VESICULOBULLOUS DISEASE: VIRAL DISEASE:
HERPES SIMPLEX INFECTION
Herpes simplex virus (HSVs) infections are
common vesicular eruptions of the skin and
mucosa that occur in two forms:
 Primary (systemic) as the result of initial
infection in a previously uninfected
person.
 Secondary (localized) as the result of viral
reactivation in a previously infected
individual.
 Both forms are self-limited in the
immunocompetent host, but recurrences
of the secondary form are common
because the virus can be sequestered in a
Primary Infection
latent state within ganglionic tissue.
The incubation period after exposure ranges
from several days to two weeks.
ETIOLOGY
 For a seronegative individual who has not
been previously exposed to the virus
 Possibly for someone with a low titer of
protective antibody to HSV physical
contact with an infected individual
 Exposure to body fluids is the typical
route of HSV inoculation and
transmission
PATHOGENESIS
Secondary Infection
 Fusion of the viral membrane and the
host cell membrane is mediated by the
sequential binding of cell surface viral
glycoproteins to the host cell membrane.
 This leads to transmembrane cytoplasmic
insertion and sequential activation of
specific genes during the lytic phase of
infection.
 These genes include
o immediate early (IE) and early (E)
genes, coding for regulatory
proteins and for DNA replication,
and
o late (L) genes, coding for structural
proteins.
 Small percentage of individuals show
clinical signs and symptoms of infectious
systemic disease
 Vast majority experience only subclinical
disease.
 The vast majority group, now
seropositive, can be identified through
laboratory detection of circulating
antibodies to HSV.
 In symptomatic primary disease, a
vesiculoulcerative eruption (primary
gingivostomatitis) occurs in the oral and
perioral tissues usually at the original site
of contact.
 After resolution of primary herpetic
gingivostomatitis, the virus is believed to
migrate, through some unknown
mechanism, along the periaxonal sheath
of the trigeminal nerve to the trigeminal
ganglion, where it is capable of remaining
in a latent or sequestered state.
 During latency, no infectious virus is
produced; early, but not late, genes are
expressed, and no free virus is present.
  HSV is able to evade host immune
response by interfering with major
histocompatibility complex (MHC)
antigen class I presentation on the cell
surface that prevents activation of
cytotoxic T cells.
 Reactivation of virus may follow exposure
to sunlight (fever blisters), prior to a cold
(cold sores), trauma, menstrual cycle,
stress, or immunosuppression causing a
secondary or recurrent infection.
 An immunocompromised host may
develop severe secondary disease.:
o HSV-seropositive patients being
prepared for bone marrow
transplants with
chemotherapeutic drugs
(conditioning with or without
total-body radiation)
o Post-transplant chemotherapy also
predisposes seropositive patients
to severe recurrent oral infection.
o Individuals who are
immunocompromised as the result
of human immunodeficiency virus
(HIV) infection may also exhibit a
significantly worse secondary
disease.
o Seronegative patients who are
immunosuppressed in preparation
for organ transplantation may
rarely be affected with herpetic
disease.
 The reactivated virus, residing dormantly
in the trigeminal ganglion, travels along
the course of the trigeminal nerve to the
originally infected epithelial surface,
where replication occurs, resulting in a
focal vesiculoulcerative eruption.
There are two types of HSV:
 Type 1 (HSV1)
o Typically affects the orofacial
region
o Most oral-facial herpetic lesions
are due to HSV1
 Type 2 (HSV2)
o Affects the genital region.
o Although a small percentage may
be caused by HSV2 as a result of
oral-genital contact.
o HSV2 infection in the genital
region is sexually transmitted but
has a pathogenesis similar to that
of HSV1 infection of the head and
neck.
o Latent virus, however, is
sequestered in the lumbosacral
ganglion.
o Previous HSV1 infection may
provide some protection against
HSV2 infection because of
antibody cross-reactivity
Viral Shedding
 A phenomenon in which a previously
infected but asymptomatic individual may
be capable of transmitting the virus
 Asymptomatic shedding of intact HSV
particles in saliva can be identified in
approximately 2% to 10% of healthy
adults in the absence of clinical disease.
 The infection risk from “shedders” to
others has not been measured, although it
is probably low and dependent on the
quantity of shed viral particles and the
susceptibility of the new host.
CLINICAL FEATURES:
 Primary Herpetic Gingivostomatitis
 o Primary disease is usually seen in pain in the site at which lesions
children, although adults who have will appear.
not been previously exposed to o Within a matter of hours, multiple
HSV or who fail to mount an fragile and short-lived vesicles
appropriate response to a previous appear. These become unroofed
infection may be affected. and coalesce to form map-like
o By age 15, about half the superficial ulcers.
population is infected. o The lesions heal without scarring
o The vesicular eruption may appear in 1 to 2 weeks and rarely become
on the skin, vermilion, and oral secondarily infected.
mucous membranes.
o Intraorally, lesions may appear on
any mucosal surface
o Recurrent form of the disease, in
which lesions are confined to the
lips, hard palate, and gingiva.
o The primary accompanied by
fever, arthralgia, malaise, anorexia,
headache, and cervical
lymphadenopathy.
o After the systemic primary
infection runs its course of about 7
to 10 days, lesions heal without
o The number of recurrences is
scar formation. By this time, the
virus may have migrated to the variable and ranges from one per
trigeminal ganglion to reside in a year to as many as one per month.
latent form. The recurrence rate appears to
decline with age. Secondary
lesions typically occur at or near
the same site with each
recurrence.
o Regionally, most secondary lesions
appear on the vermilion and
 Secondary, or Recurrent, Herpes surrounding skin. This type of
Simplex Infection disease is usually referred to as
o The pathophysiology of recurrence herpes labialis.
has been related to a breakdown in
local immunosurveillance or an
alteration in local inflammatory
mediators that allows the virus to
replicate.
o Patients usually have prodromal
symptoms of tingling, burning, or
  Herpetic whitlow is a primary or a
secondary HSV infection involving the
finger(s)

