HERPESVIRUS

Titiek Djannatun ​Bagian Mikrobiologi FK

Universitas YARSI
Insiden meningkat ​→ ​Inggris, Wales,
Ireland, USA ​(1995-2000) ​→ ​Seluruh
dunia:
Bertambah padat populasi manusia
Bertambah mobilitas manusia
Kemajuan teknologi ​→ ​Mengubah
perilaku sex
Tidak adanya vaksin untuk sebagian
besar STD ​→ ​Herpes simpleks dan HIV
tersedia
Kondom ​→ ​melindungi
Orang yang tidak disirkumsisi ​→ ​Resiko
tinggi
Infeksi Gonorrhoea ​→ ​Mudah terkena
Herpes ​genital
PENDAHULUAN
VIRUS PENYEBAB STD
ORGANISME PENYAKIT KETERANGAN TERAPI
PAPILLOMAVIRUS (Tipe 6 & 11 ​→ ​Genital Warts)
Genital Warts, Dysplasia
Paling sering ​→ ​Kanker servix, Kanker penis, dll
Podophylin, Cryotherapy
Herpes Simplex virus tipe 1 dan 2
Genital Herpes Meningkat ​→ ​Masalah
laten dan reaktivasi
Aciclovir, valaciclovir, Famciclovir
HIV AIDS Insiden meningkat di
seluruh dunia
Nukleosida, Nukleotida, Non- Nucleoside reverse ​transcriptase inhibitors, Fusi
inhibitors, Protease inhibitors
Virus Hepatitis B Hepatitis 300 Juta carrier di seluruh
dunia
Lamivudin, Adefovir, IFN α

Congenital, Perinatal, and

Neonatal Viral ​Infections
Intrauterine Viral Infections
Rubella ​Cytomegalovirus (CMV) ​Parvovirus B19
Varicella-Zoster (VZV) Enteroviruses ​HIV ​HTLV-1
Hepatitis C ​Hepatitis B ​Lassa Fever Japanese
Encephalitis
Perinatal and Neonatal Infections
Human Herpes Simplex ​VZV ​Cytomegalovirus (CMV
Enteroviruses HIV ​Hepatitis B ​Hepatitis C HTLV-1
 STRATEGI VIRUS MELAWAN
PERTAHANAN HOSPES
PERTAHANAN HOSPES
STRATEGI VIRUS CONTOH
Urine flow (untuk infeksi ​uretra)
Infeksi sel epitel atau sub ​epitel uretra
Herpes Simplex virus
Inflamasi Merangsang respon inflamasi
kuat
Herpes Simplex virus
Cell Mediated Immune Response (Sel T, Limfokin, Sel NK, dll)
Variasi antigenik, disertai reinfeksi Variasi antigenik diantara individu
Faktor yang tidak diketahui ​→ ​Sebabkan respon CMI tidak egektif F
Papillomavirus
HIV
HIV

Properties of
herpesviruses
▪ Enveloped double stranded DNA viruses.
▪ Genome consisits of long and short fragments
which may be orientated in either direction, giving a
total of 4 isomers.
▪ Three subfamilies:
– Alphaherpesviruses - HSV-1, HSV-2, VZV –
Betaherpesviruses - CMV, HHV-6, HHV-7 –
Gammaherpesviruses - EBV, HHV-8
▪ Set up latent or persistent infection following
primary infection
▪ Reactivation are more likely to take place during
periods of immunosuppression
▪ Both primary infection and reactivation are likely to
be more serious in ​immunocompromised patients.
(Linda Stannard, University of Cape Town, S.A.)

Herpesvirus Particle
HSV-2 virus particle. Note that all herpesviruses
have identical morphology and cannot be
distinguished from each other under electron
microscopy.

Pathway of a Herpes Infection

Herpesvirus ​enters ​the body

Herpesvirus lies ​do​rmant ​in ​the ner​ves
Herpesvirus is rea​c​tivated, ​causing
another outbreak
IIIIIIIIIIIIIIIIIIIIIIIIII
IIIIIIIIIIIIIIIIIIIIIIIIIII
LII
IUTI

Herpesvirus enters bo​d​y ​through ​skin ​or

muco​us ​membranes
After initial infection​,
her​pesvirus settles in ​i nerves near the
spine
Herpesvirus trave​ls along t​ he nerv​es​, ​ba​ck to the
skin to form new ​blisters

