Herpes
simplex viruses - orofacial
Salient
features
·
Herpes
simplex viruses (HSVs) are common human DNA viral pathogens that intermittently
reactivate. After replication in the skin or mucosa, the virus infects the
local nerve endings and ascends to the ganglia where it becomes latent until
reactivation.
·
There
are two types of HSV: HSV-1 and HSV-2. HSV-1 is mostly associated with
orofacial disease, whereas HSV-2 usually causes genital infection, but both can
infect oral and genital areas and cause acute and recurrent infections.
·
Most
of the adult population is seropositive for HSV-1, and the majority of
infections are acquired in childhood. About one-fourth of adults are infected
with HSV-2 in the United States. Acquisition of HSV-2 correlates with sexual
behavior.
·
Most
primary HSV infections are asymptomatic or not recognized, but they can also
cause severe disease. Most recurrences are not symptomatic and most
transmissions occur during asymptomatic shedding.
·
Genital
herpes is the most prevalent sexually transmitted disease worldwide and is the
most common cause of ulcerative genital disease; it is an important risk factor
for acquisition and transmission of HIV.
·
HSV
can cause diseases involving the eye, CNS, and neonatal infection. Cellular
immunity defects are a risk factor for severe and disseminated disease.
·
Diagnosis
is made by polymerase chain reaction, viral culture, or serology, depending on
the clinical presentation.
·
Treatment
is with acyclovir, valacyclovir, or famciclovir. Regimens and dosages vary with
the clinical setting. Resistance is rare, other than in immunocompromised
patients.
Introduction
Herpes simplex viruses (HSVs) are common human DNA viral
pathogens that intermittently reactivate. After replication in the skin or
mucosa, the virus infects the local nerve endings and ascends to the ganglia
where it becomes latent until reactivation. The herpes
simplex virus (HSV) is neurotropic and epidermotropic. It can cause a wide
range of clinical disorders, depending on the age and immune status of the
patient, and also whether it is a primary or secondary infection.
There
are two types of HSV: HSV-1 and HSV-2. HSV-1 is generally associated with oral facial
infections, and HSV-2 is associated with genital and perigenital infections. HSV-1 genital infections and HSV-2 oral infections are
becoming more common, possibly as a result of oral-genital sexual contact. Both
types seem to produce identical patterns of infection. HSV infections have two
phases: the primary infection, after which the virus becomes established in a
nerve ganglion; and the secondary phase, characterized by recurrent disease at
the same site. The rate of recurrence varies with virus type and anatomic site.
Genital recurrences are nearly six times more frequent than oral-labial
recurrences; genital HSV-2 infections recur more often than genital HSV-1
infections; and oral-labial HSV-1 infections recur more often than oral HSV-2
infections. Infections can occur anywhere on the skin. Infection in one area
does not protect the patient from subsequent infection at a different site.
Lesions are intraepidermal and usually heal without scarring.
Clinical manifestations produced by herpes
simplex viruses: the sites of infection by herpes simplex viruses include brain
(meningitis, encephalitis), infections in the ocular area (eyes: keratitis,
retinitis and conjunctivitis; mouth: lips and gingivostomatitis; facial nerves:
facial paralysis), torso, limbs and genitals (neck, arms, hands, fingers, legs,
genitals) and internal organs, such as lungs, kidneys and liver. The most
frequent HSV serotype isolated for each pathology is indicated.
Basic
biology
All persons infected with HSV-1 and 2
viruses are potentially infectious even if they have no clinical signs or
symptoms. Transmission
occurs via inoculation onto susceptible mucosal surface or break in keratinized
skin. The virus can be inoculated into any
site to cause a new infection, whether or not there has been previous infection
with either type. The source may be endogenous (autoinoculation), for example
to the finger especially in nail biters or thumb suckers from their infected
mouth. Examples of exogenous inoculation are lesions of the hand in health care
workers, facial lesions contracted during contact sports, and infection of a
breastfeeding mother's nipples from the infected mouth of her baby.
Following primary infection, humoral
and cell‐mediated immune responses take place, the latter probably
being more important. They do not fully protect against reinfection or
recurrent disease. Where immunity is deficient, both primary and recurrent
herpetic infections may be increased in incidence and severity, and may run a
prolonged and atypical course. Examples include: HIV disease, malignancy (leukemia/lymphoma),
transplantation (bone marrow, solid organ), chemotherapy, systemic
glucocorticoids and other immunosuppressive drugs, and radiotherapy.
