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Human Herpesvirus Infections
Dr. Ghazi F. AI- Haji
Cardiologist
2010
lessons
Epidemiology:.
Pathogenesis
Clinical manifestations
Diagnosis
Patient management
Prevention
Characteristics of herpes viruses
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Persistence
Latency
Reactivation
Tissue tropism
Human Herpes Viruses
• Alphaherpesviruses
• HSV-1 and HSV-2
• Varicella-zoster virus (VZV)
• Betaherpesviruses
• Cytomegalovirus (CMV)
• HHV-6 and HHV-7
• Gammaherpesviruses
• Epstein-Barr Virus (EBV)
• Kaposi’s sarcoma-associated herpesvirus (KSHV,HHV-8)
Cell types infected by different
herpesviruses
• VZV and HSV
• Epithelial cells and neurons
• CMV
• Ductal epithelium, leukocytes
• EBV
•Oropharyngeal epithelium, B lymphocytes
• KSHV
•Endothelium, B cells
Herpes simplex virus
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Ubiquitous virus that infects greater than 75% of the adult population (HSV-1) and to
varying degrees in the case of HSV-2, depending on the population studied.
There are many manifestations of HSV infection in addition to the common cold sore or
fever blister.
Manifestations depend on anatomic site involved, age, immune status of the host
Herpes labialis
Genital herpes
Herpes gladiatorum
Herpetic whitlow
Eczema herpeticum
Congenital HSV infection
Herpetic gingivostomatitis
Disseminated infections
Pneumonia
Esophagitis
Hepatitis
Encephalitis
Chronic and resistant infections
Infection Type
Lesions/
Symptoms
Type-specific antibody at time of
presentation
HSV-1
HSV-2
First episode,
Primary
(Type 1 or 2)
+/Severe, bilateral
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First episode,
Non-primary
Type 2
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First episode,
Recurrence
Type 2
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Symptomatic,
Recurrence
Type 2
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unilateral
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Asymptomatic,
Infection
Type 2
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Oral-Facial Herpes
Gingivostomatitis and
pharyngitis most common
manifestation of primary
HSV−1 infection. in children
and young adults and may be
subclinical, symptoms and signs
include fever, malaise, myalgias,
inability to eat, irritability, and
cervical adenopathy, may last 3–
14 days.
Recurrent herpes labialisreactivation from trigeminal
ganglia-lesions
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Rx:
Acyclovir, Famciclovir,
Valacyclovir.
Antivirals-HSV
Require TK phosphorylation
for activity
 ACV binds to replicating viral
DNA causing premature chain
termination
 ACV and Famciclovir both
inhibit viral DNA polymerase
 Resistance mediated by
reduction in viral TK
 Valacyclovir rapidly converted
to ACV and higher levels
achieved
 Excellent activity against HSV
 Moderate activity against VZV
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Genital Herpes
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Primary episode: Fever, headache,
myalgias, dysuria, vag/urethral
discharge lymphadenopathy
Lesions: vesicles, pustules,
erythematous ulcers
Can be caused by HSV-1 & 2
Recurrence rate higher with HSV-2
infection
HSV proctitis (ulcerative lesions on
sigmoidoscopy) and perianal
lesions: HIV, rectal intercourse
Trigeminal ganglia & sacral
ganglia- most common sites of
HSV-1 and HSV-2 latency
Rx: Acyclovir, Famciclovir,
Valacyclovir
Neonatal Herpes
Neonates
may develop primary
HSV infection following vaginal
delivery in the presence of active
genital HSV infection in the
mother. Caesarean section should
therefore be considered.
