyromonas gingiva-
lis, Tannerella forsythia, and Prevotella intermedia with the presence of
12
HSV 1 was found. A meta-­analysis from case–control studies re-
vealed a significant association between HSV 1 and aggressive peri-
odontitis suggesting a contribution of HSV 1 in the etiopathogenesis
of periodontitis.5,9 Here, HSV 1 may facilitate the development of
the microbial dysbiosis in the context of polymicrobial microbio-
logical changes triggering periodontal inflammation, and perhaps,
exert synergistic interactions with pathogenic periodontal bacte-
ria.5,7 The above-­mentioned disruption of the epithelial tissue due
to periodontitis may also allow for exposure of nectin-­1, and thus,
an easier entry of HSV 1 into epithelial cells. Hence, periodontal im-
mune responses may be further accelerated in patients with juvenile
(molar-­incisor pattern) periodontitis, which may be interpreted as a
link between both bacterial and viral factors in the etiopathogenesis
of fast progressing periodontitis. 23
2.1.3 | Management
Treatment for primary infection is palliative and maybe supported
by hydration, fever, and pain management (analgesics, antipyretics),
and topical anesthetics. If started within 24 h, antiviral therapy with,
for example, acyclovir, famciclovir, or valaciclovir reduces symptoms
and prevents spreading. So far, a vaccination against the acquisition
of HSV 1 is not available.
2.2 | HSV reactivation
2.2.1 | Epidemiology
In a prospective population-­based study among individuals from
Norfolk/England aged 40–79 years, 17.63% experienced frequent
|
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3
oro-­labial reactivation. 24 This figure does not differ from a Swedish
study by Axéll from 1976, who reported a value of 17% in the 2-­year
medical history. 25 In Germany, the prevalence was stated at 32%
in people aged between 35 and 44 years, and 20% in those aged
65–74. 26
2.2.2 | Clinical features—oral manifestations
The clinical features of reactivated HSV infection are usually found
at the mucocutaneous junction of the lips (labial herpes, Figure 1A).
In leukemic patients or immunosuppressed individuals, these lesions
are also found intraorally. Lesions in immunocompetent patients
tend to be localized on the lip and not intraorally. If they do occur
intraorally, they are typically located on the hard palate or gingiva.
Secondary recurrent infections are fostered by trauma, immune de-
ficiency (HIV infection, iatrogenic immunosuppression), menstrua-
tion, pregnancy, allergy, sunlight exposure, emotional stress, and
upper respiratory tract infections. Intraoral herpes infection is dif-
ficult to distinguish from the herpetiform type of recurrent aphthae
or other ulcerative viral infections.
2.2.3 | Management
As with primary infection, recurrent infections in immunocompe-
tent patients are treated symptomatically. Symptomatic treatment
may be performed by prescription of nonsteroidal anti-­inflammatory
drugs, such as ibuprofen. Topical application of acyclovir may also
be suitable, but only in the early stage of recurrence. Only in im-
munocompromised individuals and in case of severe and painful
recurrences antiviral therapy, for example, systemic application of
acyclovir, is required.
3 | VA R IZE LL A ZOS TE R V I RU S
3.1 | Primary infection: Varicella (chickenpox)
3.1.1 | Epidemiology
Primary infection with varicella zoster virus (VZV) leads to the so-­
called chickenpox (varicella). It is one of the pediatric diseases due
to school contact and highly transmissible, with an infection rate of
90% in close contacts, therefore, most individuals become infected
before adulthood. 27 VZV is an exclusively human pathogen.
3.1.2 | Clinical features—oral manifestations
Chickenpox are characterized by exanthema, enanthema, and oral ulcers
of the buccal mucosa, gingiva, and palate. The lesions resemble aphthous
ulcers but are comparatively painless. Immunosuppressed individuals,
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4 DOMMISCH and SCHMIDT-­WESTHAUSEN
babies and pregnant women never exposed to HHV3 before, are at in-
creased risk of developing severe forms of varicella. VZV remains latent
in the ganglia and can be reactivated particularly in elderly patients and
immunocompromised, for example, patients after organ transplantation,
HIV-­positive persons and patients with leukemia.
3.1.3 | Management
Clinical features of chickenpox are pathognomonic, and manage-
ment is only symptomatic (bed rest, fever control by paracetamol,
hydration, lukewarm baths, and lotions to reduce itching). In severe
cases, antiretroviral therapy is advised. 28
3.2 | Reactivation: Herpes zoster (shingles)
3.2.1 | Epidemiology
VZV may reactivate at an advanced age in about one third of
the affected patients. The individual lifetime risk of developing
herpes zoster is between 20% and 30% and is increasing for pa-
tients at the age of 85 or older, with an incidence of 50%. In a
Swedish study by Nilsson et al., 29 the incidence of herpes zoster
was estimated to numbers ranging between 315 and 577 cases per
100 000 citizens.
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3.2.2 | Clinical features—oral manifestations
Exanthema occurs in spread of the nerve (Figure 2A–D), accompa-
nied by neuralgia and pain, which may persist after the exanthema
has resolved.30 If the maxillary or mandibular branch of the trigemi-
nal nerve is involved, unilateral oral ulcers appear in 15% of cases31
(Figure 2C,D). The pain caused by trigeminal VZV infection may
mimic toothache (Figure 2C).
3.2.3 | Management
Herpes zoster is treated with antivirals and analgesics. However,
treatment should be started within 48 h of the appearance of ef-
florescences, but no later than 72 h.
Systemic intravenous treatment is recommended for immu-
nocompetent patients with moderate or severe pain, nontruncal
involvement, severe rash, and age older than 50 years, as well as
immunocompromised patients and patients with CNS, visceral or
disseminated infections.
3.3 | Prevention and vaccination
Vaccination against varicella is recommended by the Standing
Commission on Vaccination (STIKO) from the 11th month of life.
F I G U R E 2 Clinical manifestation of
various Herpes zoster infections. (A) and
(B) Skin efflorescence in the innervation
area of V2 (Nervus maxillaris, right face);
(C) intraoral lesions prominent at the
hard and soft palatum; (D) intraoral
manifestation at the buccal mucosa in the
innervation region of V2 (N. maxillaris, left
face).