Epidemiology
Herpes simplex viruses have a worldwide distribution. Their interaction
with human hosts has the following components: (1) primary infection – initial HSV infection, without
pre-existing antibodies to HSV-1 or HSV-2; (2) non-primary
initial infection – infection with one HSV type in an
individual with pre-existing antibodies to the other HSV type; (3) latency – virus in sensory or autonomic ganglia;
and (4) reactivation – recurrent infection with
asymptomatic viral shedding or clinical manifestations (recrudescence).
Primary, non-primary initial and recurrent infections can each be symptomatic
or asymptomatic. It is estimated that approximately one-third of the world’s
population has experienced a symptomatic HSV infection.
Etiology
·
Oro-facial:
HSV-1 > HSV-2.
·
Genital:
HSV-2 > HSV-1.
·
Herpetic
whitlow: <20 years of age usually HSV-1; >20 years of age, usually HSV-2.
Pathogenesis
Both
type 1 and type 2 HSV are acquired by direct contact with an active lesion, or
contact with virus-containing fluid such as saliva or genital secretions in
patients with no evidence of active disease, entering via skin or mucous
membrane, where first episode infection may become evident; usually skin-skin,
skin-mucosa, mucosa-skin contact. Most transmission occurs when
persons shed virus in saliva or genital secretions during asymptomatic stage, although the amount shed from active lesions is 100–1000
times greater.
HSV
infections can be divided into three stages: (1) acute infection, (2)
establishment and maintenance of the latency, and (3) reactivation of virus.
During
acute infection, the virus
replicates in epithelial cells at the
mucocutaneous site of infection, causing lysis of infected cells, vesicle formation, and local
inflammation,
resulting in primary lesions from which virus rapidly spreads to infect local
nerve terminals, where it travels by retrograde axonal transport along the peripheral nerves to enter neuronal
nuclei in regional sensory or autonomic ganglia, where latency is established.
Latency
can occur after both symptomatic and asymptomatic primary infection. The virus produces no viral proteins whilst latent and can
therefore remain undetected by host defense mechanisms. Latency enables the
virus to exist in a relatively non-infectious state for varying periods of time
in its host.
In the
last stage, HSV may reactivate
periodically from its latent state and newly assembled virus particles then
travel by ante grade axonal transport along neurons to peripheral skin and
mucosal sites,
at or near the original portal of entry to cause recurrent disease, which may be clinically
symptomatic or asymptomatic. HSV-1 reactivates most efficiently and frequently from
trigeminal ganglia, whereas HSV-2 reactivates primarily from sacral ganglia.
The rate of reactivation of HSV appears to be influenced by the quantity of latent
viral DNA in the ganglia.
HSV
can be reactivated spontaneously or by a trigger such as local skin trauma
(e.g., ultraviolet light exposure, chapping, abrasion) or systemic changes
(e.g., menses, fatigue, fever, upper
respiratory tract infections emotional stress and immunosuppression). Typically,
reactivation produces vesicular lesions localized to the skin. However, viremia
followed by widespread internal organ involvement can occur in
immunocompromised hosts.
A. Primary
infection B. latent phase C. Recurrence
Herpes labialis
A.
With primary herpes simplex virus infection, virus replicates in the
oropharyngeal epithelium and ascends peripheral sensory nerves into the
trigeminal ganglion. B. Herpes simplex virus persists in a latent phase within
the trigeminal ganglion for the life of the individual. C. Various stimuli
initiate reactivation of latent virus, which then descends sensory nerves to
the lips or perioral skin, resulting in recurrent herpes labialis.
Stages
of HSV infection
(A) HSV replicates initially in
epithelial cells at the genital or oral mucosal surface. The virus enters
innervating sensory neurons where it travels up the axon to the neuronal cell
body. Once in the neuron, the virus establishes a latent infection that may
last the lifetime of the host. (B) Upon the proper stimulus, the virus can
reactivate, travel back down the axon, and establish another round of lytic
replication
Clinical Manifestation
The clinical manifestations of HSV infection depend on
the site of infection and the immune status of the host. Primary infections
with HSV, namely those that develop in persons without preexisting immunity to
either HSV-1 or HSV-2, are usually more severe, frequently with systemic signs
and symptoms, and they have a higher rate of complications, than recurrent
episodes.
