HERPES VIRUS TYPES THAT

INFECT HUMANS
• Herpes simplex virus Type 1 (HSV-1)
• Herpes simplex virus Type 2 (HSV)
• Epstein Barr virus (EBV)
• Cytomegalovirus (CMV)
• Varicella Zoster Virus (VZV)
• Human herpes virus 6 (exanthum subitum or
roseola infantum)
• Human herpes virus 8 (Kaposi's sarcoma-
associate herpes virus)
• The herpes simplex viruses comprise 2 distinct types of DNA
viruses:
• herpes simplex virus (HSV)-1 and HSV-2.
• HSV-1 causes oral lesions in approximately 80% of cases and
genital lesions in 20% of cases.
• In adolescents, as much as 30%-40% of genital herpes is caused by
HSV-1 because this proportion is thought to be increasing in the
developed world, due to increased orogenital contact.
• The reverse is true for HSV-2, which causes genital lesions in 80%
of cases and oral lesions in 20% of cases.
• Antiviral drugs with activity against viral DNA synthesis have been
effective against HSV infections.
• These drugs inhibit virus replication and may suppress clinical
manifestations but are not a cure for the disease.
• Members of the human herpesvirus (HHV) and
HPV families are the most common causes of
primary viral infections of the oral cavity.
• Recurrent HHV type 1 is occasionally observed
intraorally. Recurrent herpes typically affects
only keratinized tissues inside the oral cavity,
such as the gingiva or the hard palate. Vesicles
often break quickly, so the clinician may observe
small clustered ulcers
• HHV-1, also known as HSV-1, causes primary
herpetic gingivostomatitis, or oral herpes.
• In some hosts, it becomes latent and may
periodically recur as a common cold sore
• HHV-2, also known as HSV-2, causes genital
herpes and occasionally causes oral disease
that is clinically similar to that of HHV-1
infectionAs with HSV-1, there is no cure.
However, antiviral drugs can make outbreaks
less frequent and help clear up symptoms more
quickly.
• Primary HSV gingivostomatitis in an infant
is shown. This same patient also had
concomitant herpes whitlow, as shown in
next slide.
• Painful vesicular or ulcerative lesions may
appear similar to chancroid or syphilis.
The image shows a penile infection with
HSV-2.
• The incidence of genital herpes has been
estimated to be 500,000-1,000,000 cases
per year, with a prevalence of 40-60
million affected individuals. Women often
present with complaints of genital swelling,
discharge, and dysuria
• Mother with cold sore on lip holding baby with eczema
herpeticum
 Eczema herpeticum
• This is found in children with active
eczema, preexisting atopic dermatitis, and
can spread over the skin at the site of
eczema lesions
• The virus can spread to other organs
such as the liver and adrenals.
• A similar disease may also be caused by
vaccinia (eczema vaccinatum).
 Herpes simplex virus pneumonia