Viral Latency
Alphaherpesvirus
Lesions
Alphaherpesvirus
Lesions
 Herpes Simplex
Viruses
Properties
• Belong to the alphaherpesvirus
subfamily of ​herpesviruses
• Double stranded DNA enveloped
virus with a ​genome of around 150 kb
• The genome of HSV-1 and HSV-2
share 50 - 70% ​homology.
• They also share several
cross-reactive epitopes with each
other. There is also antigenic cross-
reaction with VZV.
• Man is the only natural host for
HSV.
Epidemiology (1)
• HSV is spread by contact, as the virus is
shed in saliva, tears, genital and other
secretions.
• By far the most common form of infection
results from a kiss given to a child or adult
from a person shedding the virus.
• Primary infection is usually trivial or
subclinical in most individuals. It is a
disease mainly of very young children ie.
those below 5 years.
• There are 2 peaks of incidence, the first at
0 - 5 years and the second in the late teens,
when sexual activity commences.
• About 10% of the population acquires
HSV infection through the genital route and
the risk is concentrated in young adulthood.
Epidemiology (2)
• Generally HSV-1 causes infection above
the belt and ​HSV-2 below the belt. In fact,
40% of clinical isolates from genital sores
are HSV-1, and 5% of strains isolated from
the facial area are HSV-2. This data is
complicated by oral sexual practices.
• Following primary infection, 45% of orally
infected individuals and 60% of patients
with genital herpes will experience
recurrences.
• The actual frequency of recurrences
varies widely between individuals. The
mean number of episodes per year is about
1.6.
Tersebar di seluruh dunia
Banyak inang
Replikasi pada banyak jenis sel
Infeksi pada organ genital ibu ​→ ​neonatus
Siklus pertumbuhannya 8 – 16 jam
Sering pada orang dengan gangguan immunitas
Disebabkan infeksi virus Herpes simpleks-2
Herpes simpleks – 1 ​→ ​???
HSV-1 dan HSV-2 ​→ ​berbeda secara biologik dan
antigenik
Terdapat sedikit imunitas silang
Dapat ditemukan oral dan genital
HERPES GENITAL
SIFAT-SIFAT PENTING VIRUS
HERPES
VIirion ​→ ​Bulat, Diameter 150-200nm,
kapsid ​ikosahedral
Genom ​→ ​DNA untai ganda, Linier, BM
95-150 juta, 124-235 kbp, urutan diulang
Protein ​→ ​Lebih 35 protein dalam virion
Selubung ​→ ​Glikoprotein, Reseptor Fc
Replikasi​→ ​Inti, bertunas di membran
inti
Ciri khas​→ ​Mengkode banyak enzim;
Infeksi laten, ​bertahan secara tak
terbatas pada hospes terinfeksi,
Diaktifkan kembali bila fungsi imunnya
tertekan​→ ​INFEKSI RECURRENT ​→
komplikasi kesehatan ​berbahaya;
beberapa menyebabkan kanker
REPLIKASI VIRUS HERPES
KLASIFIKASI VIRUS HERPES
MANUSIA
SUBFAMILIA
SIFAT BIOLOGIK
CONTOH
SIKLUS PERTUMBUH AN
SITOPATOLO GI
INFEKSI LATEN
GENUS NAMA
KHUSUS
NAMA UMUM
Alfaherpesvirinae Pendek Sitolitik saraf ​SIMPLEX
VARICELLO
Herpesvirus 1 manusia Herpesvirus 2 manusia Herpesvirus 3 manusia
HSV – 1
HSV – 2
Varisela - Zooster
Betaherpesvirinae Panjang sitomegalik Kelenjar,
ginjal
 Herpesvirus
CYTOMEGA LO ​
5 manusia
Sitomegalovir us
Jaringan limfoid
ROSEOLO ​Herpesvirus
6​1 ​manusia Herpesvirus 7​1 ​manusia
Herpesvirus 6 manusia Herpesvirus 7 manusia
Gamaherpesvirina e
Variasi limfoprolifer
atif
Jaringan limfoid
LYMPHOC RYPTO Rhadino
Herpesvirus 4 manusia Herpesvirus 8​1 ​manusia
Virus Epstein barr Herpesvirus 8 manusia
1 ​SULIT DIKLASIFIKASI, VIRUS MENGINFEKSI LIMFOSIT, TETAPI GENOM MENYERUPAI

