DOI: 10.1111/prd.
12273
REVIEW ARTICLE
Viral, bacterial, and fungal infections of the oral mucosa: Types,
incidence, predisposing factors, diagnostic algorithms, and
management
H. M. H. N. Bandara1 | Lakshman P. Samaranayake2
1
Bristol Dental School, University of Bristol, Bristol, UK
2
Department of Oral and Craniofacial Health Sciences, College of Dental Medicine, University of Sharjah, Sharjah, UAE
Correspondence
Lakshman P. Samaranayake, College of Dental Medicine, University of Sharjah, Sharjah, UAE.
Email: lsamaranayake@sharjah.ac.ae
1 | I NTRO D U C TI O N
Skin and the mucous membranes in the orofacial region are often
affected by a diverse spectrum of bacterial, viral, fungal, chlamydial,
rickettsial, protozoal, and helminthic infections. Such conditions may
clinically appear as small, localized lesions to diffuse and invasive va-
rieties that extend beyond natural barriers, often causing potentially
life-­threatening complications. Partly due to the narrow geograph-
ical distribution and effective preventive strategies in much of the
world, few clinicians will have personally examined or be familiar
with the clinical presentations and laboratory investigations of some
of the orofacial infections described here.
Regardless of the prevalence, incidence, and the advancement of
treatment strategies, orofacial infections, either local or the manifesta-
tions of a generalized infection, may cause significant discomfort and suf-
fering. Thus, the recognition of the clinical presentation of these infections
is paramount to their diagnosis, clinical management, and appropriate
referral. A critical assessment of clinical signs and symptoms, likelihood
of individual and communal predisposition, the past medical, dental and
social history, appropriate sampling, and accurate interpretation of the
laboratory results are all essential in determining definitive diagnoses and
management protocols. Therefore, in this paper, we discuss the types, in-
cidence, predisposing factors, diagnostic algorithms, and management of
common orofacial infections of viral, bacterial, and fungal origin.
2 | V I R A L I N FEC TI O N S
2.1 | Human herpesviruses
Although many viruses can infect the oral cavity, members of the
human herpesvirus family cause the most common viral infections
with variable clinical presentations. All herpesviruses are structurally
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© 2019 John Wiley & Sons A/S.
Published by John Wiley & Sons Ltd
similar (enveloped, icosahedral, with double-­
stranded DNA), and
they infect both humans and animals. Additionally, all herpesviruses
are neurotropic and have the important property of remaining la-
tent, with the ability to reinfect the host and cause recurrent infec-
tion after a variable period of the primary infection.
A range of different human herpesviruses have been identified, and
they are numbered from 1 to 8. Human herpesvirus 1 (also called her-
pes simplex 1) causes oral and genital herpes (predominantly orofacial).
Human herpesvirus 2 also causes oral and genital herpes simplex; how-
ever, genital manifestations are predominant. The primary infection of
varicella zoster virus (human herpesvirus 3) is chicken pox, and the reac-
tivation of the virus results in shingles. Human herpesvirus type 4, also
called Epstein-­Barr virus, is known to cause infectious mononucleosis,
Burkitt's lymphoma, and central nervous system lymphoma in acquired
immune deficiency syndrome (AIDS) patients. Oral hairy leukoplakia, first
identified in people with HIV disease, is also caused by Epstein-­Barr virus.
Individuals infected with cytomegalovirus, the fifth human herpesvirus,
exhibits infectious mononucleosis like symptoms. Roseolovirus (human
herpesvirus 6) and human herpesvirus 7 cause a similar infection known
as roseola infantum or exanthem subitum. Human herpesvirus 8 mainly
causes Kaposi's sarcoma and primary effusion lymphoma; thus, it is called
associated herpesvirus.1 The following sections de-
Kaposi's sarcoma-­
scribe orofacial manifestations of human herpesvirus 1 to 3. Epstein-­Barr
virus and cytomegalovirus infections are summarized in Table 1.
2.2 | Herpes simplex infections (human herpesvirus
1 and 2)
2.2.1 | Epidemiology
Children between 6 months and 3 years of age are at higher risk to
exposure to herpes simplex virus type 1 through direct contact with
Periodontology 2000. 2019;80:148–176.
BANDARA and SAMARANAYAKE
another individual carrying the virus. Approximately 60% of the pop-
ulation has been infected by the age 14-­49 years, and the infected
population rises up to 80%-­85% by the age of 60 years.2 Herpes sim-
plex virus type 2 is one of the most common sexually transmitted dis-
eases, and approximately 17% of US adults between 14 and 49 years
of age are chronically infected with herpes simplex virus type 2.3,4
Alarmingly, 95% of herpes simplex virus type 2 seropositive individu-
als are estimated to be shedding herpes simplex virus type 2 asymp-
tomatically.5 Recent reports suggested that, in Western countries, the
incidence of herpes simplex virus type 1 in children is decreasing and
many are exposed to herpes simplex virus type 1 for the first time dur-
ing their adolescence as a result of an active sexual lifestyle.6
2.2.2 | Predisposing factors
Children between 6 months and 3 years are at high risk for herpes
simplex virus type 1 exposure, especially through kissing, touching
the person's skin, such as pinching a child's cheek; and sharing ob-
jects such as silverware, lip balm, or a razor can predispose an indi-
vidual to be exposed to herpes simplex virus type 1.
The susceptibility to herpes simplex virus type 2 infection is
higher among females. In addition, individuals who have had many
sex partners, had sex for the first time at a young age, have (or had)
another sexually transmitted infection and have a weakened immune
system due to a disease or medication are more prone to be infected
with herpes simplex virus type 2. However, greater human immuno-
deficiency virus (HIV)/herpes simplex virus type 2 coinfection rates
were estimated among heterosexuals in sub-­Saharan Africa and men
who have sex with men in the Americas.7-10 Recurrent herpes infec-
tions are commonly diagnosed in patients receiving cancer chemo-
therapy or immunosuppressive drugs to prevent graft rejection after
transplantation or with advanced AIDS.11,12
2.3 | Pathogenesis of herpes simplex
type 2 infections
Herpes simplex viruses enter host cells by interaction of their surface
glycoproteins (glycoprotein B, C, D, H, and L) with various host cell
surface receptors. 13,14
Alternatively, herpes simplex virus may enter
the host cell via endocytosis. 15,16
Regardless of the method of entry,
viral membranes fuse with the host cell membrane to facilitate the
entry of viral capsid and accompanying tegument (viral proteins) into
the cytoplasm. 17
Subsequently, the viral capsid released to host cell
cytoplasm reaches the outer nuclear membrane by linking tegument
to host cell microtubules. Viral capsid binds to the host nuclear pore
complex and releases the viral DNA into the host nucleus.17,18 Using
host RNA-­
polymerase II, viral DNAs are sequentially transcribed
19,20
in order to encode for proteins required to evade host immu-
nity, replicate viral DNA, synthesize structural components of virions,
including tegument, capsid, and other surface proteins.21,22 Capsid
proteins synthesized in the cytoplasm migrate in to the nucleus and
assemble with newly transcribed viral DNA to create new virions. 23
|
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Consequently, the capsid travels to cytoplasm and is coated with
additional tegument proteins and enveloped in the trans-­Golgi net-
work.24 Finally, the virions are carried to the cell surface via vesicles
and secreted. In contrast, some evidence has shown that herpes sim-
plex viruses are capable of propagating to adjacent cells directly via
cell-­cell interactions, particularly when infecting T cells.25,26
As a well-­evolved virus, herpes simplex virus targets multiple host
immune components to evade the immune response. These host
components include antibodies, natural killer cells, complement pro-
teins, and major histocompatibility complex class I or II molecules.27,28
Once the primary herpes simplex virus infection is established, the
virus internalizes by fusing the viral envelope with neuronal cells at
sensory nerve terminals and travels to trigeminal nerve ganglia via
retrograde axonal transport. Herpes simplex virus resides within tri-
geminal nerve ganglia and may reactivate with appropriate triggering
factors.29,30 Once reactivated, viruses travel along the neurons and
develop secondary infection in relevant dermatomes.
2.3.1 | Clinical presentation
Classically, herpes simplex virus type 1 is known to cause infections
above the waist, including oral and pharyngeal infection, menin-
goencephalitis, and dermatitis, whereas herpes simplex virus type 2
causes infections below the waist, such as genital and anal infec-
tions. However, both viruses have been isolated in primary or re-
current infections in the oral, perioral, or genital area as a result of
different sexual practices.11,12
Primary infection (primary herpetic gingivostomatitis)
In most cases of herpes simplex virus infections, patients experience
prodromal symptoms such as burning, itching, or tingling sensations of
the skin or mucosa for a day or so.11,12 Primary herpes simplex virus
infection appears with systemic symptoms, which may include fever,
headache, malaise, nausea, vomiting, and accompanying lymphade-
nopathy.31,32 Usually, herpes simplex virus infections are subclinical or
may cause pharyngitis. As a result, it is often misdiagnosed as an upper
respiratory tract infection. Oral lesions appear on the lip or around the
mouth, less frequently on the tongue, palatal and buccal mucosae, and
the face. The blisters or vesicles erupt as clusters and ooze with a clear
to yellowish fluid that may develop into a yellowish crust. These erup-
tions are extremely painful and break down rapidly and appear as tiny,
shallow-­grey ulcers on a red base. Subsequently, they become crusted
or scabbed and appear drier and become more yellowish in several
days.2 Primary herpetic gingivostomatitis can also manifest as vesicles
and ulcers on the oral mucosa and in marginal gingiva, causing acute
generalized marginal gingivitis. The ulcers cause intense erythema in
the gingiva and possible bleeding.11,12 Cervical lymphadenopathy is a
common finding in herpes simplex virus infections.2
Recurrent infections
Upon recovery from the clinical infection, the virus could be-
come dormant in trigeminal ganglia. Reactivation of this latent virus
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150       BANDARA and SAMARANAYAKE

TA B L E   1   Viral infections in the oral mucosa: the epidemiology, predisposing factors, clinical presentation, diagnosis, and treatment
options of primary and oral manifestations of systemic viral infections

Infection Epidemiology Predisposing factors Clinical presentation Diagnosis Treatment

Infectious • Causative agents: EBV • Deep kissing with infected • Sudden onset of sore throat • Clinical presentation • Usually self-limiting, and
mononucleosis (90% of the cases) individual • Slow development of malaise, • Heterophile antibody management largely
cytomegalovirus, • Blood transfusion, solid myalgia, fever, loss of appetite, test/monospot test: consists of supportive
human herpesvirus 6, organ transplantation, headache and fatigue263 the hallmark of an treatment, rest, and
toxoplasmosis, HIV, and hematopoietic cell • Other orofacial involvement: EBV infection265 analgesics
adenovirus257 transplantation. 260-262 Posterior cervical lymphadenopathy, • Enzyme immunoas- • Antiviral treatment or
• 90%-95% of world • Can spread from infected exudative pharyngitis, tonsillitis, and says: specific corticosteroids may be
population is infected parents or siblings splenomegaly264-266 antibody tests are indicated for immuno-
with EBV258,259 • Palatal petechiae (blotchy red VCA IgM, VCA IgG compromised
• The highest prevalence macules; can mimic streptococcal and EBNA-1 IgG263 individuals265
among adolescents and pharyngitis267
young adults258,259 • Can cause facial swelling and eyelid
edema in extreme cases268