• is a rare cause of lower respiratory tract

infections
• HSV pneumonia develops either
secondary to upper airway infection
because of direct extension of the virus
from the upper to the lower respiratory
tract or following viremia secondary to
dissemination of HSV from genital or oral
lesions.
• HSV is seen primarily in severely
immunocompromised patients:
- primarily HSCT (hematopoietic stem
cell transplant)
- SOT recipients(solid organ transplant)
- patients who are undergoing
chemotherapy/are neutropenic, or those
who have congenital immunodeficiency.
This virus will almost universally reactivate
after HSCT or SOT.
Like CMV, the mortality rate is high if
disease remains untreated in
immunosuppressed patients (>80%
mortality).
• Intravenous acyclovir (250 mg/m2 q8h)
is the treatment of choice for herpes
simplex virus (HSV) pneumonia.
• Acyclovir inhibits viral DNA synthesis by
competitively binding to viral DNA
polymerase
• in patients with progressive HSV
pneumonia who are unresponsive to
antiviral therapy, empirical broad-spectrum
antibiotic therapy that includes an
antistaphylococcal drug should be
instituted
• HSV infection of neonates
This results from HSV-2 and is often fatal, although such
infections are rare.
• Infection is especially possible if the mother is shedding
virus at the time of delivery.
• Thus prospective mothers should avoid contracting
herpes during pregnancy.
• A first episode of HSV-2 infection during pregnancy
creates a greater risk of transmission to the newborn.
• If a woman has active genital herpes at delivery, a
cesarean-section delivery is usually performed.
• The virus can either be obtained in utero or during birth
with the latter being more common. Because the
neonate has an underdeveloped immune system, the
virus can spread rapidly to many peripheral organs (e.g.
lungs and liver) and can infect the central nervous
 Diagnosis of HSV Infections
• Cells may be obtained from the base of the lesion (called a Tzank
smear) and histochemistry performed. Since a characteristic of
herpes virus is fusion at neutral pH, infected cells can fuse forming
syncytia. These can be seen in the smears as multinucleated giant
cells and contain Cowdry type A inclusion bodies
• The cells can also be stained with specific antibodies in an
immunofluorescence test and it is also possible to detect viral DNA
by in situ hybridization. Type-specific antibodies can distinguish
between HSV-1 and HSV-2.
• Virus can be isolated from biopsy specimens, that is from the
lesions, and grown on tissue culture cells where it forms
characteristic cytopathic effects (plaque) including multinucleated
cells .
• The presence of anti-HSV antibodies in the patient can be used to
form a diagnosis of the primary infection but recurrence is not
usually accompanied by a rise in antibody levels.
• Herpes simplex 1: Histological stain. Note the multinucleate cell with dark
staining inclusions.
• HHV-3, also known as varicella-zoster virus
(VZV), causes the primary infection chickenpox
and the secondary reactivation disease herpes
zoster.
• Chickenpox spots can be staged: blistering,
bursting, drying, and crusting.
• Chickenpox is uncommon as a result of the use
of varicella zoster vaccine in the pediatric
population.
• Adults who have had chickenpox as a child
are at risk for shingles developing later in life
as a result of a reactivation of the virus
• Chickenpox is caused by varicella-zoster virus, and 90%
of cases occur in children younger than 10 years of age.
• It is usually acquired by inhalation of airborne respiratory
droplets from an infected host, but viral transmission
may occur through direct contact with vesicles.
• The typical presentation is an incubation period of 10-21
days followed by the development of numerous small
erythematous macules which rapidly progress over 12-
14 hours to papules, clear vesicles, and pustules .
These will develop subsequent central umbilication and
a crust will form.
• Vesicles may appear on the mucous membranes with
painful, shallow ulcers.
• Diagnosis can usually be made on clinical grounds.
• Secondary bacterial infection is the most common
complication.
• Infection is usually self-limited in healthy children
and confers lifelong immunity.
• Excoriation may induce scarring..
• Treatment is with acyclovir for immunocompromised
children and with VariZIG™Varicella-zoster
immune globulin for highly susceptible individuals
within 96 hours of exposure.
 Treatment
• Children >1 year who have encephalitis or pneumonia or are
immunocompromised:
• Acyclovir 500 mg/m2 IV q8h for 7-10 days

• Children 2-12 years who are at increased risk for complications:

• Acyclovir 20 mg/kg PO 4 times daily for 5 days; not to exceed 3200 mg/day
• Valacyclovir 20 mg/kg PO 3 times daily for 5 days; not to exceed 1 g/dose 3 times
daily

• Children < 1 year who are immunocompromised:

• 30 mg/kg/day IV in 3 divided doses for 7-10 days

• Children 2-12 years with uncomplicated varicella:

• Use of acyclovir is not routinely recommended
• Acyclovir use does not affect incidence of pruritus, complications, or secondary
transmission in children with varicella
• Consider acyclovir use in secondary household cases, in which the disease is usually
more severe
 Varicella-zoster virus
- highly contagious herpes virus
- Primary infection manifests as chickenpox; the
reactivation results in zoster (shingles).
- Hosts who are immunocompromised
(including pregnant hosts) are especially prone
to developing pneumonia and its complications:
- secondary bacterial infections
- encephalitis
- hepatitis
- with concomitant aspirin use, Reye syndrome.
• Varicella pneumonia complicates
approximately 2-10% of the cases of VZV
infection in adult
• The severity of varicella pneumonia is
highest in immunosuppressed persons,
with mortality rates of 15-18%, and in
pregnant women in the second/third
trimesters, with a mortality rate of 41%.
• pneumonia, typically appears 3-5 days
into the illness
– is associated with:
• tachypnea
• cough,
• dyspnea,
• fever
• although some patients may be asymptomatic;
• Treatment of varicella pneumonia includes
respiratory isolation until skin lesions heal,
supportive care, administration of antiviral
agents, and active and passive
immunization.
• For treatment of documented varicella
pneumonia in patients who are
immunocompromised, acyclovir (10 mg/kg IV
q8h for 7 d) has been shown to be effective.
• For pregnant women in third trimester, acyclovir
at 10 mg/kg IV q8h for 5 days should be given
and consideration should be given for varicella-
zoster immune globulin (VZIG) therapy.
• VZIG is indicated in pregnant women for the
prevention or reduction in severity of maternal
infection within 10 days (ideally within 96 hours
of exposure to VZV).
 VZIG should be given to an infant if the mother
develops varicella from 5 days before to 2 days
after delivery.
• VZIG should be given to hospitalized premature
infants of ≥28 wk gestation whose mothers have
no history of varicella infection; also, VZIG
should be given to hospitalized premature
infants < 28 wk gestation or weighing ≤1000 g at
birth regardless of maternal history when a
significant exposure has occurred
• Recommended dose is 125 IU/10 kg body
weight
 Congenital Varicella syndrome

• Major problems may be caused by infection in utero during the

first trimester. This is congenital varicella syndrome which leads to
scarring of the skin of the limbs, damage to the lens, retina and brain
and microphthalmia.
• Infection of the mother, who presumably has not previously been
infected and therefore does not have anti-varicella antibodies, at
around the time of birth can lead to the infection of the infant.
• Since the infant will not have maternal antibodies against varicella
and has immature cell-mediated immunity, it may succumb to the
disease with a mortality rate of up to 35%.
• If the mother becomes infected near to term, both she (before
delivery) and her infant (immediately after delivery) should be
treated with varicella immune globulin.
• Most infants, however, get maternal antibodies trans-placentally and
are protected from the disease.
 Varicella virus vaccine
live(Varivax)
• Used for vaccination against varicella in individuals 1 y
and older.
• Children 1-12 years:
• Administer first dose of 0.5 mL subcutaneously at age
12-15 mo
• Second dose is routinely administered at age 4-6 y;
second dose can be given at any age as long as it has
been at least 3mo since first dose
• Adults and children 13 years and older with no evidence
of immunity :
• Administer 2 doses of 0.5 mL subcutaneously 4-8wk
apart
• Herpes zoster, or shingles, is the most common
presentation of reactivated VZV.
• The majority of cases of shingles occur in adults.
Patients will typically report a prodromal illness
of pain, pruritus, burning, and/or paresthesias.
Over the next few days, erythematous macules
and papules develop along a single dermatome.
The macules and papules then progress to
vesicles that eventually crust and heal over
• Herpes zoster ophthalmicus is a latent
VZV infection involving the ophthalmic
division of the trigeminal nerve.
• It accounts for 10%-25% of all cases of