SITOMEGALOVIRUS

PERBANDINGAN HSV-1 DAN

HSV-2
CIRI KHAS HSV-1 HSV-2
BIOKIMIA
Komposisi dasar DNA virus (Guanin – Sitosin) ​Densitas Berat Jenis
DNA (g / cm​3​) ​Densitas Berat Jenis virion (g / cm​3​) Homologi antara
virus DNAs
67% ​1,726 ​1,271 - 50%
69% ​1,728 ​1,267 - 50%
BIOLOGIK
Reservoir atau vektor hewan ​Lokasi bentuk laten
Tidak ada ​Ganglion trigeminal
Tidak ada ​Ganglia sakral
EPIDEMIOLOGIK
Usia infeksi primer Penularan
Anak kecil Kontak (Sering air liur )
Dewasa muda Seksual

PERBANDINGAN HSV-1 DAN

HSV-2
Ciri khas Hsv-1 Hsv-2
KLINIK
Infeksi primer
Gingivostomatitis Faringotonsilitis Keratokonjungtivitis ​Infeksi neonatus
INFEKSI KAMBUHAN
Lesi dingin, DEemam lepuh Keratitis
INFEKSI PRIMER ATAU KAMBUHAN
Herpes Kutaneus
Kulit sebelah atas pinggang Kulit sebelah bawah pinggang Lengan atau tangan
Herpes Whitlow Eksema Herpetikum ​Herpes Genital ​Ensefalitis Herpes Meningitis
Herpes

+ ​+ + + + + - + + + +

- ​- - ​+ ​- - - + + + - ​+ ​- +

Pathogenesis
• During the primary infection, HSV spreads
locally and a ​short-lived viraemia occurs,
whereby the virus is ​disseminated in the
body. Spread to the to craniospinal ganglia
occurs.
• The virus then establishes latency in the
craniospinal ganglia.
• The exact mechanism of latency is not
known, it may be true latency where there
is no viral replication or viral persistence
where there is a low level of viral
replication.
• Reactivation ​- ​It is well known that many
triggers can provoke a recurrence. These
include physical or ​psychological stress,
infection; especially pneumococcal and
meningococcal, fever, irradiation; including
sunlight, and menstruation.
HSV ​→ ​Infeksi sitolitik ​→ ​Nekrosis sel +

Peradangan ​→ ​Mirip ​dengan Varicella Zooster

Perubahan Histopat ​→ ​Pembengkakan sel ,

Pembentukan ​Badan Inklusi ​COWDRY TIPE A​,

Pembentukan sel Raksasa berinti banyak

Cairan edema (Vesikuler) menumpuk diantara
lapisan ​epidermis dan dermis ​→ ​Berisi sel yang

bebas virus, sisa sel radang

Di kulit ​→ ​Cairan tersebut diabsorpsi

membentuk keropeng ​→ ​Sembuh tanpa jaringan

parut
Pada sel mukosa ​→ V
​ esikel pecah membentuk

ulkus yang ​dangkal

​ erivaskuler dan
Herpes neonatal ​→ ​Cuffyng p

daerah nekrosis ​hemorrhagik

PATOGENESIS
HSV-1 dan HSV-2 ​→ ​Aseptik meningitis
dan ensefalitis pada orang dewasa
Herpes neonatus ​→ ​75% HSV-2 ​→
ditularkan dari ibu penderita ke anak
melalui jalan kelahiran ​→ ​Untuk
menghindar ​→ ​Bedah Caecar
Herpes Neonatus :
Lokalisasi lesi pada kulit, mata, mulut
Ensefalitis dengan atau tanpa lesi kulit
Neonatal Disseminated ​Herpes ​→
Organ–organ dan SSP
PATOGENESIS
Port D’Entry ​→ K​ ulit atau mukosa yang luka
HSV-1 ​→ ​Orofaring (Terutama pada anak-anak)
dan Cold sores ​(Virus reaktif ​→ ​Virus menyebar
melalui droplet/air liur
HSV-2 ​→ ​Veneral route ​(Seksual) ​→ ​Infeksi
primer ​→ ​Ujung saraf ​→ ​Akar ganglion ​→ ​Laten
sampai akhir hidupnya ​→ ​Teraktivasi ​→ ​Virus
mengikuti jalannya axon kembali ke perifer ​→
Berkembang biak di kulit dan sel mukosa (
Infeksi laten) ​→ ​Infeksi tidak begitu luas karena
respon imunitas
HSV-2 ​→ ​Lesi genital primer pada penis/ vulva
(3-7 hari setelah infeksi) ​→ ​Ulcer yang sakit ​→
Lymfonoduli lokal bengkak + demam, Sakit
kepala, malaise ​→ ​2 minggu sembuh ​→ ​Laten
(Dorsal akar ganglion saraf) ​→ ​Reaktivasi ​→ ​Lesi
Recurrent (Genital Cold sores)
INFEKSI PRIMER
Clinical Manifestations
HSV is involved in a variety of clinical
manifestations which includes ;-
1. Acute gingivostomatitis ​2. Herpes
Labialis (cold sore) ​3. Ocular Herpes 4.
Herpes Genitalis ​5. Other forms of
cutaneous herpes ​7. Meningitis 8.
Encephalitis ​9. Neonatal herpes