Cytomegalovirus • Seroprevalence among • Individuals with poor Common manifestations • Serological detection • Intravenous ganciclovir
infections adults of 50%-100% socioeconomic status • persistent, atypical oral mucosal ulcers of CMV-specific and alternatively with
• Seropositivity is and/or in developing (long lasting, solitary or numerous, antibodies or IgG foscarnet or cidofovir
50%-80% in countries painful or painless, medium-sized, • CMV-specific IgM • Induction doses for at
HIV-negative • Body fluids or bone shallow ulcerations. most common in antibodies least 2 weeks are
heterosexual marrow/solid grafts both hard and soft palate269 (complement fixation, generally recommended,
individuals • Neonate or an • Major salivary gland infections, with anticomplement followed by maintenance
• Homosexual immunosuppressed or without altered salivary flow272,273 immunofluorescence, dosing for another
HIV-positive males are individual270,271 Rare manifestations: indirect hemaggluti- 3-4 weeks.
almost always • Patients receiving • Gingival hyperplasia, gingivitis nation, and • Continued close
seropositive for CMV269 chemotherapy for cancer • Periodontitis, osteomyelitis of the radioimmunoassay)276 virological monitoring is
or collagen disease270 jaw, sinusitis recommended277
• Oral mucosal hyperplasia
• Concurrent infections in Kaposi’s
sarcoma recurrent aphthous
stomatitis270,272,274,275

Herpangina • Common in children • Occurs seasonally, esp.
between 3 and 10 years autumns and summer in
• Caused by coxsackie temperate climates and
group A viruses278 year around in tropical
climates
• School environments279
• Fever, headache, loss of appetite • Clinical presentation • Self-limiting infection.
• Sore throat, or painful swallowing 279 Recovery uneventful in
• Multiple painful ulcers in the less than a week 278
posterior oral cavity and pharynx, • Symptomatic treatment
lesions preceded by vesicles with analgesics,
• Ulcers are light grey in color, often antipyretics, and topical
with a red border280 anesthetics
• Similar ulcers on the feet, hands, and • Nonirritant food279
buttocks278

Hand, foot, and • Common in children • Age. Children are mainly • Manifestations are limited to skin • Clinical presentation • Disease usually improves
mouth disease under 10 years. affected • Mild fever and constitutional • Viral cultures from spontaneously after
• Caused mainly by • Geographical predisposi- symptoms may precede or stool, throat swab, 7-10 days without any
coxsackie group A tion (Asians) is accompany the skin eruptions vesicle fluid to identify complication278
viruses and human controversial281 • Sudden appearance of erythematous, the specific virus
enterovirus 71281 round or oval-shaped papulo through observation
• Only small-scale vesicular eruptions of the cytopathic
outbreaks have been • Eruptions appear as crops effect in cell culture or
reported from United • Vesicles rapidly become pustules with formation of plaques
States, Europe, a characteristic perilesional erythema in a cell monolayer
Australia, Japan, and • Lesions appear hand, feet, perioral (plaque assay)286-288
Brazil for last three area, knees, buttocks and also • Plaque reduction
decades281 intraorally neutralization test to
• In severe cases, cardiovascular, detect neutralizing
respiratory, and neurological antibody of HEV71289
involvements can be seen282-285 • ELISA for detection of
IgM
• Serotyping via
RT-PCR 290-292

HPV infections • The most common • Multiple sexual partners
sexually transmitted • Increased susceptibility to
disease HPV infection when
• The population coinfection of other
prevalence of HPV sexually transmitted
infection among women diseases with vaginal
around the world infections such as
ranges from 2% to bacterial vaginosis,
44%293 trichomoniasis, herpes
• Over 40% of HPV simplex virus infection,
infections are and vulvar warts296
anogenital294 • Smoking 297
• Highest among women • Age and racial
between 20-24 years predisposition295
and among non-His- • HIV infection: CD4 counts
panic blacks295 and HIV RNA levels
correlate with the
incidence of high-risk HPV
infections298,299
• Results in oral warts • The US FDA-
• Lesions present as cauliflower-like approved HPV tests:
spiked or raised lesions with a flat • Digene Hybrid
surface300 Capture 2 high-risk
HPV DNA test
• Cervista HPV HR
• Cervista HPV 16/18
• Cobas HPV test
• APTIMA HPV
assay301
• Surgery, laser surgery, or
cryotherapy
• Topical treatment options
include imiquimod,
podofilox, and
5-fluorouracil
preparations
• Imiquimod or podofilox
should be used in African
Americans to avoid the
risk of hypopigmentation
associated with
5-fluorouracil300

(Continues)
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TA B L E   1   (Continued)

Infection Epidemiology Predisposing factors Clinical presentation Diagnosis Treatment

Mumps • Mumps antibody • Young children attending • The prodromal symptoms: myalgia, • Clinical presentation • Disease usually improves
seroprevalence from primary grade school 303 anorexia, malaise, headache, and • Virus detection by spontaneously after
1999 to 2004 is 90% 302 • Household members of an low-grade fever303 culture or PCR 7-10 days without any
• Prior to vaccination, infected person Parotitis303 • Viruses can be complication
peak incidence of • Unilateral/bilateral isolated from the • Vaccination for
mumps in United States • Typically develops 16-18 days after swabs of parotid duct prevention303
was in winter to early exposure • Immunological tests
spring with some • Noted as earache ELISA or EIA: serum
sporadic outbreaks 302 • Tenderness on palpation of the angle mumps IgM, IgG
of the jaw (false-negative results
• Symptoms decrease after 1 week and may appear in
resolve after 10 days vaccinated
• Complications302 persons)303
• Orchitis (testicular inflammation)
• Pancreatitis
• Oophoritis
• Aseptic meningitis
• Death

Measles • Occurs throughout the • Hispanic and black races • Prodromal symptoms occur 14 days • Virus isolation from • Spontaneous recovery
world • Children younger than after exposure urine, nasopharynx, • Rest, pain killers,
• Prevalence is 5 years of age • Prodromal symptoms include fever blood, throat increased fluid intake,
significantly reduced • Vitamin A deficiency (stepwise increase, often peaking • Serology: significantly vitamin A supplements
after introducing • Unvaccinated children304 103°F-105°F), cough, coryza (runny raised measles IgG by • Prevention through
vaccines nose), and conjunctivitis any standard vaccination304
• Dramatic increase in • Koplik spots (mucosal rash): punctate serologic assay (eg,
the incidence was blue-white spots on the bright red EIA, HI)
reported in United background of the buccal mucosa; • Positive serologic test
States between lasts for 5-6 days for measles IgM
1989-1991 peak in late • The measles rash starts at the antibody
winter-spring304 hairline and proceeds downward and • Clinical picture:
outward Koplik spots 304
• Measles rash is a maculopapular
eruption and discrete; may confluent
on the upper body
• Other symptoms: anorexia; diarrhea,
especially in infants; and generalized
lymphadenopathy304

CMV, cytomegalovirus; EBNA-­1, Epstein–Barr nuclear antigen-­1; EBV, Epstein-­Barr virus; EIA, enzyme immunoassay; ELISA, enzyme-­linked immuno-
sorbent assay; FDA, Food and Drug Administration; HI, hemagglutination inhibition; HIV, human immunodeficiency virus; HPV, Human papillomavirus;
Ig, immunoglobulin; RT-­PCR, reverse transcription polymerase chain reaction; VCA, viral capsid antigen.