< 6weeks of age
Without therapy mortality is
approx 65%
Skin lesions most commonly
recognized feature - may not
appear or may be delayed
Acquired perinatally from
contact with genital secretions
or close contact with family
member
 30% due to HSV-1 and 70%
HSV-2 ---Rx- IV Acyclovir
 Infection of the finger
 Occurs as complication of
primary oral or genital herpes,
direct innoculation,
occupational exposure
Vesicular or pustular lesion
Abrupt onset erythema,
localized tenderness
Fever, lymphadenitis,
lymphadenopathy are common
Prompt diagnosis
Herpes Gladiatorum
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Any skin area may be
infected
Transmission facilitated
by trauma
Prompt diagnosis to
contain the spread
Eczema Herpeticum
 Potentially life-threatening viral infection that arises in pre-existing skin
conditions like atopic dermatitis
 In some cases may lead to fulminant life threatening disseminated infection
 Acyclovir, Valacyclovir. Antibiotics may be needed as well
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Rare entity
Skin lesions, chorioretinitis,
microcephaly
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H in TORCH infections
Herpes Encephalitis
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Accounts for 10-20% of
viral encephalitis
2.3 cases per 1 million
HSV-1 >95% cases
Biphasic- 5-30, >50yrs
Primary infection or
reactivation
Fever, altered mental
status, bizarre behavior,
seizures
Temporal lobe involved
 Diagnosis: LP: Increased CSF protein, leucocytes with lymphocytic
predominance and increased CSF RBCs due to hemorrhagic necrosis
 CSF HSV PCR: High sensitivity and specificity
 Treatment: IV Acyclovir, reduces mortality. Despite treatment mortality
upto 15% with survivors with longterm cognitive impairments
Eryrthema Multiforme
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EM is a acute self limiting,
sometimes recurring skin condition
considered to be a Type IV
hypersensitivity reaction associated
with certain infections, medications.
Cell mediated immune reaction
associated with HSV antigens
Antigens may be detected in
keratinocytes by IF or HSV DNA
detected by PCR
Typical “Target Lesions”
Suppression of HSV may prevent
EM. Once EM erupts antivirals not
effective
“B” virus, Herpesvirus simiae
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Endemic HSV homolog of nonhuman primates
Risk for those handling animals
Causes a fulminant neurologic syndrome in
humans
May be treatable with acyclovir
Varicella-Zoster Virus Infections
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Varicella (Chickenpox)
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Bacterial superinfection
CNS: aseptic meningitis, transverse myelitis, GBS, encephalitis, Reye’s
syndrome
Varicella pneumonia
Myocarditis, nephritis, hepatitis
Perinatal varicella: high mortality
Herpes Zoster (Shingles)
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T3-L3 dermatomes most frequently involved
Zoster opthalmicus: Opthalmic branch of Trigeminal Nerve involved
Ramsay Hunt syndrome: vesicles , loss of sense of taste in ant 2/3rds of
tongue, ipsilateral facial palsy: geniculate ganglia of sensory branch of
Facial Nerve involved.
Chickenpox
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Childhood disease
Highly contagious: pt infectious
48hrs prior to rash.
IP: 10-21 days
Fever, malaise, skin lesions:
maculopapules, vesicles, pustules,
scabs in various stages of evolution
Early lesions “dew drop on rose
petal”
Diagnosis: clinical, VZV DNA PCR,
Tzanck smear demonstrating
multinucleate giant cells, Direct
immunofluorescence
Acyclovir therapy efficacious if used
<24hrs
Immunocompromised: IV Acyclovir
Chickenpox pulmonary x-ray
Herpes zoster(shingles)
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Shingles never occurs as a
primary infection but
results from reactivation of
latent VZV from dorsal root
and/or cranial nerve
ganglia.
It produces skin lesions
similar to chickenpox,
although classically they
are unilateral and restricted
to a sensory nerve
(dermatomal) distribution.
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Shingles occurs at all ages
but is most common in the
elderly, immune deficiency
state or after intra-uterine
infection.
The onset of the rash of
shingles is usually preceded
by severe dermatomal pain
(Burning pain), due to
involvement of sensory
nerves.
complication
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The most common and
troublesome complication is
post-herpetic neuralgia:
(persistence of pain for 1-6
months or more following
healing of the rash).
Shingles involving the
ophthalmic division of the
trigeminal nerve can result
in blindness in the absence
of antiviral therapy.
Herpes Zoster
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Opthalmic division of
Trigeminal Nerve
Adapted from: gb.udn.com
HZ: Involvement of tip of nose is classic indicator of
ocular involvement (Hutchinson’s sign)
Herpes Zoster treatment
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Treatment with acyclovir,
Famciclovir or valacyclovir is
beneficial with accelerated
healing of lesions and
resolution of neuralgia
Immunocompromised should receive initial reaction
with IV Acyclovir
CMV disease
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β Herpes virus dsDNA
Spread by repeated prolonged
exposure
CMV present in breast milk, saliva,
feces, urine, semen, cervical
secretions
Daycare centers
Once infected person carries CMV
for life.