Primary HSV Infection
Symptomatic primary HSV infections
typically occur within 3 to 7 days after contact. A prodrome of tender regional lymphadenopathy and systemic symptoms (fever, headache, malaise, and
myalgia) as well as localized pain, tenderness, burning or
tingling occurs before the onset of mucocutaneous lesions. Erythematous papules that quickly evolve to painful,
grouped vesicles appear on an erythematous base and may become umbilicated,
followed by progression to pustules. The vesicles in primary herpes simplex are
more numerous and scattered than those in the recurrent infection. The vesicles
of herpes simplex are uniform in size in contrast to the vesicles seen in
herpes zoster, which vary in size. Vesicles
and pustules are often fragile, rupturing easily, to form erosions as
the overlying epithelium sloughs. Erosions may enlarge to
ulcerations. Erosions and ulcerations have characteristic scalloped border. Mucous
membrane lesions accumulate exudates and remain moist, whereas skin lesions
form a crust. These epithelial defects heal in 2–4 weeks without scarring,
often with resultant post inflammatory hypo- or hyperpigmentation, uncommonly
with scarring. A similar prodrome can
precede recurrent lesions, but these are often fewer in number, with decreased
severity and duration compared to those of a primary infection.
Herpes simplex—evolution of
lesions
A,
Vesicles on a red base are the primary lesions. B, Vesicles evolve to pustules
and become umbilicated. C, Umbilication becomes more pronounced. D, Lesions dry
and form discrete crusts.
Primary herpetic gingivostomatitis
Over
90% of primary orofacial HSV infections are subclinical. Only 10% develop
clinical disease, which often present as acute gingivostomatitis in children between
1 and 5 years of age or as acute herpetic pharyngotonsilitis in young adults.
After
an incubation period of approximately 5 days, the stomatitis begins with abrupt
onset of fever, malaise, and a painful mouth; often the first sign of the
disease is a refusal to eat. Gingivitis is the most striking feature, with
markedly swollen, erythematous and friable gums that bleeds easily. Painful
vesicles occurring anywhere in the oral cavity including the hard and soft palate,
tongue, and buccal mucosa, as well as lips and neighboring facial perioral
skin. The vesicles rapidly coalesce and erode with a white, then yellow,
superficial, purulent exudates; and tend to spare the posterior mouth. Marked salivation and foul-smelling breath
is typical. The anterior cervical lymph nodes are enlarged and tender.
In
young adults, oral HSV-1 causes pharyngitis and tonsillitis more often than
gingivostomatitis. Vesicles rupture to form erosions with grayish exudates on
the tonsils and posterior pharynx. Fever, malaise, headache and sore throat
present.
After
3–5 days, the fever subsides and oral pain and erosions are usually gone in 2
weeks; in severe cases, they may last for 3 weeks.
In immunocompromised persons, diagnosis can be
difficult since herpes may manifest with chronic ulcers.
Management
For most, management is supportive with
antipyretic analgesics (e.g. acetaminophen/paracetamol), sponging with tepid
water and a high fluid intake. Analgesics (as elixirs or syrups for children)
and, in adults, lidocaine mouth baths help ease discomfort and 0.2% aqueous
chlorhexidine mouth baths aid resolution. An antihistamine such as promethazine
may help sedate an irritable child.
Specific antiviral therapy is usually justified to reduce the duration of symptoms and is most useful in the very early stages of disease
(though most patients present later) and for immunocompromised patients who may
otherwise suffer severe infection.
First
line
For
less severe infections and when swallowing is not impaired, oral acyclovir
treatment is adequate. The usual oral dose is 200 mg five times daily for 7-10 days or until
resolution of symptoms. In young children, the oral suspension given at 15 mg/kg (200 mg
max) five times per day for 7 days. When
it is started within 3 days of onset of the disease, this regimen reduces the
duration of oral and extra oral lesions, fever and eating and drinking
difficulties. Children 40 kg and above should receive the adult dose.
Neither valacyclovir
nor famciclovir is approved by US FDA for use in children.
Second
line
Severely ill children need to be
hospitalized for hydration, and intravenously
acyclovir may be necessary. Treatment should be started as soon as possible.
The usual dose is 5 mg/kg 8‐hourly intravenously. As the drug is
excreted via the kidneys, the dose must be scaled down in renal failure. Transient
rises in blood urea and creatinine may occur with bolus injections; slow
infusion over 1 h in an adequately hydrated patient is recommended.