can result in recurrent herpes infections. Reactivation is usually
triggered by exposure to cold, sunlight, traumatic events, stress
or immune suppression.11,12 The most common manifestation of
a recurrent herpes simplex virus infection is herpes labialis, which
typically appears at the mucocutaneous junction of the lip, often
referred to as “cold sores” or “fever blisters” (Figure 1). Herpes la-
bialis also exhibits burning or tingling sensations of the site of future
blisters. Small fluid-­filled semi-­translucent blisters appear on the lips
and may coalesce to form a large blister. Blisters dry out within sev-
eral days, resulting in scab formation. 2
2.3.2 | Management
When the clinical infection is present, diagnosis is made mainly with
clinical presentation. However, laboratory tests may be necessary to
33
confirm and to establish the diagnosis of atypical presentations.
These include virologic tests in which the presence of the virus is
confirmed by the cytopathic changes in a tissue culture infected with
the virus.11,12 In addition, cytology smears stained with Giemsa or
Papanicolaou stain are used to identify the characteristic cytopathic
and viral features in the suspected smear.34 Immunological tests,
such as direct fluorescent assay, detection of viral DNA through
polymerase chain reaction (PCR) assays (the test of choice for her-
pes simplex virus) and serological tests to detect anti-­herpes simplex
virus antibodies in serum, are commonly used in the diagnosis.35-37
The treatment for primary infection is usually palliative. Mild
cases of the infection are managed by supportive care, which in-
cludes adequate hydration, pain and fever management with analge-
sics and antipyretics, topical anesthetics, such as viscous lidocaine,
or a mixture of liquid Benadryl, milk of magnesia, and carafate to
decrease oral pain.38,39 Antiviral therapy with acyclovir, valacyclo-
vir and famciclovir are proven to reduce the symptoms if started
48 hours of vesicle eruption.31,32,40,41 Recurrent infec-
within 24-­
tions in otherwise healthy patients are also treated symptomatically.
However, patients with chronic immune suppression or with severe,
painful, or deforming recurrent herpes may require systemic antivi-
ral medications.42
Despite multiple attempts made to develop vaccines against
herpes simplex virus infections during the last two decades, the
success of such trials appears to be minimal and ineffective in
either preventing the occurrence or shedding of the virus 43,44;
usage of viral subunits has also raised concern about potentially
developing infection, and application of neutralizing antibodies in-
stead has also been under discussion. However, in a recent trial, a
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152       BANDARA and SAMARANAYAKE
F I G U R E   1   Herpes labialis on the mucocutaneous junction of the
upper lip. From Samaranayake247
vaccine containing herpes simplex virus 2 glycoprotein D showed
superior effect against herpes simplex virus 1–induced genital in-
fections compared with herpes simplex virus 2 infections in the
same site.43-47 The latter finding encourages one to think that
promising vaccines against herpes simplex viruses are likely to be-
come a reality, and the field of novel microbicides against herpes
simplex viruses is promising and is likely to generate agents that
can cure the infection permanently.48
2.4 | Human herpesvirus 3 primary infection:
Varicella zoster
2.4.1 | Epidemiology
Varicella zoster infection is prevalent worldwide. Prevalence in
adults is higher than in children. The occurrence is higher in tropical
countries than in other climates. Varicella exhibits classical seasonal
fluctuations in temperate climates, with the highest incidence of the
infection occurring in winter and early spring. The seasonal varia-
tions are less commonly experienced in tropical areas.49
2.4.2 | Predisposing factors
Newborn babies, specially within first 28 days of life, pregnant
women who have not been exposed to chicken pox before, and
immunocompromised individuals such as those with leukemia or
Hodgkin's disease, or those taking immunosuppressive medications,
are at higher risk of developing longer and more serious illness. 50
Varicella is extremely contagious, and the risk of secondary attack
among susceptible household contacts is as high as 90%.49
2.4.3 | Clinical presentation
Chicken pox is a benign infection in childhood. It spreads by
direct contact with an infected individual, especially with skin
lesions or nasopharyngeal secretions.11,12 Symptoms of the in-
fection usually appear after an incubation period of 10-­21 days.
Skin lesions are intensely pruritic and maculopapular in appear-
ance. The rash rapidly develops into fluid-­filled vesicles with
an erythematous base (dew drop on a rose petal). Oral lesions,
mainly vesicles and ulcers, are similar to herpes simplex virus
infections and commonly seen on the palate, pillars of fauces,
and uvula. 42
2.4.4 | Management
Clinical presentation of the infection is pathognomonic. When
symptoms are not present, identification of viral DNA in serum, sa-
liva, or cerebrospinal fluid aids diagnosis.42 Management of chicken-
pox is symptomatic, such as adequate hydration, bed rest, and fever
control by paracetamol (aspirin should be avoided). Lukewarm baths
and lotions are useful to reduce itching.50 However, in severe cases,
antiviral therapy is recommended.
2.5 | Human herpesvirus 3 reactivation:
Herpes zoster
2.5.1 | Epidemiology
Herpes zoster (shingles) is a sporadic disease, and the lifetime in-
cidence is estimated to be 10%-­20%. Incidence of shingles rises
with aging, doubling in each decade past the age of 50 years. In the
United States, approximately 50% of persons living until the age of
85 years will develop zoster.49 There is a 15 times higher incidence
of shingles in HIV-­infected patients compared with uninfected, and
blacks are one fourth as likely as whites to develop herpes zoster.
There is 15% household transmission rate.51-54 The lifetime risk of
herpes zoster is estimated to be at least 32%. Herpes zoster has no
seasonal variation and may be reported throughout the year.
2.5.2 | Predisposing factors
Patients who have had varicella zoster, those who are older than
50 years, and those who have compromised immune status (eg, HIV
infections, diabetes, under steroids or cytotoxics) or are suffering
from cancer are at high risk of having shingles. Stress and trauma are
also known precipitation factors.54
2.5.3 | Clinical features
The initial symptoms range from pain, tenderness, and paresthe-
sia along the course of the affected nerve. Vesicles appear unilat-
erally after 3-­5 days in the dermatome supplied by the affected
nerve. Vesicles have inflamed bases. Herpes zoster can affect
the motor nerves occasionally. When facial nerves (geniculate
ganglia) are affected, lesions appear unilaterally along the exter-
nal ear, face, and oral mucosa. Unilateral facial paralysis is not
BANDARA and SAMARANAYAKE
F I G U R E   2   Herpes zoster of the tongue. Note the unilateral
lesion due to reactivation of the infection via lingual branch of the
right trigeminal nerve. From Samaranayake247
H unt syndrome.11,12 Ophthalmic,
uncommon, causing Ramsey-­
maxillary, or mandibular branches of the trigeminal nerve can
be affected, and this results in painful skin lesions as well as in-
traoral lesions along the course of the affected branch (Figure 2).
Intraoral lesions are intensely painful.42 Post–herpetic neuralgia
may develop as a consequence of herpes zoster due to scarring of
the nerve involved during the infection.11,12 Post–herpetic neu-
ralgia is an intensely painful and debilitating condition that may
last for many months to years.
2.5.4 | Management
Diagnosis is based on clinical presentation. Laboratory tests may
be necessary for less-­t ypical presentations. These tests include di-
rect fluorescent antibody staining of varicella zoster virus–infected
cells, the use of PCR to detect varicella zoster virus DNA, and sero-
logic tests. However, it is difficult to distinguish herpes zoster from
varicella zoster by serologic tests. 55 One study showed that the
sensitivity and specificity of detecting varicella zoster virus DNA in
cells from the base of lesions after they are unroofed by PCR was
95%-­100%, whereas immunofluorescent tests in detecting viral
antigens were only 82% sensitive and 76% specific. 56 When there
is a systemic involvement, PCR assays are used to detect viral DNA
in cerebrospinal fluid and blood. It has been recently shown that el-
evated ratio of varicella zoster virus antibody level in cerebrospinal
fluid to blood is a more sensitive parameter in diagnosing central
nervous system involvement of varicella zoster virus. 57
Antiviral drugs speed healing of the lesions and reduce the dura-
tion of severe pain (valacyclovir 1 g three times a day for 7-­10 days).
Intravenous acyclovir is required for immunocompromised patients.
Short courses of corticosteroids, such as oral prednisone, are often
used to control the inflammatory response associated with severe
|
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pain.58 In addition to antiviral therapy and corticosteroids, post–her-
petic neuralgia is treated with gabapentin, tricyclic antidepressants,
opioids, topical capsaicin, and topical lidocaine patches to assist with
pain control.11,12,59
2.6 | Other oral viral infections
The foregoing describes only the most frequent oral viral infections
belonging to the herpes group of viruses. Yet, dentists frequently
see patients with an assortment of infections caused by RNA vi-
ruses, such as the rhinovirus (common cold virus), influenza virus,
coxsackievirus (hand, foot, and mouth disease), and measles and
mumps viruses. These infections may or may not present with oral
manifestations, but they are important in the context of infection
control aspects of dentistry.
There are new viral infections re-­e merging and emerging in-
cessantly in different regions of the world, such as the recent
Ebola virus outbreak and Zika virus infection in Africa and South
America respectively. Increase in host susceptibility due to poor
personal and social hygiene, overcrowding, societal breakdowns
(such as wars and civil chaos), poverty, and lack of public health
care, and human factors such as sexual and substance abuse activ-
ities can create favorable environments for new and re-­e merging
viral infections. 60 Natural mutations of viruses that increase viral
virulence (eg, influenza), geographical transfer of viruses to dis-
tinct human populations (eg, chicangunya) and viruses crossing the
species-­specific barriers (eg severe acute respiratory syndrome,
HIV infection, and Ebola) also have a major impact on emerging
new infections. Though there is a lack of reports on oral manifes-
tations of the new, re-­e merging viral infections, it is still too early
to exclude the potential of oral complications of these diseases.
Table 1 provides a guide to some of these infrequent viral infec-
tions that may manifest in the oral cavity.
With emerging new infections as well as isolation of mutant and
drug resistant variants of existing viral pathogens, specific and sen-
sitive diagnosis are of paramount importance in managing existing
infections and preventing further individual and communal dissem-
ination. The new era of clinical virology is moving towards highly
specific new generation diagnostic tools such as nucleic acid ampli-
fication tests, real time quantitative PCRs, next generation sequenc-
ing, and mass spectrometry. These technologies not only possess
extreme sensitivity and specificity, low detection limits, but also
produce fast and automated results facilitating early interventions.61
3 | BAC TE R I A L I N FEC TI O N S
3.1 | Actinomycosis
3.1.1 | Incidence
Actinomycosis is an infrequent invasive bacterial disease caused
by Actinomyces species. These are filamentous anaerobic Gram-­
positive bacilli, commonly isolated in the human commensal flora
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154       BANDARA and SAMARANAYAKE
of the oropharynx, gastrointestinal tract, and urogenital tract.62
Orofacial structures, respiratory tract, bone and joint, genitou-
rinary tract, gastrointestinal tract, central nervous system, skin,
and soft tissue structures can be affected with actinomycosis.63-65
Though there are over 30 Actinomyces spp. described, Actinomyces
63-67
israelii is the most isolated species in clinical disease in humans.
Occasionally, Actinomyces viscosus and Actinomyces meyeri are also
reported.67,68
Human oropharynx, tonsillar crypts, gingival crevices, peri-
odontal pockets, and dental plaque (both supra-­and subgingival
plaque biofilms), and carious teeth harbor Actinomyces as an oro-
63-65
facial commensal. Thus, actinomycosis in the orofacial region
(also called “lumpy jaw syndrome”) is considered to have endoge-
nous origin. Actinomycosis in the orofacial region (also known as
cervicofacial actinomycosis) is the most frequent clinical form of
actinomycosis, representing approximately 60% of all reported
cases.63-65,69 Patients with odontogenic maxillary sinusitis may be
70
infected with Actinomyces, leading to maxillary osteomyelitis.
Although more than 30 species of Actinomyces have been identified,
over 70% of oro-­cervicofacial infections are caused by A. israelii and
Actinomyces gerencseriae (formerly A. israelii serotype 2).67 A. meyeri,
Actinomyces odontolyticus, Actinomyces naeslundii, Actinomyces geor-
giae, Actinomyces pyogenes, or A. viscosus have also been isolated in
some cases.67 Although most infections are monomicrobial in nature
(ie, with Actinomyces alone causing the disease), a significant propor-
tion of infections could be polymicrobial, with other bacteria such
as Aggregatibacter actinomycetemcomitans, Haemophilus spp. and an-
aerobes acting as co-­infecting agents.42
3.1.2 | Predisposing factors
Over 80% of actinomycosis cases were reported in young adults
over the age of 20 years. However, it has been reported that
actinomycosis can primarily affect between the third and sixth
decades of life.71 When children are affected, it rarely spreads
beyond cervicofacial lesions.72 Local predisposing factors of ac-
tinomycosis include poor oral hygiene (dental caries, gingivitis,
and teeth with gangrenous pulps and pericoronitis) and trau-
matic events to oral mucosa, including dental extraction, gin-
gival trauma, irradiation, neoplasms, and cervicofacial surgery.
Men are more susceptible than women for reasons that are un-
clear. Several early studies suggested that there is a significant
3 : 1 to 4 : 1 predilection among the male population compared
with females. However, consequential studies have shown that