DOMMISCH and SCHMIDT-­WESTHAUSEN
Two mono-­v aricella vaccines (e.g., Varilrix®, Varivax®) are ap-
proved, which can be vaccinated in early childhood. Vaccination
does not only prevent harmless chickenpox but also the complica-
tions of VZV infection such as perinatal chickenpox (lethality of
up to 30% for the child), congenital chickenpox, which can lead to
serious developmental disorders of the unborn child, chickenpox
meningitis with possible neurological deficits, the rare but serious
varicella pneumonia and the reactivation of the virus with gen-
eralization or involving major organs (CNS, sensory organs, optic
nerve, inner ear, etc.).
Since 2006, a live vaccine (Zostavax®) has been approved for
vaccination from the age of 50 against the virus. It is intended
to reduce the risk of herpes zoster in risk groups, even after pri-
mary infection has occurred. However, Zostavax® is not recom-
mended as a standard vaccination by the Standing Committee on
Vaccination “STIKO” due to its limited efficacy and its limited du-
ration of action. 32
As of December 2018, the Standing Committee on Vaccination
recommends vaccination with an adjuvanted herpes zoster subunit
dead vaccine (Shingrix®) to prevent herpes zoster and postherpetic
neuralgia (PHN) in all persons 60 years of age and older (standard
vaccination). For persons with underlying disease or immunodefi-
ciency, the Commission recommends vaccination as early as age 50
(indicated vaccination).33
4 | OTH E R I N FEC TI O N S BY H U M A N
H E R PE S V I RU S E S
Viruses of the herpes group cause a number of vesicular oral mucosal
lesions (Table 1). All herpesviruses have a propensity for subclinical
infection, latency period after initial infection, and reactivation. The
most important herpesviruses for humans include herpes simplex
virus types 1 and 2 (HSV 1, HSV 2), herpes zoster virus, Epstein–
Barr virus (EBV), and cytomegalovirus (CMV). In 1994, a new herpes
TA B L E 1 Overview of human herpes viruses and their corresponding diseases.
Subfamily Genus
α-­V irinae HHV1 Herpes simplex virus 1 (HSV1)
HHV2 Herpes simplex Virus 2 (HSV2)
HHV3 Varicella zoster virus (VZV)
γ-­V irinae HHV4 Epstein Barr virus
β-­ Virinae HHV5 Cytomegalovirus
γ-­V irinae HHV6
HHV7
HHV8 Kaposi's sarcoma herpes virus (KSHV)
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5
virus, human herpes virus 8 (HHV-­8) has been detected in Kaposi's
sarcomas of HIV-­infected individuals.34 There are many common
features within the HHV group, which can complicate differential
diagnosis.
4.1 | Epstein–Barr virus
4.1.1 | Epidemiology
EBV is common in the normal population, with antibodies detect-
able in approximately 90% of adults. In vivo, infection is limited
to two target cells, the epithelial cells of the oro-­naso-­p haryngeal
region or/and the salivary gland epithelium and B-­lymphocytes.
Saliva is the only body fluid that contains replication-­competent
viral particles. Immunological parameters control the balance be-
tween chronic viral replication in the oropharynx and the popu-
lation of EBV-­infected transformed B-­lymphocytes, which have
unlimited growth potential.1 There is strong evidence that EBV is a
major co-­f actor for endemic Burkitt's lymphoma and nasopharyn-
geal carcinoma. 35
4.1.2 | Infectious mononucleosis (Syn.: Glandular
fever)
Clinical features—oral manifestations
This viral infection leads to hyperplasia and hypertrophy of the
lymphatic tissue with characteristic changes in the blood count;
generalized swelling of the lymph nodes with diphtheria-­like ton-
sillitis is typical. However, the coatings tend to be dirty gray and
do not spread to the area around the tonsils. Generally, patients
are in a relatively good general condition. In 25% of patients,
sharply circumscribed petechiae are found at the transition from
the hard to the soft palate, which develop symmetrically during
Disease
Gingivostomatitis herpetica
Herpes labialis/genitalis, rare: Vulvovaginitis herpetica, herpes corneae
Herpes genitalis/labialis
Gingivostomatitis herpetica
Vulvovaginitis herpetica, herpes corneae
Varicella (chickenpox), zoster (shingles)
Infectious mononucleosis
Burkitt's-­lymphoma
Oral hairy leukoplakia
