Herpes
simplex virus – cutaneous
Other Clinical Presentations of HSV
Infection
HSV
infection can occur anywhere on the skin or mucous membranes. The clinical
settings and manifestations of other cutaneous and extracutaneous presentations
of HSV infection, including those in immunocompromised individuals and neonates,
are summarized below:
|
OTHER CLINICAL PRESENTATIONS OF HERPES SIMPLEX VIRUS
INFECTIONS |
||
|
Form
of infection |
Clinical
settings and HSV type(s) |
Cutaneous
and/or extracutaneous findings |
|
Predominantly
mucocutaneous |
||
|
Eczema herpeticum
(Kaposi’s varicelliform eruption) |
1.
Most often in infants/children > adults with atopic
dermatitis; risk is associated with mutations in the gene encoding filaggrin 2.
A similar presentation can occur in
patients with an impaired skin barrier due to other conditions such as burns,
pemphigus (foliaceus, vulgaris), Darier disease, Hailey–Hailey disease,
mycosis fungoides, Sézary syndrome and ichthyoses 3.
Usually due to HSV-1 |
1.
Rapid, widespread cutaneous dissemination of HSV
infection in areas of dermatitis/skin barrier disruption 2.
Monomorphic, discrete, 2–3 mm punched-out erosions with
hemorrhagic crusts are evident more
often than intact vesicles 3.
May have fevers, malaise and lymphadenopathy 4.
Occasionally complicated by bacterial super infections
(e.g. with Staphylococcus aureus and/or group A streptococci) or
systemic dissemination of HSV infection 5.
Differential diagnosis includes “eczema
coxsackium” due to coxsackievirus A6 infection and streptococcal infection |
|
Herpetic whitlow |
1.
Often in young children (usually due to HSV-1; 2.
Increasing frequency in adolescents/adults secondary to
digital–genital contact (usually due to HSV-2 3.
Historically in dental and medical personnel who did
not use gloves |
1.
Pain, swelling and clustered vesicles on a digit;
appearance of vesicles may be delayed 2.
Recurrences in the same location can be a clue to the
diagnosis 3.
Often misdiagnosed as blistering dactylitis or
paronychia |
|
Herpes gladiatorum |
1.
Participation in contact sports such as wrestling 2.
Usually due to HSV-1 |
1.
Distribution of cutaneous HSV infection reflects sites
of contact with another athlete’s skin lesions and is sometimes widespread |
|
Herpes simplex
folliculitis |
1.
Shaving with a blade razor (e.g. herpetic sycosis
in a man’s beard area) 2.
Usually due to HSV-1 3.
HIV-positive or otherwise immunocompromised individuals |
1.
Rapid development of follicular vesicles and pustules |
|
COMPLICATIONS Severe/chronic HSV
infections |
Immunocompromised patients, e.g.
hematopoietic stem cell or solid organ transplant recipients and individuals
with HIV infection or leukemia/lymphoma |
1.
Most common presentation is chronic, enlarging
ulcerations 2.
Cutaneous lesions may affect multiple sites or be disseminated 3.
Skin findings are often atypical, e.g. verrucous,
exophytic or pustular lesions 4.
Recurrences can involve oral mucosa, including the
tongue and movable areas that do not overlie bone 5.
Involvement of the respiratory tract, esophagus and
remainder of the gastrointestinal tract may also occur |
|
Ocular HSV infection |
1.
Newborns (often due to HSV-2) 2.
Usually due to HSV-1 in children and adults 3.
The majority of HSV eye disease is caused by
reactivation of the virus in the trigeminal ganglia, but primary infections
of the eye can also occur. |
1.
Primary infection: unilateral or bilateral
keratoconjunctivitis with eyelid edema, tearing, photophobia, chemosis, and
preauricular lymphadenopathy 2.
Branching
dendritic lesions of the cornea represent a pathognomonic finding 3.
Recurrent
episodes are common and typically unilateral 4.
Complications
include corneal ulceration and scarring, globe rupture, and blindness |
|
Herpes encephalitis |
1.
Most common cause of fatal sporadic viral encephalitis 2.
Associated with mutations in the genes encoding
Toll-like receptor 3 or UNC-93B, which impair interferon-based cellular
antiviral responses 3.
Usually due to HSV-1 4.
Natalizumab, an anti-α4 integrin monoclonal antibody used for the
treatment of multiple sclerosis and Crohn disease, increases the risk of
encephalitis and meningitis due to HSV and VZV |
1.
Usually presents with acute onset of focal neurologic
symptoms, altered mental status, bizarre behavior and fever. 2.
Involvement of the temporal lobe is a characteristic
feature of this disease 3.
Mortality ≥70% without treatment; residual neurologic
defects in most survivors 4.
Herpes labialis is a coincidental finding |
|
Neonatal HSV
infection |
1.