there are no sexual or racial predispositions to actinomycosis, as
the infection mainly disseminates through orofacial trauma with
mucosal rupture.71,73,74 Those with uncontrolled diabetes mel-
litus, immunosuppression, alcoholism, and malnutrition are also
more prone to actinomycosis. 63-65,67,75-77 However, in an early
study, Lerner and others noted that the association of immuno-
compromised status due to leukemia, renal failure, metastatic
carcinoma, or AIDS with the susceptibility to actinomycosis is
marginal.73,78
3.1.3 | Pathogenesis
Actinomyces carries a very low potential for virulence and remains
mostly as an oral commensal. The bacterium is considered nei-
ther opportunistic nor communicable. The onset of actinomycosis
appeared to be multifactorial, as shown by its unpredictable as-
sociation with the extent of the mucosal breach. For instance, ac-
tinomycosis can develop after minor oral mucosal trauma, as in a
simple tooth eruption, whereas in other cases, even with significant
orofacial lacerations, there are no reported incidences of actinomy-
cosis.74 In addition, the repeated exposure of the site of mucosal
trauma to Actinomyces is also considered an important determinant
of actinomycosis onset.78
The organism prefers low oxidoreductive environments; thus,
the bacterium inhabits polymicrobial communities that create favor-
able anaerobic niches. During pathogenesis, Actinomyces destroys
highly vascularized mucosal tissues and replaces them with poorly
irrigated and scarcely vascularized granulated tissues; these, in turn,
further support the bacterial growth, providing favorable low ox-
ygen tension. Actinomycotic granulomata are histopathologically
presented as isolated granulomatous inflammatory lesions with
suppurative central necrosis or isolated foci of suppurative necrosis.
Filamentous “sulfur” granules develop in necrotic foci as a character-
istic “sunburst radiation” or furry appearance.73 Sulfur granules are
mineralized host calcium phosphate produced during inflammation
in the surrounding tissues. The ends of the sulfur granules may pro-
vide adhesion sites for neutrophils or other polymorphonucleocytes
to form club-­shaped extensions or rosettes.73 Actinomyces bacteria
can be seen within the aggregates of sulfur granules as well as the
outer margin of the necrotic core.73 The outer surface of the lesion
is covered with lipoid cells and encased in inflammatory cell popu-
lations consisting of lymphocytes, epithelioid cells, plasma cells, and
histiocytes and occasionally giant cells.72 The lesion is limited with a
remarkably avascular, collagenous, and fibrotic tissue. The lesion can
expand to surrounding tissues slowly with time when there are no
bony impediments.72
3.1.4 | Clinical presentation
Cervicofacial actinomycosis commonly affects the submandibular
region and rarely the maxillary antrum, salivary glands, and tongue.42
Approximately 50% of the cases affect the mandible itself, and
the remaining affected areas include cheek (15%), chin (15%), and
submaxillary ramus and angle (10%).79 Other nonodontogenic oro-
facial locations, such as the tongue, paranasal sinuses, middle ear,
larynx, lachrymal pathways, and thyroid gland, may also rarely be
affected.80-84
Typical presentation of the disease is a slow-­growing painless
indurated localized or diffuse mass that could lead to multiple ab-
scesses with discharging sinuses to skin or oral mucosa. Classically,
the discharge contains visible granules that are gritty to touch, yel-
low, and are known as “sulfur granules” (a descriptive term, as sulfur
is not found). These granules in pus are almost pathognomonic of the
BANDARA and SAMARANAYAKE
disease. Pain and trismus may occur in the advanced stage. Acute
suppurative episodes present with fever and pain. Fibrosis around
the swelling and the involvement of infected teeth are common.
Bone involvement is observed in approximately 10% of cases, and
regional adenopathy is rare.63-65,69,79,85
3.1.5 | Management
Dental panoramic radiography is mandatory to assess apical le-
sions, and computed tomography and magnetic resonance imag-
ing may be useful to assess any extensive bone involvement. 86
If a fluctuant abscess is present, aspiration biopsy must be con-
ducted to examine pus for the presence of “sulfur granules”; the
crushed granules are cultured anaerobically for 7 days to observe
colonies of typical “molar tooth” morphology (Figure 3). Biopsies
stained with hematoxylin and eosin and special stains such as
Gomori methenamine silver, p-­
a minosalicylic acid, McCallen-­
Goodpasture, and Brown-­B enn facilitate the identification in his-
topathological sections. 69 A Gram staining of a colony will reveal
moderate to large clumps of Gram-­p ositive branching filaments.42
It is important that specimens are collected and transported an-
aerobically and cultured in strict anerobic environment for up to
14 days in liquid or solid media, such as thioglycolate liquid media,
brain heart infusion, or blood agar.74 Pure cultures are needed to
be identified using immunological techniques using monoclonal
69
antibodies.
With other pathological conditions, such as tuberculosis (TB),
systemic mycoses, nocardiosis, periodontal abscess, and dentoalve-
olar abscess, that exhibit similar clinical manifestations, the diagno-
sis of orofacial actinomycosis can be challenging.63-65 In particular,
F I G U R E   3   Typical “molar tooth” morphology of Actinomyces
israelli colonies. From Samaranayake247
|
      155
early prescriptions of an antimicrobial prior to surgery may compli-
cate the pathogen identification, resulting in false-­negative findings.
Thus, it is usually recommended to discontinue antimicrobial ther-
apy 2 weeks prior to facilitate bacterial growth in cultures isolated
from patients with chronic mandibular osteomyelitis suspected to
have cervicofacial actinomycosis. However, patients with lumpy jaw
syndrome have always been prescribed anti-­actinomycotic drugs
regardless of the microbiological test findings.62
Acute lesions are managed by removal of any associated dental
focus, often necessitating dental extractions, incision and drain-
age of the facial abscesses, and a 2-­to 3-­week course of antibiot-
ics—penicillin being the drug of choice. However, poor vascularity
and solid capsule may delay/hinder the penetration of antibiotics,
penicillin in particular, into the lesion. 87 In the case of penicillin
hypersensitivity, erythromycin, tetracycline, and clindamycin are
considered good alternatives as they are claimed to penetrate
bone.72,88
In the case of subacute or chronic voluminous lesions surgi-
cal interventions such as marsupialization or excision and/or de-
bridement of necrotic bone are indicated. 63-65,69,89 Though there
are no reliable data from randomized controlled clinical trials on
antibiotic treatment regimens on chronic cervicofacial actinomy-
cosis, a longer antibiotic course up to 6 weeks may be necessary
for those who are chronically affected and surgically treated.
New concepts of adjunct therapy of antimicrobial agents, partic-
ularly beta lactamase inhibitors and metronidazole with forgoing
antibiotics are emerging; however, their efficacy is yet to be fully
established.90
3.2 | Syphilis
3.2.1 | Incidence
Syphilis, caused by Treponema pallidum, is a relatively common sexu-
ally transmitted infection. In 2008, 36.4 million infected adults and
10.6 million new cases of syphilis were reported worldwide.91,92
Syphilis was frequent in the early 1900s and was a leading cause
for heart and neurological diseases.93-95 There was a progressive
reduction of the prevalence of syphilis, and in 2000-­2001 the low-
est prevalence was reported (2.1 cases per 100 000 population) in
the United States.91,96-99 However, during the last two decades, the
disease has been resurgent in countries in North America, Europe,
Russia, and China.95-104 For instance, the primary and secondary
syphilis rate increased to 6.3 cases per 100 000 in the United States
in 2015.91 Sexual promiscuity, decreasing use of barrier protection
(ie, condoms), and HIV co-­infection are blamed for the change in
syphilis epidemiology.42
3.2.2 | Predisposing factors
More than 50%-­60% of new cases are reported among men who
have sex with men (ie, gay, bisexual, and other men who have sex
with men). HIV infection, high-­risk sexual behaviors, drug abuse,
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156       BANDARA and SAMARANAYAKE
increased travel and migration that indirectly increase the preva-
lence of HIV and other sexually transmitted infections, low educa-
tion, and alcohol use are associated with the increase in the incidence
of syphilis.93,100,103-106
3.2.3 | Pathogenesis
Despite a large number of in vivo studies having been reported in
animal models, the data on syphilis pathogenesis in humans are lim-
ited. This is likely due to the ethical considerations of clinical trials
of syphilis in human subjects. T. pallidum is assumed to penetrate
into the body through various degrees of skin or mucosal membrane
breaches.107-109 As evidenced in some animal and human studies,
the incubation period and onset of the primary syphilis are deter-
mined by the size of the initial inoculum of the pathogen.110,111 Once
entered through the skin/epithelial barrier, T. pallidum rapidly dis-
seminates to lymph nodes, brain, and aqueous humor, and in the cer-
112-114
ebrospinal fluid and other distal organs within hours. Infected
rabbit and human tissue samples have confirmed that T. pallidum is
capable of attaching to a wide variety of cell types, including epithe-
lial, endothelial, and fibroblast-like cells.115-118
Owing to the specific bacterial adhesin-­host ligand interactions,
it is said that the number of bacteria that can attach per host cell
is limited despite the size of inoculum being an important parame-
ter of the onset of the infection as mentioned above.113,116,119 Until
recently, the mechanism of T. pallidum attachment to cells was not
well understood. However, recent studies have indicated that the
tpr family of genes encode proteins that facilitate attachment to
host tissue.113,120 It is believed that host cell integrins act as the host
ligands for the treponemes.117 Interestingly, a tpr protein, Tpr K is
targeted by host opsonic antibodies and the opsonized T. pallidum
can be phagocytosed by activated macrophages.121,122 However, it
is argued that these proteins show antigenic variations through gene
conversions to avoid host immune response. Such theories are yet to
be established.113,119,123-126 T. pallidum is considered highly invasive,
and its motile nature facilitates this essentially critical virulence fac-
tor. T. pallidum is shown to penetrate endothelial cell monolayers and
118,127
intact membranes with extreme efficacy.
Irrespective of the stage, all syphilitic lesions exhibit character-
istic endarteritis and periarteritis in the vascular involvement stage
and granulomatous inflammation in the gummatous stage. In pri-
mary syphilis, rete ridges are widened and elongated with epidermal
128
hyperplasia. Once ulcerated, the infection site is covered with
an exudate rich in polymorphonuclear leukocytes, necrotic tissue
fragments, and fibrin. Adjacent dermis is infiltrated densely with
inflammatory cells, including lymphocytes, plasma cells, polymor-
phonuclear cells, and histiocytes. Swelling of endothelial cells can be
observed in the perivascular area in primary syphilis. Colonization
of T. pallidum can be seen at the dermal-­epidermal junction in the
129
perivascular area at this stage.
Secondary syphilitic lesions exhibit complex histological changes.
Almost every patient (75%-­100%) affected with the secondary stage
of the infection shows dermis infiltrated by dense populations of
lymphocytes and plasma cells. These infiltrates may progress into
granulomatous lesions. Endothelial swelling is spread to small blood
vessels. Epithelial cells in the epidermis exhibit a variety of changes,
including acanthosis, exocytosis, spongiosis, and parakeratosis.
Treponemes are present in up to 70% of affected individuals at this
stage.128,130
T. pallidum possesses several interesting mechanisms of immune
evasion. In particular, treponemes maintain few organisms in dis-
tant anatomical sites during the episode of infection, and there are
even lesser numbers in the latent stages, attributed to their slow
rate of cell division. As a consequence, bacteria manage to maintain
antigenic masses lower than the “critical” level that is required to
trigger a host response.131,132 Consequently, latent syphilis must
be treated by a prolonged course of penicillin to prevent treatment
failure.133,134 Nonetheless, detailed genetic, histopathological, and
clinical data derived from infected human tissues are essential to un-
ravel the physiological, pathological, and biochemical function and
processes of T. pallidum. Such knowledge, in turn, is likely to yield
better insight into the pathogenesis of syphilis and facilitate gener-
ating novel therapeutic targets.
3.2.4 | Clinical presentation
Syphilis has an incubation period of 10-­90 days (average 3 weeks)
and is characterized by four main clinical stages: primary, secondary,
tertiary, and late or quaternary.42
3.2.5  | Primary syphilis
After a 3-­to 4-­week incubation period, a primary chancre develops
at the site of entry. This is usually on genital mucosae but may be
seen in the mouth or oropharynx. A chancre is a flat, red, indurated,
painless, highly infectious ulcer with a clean base and a serous exu-
date. Ulcers are marginated with surrounding tissue edema, and the
size varies from 0.3 to 3 cm in diameter. However, clinical and re-
search reports have indicated that the morphologic presentation of
chancres could exhibit significant variability, making clinical diagno-
sis unreliable.135-137 The ulcerations can be single or multiple and last
for about 2-­8 weeks and regress spontaneously. About 7-­10 days
after the development of the genital chancre, 80% of cases develop
regional lymphadenopathies that are firm, painless, and discrete
with a rubbery consistency on examination.94,138-140
3.3 | Oral manifestations
Though the chancre primarily appears on genitalia, extragenital
primary lesions may occur in about 4%-­12% of patients with syphi-
lis.141-143 Approximately 40%-­75% of extragenital chancres occur in
the oral cavity, especially on the tongue, gingiva, soft palate, and
lips.144 A chancre of the lips is the most common extragenital orofacial
site, affecting 60% of cases (Figure 4). Chancres in the upper lip are
common in men, whereas the lower lip is more commonly involved in
women.42 In contrast to painless extraoral lesions, intraoral chancres
BANDARA and SAMARANAYAKE |
      157