Inapparent in immunocompetent, in immunocompromised individuals:
(chorio-­)retinitis, pneumonia, hepatitis, splenomegaly
Erythema subitum in 1st and 2nd year of life
Probably asymptomatic, no disease known
Viral-­DNA-­sequences in Kaposi's sarcoma cells
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6 DOMMISCH and SCHMIDT-­WESTHAUSEN
the disease. Likewise, acute ulcerative gingivitis and/or stomatitis
36
may develop.
EBV-­1 has been detected in 63.6%–72.2% of patients with rap-
idly progressive periodontitis (juvenile periodontitis, aggressive
periodontitis).12,14
Management
The prognosis of acute disease is good; in patients with cellular im-
munodeficiency reactivation of EBV occurs on the oral mucosa in
the form of hairy leukoplakia or leads to localized or systemic lym-
phoproliferative disease.
Reactivation: Oral hairy leukoplakia
Oral hairy leukoplakia (OHL) takes on a special significance among
viral infections, since it is considered a marker of the Acquired
Immunodeficiency Syndrome (AIDS). OHL was first observed
in San Francisco in 1984, mainly in men who have sex with men
(MSM). 37
Clinical features—oral manifestations. Clinically white, this lesion
cannot be wiped off and is usually seen on the lateral margin of
the tongue (Figure 3). The surface is corrugated, in cases where it
occurs on the undersurface of the tongue or buccal mucosa it may
be homogeneous. While OHL was previously considered to be a
pure AIDS-­a ssociated opportunistic infection, it has been known
that it is not a specific sign of HIV infection but can be observed
in the setting of other immunosuppressive conditions as well. 38-­4 0
Although the histological characteristics (hyperparakeratosis
with ballooned cells in the epithelium, lack of inflammatory
reaction in the connective tissue, reduction of Langerhans' cells)
have been described, difficulties often arise in the context of
morphological diagnosis. Various detection methods (electron
microscopy, in situ hybridization, immunohistochemistry) must
be used to detect Epstein–Barr virus in order to make a definitive
diagnosis.
F I G U R E 3 Clinical manifestation of an oral hairy leukoplakia
(OHL) with a prominent corrugated surface the togue mucosa and
the mucosa of the floor of the mouth.
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Management. Although EBV-­associated, OHL does not develop
features of oral potentially malignant disorders. Therapy is not required.
4.2 | Cytomegalovirus infections—HHV5
4.2.1 | Epidemiology
CMV is an important pathogen of immunocompromised individuals,
including HIV patients, organ transplant recipients, and neonates.
In HIV patients in the state of immunosuppression, reactivation
of the endogenous virus may occur after initial infection (transmis-
sion by blood products, less so from person-­to-­person).
4.2.2 | Clinical features—oral manifestations
Previously, CMV was thought to rarely cause oral mucosal changes
(Figure 4). However, it has been shown that CMV DNA has been isolated
from chronic ulcers of the oral mucosa of HIV-­seropositive and HIV-­
seronegative individuals, and that in HIV-­seropositive patients dissemi-
nated CMV infection may manifest as an ulcer on the oral mucosa.1,41,42
HCMV has been identified in 63.3% to approximately 72% of pa-
tients with rapidly progressive periodontitis (juvenile periodontitis,
aggressive periodontitis).10,12,14 In a meta-­analysis from case–control
studies, a significant association was reported for HCMV and ag-
gressive periodontitis.9
4.2.3 | Management
Ganciclovir is used for immunosuppressed or immunodeficient in-
dividuals with life-­threatening illnesses. Valganciclovir is a pro-­drug
that gets converted into ganciclovir but is better absorbed orally
than ganciclovir. However, therapeutic efficacy is often diminished
by the emergence of drug-­resistant viral isolates.
Foscarnet or cidofovir are administered only to patients with CMV
resistant to ganciclovir, due to foscarnet's high nephrotoxicity.43
F I G U R E 4 Intraoral manifestation of a Cytomegalovirus
infection at the mucosa of the right togue.
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DOMMISCH and SCHMIDT-­WESTHAUSEN 7