Oral-facial Herpes
• Acute Gingivostomatitis
– Acute gingivostomatitis is the commonest

manifestation of primary ​herpetic infection. –

​ The
patient experiences pain and bleeding of the gums.

1 - 8 mm ​ulcers with necrotic bases are present.

Neck glands are commonly ​enlarged accompanied

by fever. –
​ Usually a self limiting disease which lasts
around 13 days.
• Herpes labialis (cold sore)
– Following primary infection, 45% of orally infected

individuals will ​experience reactivation. The actual

frequency of recurrences varies widely between

individuals. –
​ Herpes labialis (cold sore) is a
recurrence of oral HSV. – A prodrome of tingling,
warmth or itching at the site usually heralds the

recurrence. About 12 hours later, redness appears

followed by papules and then vesicles.

Gingivostomatitis
Ocular Herpes
HSV causes a broad spectrum of
ocular disease, ranging from mild
superficial lesions involving the
external eye, to severe
sight-threatening diseases ​of the
inner eye. Diseases caused include
the ​following:-
– Primary HSV keratitis ​– ​dendritic
ulcers ​– Recurrent HSV keratitis ​–
HSV conjunctivitis ​– Iridocyclitis,
chorioretinitis and cataract
Genital Herpes
• Genital lesions may be primary, recurrent or initial.
• Many sites can be involved which includes the

penis, vagina, cervix, ​anus, vulva, bladder, the

sacral nerve routes, the spinal and the meninges.

The lesions of genital herpes are particularly prone

to secondary bacterial infection eg. S.aureus,

Streptococcus, Trichomonas ​and Candida Albicans.
• Dysuria is a common complaint, in severe cases,

there may be urinary ​retention.

• Local sensory nerves may be involved leading to

the development of a ​radiculitis. A mild meningitis

may be present.
• 60% of patients with genital herpes will experience

recurrences. ​Recurrent lesions in the perianal area

tend to be more numerous and persists longer than

their oral HSV-1 counterparts.

Herpes Simplex Encephalitis

• Herpes Simplex encephalitis is one of the
most serious complications of herpes
simplex disease. There are two forms:
• Neonatal – there is global involvement
and the brain is almost liquefied. The
mortality rate approaches 100%.
• Focal disease – the temporal lobe is most
commonly affected. This form of the
disease appears in children and adults. It is
possible that many of these cases arise
from reactivation of virus. The mortality rate
is high (70%) without treatment.
• It is of utmost importance to make a
diagnosis of HSE early. It is general
practice that IV acyclovir is given in all
cases of suspected HSE before laboratory
results are available.
Neonatal Herpes Simplex (1)
• Incidence of neonatal HSV infection varies
inexplicably ​from country to country e.g.

from 1 in 4000 live births in ​the U.S. to 1 in

10000 live births in the UK

• The baby is usually infected perinatally
during passage ​through the birth canal.
• Premature rupturing of the membranes is
a well recognized ​risk factor.
• The risk of perinatal transmission is
greatest when there is ​a florid primary

infection in the mother.

• There is an appreciably smaller risk from
recurrent lesions ​in the mother, probably

because of the lower viral load and the

presence of specific antibody

• The baby may also be infected from other
sources such as ​oral lesions from the
mother or a herpetic whitlow in a nurse.
Neonatal Herpes Simplex (2)
• The spectrum of neonatal HSV infection
varies from a ​mild disease localized to the

skin to a fatal disseminated infection.

• Infection is particularly dangerous in
premature infants.
• Where dissemination occurs, the organs
most commonly ​involved are the liver,

adrenals and the brain.