buccal mucosa; gingival tissues are more rarely affected.138,141,143

The surface of these lesions is covered with a greyish membrane
that can be easily removed and contains many spirochetes.42,144
When multiple mucous patches become confluent, characteristic
“snail tracks” and mucous patches can result and are seen in about a
third of those affected (Figure 5). Nonspecific pharyngitis, tonsillitis,
and laryngitis are often associated with secondary syphilis, and le-
sions on the larynx and pharynx may cause hoarseness.141,143,149-151
Similar to the primary chancres, these lesions are also highly in-
fectious and heal spontaneously in 2-­6 weeks. The differential di-
agnosis of secondary syphilis includes aphthous ulcers, erythema
multiforme, lichen planus, and tonsillitis.42

F I G U R E   4   Primary syphilitic chancre at the angle of the mouth.

3.4.1 | Tertiary syphilis
From Samaranayake247 (Retraction is with the patient's fingers)
Tertiary syphilis is rarely seen today owing to advancement of
are usually slightly painful due to secondary bacterial infections, as disease control. However, if left untreated, one third of the cases
are the enlarged lymph nodes in the submaxillary, submental, and could develop tertiary syphilis at any time from 2 to 3 years after
cervical regions. Lesions are usually single and highly infectious.141-143 the primary infection.94,139,140 Gummata, the classical lesion in ter-
The differential diagnosis of primary syphilis includes ruptured vesi- tiary syphilis, develops in skin, central nervous system, liver, spleen,
cles of herpes simplex, traumatic ulcers, and carcinoma.42 bones, and other organs.94,139,140 These lesions range from a pinhead
size to several centimeters in diameter. They can present as solitary
or multiple lesions and are noninfective as the tissue damage is due
3.3.1 | Secondary syphilis
to a type IV delayed hypersensitivity reaction.42
Secondary syphilis develops 2-­
12 weeks after first contact and
2 months after healing of primary syphilis. However, it is not unusual
3.5 | Oral manifestations
to observe lack of demarcation between these two stages, as about
one third of patients with secondary syphilis may have primary chan- Gummata are usually isolated to the hard plate; however, the soft pal-
cres present at the same time.145-147 Secondary infection is due to ate, lips, tongue, and face are also relatively commonly involved.42,144
hematogenous dissemination of the pathogen and results in consti- The lesion initiates as a small, pale, raised area and rapidly develops to
tutional and mucocutaneous manifestations. The signs of secondary an ulcer that progresses to a large zone of necrosis. The process could
syphilis can vary among individuals and depend on the organs af- denude underlying bone, and palatal lesions may eventually perforate
fected. A skin rash with symmetrical 3-­10 mm pink or red macules, into the nasal cavity.42 The midline of the plate is usually affected, and
papules, or pustules are the frequently presenting clinical feature the involvement of soft palate is rare. The lesions are painless and have
(75% of cases) and can be located on arms, palms, flanks, and soles of low infectivity.42 In rare cases, syphilis can affect the mandible and
feet.94,138-140,148 A minor proportion of the infected population has maxilla in the form of osteomyelitis. The condition resembles pyogenic
experienced varying degrees of pruritic rash, though these rashes
are generally known to be nonpruritic.145 These lesions usually heal
within several weeks if left untreated and may result in scarring and
hyper-­or hypopigmentation. When the scalp is involved, a classic
“moth-­eaten” appearance can be observed as a result of alopecia
in up to 7% of affected individuals. Other symptoms include mul-
tiple mucous patches (33% of cases), generalized lymphadenopathy
(50% of cases), condyloma latum in intertriginous areas, and ocular
involvement (such as uveitis, iritis, optic neuritis), joint involvement
(arthritis, periostitis), glomerulonephritis, and neurological involve-
ment. Systemic symptoms are “influenzalike,” and include fever,
headache, weight loss, malaise, and general aches and pains.42,144

3.4 | Oral manifestations
F I G U R E   5   Secondary syphilis: Mucous parches (on the patient's
The classic oral lesions are slightly raised, greyish white, glisten- right) and a snail-­track ulcer (left) of the oral mucosa. From
ing multiple mucosal patches on the tonsil, soft palate, tongue, and Samaranayake247 (Retraction is with the patient's fingers)
 |
158       BANDARA and SAMARANAYAKE
osteomyelitis both clinically and radiologically, with symptoms of pain,
42
swelling, suppuration, and sequestration. Atrophic/interstitial glos-
sitis can also be the result in tertiary syphilis. Atrophy of the filiform
and fungiform papillae exposes the tongue to many noxious stimuli, and
leukoplakia frequently develops. However, the relationship between
42
tertiary syphilis and carcinogenic potential is yet to be determined.
Secondary and tertiary syphilis also have been reported in salivary
glands.42
3.5.1 | Congenital syphilis
T. pallidum is capable of crossing the placental barrier. Consequently,
the fetus can be infected during the second or third trimester from a
mother either in the primary or secondary stage of syphilis.42 If left
untreated, syphilis during pregnancy can lead to profound undesir-
able outcomes, including spontaneous abortion, premature delivery,
stillbirth, or perinatal death.152-157 Up to 40% of infants have been
reported to be born to untreated syphilitic mothers prematurely and
158,159
with low birth weights.
3.6 | Oral manifestations of congenital syphilis
Infection of the developing tooth germ by T. pallidum can result in
various dental anomalies. Deciduous teeth are minimally affected.
Infection of the developing permanent tooth germ results in either
the complete failure of development or a malformation. Early orofa-
cial manifestations of congenital syphilis include periostitis (frontal
bossing of Parrot), diffuse maculopapular rash, and rhinitis. Late mani-
festations, such as dental anomalies, sensorineural hearing loss, and
interstitial keratitis of the cornea, may appear at least 24 months after
birth.42
The common dental manifestations include small, hypoplastic
first permanent molar teeth with poorly developed cusps (“mulberry
molar” teeth) and the upper central incisors with crescentic notches
in the middle of the incisal edge (Hutchinson's incisors). Owing to
their calcification process during the first year of the infant's life, it
is mainly the permanent incisors and first molars that are affected
142
by congenital syphilis. Lower incisors are less affected. Infection
of the developing bones of the face may lead to open bite and a
“dished” appearance to the face.42 Atrophic glossitis, a high and nar-
row palatal vault and (Parrot's) radial scars (rhagades) of the lips are
42
less common manifestations.
3.6.1 | Management
Dark-­field microscopy and direct fluorescence using a fluorescein-
labeled antitreponeme serum is often used to identify the patho-
gen from the primary and secondary lesions.93,94,140,160,161 However,
both dark-­field microscopy and direct fluorescent antibody testing
carry limited value in distinguishing T. pallidum from the other patho-
119,161
genic treponemes.
Serological tests for syphilis can be either nontreponemal
tests for screening or treponemal tests for confirmation.93,94,161
Nonspecific nontreponemal reaginic antibody tests such as the
Venereal Diseases Research Laboratory test, rapid plasma reagin
test, and microhemagglutination assay are inexpensive, rapid, and
convenient for screening a large number of sera.144 Nontreponemal
tests detect an anticardiolipin antibody present in the syphilitic pa-
tients’ sera using an antigen comprising lecithin, cholesterol, and
purified cardiolipin. These antibodies can be used to monitor the
efficacy of antimicrobial therapy.42 However, nontreponemal tests
are known to possess less sensitivity in early and late syphilis, with a
higher ratio of false-­positive reactions. False-­positive reactions are
more prominent with increased age, pregnancy, malignancy, drug
addiction, and autoimmune diseases (eg, systemic lupus erythema-
tosus) and viral, protozoal, or mycoplasmal infection.158,161-163 The
treponemal tests are considered most sensitive and specific.94,161
These tests include T. pallidum hemagglutination test, fluorescent
treponemal antibody-­absorption test, which detects both immuno-
globulin (Ig)M and IgG antibody, and enzyme-­linked immunosorbent
assay.42 With recent advances in diagnostics, PCR and multiplex PCR
have been applied in identifying T. pallidum DNA and are known to
possess very high sensitivity and are becoming increasingly popular
in routine clinical use.119
Despite the diagnosis of syphilis being based on clinical presen-
tation and serological findings, in rare cases, such as oral lesions
and unusual presentations in HIV-­positive patients, histopatholog-
ical examinations can be used to confirm the diagnosis.94,140,164-166
These reveal a characteristic histopathological picture, such as focal
collections of plasma cells, angiogenesis, dilation and thickening of
blood vessels, mural edema and large endothelial cells, perivascular
infiltration of plasma cells in secondary syphilis, and vasculitis and
fibrinoid materials with necrosis in so-called “malignant” syphilis.
The drug of choice for all forms of syphilis is procaine benzyl-
penicillin. doxycycline, tetracycline, or erythromycin can be effec-
tive for patients hypersensitive to penicillin. Follow-­up with regular
clinical and serological examinations is necessary for at least 2 years,
and contact tracing is recommended.42,140,144,167 The type, dose,
and the duration of the antibiotic treatment is determined by the
stage of syphilis. Factors such as the degree of spirocheticidal action,
variability in absorption, level of patient compliance, and individual
circumstances, such as pregnancy, must also be considered when
determining the choice of antibiotic.168,169 Some studies have shown
that there is a likely potential of T. pallidum to develop antibiotic re-
sistance; however, there are no follow-­up studies conducted or mea-
surable penicillin resistance reported so far.168,170
3.7 | Tuberculosis
3.7.1 | Incidence
TB is caused by various strains of mycobacteria, usually
Mycobacterium tuberculosis in humans.171 According to the World
Health Organization report in 2013, nearly 8.6 million people world-
wide became infected with TB. There were around 1.3 million TB-­
related deaths worldwide in 2013.172
BANDARA and SAMARANAYAKE
Oral lesions due to TB are extremely rare and seen in only 0.1%-­
172
5% of all TB infections. They may be due to secondary inoculation
with infected sputum or arise from hematogenous spread. Recent
outbreaks of extrapulmonary infections of TB are reported due to
the emergence of drug-­resistant TB and AIDS.173,174
3.7.2 | Predisposing factors
Crowded urban living, poor health and hygiene, poverty, drug abuse,
AIDS, and immunosuppression are established predisposing factors
for the development of TB.175 In addition, local factors such as poor
oral hygiene, local trauma, and irritation may facilitate the pathogen
to invade oral mucosa.176-178
3.7.3 | Pathogenesis
Alveolar macrophages express various surface receptors, such as
C-­t ype lectin receptors (eg, macrophage mannose receptors), scav-
enger receptors (eg, Class A and B scavenger receptors), and com-
plement receptors (eg, complement receptor 3), to bind and ingest
M. tuberculosis when first inhaled and reach the distal alveoli.179
Although studying mycobacteria and receptor interactions is dif-
ficult due to the complexity of uptake mechanisms, it is believed
that the intracellular fate of ingested bacteria depends on the spe-
cific receptor.180-182 Despite most studies on mycobacterial entry
having been conducted on alveolar macrophages, other phago-
cytic cells, such as neutrophils, monocyte-­d erived macrophages,
and dendritic cells, within alveoli are also capable of ingesting
mycobacteria.183 It has long been believed that once ingested, M.
tuberculosis prevents maturation of the phagosome using various
mycobacterial lipid and protein effectors to reside long term in it
(“intracellular bacterial trafficking”).182 The arrest of phagosome
maturation allows the mycobacteria to prevent development of
an intraphagosomal acidic, degradative environment as well as to
acquire nutrients by recycling endosomes.184 Recent findings sug-
gested that the bacterium can even continue to grow and prolifer-
ate within the immature phagosome.185-187 As a consequence of
complex interactions between the intracellular mycobacteria and
the host cells, the latter undergo necrosis or apoptosis. Necrotic
macrophages containing mycobacteria trigger recruitment of new
macrophages and initiate granuloma formation.188 The necrotic
cells are rapidly ingested by newly recruited macrophages, allow-
ing remaining mycobacteria to further expand the population. 3,68
Importantly, a fraction of infected macrophages depart from the
189,190
early granuloma to initiate infection at distant sites.
3.7.4 | Oral manifestations
Oral TB can be present as ulcers, tuberculomas, and nodules,178,191,192
and it commonly affects the tongue. Other frequently affected sites
include the palate, lips, buccal mucosa, gingiva, palatine tonsil, uvula,
191
floor of the mouth, and salivary glands. Occasionally, a periapical
granuloma may develop as a result of TB.
|
      159
Primary oral TB lesions are rare, and usually affect young
adults. The lesion typically presents as a single painless ulcer as-
sociated with enlarged regional lymph nodes. Most commonly,
these lesions are secondary to pulmonary disease. These le-
sions appear as single, indurated, irregular, painful ulcers cov-
ered by inflammatory exudates. Classically, tuberculous ulcers of
the tongue are pale, irregular, and indolent with inverted mar-
gins and granulations on the floor with sloughing tissue and are
often misdiagnosed as malignant ulcers.193 Though individuals in
any age group may be affected, the disease is more common in
the middle-­a ged and elderly. Medically compromised individu-
als, such as those with HIV disease, may exhibit TB at younger
ages.172,178,194
3.7.5 | Management
Diagnosis of tuberculosis is often made with history, clinical ex-
amination, chest X-­ray, and sputum cultures and histopathology for
detection of acid-­fast bacilli. Oral TB lesions can be diagnosed in
biopsies for the presence of acid-­fast mycobacterium using Ziehl-
Neelsen stain. Fine-­needle aspiration cytology is indicated for iden-
tifying TB in the major salivary glands.172,195
The management of oral manifestations of TB must be co-
ordinated in liaison with a respiratory physician, and a full work
up of the patients is necessary. The current regimen of anti-­T B
therapy is based on daily administration of a combination of four
drugs (isoniazid, rifampicin, pyrazinamide, and ethambutol) for
the first 2 months, followed by a course of two drugs (isoniazid
and rifampicin) for an additional 4 months.192 The World Health
Organization launched the directly observed therapy short course
in 1997 due to the complexity of the traditional TB management
regimen.172
Drug resistance of M. tuberculosis is a global issue of major con-
cern. Approximately 580 000 multidrug resistant cases have been
estimated in 2015.196 Multidrug-­resistant TB exhibits resistance to
first line anti-­TB medications (isoniazid and rifampicin), while ex-
tensively resistant-­TB is resistant to both first-­line and second-­line
agents (aminoglycosides and/or cyclic polypeptides—capreomycin,
kanamycin, and amikacin) and fluoroquinolones. Fifty percent of
reported multidrug-­resistant TB patients showed resistance to a
fluoroquinolone, to a second-­line injectable drug, or both.196 Novel
drugs, such as nitroimidazoles, diarylquinolines, and oxazolidinones,
have been recently introduced to overcome both multidrug-­and ex-
tensively resistant-­TB.172
Precautions must be taken by dental practitioners when treat-
ing patients with tuberculosis. Thorough medical history must be
taken, and only essential treatments should be provided for those
with active TB. Usage of routine barrier protection to prevent con-
tact with blood, body fluids, and mucous membranes of the patient,
with standard infection control protocols and an appropriately
equipped room with effective air evacuation are recommended.172
The oral cavity may manifest many other rare bacterial infec-
tions. Please refer to Table 2 for further information.
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160       BANDARA and SAMARANAYAKE
4 |  FU N G A L I N FEC TI O N S
Fungi are a large, complex group of eukaryotes, increasingly rec-
ognized as emerging pathogens. The traditional thinking was that
Candida species were the major eukaryote present in the oral cavity.
However, the arrival of new methodologies, such as pyrosequenc-
ing and new-­generation sequencing techniques, have revolution-
ized the traditional views and have revealed a novel oral mycobiome
197
hitherto unimagined. For instance, recent data indicate a high
prevalence and abundance of the genus Malassezia, an important
pathogen of the skin, in the healthy human oral cavity. Despite
these findings, Candida infections remain as the predominant fun-
gal infections that are seen by dentists. It is noteworthy, however,
that rare fungal diseases caused by species such as Histoplasma,
Geotrichum, Penicillium, and Aspergillus species, essentially seen in
compromised population groups, are not discussed in the following.
4.1 | Candidiasis
4.1.1 | Epidemiology
Oral candidiasis is the most common human fungal infec-
tion.198,199,200 It is estimated that approximately 5%-­7% of infants
less than 1 month old, and 9%-­31% of AIDS patients, 65% of denture
wearers, and nearly 20% of cancer patients develop oral candidi-
asis.199,201 Candida carriage in the oral cavities of the general popula-
tion is reported to be between 20% and 75%. 200 In particular, 45%
of neonates, 45%-­6 4% of healthy children, 30%-­45% healthy adults,
50%-­65% of those who wear removable dentures, 65%-­68% of indi-
viduals in acute and long-­term care facilities, 90% of patients under
chemotherapy for acute leukemia, and 95% of patients with HIV in-
fection carry Candida albicans in their mouth. 202-211
4.1.2 | Predisposing factors
Similar to many other opportunistic infections, candidiasis generally
occurs in immunocompromised patients. Oral candidiasis is usually
seen in patients with impaired salivary gland functions, on medica-
tions (such as steroid inhalers, psychotropic drugs, immunosuppres-
sives, and broad-­spectrum antimicrobial therapy), denture wearing,
high-­carbohydrate diets, age (infants and older geriatric populations),
smoking, diabetes, malignancies, Cushing's syndrome, HIV/AIDS and
other immune-­deficient conditions.199 In essence, oral candidiasis is
a disease of the “very young, the very sick and the very old.”
4.2 | Pathogenesis
Candida spp. possess a wide variety of virulence attributes to facil-
itate their colonization and causation of superficial and/or deep-­
seated systemic infections. Like most other microbial pathogens,
the key to infect the host by Candida is its successful coloniza-
tion within the host tissues. In susceptible individuals, Candida at-
taches to the epithelial surfaces and acquire nutrients from the
host to generate pathogenic colonies. This process of colonization
is mediated by an array of Candida virulence factors, which include
adhesins, hydrolytic enzymes, formation of hyphae, phenotypic
switching, and molecular mimicry. 212,213 Adhesins, arguably one of
the most vital virulence determinants of Candida, are a specialized
set of proteins that facilitate the fungus to adhere to both biotic
and abiotic surfaces. Among these adhesins are agglutinin-­like
sequence proteins, 214217 morphology-­associated proteins (eg, hy-
phal wall protein; Hwp1), and morphology-­independent proteins.
These include glycosylphosphatidylinisotol-­linked proteins (Eap1,
Iff4, and Ecm33), cell-­surface-­associated proteases (secreted as-
partyl proteinases: Sap9 and Sap10), noncovalent wall-­associated
proteins (putative β-­glucanase: Mp65; and β-­1,3-­glucanosyl trans-
ferase: Phr1), and the integrin-­like surface protein (Int1), which
have been shown to mediate Candida adhesion. 218,219 Despite the
existence and the role of extracellular proteinases most dimorphic
human pathogenic fungi are yet to be fully elucidated, the proteo-
lytic system of C. albicans is well understood. 220,223 Recent stud-
ies suggested that non-­a lbicans Candida species, such as Candida
dubliniensis, 224 Candida tropicalis, 225,227 and Candida parapsilo-
sis, 225,228 also possess the machinery of synthesis of secreted as-
partyl proteinases (Sap), major class of extracellular secreted by
C. albicans. Interestingly, Sap production is interlinked with other
Candida virulence attributes, such as adhesion (Sap 9 and 10),
hyphal formation, and phenotypic switching. The precise role of
secretory proteinases during human infections is yet to be fully
established. 213 Although morphological switching such as forma-
tion of hyphae is well known to assist Candida attachment, the role
of white opaque switching is yet to be fully unraveled.
Unlike most other pathogens, Candida utilizes more than a
single mechanism of tissue invasion; that is, induced endocytosis
and active penetration. 218,219,229,230 During induced endocytosis,
Candida binds to host ligands such as E-­c adherin on epithelial cells
and N-­c adherin on endothelial cells using invasins, a group of spe-
cialized cell surface proteins. 216 Fungal invasin-­h ost ligand interac-
tion triggers host cell mechanisms of fungal engulfment. Candida
Als3 and Ssa1 have been identified as two major cell surface in-
vasins that induce endocytosis. 216,231 Interestingly, the viability
of the yeast or the morphological status do not play a critical role
during engulfment. 229,232 In contrast, only viable Candida is capa-
ble of penetrating host tissues and hyphae play an essential role
in active penetration. Despite little being known about the driving
factors of invasion of epithelium by hyphae, the latest evidence
suggests that fungal adhesion and physical forces, Sap proteins,
but not lipases and phospholipases, may mediate active penetra-
tion. 229,218,233 Once invaded, Candida continues to degrade host
proteins using hydrolytic enzymes and establishes a superficial
candidiasis. 218 In some cases, Candida continues to penetrate tis-
sues and blood vessels to develop deep-­s eated infections. There
are many mechanisms described in relation to immune evasion of
Candida, particularly using immune modulators and host mimicry,
but these are beyond the scope of this review. Deep-­s eated infec-
tions, with continuing host immune suppression, such as in HIV
BANDARA and SAMARANAYAKE |
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TA B L E   2   Bacterial infections in the oral mucosa: the epidemiology, predisposing factors, clinical presentation, diagnosis and treatment
options of primary and oral manifestations of systemic bacterial infections