Reactivation syndromes: T cell
mediated immunity compromised
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Pneumonitis
 Bone marrow transplant
Colitis
 AIDS, solid organ transplantation
Retinitis
 AIDS
Hepatitis
 SOT
Nephritis
 Kidney transplantation
Mononucleosis: F/C, malaise, fatigue,
splenomegaly, atypical lymphocytosis,
leucopenia, LFT abnormalty
Congenital infection: microcephaly,
chorioretinitis
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When GCV(ganciclovir)
enters cells, it must undergo a
series of phosphorylations until
it is active to be able to inhibit
viral DNA polymerase.
The initial phosphorylation
step is done by a viral protein
kinase that's encoded by UL97.
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Mutations in UL97 or in the
viral DNA polymerase are the 2
major mechanisms that
underlie ganciclovir resistance
and antiviral resistance in
general
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Activity: CMV, HSV, varicella
Adapted from: medscape.com
Cidofovir
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Analog of deoxycytidine
monophosphate causes premature
chain termination of viral DNA and
inhibits DNA polymerase
Does not require TK
ACV resistant strains usually not
resistant to cidofovir
HSV, CMV, HHV6 & 8, VZV
Nephrotoxic and BM toxicity
Foscarnet
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Blocks binding of deoxynucleotidyl
triphosphate to viral DNA
polymerase
CMV, HSV, VZV
CMV retinitis and ACV resistant
HSV, GCV resistant CMV
Nephrotoxicity and electrolyte
abnormalities
CMV Retinitis
Normal Fundoscopic exam
www.kellogg.umich.edu/.../cmv-retinitis.html
Hemorrhages, vessel sheathing, retinal edema
AIDS with CD4<50
IV Ganciclovir then oral Valganciclovir until CD4>100-150
CMV Pneumonitis
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Highest risk in Lung transplant
and BMT patients
High mortality
Diagnosis with
BAL(bronchoalveolar lavage)
with cells showing viral and
inclusions body, PCR. Lung
biopsy-gold std
Treatment with IV Ganciclovir
CMV inclusions in lung
http://library.med.utah.edu/WebPath/TUT
ORIAL/AIDS/AIDS021.html
CMV colitis
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The transplanted organ is
particularly vulnerable as a target
for CMV infection
Patients may present with diarrhea,
heartburn, odynophagia
Diagnosis made with biopsies
obtained on endoscopy
CMV immunostain positive
IV Ganciclovir
Thank you for
attention
True( T) or false (F)
Properties of transforming
herpesviruses
• Drive infected cell proliferation
• Prevent apoptosis of infected
cells
• Avoid immune attack
• Infect new cells
Epstein Barr virus (EBV)-associated
diseases
•Infectious Mononucleosis
•Burkitt lymphoma
•Nasopharyngeal carcinoma
•Lymphoproliferative Disease
•Hodgkin’s Disease, EBV-assoc. NHL
•Gastric carcinoma
Infectious mononucleosis:
Kissing disease
Oral Hairy Leukoplakia
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White plaques on lateral
surface of tongue
Seen in HIV/AIDS,
immunocompromised
individuals
Burkitt’s Lymphoma
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Rapidly growing NHL
15% of cases in US and 90%
cases in Africa associated
with EBV
Extremely responsive to
chemotherapy and
recurrence is rare
from thacher’s.org
NPC and EBV
Figure 135-4 Nasopharyngeal carcinoma. A, Nests of metastatic undifferentiated nasopharyngeal
carcinoma in a fibrous stroma in a lymph node (hematoxylin and eosin). Metastases often lack
infiltrating lymphocytes. B, In situ hybridization for Epstein-Barr virus (EBV)-encoded RNA (EBER)
(brown) demonstrates EBV infection in most cells in the same area of the tissue. (Magnification
&#215;100.) (Courtesy of Dr. Miguel Rivera.)