4.3 | Human herpes virus 8 (Kaposi's sarcoma

herpes virus, KSHV)—HHV8

4.3.1 | Epidemiology

Viral etiology of HIV-­

associated Kaposi sarcoma (KS) has been
confirmed by the detection of DNA sequences of HHV 8 by
polymerase chain reaction. 34,44,45 Although the incidence of KS
in HIV-­positive persons is decreasing, the literature is revealing
subpopulations where it is still an issue.46 Thus, of 4455 KS cases
identified in men younger than 55 years in the US, the incidence
significantly decreased for white men between 2001 and 2013.
Among African-­A merican men in the South of the US, however, the
incidence has significantly increased between 2000 and 2013. This
indicates that geographic and racial disparities in KS incidence and
survival exist.47

4.3.2 | Clinical features—oral manifestation

Oral KS most often affects the hard and soft palate (Figure 5A), gin-
giva, and dorsal tongue (Figure 5B) with plaques or tumors of col-
oration ranging from nonpigmented to brownish-­red or violaceous.
While often appearing as flat, patchy lesions in the early stages, they
can develop distinct round, blue-­red, often ulcerated, bleeding tu-
mors in the late stages.48

4.3.3 | Management

Treatment strategies in oral KS range from no intervention for lim-
ited asymptomatic lesions, to local or regional therapy for focal or
extensive regional involvement, modification of immunosuppressive
regimens in iatrogenic cases, the institution of combined antiret-
roviral therapy (cART) for epidemic variants, and systemic chemo-­
therapy for widespread disease or endemic KS.48
5 | M O N K E Y P OX
5.1 | Epidemiology
Monkeypox (MPX) caused by the MPX virus is a disease mainly
restricted to African regions. In recent years, sporadic out-
breaks have been reported outside the virus's endemic region.
In a concise review, Samaranayake et al. reported that the lat-
ter was predominantly diagnosed among men who have sex with
men (MSM), with most cases occurring in Europe, North America,
and Australia.49 So far, only 19 cases of this disease have been
50
transmitted from women in Germany. Human-­to-­h uman trans-
mission can occur through contact with an infected person's
respiratory droplet, wound lesions, body fluids or contaminated
personal objects. 51
F I G U R E 5 Intraoral lesion of an HIV-­associated Kaposi sarcoma
(Human herpes virus 8, HHV8). (A) Manifestation at the hard and
soft palatum and (B) the tongue mucosa.
5.2 | Clinical features—oral manifestations
After an incubation period of 7–14 days, the early phase of the disease
is characterized by fever, headache, pain, fatigue, and lymphadenop-
athy. In the second phase which lasts over a period of 2–3 weeks, the
symptoms are followed by a rash spreading in a centrifugal manner.
Features of MPX on the oral mucosa include macules and vesicles,
lips may also be affected. With respect to oral mucosal lesions, it is
of interest that the primary lesions derive in the oropharynx prior to
skin involvement. One study reported that oral ulcers were present
in 23.5% of participants with MPX.52 In a small subset of patients,
the mucocutaneous rash is the only manifestation of MPX.51
5.3 | Management
MPX is a self-­limiting infection; the management is symptomatic for
no specific antiviral agents are available by November 2022. In pa-
tients with comorbidities, the antiviral agents cidofovir, brincidofovir,
 |
8 DOMMISCH and SCHMIDT-­WESTHAUSEN
and tecovirimat which have certain activity against MPX could be
53
prescribed. To prevent secondary bacterial infection, such as skin
infections, pneumonia, and conjunctivitis, administration of antibiot-
ics may be necessary.
In the U.S., a vaccine for MTX is already approved for the treat-
ment against monkeypox in adults aged 18 and older under the name
Jynneos®. Currently, this product is being supplied and used for
vaccination in the European Union.54 In the EU, a vaccine under the
name Imvanex® is currently not approved for use against MPX, in-
oculation of this vaccine against MPX is an off-­label-­use application.
A corresponding approval to extend the field of application to MPX
is in preparation.54
6 | COV I D -­1 9
6.1 | Epidemiology
Covid-­19 is an infectious virus caused by SARS-­CoV-­2. The first
known outbreak of the pandemic started in Wuhan, Hubei, China,
in November 2019. Globally, a large and still increasing number of
confirmed SARS-­CoV-­2 infections and associated death due to
55
COVID-­19 were and are, respectively, reported to the WHO. The