Infection Incidence Predisposing factors Oral clinical presentations Diagnosis Treatment

Leprosy (Hansen’s • Caused by • Mouth breathing, which Nonspecific lesions: • History, clinical • Multidrug therapy of
disease) Mycobacterium lowers the temperature, • Exanthem of palate or uvula examination rifampicin, clofazi-
leprae especially over the dorsum Specific lesions: • Lepromin skin test mine, and dapsone
• 19%-60% of leprosy of the tongue and the hard • Lips: Flat-topped nodules, for microbiological aiming to eliminate
cases involve in oral and the soft palate307,308 macrocheilia, identification of M. leprae effectively in
cavity305 • Males > Females309 microstomia311 M. leprae318 the shortest possible
• Anterior hard palate • People living in leprosy- • Tongue: multiple superficial time to prevent
is the most endemic areas and patients ulcers, mild glossitis, loss of resistance from
frequently affected with leprosy papillae, fissured tongue, occurring
oral site (75%), seropositivity310 nodules of anterior tongue, • The duration of
followed by the soft • Crowded households310 atrophy, pavement-like therapy
palate, labial appearance 312-314 12-24 months319
maxillary gingival, • Buccal mucosa: diffuse
tongue, lips, buccal infiltration, papulonodules
maxillary gingival, and ulcerations, pale mucosa
labial mandibular • Hard and soft palate: loss of
gingival, and the shininess of the mucosa,
buccal mucosa306 erythematous papules,
nodular submucosal
infiltrate, palatal ulcerations,
palatal perforations315,316
• Uvula and fauces: military
papules and nodules,
triangular deformity of
fauces 315,316
• Dental: gingivitis,
periodontitis, periodonto-
clasia, specific pulpitis,
periapical granulomas317
Anthrax • Caused by Bacillus • Individuals who work with • Painful swelling in the hard • Bacteriological tests • The antibiotic of
anthracis animals, eat contaminated palate • Identification of the choice is penicillin or
• Primarily a disease meat or handle animal • Radiographic evidence of pathogen in swab/ doxycycline320,318
of animals, anthrax products such as hides, alveolar bone loss around blood cultures • Chloramphenicol,
is now extremely skins, bone meal, hair or the upper molar teeth • Antibiotic- erythromycin,
rare in the Western bristles318 • Mucosal lesions in plate, susceptibility testing tetracycline, or
world and very rare • Spores enter abrasions on tongue and tonsils should be performed ciprofloxacin can be
in the orofacial the skin or are inhaled318 • Marked edema on all isolates administered to
region318 • Vesicular lesions of the oral • Serologic and patients who are
• Could be a mucosa which quickly immunologic tests320 allergic to penicillin320
secondary to ruptured and formed scabs • Detection of capsular • Prophylaxis320
gastrointestinal • Oropharyngeal lesions antigen, protective • Six-week course of
form320 • Located in tonsils, antigen, lethal factor doxycycline or
posterior pharyngeal wall, or edema factor ciprofloxacin for
or hard palate and • The skin test asymptomatic patients
appeared ulcerated or • Chemical extract of with suspected
pseudomembranous an attenuated strain exposure to anthrax
• Fever and nec swelling of B. anthracis spores
• Sore throat • Suitable for both • Standard anthrax
• Dysphagia rapid diagnosis of vaccine in the United
• Marked lymphadenitis acute cases and the States for persons at
• Gingival bleeding318,321, 322 retrospective analysis risk for exposure to
of anthrax infections anthrax spores
Tetanus • Caused by Clostridium • Maternal infection occurs • Tonic rigidity of the muscles • Clinical history and • Administration of
tetani after abortion, miscar- of mastication presentation antitoxin, preferably
• Rare in developed riages, or unhygienic • Stiffness of the face • The isolation of human tetanus
countries due to high delivery practices324 followed by difficulty in C. tetani from the immunoglobulin
immunization rates323 • Neonatal tetanus infection chewing and swallowing wound is often • Thorough wound
• Infection is most usually occurs through the • Edentulous patient may difficult318 debridement
likely in older people umbilical stump after complain of an inability to • Antibiotics, usually
who have never been delivery324 insert his/her dentures penicillin, and
immunized or who • Individuals who may • Increase in the spasms of the sedatives to control
have waning and contact animal excreta324 muscles of mastication till muscle rigidity and
inadequate immunity the jaws are locked and the spasm325
• Common in mouth cannot be opened
developing countries • Involvement of muscles of
with low immuniza- facial expression: risus
tion rates323 sardonicus318
(Continues)
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162       BANDARA and SAMARANAYAKE

TA B L E   2   (Continued)

Infection Incidence Predisposing factors Oral clinical presentations Diagnosis Treatment