Occurs in approximately 1:10 000 newborns, usually
resulting from exposure to HSV during a vaginal delivery 2.
Risk of transmission is highest (30–50%) for women who
acquire a genital HSV infection (primary) (which is often asymptomatic) near
the time of delivery 3.
Risk of transmission is low (<1–3%) for women with
recurrent genital herpes 4.
Due to HSV-2 or HSV-1 (latter accounts for 30–50% of
cases) |
1.
Onset from birth to 2 weeks of age, but usually ≥5 days
of age 2.
Localized (favoring the scalp and
trunk); or disseminated cutaneous lesions; involvement of the oral
mucosa, eye, CNS, and multiple internal organs can occur 3.
Vesicles may progress to bullae and erosions. 4.
Encephalitis can present with lethargy,
irritability, poor feeding, temperature instability, seizures, and a bulging
fontanelle 5.
For CNS or disseminated disease, mortality is >50%
without treatment and ~15% with treatment; many survivors have neurologic deficits |
ECZEMA HERPETICUM
Introduction
HSV Infects altered epidermis, most commonly
the atopic dermatitis causing eczema herpetlcum. Other dermatoses subject to
HSV infection include Darier disease, thermal burns, Hailey-Hailey disease,
immunobullous disease, ichthyosis vulgaris, and cutaneous T cell lymphoma.
Epidemiology
HSV-1 > HSV-2. It is more commonly seen in
children. May be transmitted from parental herpes labialis to child with atopic
dermatitis, especially if erythrodermic.
Clinical manifestation
Primary eczema herpeticum may be associated with fever,
malaise and irritability. When recurrent, history of prior similar lesions and
systemic symptoms are less severe. Lesions begin in abnormal skin and may
extend peripherally for several weeks. Secondary infection with S. aureus is
relatively common and may be painful.
Vesicles evolve into punched-out" erosions. Vesicles
are first confined to eczematous skin.
In contrast to primary or recurrent HSV eruptions, in eczema herpeticum,
lesions are not grouped but disseminated within the dermatosis and may later
spread to normal-appearing skin. Erosions may become confluent, producing large
denuded areas. Successive crops of new vesiculation may occur. Common sites:
face, neck and trunk.
Diagnosis
Diagnosis is clinical, but can be confirmed by detection
of HSV on culture or antigen detection. Rule out secondary infection by S.
aureus.
Course
Untreated, primary episode of eczema herpeticum runs its
course with resolution in 2 to 6 weeks. Recurrent episodes tend to be milder
and not associated with systemic symptoms. Systemic dissemination can occur,
especially with host defense defects.
LABORATORY
EXAMINATIONS
The method of choice for diagnosis of HSV infection
depends on the clinical presentation that it be confirmed by laboratory testing
when possible. Multiple laboratory tests are available to diagnose HSV infection,
including viral culture, molecular techniques, direct fluorescent antibody
assays (DFA), and serology.
Viral culture
Identification of HSV can be done by viral culture. In
culture, HSV causes typical cytopathic effects, and most specimens will prove
positive within 48–96 hours after inoculation. The sensitivity of the culture
depends on the quantity of the virus in the specimen. Isolation of the virus is
most successful when lesions are cultured during their vesicular stage and when
specimens are taken from immunocompromised patients or from patients suffering
from a primary infection.
Polymerase Chain Reaction
In a matter of hours, the HSV DNA can be identified from
any tissue or fluid, fixed or fresh. PCR is more sensitive than viral isolation
and has become the preferred method for diagnosis. The detection of HSV DNA in the
cerebrospinal fluid by PCR is the diagnostic method of choice for herpes
encephalitis and aseptic meningitis and can also be used to identify the virus in
neonatal herpes. PCR is increasingly being used as a more rapid, sensitive, and
specific method for detecting HSV DNA in specimens from the skin and other
organs. Both viral culture and PCR
assays enable typing of the isolate as HSV-1 or HSV-2. This information helps
to predict the frequency of reactivation after a first-episode of HSV
infection.
Antigen Detection DFA
For
a more rapid diagnosis, viral antigen may be detectable by immunofluorescence or enzyme-coupled immunoadsorption (ELISA) using
specific
monoclonal antibodies against HSV-1 and HSV-2 in
scrapings from lesions
with a high
level of sensitivity and within a short space of time (about 1 h), but sensitivity is
lower than viral culture. A keratinocyte that is
infected with herpes simplex virus fluoresces green.
Serology
Western blot represents the gold standard for serologic
assays; it is 99% sensitive and specific for HSV antibodies. Its main function
is in differentiating a primary episode from a recurrent infection. HSV-1 and
HSV-2 infections can be diagnosed by the detection of type specific IgG
antibodies against the glycoprotein G of HSV-1(gG-1) and HSV-2(Gg-2)
respectively. The mean time to seroconversion following primary infection is
3–4 weeks.