• Where the brain is involved, the prognosis
is particularly ​severe. The encephalitis is

global and of such severity that ​the brain

may be liquefied.
• A large proportion of survivors of neonatal
HSV infection ​have residual disabilities.
• Acyclovir should be promptly given in all
suspected cases ​of neonatal HSV infection.
• The only means of prevention is to offer
caesarean section ​to mothers with florid

genital HSV lesions.

Other Manifestations
• Disseminated herpes simplex are much
more likely to ​occur in

immunocompromised individuals. The

widespread vesicular resembles that of

chickenpox. Many organs other than the

skin may be involved e.g. liver, spleen,

lungs, and CNS.

• Other cutaneous manifestations include
– eczema herpeticum which is potentially a
serious ​disease that occurs in patients with

eczema. –
​ Herpetic whitlow which arise
from implantation of the ​virus into the skin

and typically affect the fingers. – ​

“zosteriform herpes simplex". This is a rare
presentation ​of herpes simplex where HSV

lesions appear in a ​dermatomal distribution

similar to herpes zoster.
HERPES PADA ​PRIA
HERPES PADA ​WANITA
Laboratory Diagnosis
• Direct Detection
– Electron microscopy of vesicle fluid - rapid result

but cannot ​distinguish between HSV and VZV –

​
Immunofluorescence of skin scrappings - can

distinguish ​between HSV and VZV –

​ PCR - now
used routinely for the diagnosis of herpes simple

encephalitis
• Virus Isolation
– HSV-1 and HSV-2 are among the easiest viruses

to cultivate. It ​usually takes only 1 - 5 days for a

result to be available.
• Serology
– Not that useful in the acute phase because it takes
1-2 weeks for ​before antibodies appear after

infection. Used to document to ​recent infection.

Cytopathic Effect of HSV in cell culture: Note the ballooning of
cells. (Linda Stannard, University of Cape Town, S.A.)
Positive immunofluorescence test for HSV antigen in epithelial
cell. (Virology Laboratory, New-Yale Haven Hospital)

Management
At present, there are only a few indications of antiviral
chemotherapy, with the high cost of antiviral drugs being a
main consideration. Generally, antiviral chemotherapy is
indicated where the primary infection is especially severe,
where ​there is dissemination, where sight is threatened,
and herpes simplex encephalitis.
Acyclovir – this the drug of choice for most situations at
present. It is available in
a number of formulations:-
• I.V. (HSV infection in normal and immunocompromised
patients)
• Oral (treatment and long term suppression of
mucocutaneous herpes and prophylaxis of HSV in
immunocompromised patients)
• Cream (HSV infection of the skin and mucous
membranes)
• Ophthalmic ointment
• Famciclovir and valacyclovir – oral only, more expensive
than acyclovir.
• Other older agents – e.g. idoxuridine, trifluorothymidine,
Vidarabine (ara- A).
• These agents are highly toxic and is suitable for topical
use for opthalmic ​infection only
Isolasi virus dari cairan vesikel/swab ulcer ​→
FAT (Antibodi monoklonal)
Typing ​→ ​Type differentiation
​ ​Degenerasi
CPE ​→ ​1-2 Hari ​Post inoculation →
sel berbentuk ​busa dan ​Giant cell
Serologi ​→ ​Antibodi terbentuk setelah 4-7 hari
infeksi ​→ ​ELISA, RIA, Immunofluoresensi
Antibodi meningkat 2-4 minggu setelah infeksi
Terapi:
Pada kasus dengan komplikasi sistemik ​→
Aciclovir (IV) ​Cegah ​Recurrent attacks ​→ ​6-12
bulan Aciclovir dosis ​rendah
DIAGNOSA DAN TERAPI
HERPES ​GENITAL
 Varicella- Zooster
Virus
Properties
• Belong to the alphaherpesvirus
subfamily of herpesviruses
• Double stranded DNA enveloped
virus
• Genome size 125 kbp, long and
short fragments with a total of 4
isometric forms.
• One antigenic serotype only,
although there is some cross reaction
with HSV.
Epidemiology
• Primary varicella is an endemic
disease. Varicella is one of the
classic diseases of childhood, with
the highest prevalence occurring in
the 4 - 10 years old age group.
• Varicella is highly communicable,
with an attack rate of 90% in close
contacts.
• Most people become infected
before adulthood but ​10% of young
adults remain susceptible.
• Herpes zooster, in contrast, occurs
sporadically and evenly throughout
the year.
Pathogenesis
• The virus is thought to gain entry via the
respiratory tract ​and spreads shortly after to

the lymphoid system.