mode of transmission occurs in three principal ways: (1) inhalation of
respiratory droplets and aerosol particles; (2) deposition of respira-
tory droplets and particles on exposed mucous membranes in the
mouth, nose, or eye by direct splashes and sprays; and (3) touch-
ing mucous membranes with hands contaminated either directly by
virus-­containing respiratory fluids or indirectly by touching contami-
nated surfaces.56
6.2 | Clinical features—oral manifestations
Characteristic manifestations appear between 2 and 14 days after
exposure to the virus, they range from asymptomatic infections to
severe respiratory syndromes. The exact pathogenesis of these oral
symptoms is not known. Angiotensin-­converting enzyme 2 (ACE2)
cell receptors are expressed in abundance on oral mucosa allowing
severe acute respiratory syndrome-­coronavirus-­2 (SARS-­CoV-­2) to
infect them.57 Dermatologic changes including rash, urticaria, vesi-
cles, and petechiae have been described. 58 Studies of lesions in the
oral cavity such as ulcers, macular-­petechial enanthema have also
been published, and the variability of oral signs and symptoms in-
cluded among others ulcers, erosions, bullae, vesicles, pustules, fis-
sured or depapillated tongue, hemorrhagic crust, necrosis, petechiae,
59
swelling, erythema, and spontaneous bleeding. It is important to
notice that these oral signs and symptoms were also associated with
predisposing factors, such as other opportunistic infections, immu-
59,60
nosuppression, vasculitis, and lack of oral hygiene. However,
these clinical manifestations are findings commonly associated with
other viral diseases presenting oral lesions. An integrative review by
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Reis et al. found that scientific evidence was lacking to prove that
the changes mentioned above were directly caused by SARS-­CoV-­2.
It is also feasible that those could be the result of deterioration of
the immune system or drug treatment of the disease.61 Gustatory
impairment along with olfactory changes is now listed as symptoms
of Covid-­19 by the World Health Organization, but further research
is needed to confirm a link between reported additional oral symp-
toms and Covid-­19.62
6.3 | Management
According to Paul-­Ehrlich Institute, seven COVID-­19 vaccines
and four omicron-­adapted COVID-­19 vaccines are currently avail-
able.63 As of December 2022, eight medications for the treatment
of COVID-­19 were authorized for use in the European Union, with
Paxlovid® (ritonavir) being the first antiviral drug for oral use.64
Since the etiology of oral lesions seen in the course of
COVID-­19 disease is still uncertain, it is difficult to verify whether
SARS-­C oV-­2 has induced the lesions. Some authors observed that
oral manifestations resolved concurrently with the resolution of
COVID-­19. 61 In general, it may be important to notice that the
virus mainly accumulates in nasal, pharyngeal, and oral tissues so
that the use of antiseptic mouth rinses may reduce the viral load
in droplets and thus could contribute to a lower degree of virus
transmission which is of special importance for the entire dental
professional team. 65
6.4 | Sars-­COV-­2 infection in the context of
periodontitis
Recently, a case–control study analyzed the course of the Sars-­
COV-­2 infection in 568 patients of which 258 also suffered from
periodontitis, and it was found that periodontitis was associated
with COVID-­19 complications, including death due to infection,
admission in intensive care units, and the need for assisted ven-
tilation, after adjustment for potential confounding factors. In
addition, elevated levels of white blood cells, D-­dimer, and C-­
reactive protein were demonstrated in patients having both
Sars-­COV-­2 infection and periodontitis. 66 Regarding changes in
pro-­inflammatory mediators as well as the course of the Sars-­
COV-­2 infection, additional influencing factors, such as systemic
diseases like diabetes mellitus, have to be considered in the con-
text of the influence of periodontitis on the course of a Sars-­
COV-­2 infection. 67,68 However, the association of periodontitis
with severe COVID-­19 outcomes has been shown in numerous
studies. 67,69,70,71,72 Here, more advanced stages of periodontitis
(stage III and IV) led to severe courses of Sars-­COV-­2 infection
more frequently.71
The relationship between Sars-­COV-­2 infection and periodonti-
tis has been recently reviewed elsewhere.73
 |