Tzanck Smear
The Tzanck smear can be helpful in the rapid diagnosis of
herpes virus infections, but it is less sensitive than culture and DFA. It is
performed by scraping the base of a freshly ruptured vesicle and staining the
slides with Giemsa or Wright stain. Positive, if acantholytic keratinocytes or
multi- nucleated giant acantholytic keratinocytes are detected. The test is positive
in 75% of early cases, either primary or recurrent. Both HSV and
varicella-zoster virus (VZV) will cause these changes.
Dermatopathology
HSV causes typical microscopic changes with epidermal necrosis. Enlarged,
slate-gray keratinocyte nuclei with margination of chromatin represent an early
histologic finding. This is followed by intra epidermal vesiculation associated
with ballooning degeneration of keratinocytes, which is most prominent at the
vesicle base. In skin biopsy specimens, keratinocytes are enlarged, swollen,
and often separated. These swollen, pale keratinocytes often fuse to form
multinucleated giant cells and may contain eosinophilic intra nuclear inclusion
bodies surrounded by an artifactual cleft (Cowdry type A inclusions). A
variably dense dermal infiltrate of lymphocytes, neutrophils, and eosinophils
is observed, with a tendency to be milder in recurrent disease.
Antiviral therapy for
herpes simplex virus (special group)
|
Neonatal |
Acyclovir: 20 mg/kg iv q8 h ×
14–21 days |
|
Immunocompromised |
Recommend use until all
mucocutaneous lesions are healed 1.
Acyclovir:
400 mg po 5×/d or 5 mg/kg (if age ≥12 y) to 10 mg/kg (if age <12 y) iv
q8 h 2.
Famciclovir:
500 mg po BID 3.
Valacyclovir:
1 g po BID |
|
Eczema herpeticum |
Recommend use for 10–14 days
or (especially if immunocompromised) until all mucocutaneous lesions are
healed 1.
Acyclovir:
15 mg/kg (400 mg max) po 3–5×/d or, if severe, 5 mg/kg (if age ≥12 y) to
10 mg/kg (if age <12 y) iv q8 h 2.
Famciclovir:
500 mg po BID 3.
Valacyclovir:
1 g po BID |
|
Genital herpes,
recurrent in the setting of HIV infection |
Recommend use until all
mucocutaneous lesions are healed 1.
Acyclovir:
400 mg po TID 2.
Famciclovir:
500 mg po BID 3.
Valacyclovir:
1 g po BID |
|
Chronic suppression
in the setting of HIV infection |
1.
Acyclovir:
400–800 mg po BID–TID 2.
Famciclovir:
250–500 mg po BID 3.
Valacyclovir:
500 mg po BID |
|
Acyclovir-resistant
HSV in immunocompromised patients |
1.
Foscarnet:
40 mg/kg iv q8–12 h × 2–3 weeks (or until all lesions are healed) 2.
Cidofovir: 1%
cream or gel daily × 2–3 weeks or (for severe disease) 5 mg/kg iv weekly × 2
weeks then every other week (together with probenecid) |
Intravenous
acyclovir is indicated for neonatal HSV infection, severe infections in
immunocompromised hosts, severe eczema herpeticum and patients with systemic
complications. In immunocompromised patients, it is important to treat with
oral or intravenous antivirals until the cutaneous lesions are completely
healed.
The
emergence of acyclovir-resistant HSV is an increasing concern for
immunocompromised individuals. Foscarnet is the only antiviral drug approved by
the FDA for treatment of acyclovir-resistant HSV. Cidofovir is another
antiviral agent that has shown efficacy in the treatment of acyclovir-resistant
HSV. The use of foscarnet or systemic cidofovir is limited by
potentially severe side effects (particularly renal toxicity) and the
requirement for intravenous administration. Although not FDA-approved, compounded
topical cidofovir has been advocated by the CDC as a “user-friendly”,
albeit expensive, alternative treatment.
Individuals
co-infected with HIV and HSV have more severe outbreaks and more frequent viral
shedding than those without HIV infection. When added to the medical regimen of
HIV-infected patients, antiherpetic suppressive therapy appears to allow the
co-infected person to respond better to antiretroviral therapy and to reduce
genital and plasma HIV-1 RNA levels, but it does not seem to decrease the risk
of HIV-1 transmission. Oral acyclovir, famciclovir and valacyclovir can be used
for genital and orolabial HSV in the setting of HIV infection as long as there
is no evidence of acyclovir resistance.
PCR of the CSF for HSV DNA is the most sensitive
noninvasive technique to help in the diagnosis of HSV encephalitis. Patients
with presumed HSV encephalitis should be treated empirically with intravenous acyclovir
until the diagnosis is confirmed or an alternative diagnosis is made. However,
even with therapy, neurologic sequelae are frequent.