Meningococcal • Caused by Neisseria • Age: highest in adolescents • The organism initially • Clinical presentation • Intravenous or
meningitis meningitidis • Intimate personal contact colonizes and proliferates • Grams stain with or intramuscular
• Serogroup A • Crowding (eg, bars, in the nasopharynx without culture of injections of
N. meningitidis causes dormitories), and smoking • Petechial rash develops on cerebrospinal fluid, benzylpenicillin,
the highest incidence • Closed populations (eg, the trunk, limbs, and face or blood or skin cefotaxime,
of disease military recruits, Hajj in 50% of the patients with lesions. ceftriaxone, or
• Meningococcal pilgrims)326 acute meningococcal • Antigen and nucleic chloramphenicol
disease can vary in meningitis acid detection • Increase the
incidence from very • Petechiae may also be systems, eg, circulating blood
rare to over 1000 found on the oral mucous serogrouping and volume by fluid
cases per 100 000 membrane and conjunc- multi-locus sequence treatment326
population every year tiva. Large oral mucosal typing using
• Highest risk in lesions in severe fatal polymerase chain
Sahelian and forms of the disease. reaction326
sub-Sahelian Meningococcal pharyngitis
countries of Africa was reported318,327
(the African
meningitis belt), in
eastern and southern
Africa326
Brucellosis • Caused by Brucella • Individuals who are in • Oral manifestations are • Agglutination • Week course of a
spp. contact with animals, eg, very rare reaction (Wright combination therapy
• Pathogenicity of five veterinarians, veterinary • Red and edematous reaction) with blood of streptomycin and
Brucella species for technicians, insemination gingivae with numerous serum: anti-Brucella tetracycline is
humans has been service employees, zoo small ulcers with greyish agglutinins recommended318,332
confirmed: technicians, farmers surfaces • Complement fixation
B. melitensis, B. working on multi-herd • Enlarged and tender test: detection of the
abortus, B. suis, B. farms (production anterior cervical and level of antibodies of
canis, and B. cooperatives), eg, submental lymph nodes. 318 the IgG class
marina328 cattlemen, also private Infections in follicular cyst • Coombs antiglobulin
• Countries at high farmers, employees of of impacted maxillary third reaction
risk: the countries of slaughter houses and meat molar tooth and from the • Coagglutination test
the Mediterranean processing enterprises parotid gland330,331 • 2-Mercaptoethanol
Sea Basin (Portugal, • Individuals who consume agglutination test
Spain, south France, infected milk products329 • Burnet’s skin allergy
Italy, Greece, Turkey, test 329
North Africa)
• Also, countries of
South and Central
America, Asia, Africa
• The Caribbean and
Near East329
Acute necrotizing • Precise etiology is • Patients with HIV • Can be localized or • History (medical/ • Debridement of the
ulcerative unknown • Poor socio-economic status generalized dental) and clinical lesions under local
gingivitis • Caused by a group • Children between 3 and • Rapid/sudden onset and presentation are anesthesia
of microorganisms 10 years 333 intense pain diagnostic339 • Oral hygiene
that include • Psychological stress and Primary features improvement
Treponema spp., anxiety • Ulcerated and necrotic • Chlorhexidine 1.12%
Selenomonas spp., • Smoking papillary and marginal mouth wash twice daily
Bacteroides • Pre-existing gingivitis and gingiva • Pain control with
melaninogenicus trauma • Cratering of papillae analgesics ibuprofen
ssp., Bacteroides • Poor oral hygiene • Intense gingival pain and 400-600 mg three
intermedius and • Deficient nutrition339 spontaneous bleeding times daily
Fusobacterium spp. Secondary features • Antibiotics for
• Was first reported • Foul breath immunocompromised
in military personnel • “Pseudomembrane” (eg, AIDS, leukemia,
in western Europe (yellowish-white or grayish cyclic neutropenia)
and North slough) covering ulcerated patients or in case of
America333 papilla systemic involvement
• Prevalence in HIV • Lymphadenopathy • Amoxicillin, 250 mg
patients • Fever and malaise 3 × daily for 7 days and/
4.3%-16%334-336 • If left untreated, it can lead or
Prevalence in children to necrotizing ulcerative • Metronidazole, 250 mg
in sub-Saharan periodontitis and 3 × daily for 7 days
African countries necrotizing stomatitis or • Assess treatment
(age 3-10 years) as noma339 outcomes in 24 hr, then
high as 23%337,338 once in 2 days until
gingival health and
function are restored339
BANDARA and SAMARANAYAKE |
      163

and malignancies, may lead to disseminated infections. In such

events, Candida is capable of adhering to endothelial cells, infect-
ing distant organs, and triggering coagulation cascades, resulting
in serious complications to the host. 213,218

4.3 | Clinical features
Oral candidal infections can be essentially subdivided into three
groups as pseudomembranous, erythematous, and hyperplastic
variants, as discussed in the following. There are also a number
of other conditions, such as Candida-­associated denture stoma-
titis, angular cheilitis, median rhomboid glossitis, and the newly
described entity linear gingival erythema, which are multifactorial
in nature and not necessarily associated with candidal infections.
In clinical terms, these lesions do not often resolve by antifungal
therapy, and there may be other underlying reasons for the disease F I G U R E   7   Acute atrophic candidiasis of the palate in an HIV-­
condition. affected individual. From Samaranayake247

4.3.3 | Chronic hyperplastic candidiasis

4.3.1 | Pseudomembranous candidiasis (thrush)
Well-­
d emarcated, slightly elevated and adherent, nodular,
Oral thrush characteristically appears as extensive white plaque-
speckled or homogeneous white or translucent lesions occur
like pseudo membranes that can be easily wiped off to expose un-
characteristically on the buccal mucosa or lateral border of the
derlying erythematous mucosa. The lesions are commonly seen at
tongue 238,239 (Figure 8). Unlike the pseudomembranous variant,
labial and buccal mucosae, tongue, hard and soft palate, periodon-
these lesions cannot be wiped off. 239 The lesions may progress
tal tissues, and oropharynx (Figure 6). One third of oropharyngeal
into severe dysplasia or malignancy, and thus are referred to as
candidiasis is reported to be of pseudomembranous type.199,234
candidal leukoplakia. However, the association of Candida and the
malignant potential is still questionable. 240 There is a known asso-
4.3.2 | Erythematous (atrophic) candidiasis ciation between chronic hyperplastic candidiasis and smoking. 241

This is often asymptomatic, but in some cases the principal complaint

is a burning sensation of the oral mucosa, particularly the tongue
(Figure 7). The latter appears to be bright red and sometimes depapil-
lated due to loss of filiform papillae.235 The appearance of the tongue
mimics the manifestations of the tongue in serum B12, folate, or ferri-
tin deficiencies. “Antibiotic sore mouth” is commonly associated with
usage of broad-­spectrum antibiotics or steroid inhalers.199,236,237
4.3.4  | Candida-­associated lesions:
Denture stomatitis
Previously known as chronic atrophic candidiasis, this condition is
perhaps the most common fungal infection in the denture-­wearing
elderly. These lesions can commonly be seen as an erythematous
and edematous area in the palatal denture-­bearing mucosa, and less

F I G U R E   6   Pseudomembranous candidiasis of the palate in HIV-­ F I G U R E   8   Chronic hyperplastic candidiasis at the commissures
infected patient. From Samaranayake247 of the mouth. From Samaranayake247
 |
164       BANDARA and SAMARANAYAKE

commonly on the mandibular mucosa. 235 The denture stomatitis is

usually asymptomatic; however, mild soreness or burning sensations
may occur in some cases. Depending on the severity, denture sto-
matitis is further classified into three groups: type I (localized, simple
pinpoint inflammation or erythema; Figure 9); type II (diffuse, ery-
thematous lesions covering a part or entire denture-­bearing area;
Figure 10); and type III (granular or papillary lesions appearing on the
alveolar ridge or in the middle of the palatal mucosa; Figure 11). 242

4.3.5 | Candida-­associated lesions: Median

rhomboid glossitis
Median rhomboid glossitis, which is also known as central papillary at-
rophy, is a variant of erythematous candidiasis.243 Lesions are a well-­
demarcated, erythematous, elliptical or rhomboidal area of papillary F I G U R E   1 1   Type III chronic atrophic candidiasis. Note the
atrophy in the dorsum of the posterior tongue in front of the circumval- papillary hyperplasia of the palatal mucosa. From Samaranayake247

late papillae 244 (Figure 12). In some patients, the palate can also be af-
fected, resulting in what are called “kissing lesions.” Kissing lesions are the result of direct candidal inoculation to the palate from the lesions in the
dorsal tongue. Hence, this often called chronic multifocal candidiasis.235

4.3.6 | Candida-­associated lesions: Angular cheilitis

Angular cheilitis is characterized by erythema, crusting, and fissuring
and maceration (Figure 13). These chronic inflammatory lesions can
be exclusively seen in the labial commissures and often isolated bilat-
erally.244 Angular cheilitis is often seen in the older population due to
accentuated skin folds, as well as due to reduced occlusal vertical di-
mension, which results in pooling of saliva and providing optimal growth
conditions for Candida. In addition, lip sucking, nutritional deficiencies
such as iron, vitamin B and high-­carbohydrate diets are associated with
the pathogenesis of angular cheilitis.235 Angular cheilitis is strongly as-
sociated with mixed infections of Candida and Staphylococcus spp.245

F I G U R E   9   Type I chronic atrophic candidiasis. Note the localized, 4.3.7 | Linear gingival erythema
simple pinpoint erythema in the palatal mucosa. From Samaranayake247
This condition, defined as a localized or generalized erythema-
tous band extending along the gingival margins (between adjacent