• After an incubation period of 14 days, the
virus arrives at ​its main target organ, the

skin.
• Following the primary infection, the virus
remains latent in ​the cerebral or posterior

root ganglia. In 10 - 20% of individuals, a

single recurrent infection occurs after

several decades.
• The virus reactivates in the ganglion and
tracks down the ​sensory nerve to the area

of the skin innervated by the nerve,

producing a varicellaform rash in the

distribution of ​a dermatome.

Varicella
• Primary infection results in varicella (chickenpox)
• Incubation period of 14-21 days
• Presents fever, lymphadadenopathy. a widespread
vesicular rash.
• The features are so characteristic that a diagnosis
can usually be made ​on clinical grounds alone.
• Complications are rare but occurs more frequently
and with greater severity in adults and
immunocompromised patients.
• Most common complication is secondary bacterial
infection of the vesicles.
• Severe complications which may be life
threatening include viral pneumonia, encephalititis,
and haemorrhagic chickenpox.
VESICULAR/PUSTULAR RASH DISEASES
DISEASE CHICKENPOX SMALLPOX
Causative organism(s) Human herpesvirus 3
(Varicella zooster virus)
Variola virus
Most common modes of transmission
Droplet contact, inhalation of aerolised lesion fluid
Droplet contact, indirect contact
Virulence factors Ability to fuse cells, Ability to
remain latent in ganglia
Ability to dampen, Avoid to immune response
Culture/ Diagnosis Based Largely on clinical
appearance
Based Largely on clinical appearance
Prevention Live Attenuated Vaccine Live Virus Vaccine (Vaccinia
virus)
Tretment None in uncomplicated cases,
Acyclovir for high risk
-
Distinguishing teature ​No fever prodome, Lesions
are superficial, In centripetal distribution (Move in center of body)
Fever precedes rash, Lesions are deep and in centrifugal distribution
(more on extremites)

Rash of Chickenpox
Herpes Zooster
(Shingles)
• Herpes Zooster mainly affect a single dermatome
of the skin.
• It may occur at any age but the vast majority of

patients are more than ​50 years of age.

• The latent virus reactivates in a sensory ganglion

and tracks down the ​sensory nerve to the

appropriate segment.
• There is a characteristic eruption of vesicles in the

dermatome which is ​often accompanied by intensive

pain which may last for months (postherpetic

neuralgia)
• Herpes zoster affecting the eye and face may pose
great problems.
• As with varicella, herpes zooster in a far greater

problem in ​immunocompromised patients in whom

the reactivation occurs earlier in life and multiple

attacks occur as well as complications.

• Complications are rare and include encephalitis

and disseminated ​herpes zoster.

Shingles
Maculopapular Rash ​Maculopapular rash due
to Herpes zoster in a child with a history of leukemia
(Courtesy of the CDC)

Congenital VZV
Infection
• 90% of pregnant women already immune,
therefore ​primary infection is rare during
pregnancy.
• Primary infection during pregnancy carries
a greater risk of severe disease, in
particular pneumonia.
First 20 weeks of Pregnancy
• Up to 3% chance of transmission to the
fetus, recognised ​congenital varicella
syndrome;
– Scarring of skin – Hypoplasia of limbs ​–
CNS and eye defects ​– Death in infancy
normal

Neonatal Varicella
• VZV can cross the placenta in the late stages of
pregnancy to infect the fetus congenitally.
• Neonatal varicella may vary from a mild disease to
a fatal disseminated infection.
• If rash in mother occurs more than 1 week before
delivery, ​then sufficient immunity would have been
transferred to the fetus.
• Zoster immunoglobulin should be given to
susceptible pregnant women who had contact with
suspected cases of varicella.
• Zoster immunoglobulin should also be given to
infants whose mothers develop varicella during the
last 7 days of pregnancy ​or the first 14 days after
delivery.

Laboratory Diagnosis
The clinical presentations of varicella or
zoster are so ​characteristic that laboratory

confirmation is rarely required. ​Laboratory

diagnosis is required only for atypical

presentations, particularly in the

​ ​Virus Isolation -
immunocompromised. –
rarely carried out as it requires 2-3 ​weeks

​ ​Direct detection - electron

for a results. –
microscopy may be used for ​vesicle fluids
but cannot distinguish between HSV and

VZV. Immunofluorescense on skin

scrappings can ​distinguish between the

​ ​Serology - the presence of VZV IgG

two. –
is indicative of past ​infection and immunity.