shingles.
• The reactivated VZV may travel down the
ophthalmic division to the nasociliary
nerve, which innervates the tip of the nose
and surface of the globe of the eye
• Ramsay Hunt syndrome, or herpes zoster
oticus, is a reactivation of VZV that involves the
facial nerve.
• Cranial nerves V, VI, VIII, and IX may also be
involved.
• Patients initially report pain deep within the ear
that radiates to the pinna. The infection then
produces vesicles and ulcerations of the
external ear and ipsilateral anterior two thirds of
the tongue and soft palate.
 Herpes zoster Vaccine
The risk for shingles increases with age.
Zoster vaccine is a live virus vaccine and
is recommended for adults 60 and
older, as long as they are not pregnant
or severely immunocompromised.
The ACIP recommendation says to
vaccinate at age 60 or older, even though
FDA licensing begins at age 50.
 Varicella-zoster immune
globulin(VZIG) post exposure
• Varicella zoster immune globulin (VariZIG by Cangene)
is indicated for administration to high-risk individuals
within 10 days (ideally within 4 days) of chickenpox
(varicella zoster virus) exposure.
• If VariZIG is unavailable, intravenous immunoglobulin
(IVIG) can be used.
• High-risk groups include the following:
– Immunocompromised children and adults
– Newborns of mothers with varicella shortly before or after
delivery
– Premature infants
– Infants less than one year of age
– Adults without evidence of immunity
– Pregnant women
• HHV-4, also known as Epstein-Barr
virus, which causes the primary infection
infectious mononucleosis, is implicated in
various diseases, immunoproliferative
disorders, and nasopharyngeal carcinoma.
• HHV-4 causes oral hairy leukoplakia in
patients who are immunosuppressed.
• Oral Hairy Leukoplakia
• Epstein-Barr virus is the causative agent
of Burkitt's lymphoma in Africa, nasal
pharyngeal carcinoma in the orient and
infectious mononucleosis in the west.
• It was first discovered as the causative
agent of Burkitt's lymphoma and it was
later found that patients with infectious
mononucleosis have antibodies that react
with Burkitt's lymphoma cells
Burkitt Lymphoma
 Infectious mononucleosis
• The primary infection is often asymptomatic but the
patient may shed infectious virus for many years.
• Some patients develop infectious mononucleosis after 1-
2 months of infection.
• The disease is characterized by malaise,
lymphadenopathy, tonsillitis, enlarged spleen and
liver and fever.
• The fever may persist for more than a week. There may
also be a rash. The severity of disease often depends on
age (with younger patients resolving the disease more
quickly) and resolution usually occurs in 1 to 4 weeks.
 Epidemiology
• A large proportion of the population (90-95%) is infected
with Epstein-Barr virus and these people, although
usually asymptomatic, will shed the virus from time to
time throughout life.
• The virus is spread by close contact (kissing disease).
Infection is associated with socioeconomic factors and in
developing countries, seropositivity is observed at an
earlier age than in developed countries.
• Up to 80% of students entering college in the US are
seropositive for the virus and many of those that are
negative will become positive while at college.
• The virus can also be spread by blood transfusion.
• In infectious mononucleosis, infected B cells are
also transformed. The infected B cells proliferate
and activate suppressor CD8 T cells. These T
cells differ from normal T cells in appearance
and are known as Downey cells. The T cells
increase in number in the circulation and may
account for up to 80% of the white blood cells.
This T cell response results in enlarged lymph
glands (and enlarged liver and spleen).
 Diagnosis
• In infectious mononucleosis, blood
smears show the atypical lymphocytes
(Downey cells).
• There are also serological tests available.
Heterophile antibodies are produced by
the proliferating B cells and these include
an IgM that interacts with Paul-Bunnell
antigen on sheep red blood cells
• HHV-5, also known as cytomegalovirus,
causes a primary infection of the salivary
glands and other tissues and is believed to
have a chronic form
 Cytomegalovirus