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DOMMISCH and SCHMIDT-­WESTHAUSEN 9

7 | I N FEC TI O N S C AU S E D BY
E NTE ROV I RU S E S

Clinical manifestations of enteroviruses in the oral mucosa include

herpangina (aphthous pharyngitis, Zahorsky's syndrome) and hand-­
foot-­and-­mouth disease.

7.1 | Epidemiology

Herpangina mostly affects children and adolescents. Increased in-

cidence of the disease has been observed in summer and autumn.
The causative agent is coxsackie virus type A-­16 and enterovirus
71.74 The pathogen is transmitted via secretions from the naso-
pharynx by coughing or sneezing. Fecal-­oral transmission is also
possible.
Hand-­foot-­and-­mouth disease is also caused by a Coxsackie virus
(type A-­16, also A-­5 and A-­10).

7.2 | Clinical features – oral manifestations

Clinical manifestations of herpangina are comparatively mild and

of short duration. Intraorally, small vesicles or ulcerations on
the soft palate associated with difficulty in swallowing can be
diagnosed.
Hand-­
foot-­
and mouth disease (Figure 6A–C) is characterized
by maculopapular vesicles on the hands and feet. In the mouth,
aphthous-­like lesions and ulcers occur in 100% of cases, food intake
is difficult.75 Differential diagnosis must exclude foot-­and-­mouth
disease (contacts with endemic sites!) as well as aphthous ulcers,
HSV infection, and varicella.

7.3 | Management

7.3.1 | Herpangina

In most cases, ulcers heal within 14 days without complications.

Therefore, regularly only symptomatic therapy is required, i. e. rins-
ing with pharyngeal therapeutics such as dexpanthenol or chlo-
rhexidine solution. If the disease becomes extensive, additional
bacterial infection may occur. Therefore, the use of antibiotics may
be necessary.
F I G U R E 6 Clinical manifestation of the Hand-­foot-­and mouth
disease. (A) Maculopapular vesicle on the palm of a hand and (B) at
a fingertip; (C) manifestation at the alveolar mucosa.
8 | H U M A N PA PI LLO M AV I RU S
I N FEC TI O N S

7.3.2 | Hand-­foot-­and mouth disease
As well as with herpangina, no specific therapy is needed. Frequent
hand washing and avoiding close contact with people who have
hand-­
foot-­
and-­
mouth disease may help lower risk of infection.
Hand-­foot-­and mouth disease has been added to the Classification
of Periodontal and Peri-­implant Diseases and Conditions.76,77
More than 200 different human papillomavirus (HPV) types have
been described to date that can infect the skin or mucous mem-
branes. HPV types 1, 2, 4, 6, 7, 11, 13, 16, 18, 32, and 57 have been
detected in a number of benign oral lesions. These include verruca
vulgaris, squamous papilloma/condyloma, focal epithelial hyperpla-
sia, fibrous hyperplasia, lichen planus, and leukoplakia. A possible
role of HPV infection in the pathogenesis of precancerous lesions
 |