Recurrent oro‐facial herpes
Among individuals with latent HSV-1
infection, 20–40% develops recurrent herpes labialis due to reactivation. While
primary oral HSV is usually intra-oral, with later spread to the lips and
perioral skin, recurrent labial HSV typically involves only the lips and
immediately adjacent skin at the mucocutaneous
junction (herpes simplex labialis). Recurrent infections differ
from primary infections in the smaller size of the vesicles and their close
grouping, and in the usual absence of constitutional symptoms. Recurrent
disease begins with a prodrome of tingling, itching or burning sensation,
or simply knowing something is coming, lasting 2 to 24 hours,
resemble those of the primary infection followed by the development of grouped clear
vesicles on an erythematous base that rapidly umbilicate,
followed by progression to pustules and then rupture, forming aphthae like erosions
in the oral mucosa and erosion covered by crusts on the lips and skin. After
another interval, the crusts falls off, leaving behind nonscarring erythema. The
disease course typically lasts 7–14. Recurrent lesions appear most
often on the vermilion border of the lip. Less common sites are perioral skin,
nasal mucosa, chin and cheek. Recurrences tend to be in the same region, but
not always on the identical site. In contrast to the primary infection,
systemic symptoms and lymphadenopathy are rare unless there is secondary
infection. Recurrent intraoral HSV is rare in immunocompetent patients and
can involve attached oral mucosa overlying bone (e.g. gingiva, hard palate),
but in immunocompromised hosts, recurrent herpes infections can involve
intraoral “soft” mucosa (i.e. intraoral movable mucosa that does not overlie
bone). The most important triggers include sunlight, fever
(fever blisters) and upper respiratory infections (cold sores).Recurrences
average 2 or 3 each year but may occur as often as 12 times a year.
HSV-2 causes a primary orofacial infection that is
indistinguishable from that associated with HSV-1 except that it is usually seen
in adolescents and young adults and following genital–oral contact. Moreover,
HSV-2 orofacial infections are 120 times less likely to reactivate than is
orofacial HSV-1 disease.
Complications
and co‐morbidities
The lesions may become secondarily infected
with Staphylococcus or Streptococcus, resulting
in impetigo.
In atopic persons, the lesions may spread to
produce eczema herpeticum that can be
associated with both recurrent as well as primary HSV.
In the immunocompromised, persistent
ulcerative or verruciform lesions may occur.
If recurrent herpes simplex involves
the eye, keratoconjunctivitis, dendritic ulcers, disciform or hypopyon
keratitis and iridocyclitis may occur. An ophthalmological opinion should be
sought.
Erythema multiforme (herpes‐associated erythema multiforme)
In
65% of patients with recurrent erythema multiforme, there is a history of
herpes labialis, usually preceding the erythema multiforme by several days to 2
weeks, but occasionally seeming to coincide with it. Although virus cannot be
seen by electron microscopy or isolated, HSV antigen gB has been detected in
erythema multiforme skin lesions and HSV DNA has been demonstrated by PCR in
lesions. Treatment of recurrent HSV‐associated
erythema multiforme, if started by the patient in the prodrome stage (with a 5‐day course of acyclovir), will often prevent the development
of erythema multiforme. If that is not effective and attacks are frequent, a 6‐month course of prophylactic acyclovir should be tried even
in patients in whom HSV is not obviously a precipitating factor.
Management
of recurrent
herpes
Recurrent herpes labialis may need
no treatment if attacks are mild or infrequent.
FDA-approved
antiviral agents for treatment of more
troublesome recurrent
episodes of orofacial herpes in immunocompetent persons include oral acyclovir,
valacyclovir, famciclovir and topical treatment as mentioned. These therapies
have modest benefits, decreasing the duration of mucocutaneous lesions, viral
shedding, and pain. Treatment is only effective if used very early in the
disease (especially if started at the first symptom or sign of a recurrence). Patients
who wish treatment should have the medication available and be vigilant for the
earliest signs and symptoms of recurrence.
Recurrences of herpes labialis may
be prevented or reduced in intensity by the use of a topical sunscreen.
Prophylaxis with valacyclovir or
famciclovir may be useful against reactivation
or spread of HSV before cosmetic laser treatment of the face, as widespread
herpes has been reported following such procedures.
Treatment of HSV-1 Oral-Labial Herpes Simplex
|
Primary
herpes |
Acyclovir 200 mg five times/day for 7-10 days or until
resolution of symptoms |
|
|
Recurrent
herpes(episodic therapy) Recurrent
herpes (prophylaxis) |
Topical 1.
Docosanol10% cream: 5×/d until healed 2.
Penciclovir: 1% cream applied q2 h while awake × 4 days 3.
Acyclovir: 5% ointment applied q3 h/6 times/day × 7–10
days 4.
Acyclovir + hydrocortisone: 5%/1% cream applied 5×/d ×
5 days Oral Acyclovir 400 mg three times/day for 5 days or until
lesions are healed Acyclovir 400 mg twice a day (Start before and during
precipitating event, such as intense ultraviolet exposure) |
|
|
Recurrent
herpes (long-term suppressive therapy) |
Acyclovir 400 mg twice a day |
|
|
Severe
disease |
Acyclovir 5-10 mg/kg body weight IV every 8 hr |