The presence of IgM is ​indicative of recent

primary infection.
Cytopathic Effect of VZV
Cytopathic Effect of VZV in cell culture: Note the ballooning of
cells. (Coutesy of ​Linda Stannard, University of Cape Town, S.A.)

Management
• Uncomplicated varicella is a self limited disease
and requires no specific treatment. However,
acyclovir had been shown to accelerate the
resolution of the disease and is prescribed by some
doctors.
• Acyclovir should be given promptly
immunocompromised individuals ​with varicella
infection and normal individuals with serious
complications such as pneumonia and encephalitis.
• herpes zoster in a healthy individual is not normally
a cause for concern. The main problem is the
management of the postherpetic ​neuralgia.
• The International Herpes Management Forum
recommends that antiviral therapy should be offered
routinely to all patients over 50 years of age
presenting with herpes zoster.
• Three drugs can be used for the treatment of
herpes zoster: acyclovir, ​valicyclovir, and
famciclovir. There appears to be little difference in
efficacy between them.

Prevention
• Preventive measures should be considered for

individuals at risk of ​contracting severe varicella

infection e.g. leukaemic children, ​neonates, and

pregnant women
• Where urgent protection is needed, passive

immunization should be ​given. Zooster

immunoglobulin (ZIG) is the preparation of choice

but ​it is very expensive. Where ZIG is not available,

HNIG should be ​given instead.

• A live attenuated vaccine is available. There had

been great reluctance ​to use it in the past, especially

in immunocompromised individuals ​since the

vaccine virus can become latent and reactivate later

on.
• However, recent data suggests that the vaccine is

safe, even in children ​with leukaemia provided that

they are in remission.

• It is highly debatable whether universal vaccination

should be offered ​since chickenpox and shingles are

normally mild diseases.

Cytomegalovirus
Properties
• Belong to the betaherpesvirus
subfamily of herpesviruses
• double stranded DNA enveloped
virus
• Nucleocapsid 105nm in diameter,
162 capsomers
• The structure of the genome of
CMV is similar ​to other
herpesviruses, consisting of long and
short segments which may be
orientated in either direction, giving a
total of 4 isomers.
• A large no. of proteins are encoded
for, the ​precise number is unknown.
Epidemiology
• CMV is one of the most successful human
pathogens, it can ​be transmitted vertically

or horizontally usually with little ​effect on

the host.
• Transmission may occur in utero,
perinatally or postnatally. ​Once infected, the

person carries the virus for life which may

be activated from time to time, during which

infectious ​virions appear in the urine and

the saliva.
• Reactivation can also lead to vertical
transmission. It is also ​possible for people

who have experienced primary infection to

be reinfected with another or the same

strain of CMV, this reinfection does not

differ clinically from reactivation.

• In developed countries with a high
standard of hygiene, 40% ​of adolescents

are infected and ultimately 70% of the

population is infected. In developing

countries, over 90% of people are ultimately

infected.

Pathogenesis
• Once infected, the virus remains in the
person for life and my be reactivated from
time to time, especially in
immunocompromised individuals.
• The virus may be transmitted in utero,
perinatally, or postnatally. Perinatal
transmission occurs.
• Perinatal infection is acquired mainly
through infected genital secretions, or
breast milk. Overall, 2 - 10% of infants are
infected by the age of 6 months worldwide.
Perinatal infection is thought to be 10 times
more common than congenital infection.
• Postnatal infection mainly occurs through
saliva. Sexual ​transmission may occur as
well as through blood and blood products
and transplanted organ.

Clinical Manifestations
• Congenital infection - may result in
cytomegalic inclusion ​disease
• Perinatal infection - usually asymptomatic
• Postnatal infection - usually
asymptomatic. However, in a ​minority of

cases, the syndrome of infectious

mononucleosis may develop which consists

of fever, lymphadenopathy, and

splenomegaly. The heterophil antibody test

is negative although atypical lymphocytes

may be found in the blood.
• Immunocompromised patients such as
transplant recipients ​and AIDS patients are

prone to severe CMV disease such ​as

pneumonitis, retinitis, colitis, and

encephalopathy.
• Reactivation or reinfection with CMV is
usually ​asymptomatic except in

immunocompromised patients.