o Intraoral recurrences are almost

always restricted to the hard
palate or gingiva.

 As a complication of primary or genital

herpes infection by inoculation of the skin
through a break in skin integrity
 This type of infection typically occurred in
dental practitioners (the so-called “wet-
fingered dentist”) who had been in
physical contact with infected individuals.
In the case of a seronegative clinician,
contact could result in a
vesiculoulcerative eruption on the digit
(rather than in the oral region), along
with signs and symptoms of primary
systemic disease. Recurrent lesions, if
Immunodeficiency they occur, would be expected on the
finger(s).
 Secondary herpes in the context of
 Pain, redness, and swelling are prominent
immunosuppression results in significant
with herpetic whitlow and can be very
pain and discomfort, as well as a
pronounced.
predisposition to secondary bacterial and
 Vesicles or pustules eventually break and
fungal infection.
become ulcers.
 In contrast to those occurring in
 Axillary and/or epitrochlear
immunocompetent patients, lesions in the
lymphadenopathy may also be present.
immunodeficient patient are atypical in
 The duration of herpetic whitlow is
that they can be chronic, destructive, and
protracted and may be as long as 4 to 6
extensive.
weeks.

Histopathology
Herpetic Whitlow
  Intraepithelial vesicles containing exudate,
inflammatory cells, and characteristic virus-
infected epithelial cells are seen.
 Virusinfected keratinocytes contain one or
more homogeneous, glassy nuclear inclusions
that can be found on cytologic preparations.
 The microscopic appearances of HSV1 and HSV2
are identical and cannot be differentiated
microscopically.
DIFFERENTIAL DIAGNOSIS
DIAGNOSIS
TREATMENT
 One of the most important factors in the
treatment of HSV infection is timing.
 For any drug to be effective, it must be used as
soon as possible after recognition of early or
prodromal symptoms.
 No later than 48 to 72 hours from the onset of
symptoms is generally regarded as the ideal
time to start therapeutic measures.
 Acyclovir and its analogs have shown the
greatest efficacy in the treatment of
mucocutaneous infection.
 The rationale for the use of topical agents
resides in their ability to interrupt viral
replication through inhibition of DNA
polymerization (acyclovir, penciclovir) or by
interference with virus-epithelial interaction
and prevention of intracellular access by the
virus (docosanol).
o In herpes-infected cells, acyclovir is
converted by a viral thymidine kinase to
acyclovir triphosphate, a form that
competitively inhibits viral DNA
polymerase rather than host cell DNA
polymerase.
o The end result is interruption of viral
DNA synthesis and relative sparing of
cellular DNA synthesis.
 Systemic antiviral agents, including acyclovir
400 mg tablets three times per day or
valacyclovir 1000 mg twice per day, are
effective for control of primary genital herpes
and, to a lesser degree, primary oral herpetic
gingivostomatitis.
 Supportive therapy (fluids, rest, oral lavage,
analgesics, and antipyret-ics) is an essential
component of any primary herpes sim-plex
regimen.
 Secondary herpes can be controlled to some
degree with systemic acyclovir.
 Recurrences are not prevented, but the course
and severity of the disease are favorably
affected.
 Prophylactic systemic acyclovir is effective in
problematic cases and in immunosuppressed
patients.
 In HIV-positive patients with severe disease,
intravenous acyclovir or ganciclovir may be
necessary.
 Topical acyclovir has been advocated by some
for the treatment of secondary or recurrent
herpes but its effectiveness is limited. A 5%
acyclovir (or analog) ointment applied 5 times
per day when symptoms first appear slightly
reduces the duration of herpes lesions and may
abort some lesions. Also, topical n-docosanol
(10%) has been used effectively, although
randomized clinical trials are lacking. Topical
management does not prevent recurrence,
however, and may be ineffective in some
patients.