F I G U R E   1 0   Type II chronic atrophic candidiasis. Note

the edematous denture-­bearing mucosa of the palate. From F I G U R E   1 2   Median rhomboid glossitis. Note the characteristic
Samaranayake247 midline lesion. From Samaranayake247
BANDARA and SAMARANAYAKE
F I G U R E   1 3   Angular cheilitis. Note the yellow crusting due to
superinfection by staphylococci. From Samaranayake247
gingival papillae), was first described in HIV-­infected individuals; it
is, however, not confined to the latter group. Although Candida is
implicated in the pathogenesis, and lesions resolve after antifungal
therapy in some cases, it is likely that other cofactors, such as oral
hygiene, play an equally important role.
4.3.8 | Candidiasis and immunocompromised hosts
A few patients have chronic candidiasis from an early age, some-
times with a definable immune defect, eg, chronic mucocutaneous
candidiasis. Candidal infections in these patients are seen in the oral
mucosa, skin, and other body parts. These secondary oral candidal
infections have increased recently because of the high prevalence
of attenuated immune response, consequent to diseases such as
HIV infection, hematological malignancy, and treatment protocols,
including aggressive cytotoxic therapy.
4.3.9 | Oral candidiasis in HIV disease
Candidal infections, with oral thrush and esophagitis as frequent
clinical manifestations, are the most common opportunistic in-
fections encountered in AIDS. It has also been shown that the
occurrence of an otherwise unexpected mycosis (typically oral
candidiasis) in HIV-­infected individuals is a poor prognostic in-
dicator of the subsequent development of full-­
b lown AIDS.
However, in HIV-­infected populations on antiretroviral therapy,
the incidence of oral candidiasis has significantly declined.
4.3.10 | Management of oral candidiasis
Diagnosis of oral candidiasis is often made with a thorough history
and the clinical examination findings. Some laboratory investiga-
tions can also be used as adjuncts to confirm the clinical presenta-
tion. Candida pathogens in a smear taken directly from the lesion
are commonly identified using Gram staining or periodic acid Schiff
staining, or by culturing the pathogen in Sabaraud's dextrose
|
      165
agar. 246,247 Biopsies are useful in identifying the organisms and hy-
phae, together with histopathological changes in chronic hyperplas-
tic candidiasis. 248
Treatment of oral candidiasis is primarily based on the identi-
fication of underlying predisposing factors and correcting them.
Nutritional deficiencies, broad-­spectrum antibiotics and inhalational
steroids usage, diabetes mellitus, poor oral and denture hygiene,
ill-­fitting dentures, and salivary disorders need to be identified and
corrected. When the predisposing factors cannot be corrected, anti-
fungal agents are indicated. 238,249 The choice of the antifungal agent
is based on the clinical presentation and the medical history of the
patient. Most oral candidiasis can successfully be treated with topi-
cal azoles or polyenes.
Effective topical dosage of nystatin includes oral suspensions
(100 000 units/mL, 1 mL topically), or pastilles (100 000 IU, four
2 weeks). 249 Recommended amphotericin dos-
times daily for 1-­
age for oral candidiasis includes lozenges (10 mg) or suspension
(100 mg ⁄mL) four times daily for 2-­3 weeks. 238 Topical application of
miconazole 2% gel, four times daily for 2-­3 weeks, is also effective
against oral Candida infections. For refractory and recurrent oral
candidiasis, systemic antifungals such as ketoconazole, fluconazole
and itraconazole and amphotericin may be indicated. 249 The inabil-
ity of most antifungals to penetrate robust Candida biofilms have
resulted an ongoing challenge for both clinicians and researchers
when determining an efficient and appropriate management strat-
egy in eliminating Candida infections. In particular, efficient, low
side-­effect–carrying antifungals such as fluconazole are known to
fail in eradicating Candida biofilms. 250,251 Consequently, in recent
years, studies have been conducted in identifying novel treatment
options, such as usage of probiotics, plant derivatives, and photo-
dynamic therapy, for managing mucosal candidiasis. 252-255 Although
in vitro laboratory findings of these studies are promising, detailed
clinical evidence is necessary prior to implementing such treatment
strategies.
In addition to candidiasis, several other mycoses also cause
characteristic oral lesions. The reader is referred to Table 3 for
these rare, important fungal infections that may manifest in the
oral cavity.
5 | CO N C LU D I N G R E M A R K S A N D FU T U R E
PE R S PEC TI V E S
Global pandemics are still a major concern in health care and economic
setups, and emergence and re-­emergence of infections is not a new
phenomenon. Despite consistent uplift of primary health care, serious
infections such as HIV and TB still kill millions of individuals worldwide.
Factors such as ever-­increasing voyage frequencies of the world popu-
lation, environmental damage and natural disasters, overcrowding and
poor sanitation, human-­animal interactions, and rising sexual prom-
iscuity will continue to challenge the human body with a plethora of
hitherto characterized and new microbial pathogens, which will result
in new or re-­emergence of localized and/or general infections.
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TA B L E   3   Fungal infections in the oral mucosa: the epidemiology, predisposing factors, clinical presentation, diagnosis and treatment
options of primary and oral manifestations of systemic fungal infections

Disease Incidence Predisposing factors Clinical features Diagnosis Management

Aspergillosis • Second most • Increased risk in the • Portal of entry: • PAS-stained • Antifungal therapy
prevalent opportun- hospital setting, marginal gingiva and sections; fungal depends on the
istic fungal construction activities, gingival sulcus 344 culture location of the
infection340 rotten leaves or Oral lesions • Serology—circulat- primary infection.
• Aspergillus fumigatus insufficient • Painful gingival ing antigen • Amphotericin B,
is the most cleaning of dust can ulcerations and galactomannan itraconazole,
commonly isolated increase the risk of mucosal soft tissue • Tachypleus or voriconazole,
Aspergillus spp. in developing swellings with grey or limulus assay posaconazole, and
human341 aspergillosis342 violaceous hue (1→3)-β-d- caspofungin are
Immunocompromised • Necrosis occurs and glucans349353 approved by FDA
status343 results yellow or black • PCR (extensively
color, necrotic • Biopsy and reviewed by
ulcerated base345 histopathol- Walsh355)
• Often located on the ogy341,354
palate or posterior
tongue346,347
• Aspergillus hyphae
may invade the oral
mucosa and penetrate
the walls of small to
medium-sized blood
vessels, causing
thrombosis, infarc-
tion, and necrosis,
leading to systemic
spread 348
Histoplasmosis • Caused by • Immunocompromised • Rare manifestations • Clinical • Self-limiting in
Histoplasma individuals are • Occur as a localized presentation immunocompetent
capsulatum commonly affected lesion or in association • Histopathology patients
• Commonly found in • Humid environments, with the disseminated • Cultures • Amphotericin B is
warm, humid Soil with high form 357,359 • Serologic test the drug of choice
environment with nitrogen concentra- • Commonly seen in (compliment for pulmonary
bird/bat excreta, and tions increase the tongue, hard and soft fixation test, histoplasmosis (2 g
soil high in nitrogen risk of palate, buccal mucosa, immunodiffusion, IV for 10 weeks)
content356-358 infections357,358 gingiva, and lips 356-359 and histoplasmin • Itraconozole,
• Mainly found in the • Manifest as papular, skin test)361 ketoconazole are
Ohio and Mississippi ulcerative, nodular, also commonly
river valleys of the vegetative, furuncu- used.358
United States351 loid, granulomatous, or • Itraconozole is
• Men are more often plaque-like lesions, effective in
affected (9 : 1 ratio) • The most common preventing a
356-362
presentation is a relapse362
shallow or deep • Extensively
infiltrated ulceration discussed in Joseph
with Wheat365
pseudomem-
brane356-359,363,364
• Ulcerative and painful
granulomatous lesions
in gingivae362
• Sore throat, hoarse-
ness of voice, and
dysphagia can also
manifest 358

(Continues)
BANDARA and SAMARANAYAKE |
      167

TA B L E   3   (Continued)
Disease Incidence Predisposing factors Clinical features Diagnosis Management

Cryptococcosis • Caused by • Immunocompromised • Intraoral sites • Pulmonary • Systemic antifungal

Cryptococcus status (deficient commonly affected are infection; isolation therapy
neoformans cell-mediated gingiva, palate, and of the organism in • Antifungals
(immunocompromised immunity) tooth socket after sputum samples or indicated are
patients are affected) • AIDS extraction. bronchoalveolar amphotericin B and
and Cryptococcus gattii • Immunosuppressive • Oral lesions will appear lavage flucytosine.375
(immunocompetent monoclonal antibody as violaceous nodules • Disseminated • Fluconazole can be
individuals are therapies of granulation tissue, infections; used when
affected)366 • Solid-organ swellings and ulcers242 isolation of the amphotericin B is
• C. neoformans is transplantation • Lesions may exhibit pathogen in CSF not available371
commonly found in • Smokers ulcerated indurated and blood • Further information
the soil and in the • Underlying lung appearance similar • The ink test on is in Perfect et al375
feces of birds, such as disease, previous presentation373 CSF
pigeons, canaries, and steroid exposure, • Serology:
parrots367 history of cancer372 identification of
• C. gattii is found in the circulating
koala bear and is antigens on serum
endemic to Australia and/or CSF.
and temperate zones Histopathology for
• C. gattii is also cutaneous and
frequently found on subcutaneous
trees of the Eucalyptus forms374
genus368
• The commonest cause
for meningitis in
southern Africa (40%),
and pulmonary
cryptococcosis is
largely undiagnosed in
Africa369-371
Blastomycosis • Caused by • Immunocompromised Oral lesions • Clinical • Antifungal therapy
Blastomyces patients • Can appear as primary presentation • Itraconozole is
dermatitidis • In endemic areas, lesions or oral • Culturing the indicated for mild to
• Most common in people exposed to manifestations of pathogen moderate infections
parts of North, wooded areas, such as disseminated infections • Histopathological • Aggressive
Central, and South farmers, forestry • Ulcerating mucosal examination treatment with
America workers, hunters, and lesions, or • Mycelial identifica- amphotericin B is
• Fungus is endemic in campers42 • Sessile projections, tion using DNA indicated for severe
the Southeast and granulomatous or probes344,378 infections (Please
the Midwest United verrucous lesions 42,377 see Chapman et al
States376 for further
information379)
Coccidioidomycosis • Caused by • Individuals demo- • Oral manifestations are • Clinical • Antifungal therapy
Coccidioides immitis graphically located or extremely rare presentation • 3-6 months of
• Also called valley traveling to endemic • May appear as • Biopsy and fluconazole is
fever areas, ie, southwest- ulcerated granuloma- histopathology indicated
• The fungus is ern United States tous nodules • Coccidioidin skin • Other antifungals
commonly seen in • People over 60 years • Ulcers appear to be test42 such as ampho-
the soil in the of age nonspecific • Serology tericin B deoxycho-
southwestern United • HIV/AIDS • Usually heal by • Fungal culture late, ketoconazole,
States and parts of • Have had an organ hyalinization and • Radiographs for and itraconazole
Mexico and Central transplant scar344 pulmonary are also recom-
and South • Use of corticosteroids infections388 mended based on
America380 or TNF-inhibitors the severity of the
• Overall incidence in • Pregnant women infection (exten-
2011 was 42.6 cases • Diabetes sively reviewed in
per 100 000 • Black or Filipino Galgiani et al389)
population380 population381-387

AIDS, acquired immunodeficiency syndrome; CSF, cerebrospinal fluid; FDA, Food and Drug Administration; HIV, human immunodeficiency virus; PAS,
periodic acid–Schiff; PCR, polymerase chain reaction; TNF, tumor necrosis factor.
 |
168       BANDARA and SAMARANAYAKE
Early detection of the infection and identification of the pathogen
are essential in mitigating oral and/or general infections in humans
and animals. When determining the management of these infections,
multifaceted approaches must be followed in identifying all aspects
that confer antimicrobial resistance, immune evasion profiles, poten-
tial mutations, and genotypic disparities.61 Timely management not
only benefits the patient by preventing/limiting complications, but
also benefits the public by ceasing infection spread.
Improved continuous epidemiological surveillance (eg, com-
puter modelling of emerging infections) together with early detec-
tion and management of infectious diseases is the foundation for
successful strategies in controlling and eliminating oral and nonoral
diseases.60 Emerging novel technologies that are currently in the
conceptual and optimizing and launching stages, as well as exist-
ing technologies that are being progressively improved, are likely
to assist the infection management team to identify and treat in-
fectious diseases. Various enzyme-­linked immunoassays, such as
fluorescence polarization, microparticle enzyme, and chemilumi-
nescent immunoassays, are still widely used and consistently under-
going improvements to identify those organisms that emerge with
various mutations, whereas recently developed methods, such as
next-­generation sequencing, provide extremely high sensitivity and
specificity, quick results, lower detection limits, and automation, re-
quiring smaller sample volumes. However, implementation of such
techniques for routine practices remains unrealistic due to lack of
funding, resources, and technical expertise. However, ongoing in-
vestigations of using microfluidic technologies, such as microchips
(eg, lab-­on-­a-­chip),61,256 to facilitate diagnosis in regional, resource-­
and space-­limited settings appears to be promising in future infec-
tion diagnostic paradigms.
The importance of proper training of oral and general clinicians
and diagnostic microbiologists in all aspects of the management of
infections of interest must be routinely conducted. For instance, oral
clinicians need to be equipped with up-­to-­date knowledge of the clini-
cal pictures of new infections, approaches in accurate identification of
orally limited infections vs oral manifestations of underlying systemic
diseases. Management protocols of complicated infections, such as
those manifesting extraoral involvement or an immunocompromised
patient, must be determined by a multidisciplinary team that includes
oral clinicians, medical/surgical practitioners, microbiologists/patholo-
gists and other case-­specific specialities. Such tantalizing approaches
will not only provide personalized and superior care for the patient,
but also directly impact, medical, social, and economic outcomes
worldwide.
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How to cite this article: Bandara HMHN, Samaranayake LP.
Viral, bacterial, and fungal infections of the oral mucosa: Types,
incidence, predisposing factors, diagnostic algorithms, and
management. Periodontol 2000. 2019;80:148–176.
https://doi.org/10.1111/prd.12273