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10 DOMMISCH and SCHMIDT-­WESTHAUSEN

and carcinomas is suspected as HPV 11, 16, 18 DNA was detected
by in situ hybridization. However, normal oral mucosa also may har-
bor HPV DNA, so an association between HPV and premalignant/
malignant changes does not directly equate to a causal etiologic re-
lationship.1 Evidence is emerging which suggests that some oral HPV
infections might persist, and persistent HPV infection is mandatory
for HPV-­associated malignant transformation. However, progres-
sion of HPV-­induced lesions to malignancy requires additional co-­
factors.78 This topic is further discussed in this issue.
8.1 | Verruca vulgaris
8.1.1 | Epidemiology
8.2 | Condyloma acuminatum
8.2.1 | Epidemiology
Condyloma acuminatum, mostly caused by HPV subtypes 6 and 11,
presents as anogenital wart and is uncommon, however, in the oral
cavity. While the presence of simultaneous lesions of the genitalia
and oral cavity suggests sexual transmission, additional routes of
infection, such as through fomites, is possible. Condylomata acumi-
nata usually occur between the second and fifth decade of life.79
HIV-­seropositive individuals are more frequently affected, as there
is a correlation between HIV therapy (combined antiretroviral ther-
apy, cART) and their occurrence.80,81

Verrucae are benign hyperplastic wart-­like proliferations of the oral
epithelium, which are common and often found in the third to fifth
decade of life. Men and women are equally affected. Detection of
HPV, such as subtypes 2, 4, 6, 7, 10, 40, 57, is successful in only half
of the oral warts. In children, warts on the fingers and hands are
frequently transmitted to parts of the anterior oral cavity.
8.2.2 | Clinical features—oral manifestations
Typically, the lips, tongue, and palate are affected (Figure 8).
Condylomata are painless, round, exophytic nodes with a size of up
to 15 mm. They are broad-­based, and the color corresponds to that
of the normal oral mucosa.

8.1.2 | Clinical features—oral manifestations

Verrucae may affect the entire oral mucosa but are more frequently
found on the hard and soft palate, the lip mucosa, tongue, and gingiva
(Figure 7). They are soft, often pedunculated, and exhibit a cauliflower-­
like structure with a papillary verrucous surface of white or normal oral
mucosal color. Verrucae do not grow larger than 6 mm in size.

8.1.3 | Management

In children, spontaneous regression is common. Simple excision is

sufficient, and recurrences are rare.

F I G U R E 8 Clinical manifestation of Condyloma acuminatum at

F I G U R E 7 Diagnosis of Verruca vulgaris at the tongue margin. (A) the mucosa of the inner lip and (B) the alveolar mucosa.