• is a common, usually asymptomatic,

herpesvirus seen in the general
population.
• In hosts who are immunocompetent, acute
CMV infection causes a
mononucleosislike syndrome
• transmission is primarily through body fluid
contact
 Transmission

As with Epstein-Barr virus (also spread in saliva), seropositivity

increases with age. By college age, about 15% of the US population
is infected and this rises to about half by 35 years of age.
The virus is spread in most secretions, particularly saliva, urine,
vaginal secretions and semen (which shows the highest titer of any
body fluid).
Cytomegalovirus infection is therefore sexually transmitted.
It can also spread to a fetus in a pregnant woman and to the
newborn via lactation, though there is some doubt about the
importance of milk transmission.
In the hospital, the virus can also be spread via blood
transfusions and transplants.
In third world countries with more crowded conditions, the virus is
found in a much higher proportion of the population than in western
countries.
• CMV pneumonia is seen and is often fatal
in individuals who are
immunocompromised
- hematopoietic stem cell transplant
(HSCT)
- solid organ transplant (SOT) recipients;
• The mortality rate for CMV pneumonia in
severely immunosuppressed patients is
very high, ranging from:
- 31-100% in HSCT recipients
- 54-100% in SOT recipients
CMV is a well-recognized pathogen in patients with AIDS
manifesting as:
-retinitis
-colitis
-encephalitis
-polyradiculitis, and/or cholangiopathy)
clinically relevant pneumonia is very uncommon in this
group, even if CMV is cultured from alveolar fluid and/or
seen on lung histology.
• Symptoms in the immunosuppressed host are
rapid onset of fever, nonproductive cough,
dyspnea, and hypoxia.
• In allogeneic HSCT recipients, CMV disease
presents post engraftment (30-99 d after
transplantation) and late (>100 d) in those
with graft versus host disease and/or on higher-
dose immunosuppressive therapy.
• CMV pneumonia is seen in 10-30% of such
patients, and the median time to occurrence is
44 days after transplantation.
• Among SOT recipients, CMV pneumonia
is most common in lung transplantations,
ranging from 15-55% of cases
• Other solid organ transplantations are
associated with low rates of CMV
pneumonia: liver, 9.2%; heart, 0.8-6.6%;
and kidney less than 1%.
• The primary treatment for acute
cytomegalovirus (CMV) pneumonia in the
immunocompromised patient (both HSCT
and solid organ transplant [SOT]
recipients) is ganciclovir (5 mg/kg IV 12h
for 14-21 d, followed by valganciclovir
900 mg PO qd for suppression).
Ganciclovir prevents viral DNA replication
by inhibiting the enzyme DNA polymerase.
 Congenital disease
• There are two instances in which cytomegalovirus can
cause serious disease. During a primary infection of the
mother, the virus can spread via the placenta to the fetus
and congenital abnormalities can occur;
• this virus is the most common viral cause of
congenital disease.
• Up to one in forty newborns in the United States are
infected by the virus.
• Abnormalities include microcephaly, rash, brain
calcification and hepatosplenomegaly. These may result
in hearing loss (bilateral or unilateral) and retardation.
• Besides infection in utero, infants may be infected
perinatally.
• As noted above, one tissue in which cytomegalovirus
can set up a latent infection is the cervical epithelium
and immunosuppression associated with pregnancy can
lead to reactivation.
• About 50% of children born to such mothers are infected
and can themselves shed virus within a few weeks.
• Also breast epithelium can harbor latent virus that may
be similarly reactivated leading to infection of the infant.
In neither case is there usually a problem and the infant
remains asymptomatic.
• Neonates may also receive the virus through
infected blood transfusions. In this case, the amount
of virus is much higher and symptoms may occur. These
usually consist of pneumonia and hepatitis.
• Disease in immunosuppressed patients
In patients who have received an organ
transplant or have an immunosuppressive
disease (e.g. AIDS), cytomegalovirus can be a
major problem.
• Particularly important is cytomegalovirus-
retinitis in the eye which occurs in up to 15% of
all AIDS patients.
• In addition, interstitial pneumonia, colitis,
esophagitis and encephalitis are seen in some
patients.
• Diagnosis
Most infections are asymptomatic and
therefore go undiagnosed.
• There are fluorescent antibody and ELIZA
tests. Multinucleated (cytomegalinic) cells
with characteristic inclusions can be seen
in biopsies of many tissues
• H&E stain of CMV-infected cells in lung of
AIDS patient. Nuclear inclusions can be
seen
• HHV-6, which can produce acute infection in
CD4+ T lymphocytes, causes roseola infantum
a febrile illness that affects young children.
• It is believed to persist chronically in salivary
gland tissue in some hosts. Oral shedding is the
probable route of disease transmission.
• HHV-7 has been isolated from the saliva of
healthy adults and has been implicated as one
cause of roseola infantum and febrile seizures in
children
 Human herpes virus-6
• This a common disease of young children (in the US >45% of
children are seropositive for HHV-6 by two years of age) and
symptoms include fever and sometimes upper respiratory tract
infection and lymphadenopathy.
• The symptoms last a few days after an incubation period of around
14 days. The fever subsides leaving a macropapular rash on the
trunk and neck that last a few days longer.
• In adults, primary infection is associated with a mononucleosis. This
virus was originally isolated from patients with a lymphoproliferative
disease and may co-infect HIV-infected T4 lymphocytes
exacerbating the replication of HIV.
• Patients with HIV have a higher infection rate than the normal
population.
• HHV-6 has been associated with a number of neurological
disorders, including encephalitis and seizures.
• It has been postulated to play a role in multiple sclerosis and
chronic fatigue immunodeficiency syndrome.
• HHV-8 is associated with Kaposi sarcoma and
with body-cavity lymphomas and Castleman
disease.
• HHV-8 genomic sequences have been identified
by polymerase chain reaction in more than 90%
of all types of Kaposi sarcoma (including
epidemic and endemic forms), suggesting a
causative role for this DNA virus. The current
working hypothesis is that HHV-8 must be
present for the disease to develop.
• It is transmitted sexually and can be transmitted
by contact with saliva