Downloaded from: Principles and Practice of Infectious Diseases (on 28 February 2006 03:59 PM)
© 2005 Elsevier
Hodgkin’s lymphoma and EBV
Figure 135-3 Mixed cellularity classic Hodgkin's lymphoma. A, Lymph node architecture is
effaced by an infiltrate comprised of small lymphocytes, epithelioid histiocytes, plasma cells,
eosinophils, and Hodgkin and Reed-Sternberg cells (arrow) (hematoxylin and eosin). B, In situ
hybridization for Epstein-Barr virus (EBV)-encoded RNA (EBER) (brown) demonstrates EBV
infection in the malignant Hodgkin and Reed-Sternberg cells. (Original magnification x400.)
(Courtesy of Dr. Jeffery Kutok.)
Downloaded from: Principles and Practice of Infectious Diseases (on 28 February 2006 04:00 PM)
© 2005 Elsevier
PTLD and EBV
Figure 135-2 Post-transplantation lymphoproliferative disease involving the colon. A, The tumor
is composed of large, atypical lymphoid cells (hematoxylin and eosin). Scattered macrophages
(arrow) are seen, producing a "starry-sky" appearance. B, In situ hybridization for Epstein-Barr
virus (EBV)-encoded RNA (EBER) (brown) shows variably intense nuclear staining in the
majority of tumor cells, indicating EBV infection. (Original magnification x400.) (Courtesy of Dr.
Jeffery Kutok.)
Downloaded from: Principles and Practice of Infectious Diseases (on 28 February 2006 04:00 PM)
© 2005 Elsevier
Kaposi’s sarcoma-associated virus
(KSHV, HHV8)
•Kaposi’s sarcoma (KS)
•Multicentric Castleman’s disease
•Primary Effusion Lymphoma (PEL)
Kaposi’s sarcoma
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Classic Kaposi's sarcoma (CKS) is
a neoplasm characterized by
abnormal angiogenesis that
requires infection with a human
herpes virus, HHV-8, along with
other cofactors.
purplish, reddish blue, or dark
brown/black macules, plaques, and
nodules on the skin.
mucous membranes of mouth and
gastrointestinal (GI) tract and
regional lymph nodes may be
affected later in the course.
Biopsy for definitive diagnosis
radiation therapy, excision,
cryotherapy, laser ablation,
chemotherapy
emedicine.medscape.com/article/279734-overview
Kaposi’s sarcoma: Seen in AIDS patients
Figure 137-2 Kaposi's Sarcoma Involving a Lymph Node. Left panel, Spindle cell proliferation
(white arrows) containing poorly formed vascular spaces with entrapped red blood cells (black
arrows). Areas of uninvolved lymph node (LN) are seen at the top (H&E). Right panel,
Immunohistochemical detection of Kaposi's sarcoma-associated human herpesvirus (KSHV)
latency-associated nuclear antigen 1 (LANA1) (brown) in the nuclei of many spindle cells
indicates KSHV infection (&#215;200). (Courtesy of Dan Jones, MD, PhD.)
Downloaded from: Principles and Practice of Infectious Diseases (on 28 February 2006 03:59 PM)
© 2005 Elsevier
 Fever, LAN, hepatosplenomegaly, night sweats
 Most patients with MCD die due to fulminant infection, progressive
disease or related malignancy
Human Herpes Viruses
• Alphaherpesviruses
• HSV-1 and HSV-2
• Varicella-zoster virus (VZV)
• Betaherpesviruses
• Cytomegalovirus (CMV)
• HHV-6 and HHV-7
• Gammaherpesviruses
• Epstein-Barr Virus (EBV)
• Kaposi’s sarcoma-associated herpesvirus (KSHV,HHV-8)
Cell types infected by different
herpesviruses
• VZV and HSV
• Epithelial cells and neurons
• CMV
• Ductal epithelium, leukocytes
• EBV
•Oropharyngeal epithelium, B lymphocytes
• KSHV
•Endothelium, B cells
Take Home points
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Latency and potential for reactivation
Immunocompromised with defective cell mediated immunity at risk of severe
disease
HSV- Acyclovir
HSV encephalitis: IV ACV improves mortality
Chickenpox: lesions in various stages of development
Zoster Opthalmicus: opthalmic division of Trigeminal Nerve
VZV diagnosis: Tzanck smear- mulinucleate giant cells, PCR
CMV : Mononucleosis without exudative pharyngitis
CMV retinitis, colitis, pneumonia
CMV dx: PCR, cells with classic inclusions on biopsy
EBV: IM, Heterophile antibody positive
Transforming virus: EBV, KSHV, HHV-8