DOMMISCH and SCHMIDT-­WESTHAUSEN
8.2.3 | Management
Simple excision or ablation with CO2 laser is sufficient for treatment.
In HIV patients, recurrences up to 75% may occur.
8.3 | Focal epithelial hyperplasia (Syn.: Heck's
disease)
8.3.1 | Epidemiology
Focal epithelial hyperplasia (FEH), caused by HPV subtypes 13 and
32, is most commonly found in children In some populations, such
as the Inuits and South American natives, it is endemic,82,83 and a
report of similar lesions of indigenous people of Greenland dates to
the 1800s.83 Since these early findings, cases have been reported
around the globe and across demographics, to include elderly and
AIDS patients.83,84 Females are significantly more affected than
males, with ratios up to 5:1.84
8.3.2 | Clinical features—oral manifestations
FEH presents with multiple small, soft, flat nodules mainly on lips,
buccal mucosa, and tongue (Figure 9). These are pinkish in color and
range in size from 2 to 10 mm.
8.3.3 | Management
Spontaneous regression in children is well known. There remains no
specific therapy for FEH, although surgical removal, laser excision or
possibly topical antiviral agents may be of benefit. So far, malignant
transformation has not been described.85
9 | CO N C LU D I N G CO M M E NT S A N D
PE R S PEC TI V E S
Oral lesions caused by viruses are seen and treated in daily practice
by a variety of healthcare providers, including general practitioners,
doctors of internal medicine, dentists, oral medicine specialists, oto-
laryngologists, and dermatologists. These lesions are often difficult
to diagnose due to a variable, but sometimes indifferentiable clinical
presentation as well as a variety of causative microorganisms. DNA
viruses, including members of the Herpesviridae, Papillomaviridae
and Poxviridae families, can cause oral lesions; likewise, RNA vi-
ruses, including enteroviruses and paramyxoviruses, can also affect
the oral cavity.
In most cases, the challenge is to clinically establish a definitive
diagnosis, however, early detection of lesions may diminish the risk
of further complications. This is particularly important in certain pa-
tient groups such as HIV-­seropositive individuals, or patients with
|
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11
F I G U R E 9 Clinical manifestation of the focal epithelial
hyperplasia (Syn.: Heck's disease) at (A) the lower external lip and
(B) the mucosa of the inner lip.
AIDS, in whom the appearance of oral lesions often correlates with
disease progression.86,87
Thus, a profound diagnosis can only be made if pathological anal-
yses, including microbiological and histological procedures, were
performed. Although finding the precise diagnosis necessitates
clinical and histopathological effort, an epidemiological disease sur-
veillance is only possible when this special effort is taken. Technical
innovations regarding detection and quantification of the intraoral
microbiologic flora will foster accessibility for diagnostic centers,
and therewith, reduce the time needed for clinicians and patients to
receive a verified diagnosis.
In this context, the bacterial composition of the dental plaque
biofilm may also be of importance. Here, two different aspects
need to be considered: caries and periodontitis development and
progression as a sequela of a potentially growing biofilm (devel-
oping dysbiosis) on the tooth surface. Both diseases are the main
causes for tooth loss due to extraction, and it has been shown
that recurrence of viral infection (e.g., HSV) is associated with
tooth extraction. 88 In addition, monitoring periodontal or peri-­
implant disease development may be recommended in cases of
known viral infection with oral manifestations and/or in the pres-
ence of periodontitis in young patients. 5,23,89,90 These aspects
highlight the importance of considering the microbiologic factors
entirely, including presence of viruses or oral lesions caused by a
 |
12
specifically proven viral infection, when performing routine intra-
oral examinations.
A structured inspection of the oral cavity is crucial, and one must
keep in mind that viral infections are contagious, and thus, poten-
tial spreading of a virus must be considered when planning intraoral
examination and/or treatment. However, the accessibility of the in-
traoral mucosa allows for continuous follow-­ups to verify disease
regression. Thus, constant clinical training of intraoral examination
procedures in combination with a consequent consideration of con-
tinuous laboratory-­based analyses will increase individual compe-
tence and knowledge of intraoral lesions, including viral infections,
reduce the risk of potentially spreading viral infections, and help
with patient education regarding symptoms, complications, risks,
and healing periods. This clinical training also includes practical guid-
ance for sampling (biopsy, microbiological sampling).
Especially, data from patients with Sars-­COV-­2 infection have
demonstrated how different inflammatory diseases may influence
each other.70 Periodontitis is a common complex inflammatory dis-
ease, and associations to viral infections have been widely demon-
strated. 2,13,65,91 In this context, periodontitis should always be
considered as a potential influencing factor for viral infections per se
as the periodontal inflamed surface area can be a route for viruses
depending on the stage of periodontitis.71,92
For the daily routine, following structured management proto-
cols is crucial. Those protocols may include not only dental exam-
ination and sampling but also the approach to medical advisors and
examiners as well as access to analytic laboratories. In addition, clin-
ical guidelines and/or recommendations are part of elaborate man-
agement protocols facilitating consequent treatment of symptoms
and patient education.
AC K N OW L E D G M E N T S
Both authors (H.D. and A.M.S.-­W.) receive their salary from the
Charité – Universitätsmedizin Berlin. Open Access funding enabled
and organized by Projekt DEAL.
C O N FL I C T O F I N T E R E S T S TAT E M E N T
The authors declare that they have no conflict of interest.
ORCID
Henrik Dommisch https://orcid.org/0000-0003-1043-2651
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How to cite this article: Dommisch H, Schmidt-­Westhausen
AM. The role of viruses in oral mucosal lesions. Periodontol
2000. 2024;00:1-14. doi:10.1111/prd.12553