Congenital Infection
• Defined as the isolation of CMV from the
saliva or urine ​within 3 weeks of birth.
• Commonest congenital viral infection,
affects 0.3 - 1% of all live births. The
second most common cause of mental
handicap after Down's syndrome and is
responsible for ​more cases of congenital
damage than rubella.
• Transmission to the fetus may occur
following primary ​or recurrent CMV
infection. 40% chance of transmission to
the fetus following a primary infection.
• May be transmitted to the fetus during all
stages of ​pregnancy.
• No evidence of teratogenecity, damage to
the fetus results from destruction of target
cells once they are formed.
Cytomegalic Inclusion
Disease
• CNS abnormalities - microcephaly, mental
retardation, spasticity, ​epilepsy, periventricular
calcification.
• Eye - choroidoretinitis and optic atrophy
• Ear - sensorineural deafness
• Liver - hepatosplenomegaly and jaundice which is
due to hepatitis.
• Lung - pneumonitis
• Heart - myocarditis
• Thrombocytopenic purpura, Haemolytic anaemia
• Late sequelae in individuals asymptomatic at birth -
hearing defects and reduced intelligence.

Incidence of Cytomegalic
Disease
U.S.A. U.K.
No. of live births p.a. ​3,000,000 700,000
Rate of congenital CMV ​1% 0.3%
No. of infected infants ​30,000 2100
Symptomatic at birth (5 - 10% ) ​1,500-3,000 105
Fatal disease (​~ ​20% ) ​300-600 22
No. with sequelae (90% of survivors) ​1080-2160 83
Asymptomatic (90 - 95% ) ​27000 1995
No. with late sequelae ​1350-4550 315

Laboratory Diagnosis
(1)
• Direct detection
– biopsy specimens may be
examined histologically for CMV
inclusion antibodies or for the
presence of CMV antigens. However,
the sensitivity may be low. – The
pp65 CMV antigenaemia test is now
routinely used for the rapid diagnosis
of CMV infection in
immunocompromised patients. ​–
PCR for CMV-DNA is used in some
centers ​but there may be problems
with interpretation.
CMV pp65
antigenaemia test
(Virology Laboratory, New-Yale Haven Hospital)

Laboratory Diagnosis
(2)
• Virus Isolation
– conventional cell culture is regarded as
gold standard
but requires up to 4 weeks for result. –
More useful are rapid culture methods such
as the
DEAFF test which can provide a result in
24-48 hours.
• Serology
– the presence of CMV IgG antibody
indicates past
infection. – The detection of IgM is
indicative of primary infection ​although it
may also be found in immunocompromised
patients with reactivation.

Cytopathic Effect of
CMV
(Courtesy of Linda Stannard, University of Cape Town, S.A.)

DEAFF test for CMV

(Virology Laboratory, New-Yale Haven Hospital)

Specimens for Laboratory

Diagnosis
Site for virus culture Serology Urine Saliva Blood
Tissue affected IgG IgM
Neonates + + - - - +
Adults + - + - + +
Pregnant women - - - - + +
Immunocompromised + + + + + -

Treatment
• Congenital infections - it is not usually
possible to detect congenital infection
unless the mother has symptoms of primary
infection. If so, then the mother should be
told of the chances of her baby having
cytomegalic inclusion ​disease and perhaps
offered the choice of an abortion.
• Perinatal and postnatal infection - it is
usually not necessary to treat such patients.
• Immunocompromised patients - it is
necessary to make a ​diagnosis of CMV
infection early and give prompt antiviral
therapy. Anti-CMV agents in current use
are ​ganciclovir, forscarnet, and cidofovir.

Prevention
• No licensed vaccine is available. There is
a candidate live ​attenuated vaccine known
as the Towne strain but there are ​concerns

about administering a live vaccine which

could become latent and reactivates.

• Prevention of CMV disease in transplant
recipients is a ​very complicated subject and

varies from center to center. ​It may include

the following measures. –

​ Screening and
matching the CMV status of the donor ​and

recipient –
​ Use of CMV negative blood for
transfusions – Administration of CMV
immunoglobulin to ​seronegative recipients

prior to transplant –
​ Give antiviral agents
such as acyclovir and ganciclovir

prophylactically.

Epstein-Barr Virus
Epstein-Barr Virus
(EBV)
• Belong to the gammaherpesvirus
subfamily of herpesviruses
• Nucleocapsid 100 nm in diameter, with
162 capsomers
• Membrane is derived by budding of
immature particles through cell membrane
and is required for infectivity.
• Genome is a linear double stranded DNA
molecule with 172 kbp
• The viral genome does not normally
integrate into the ​cellular DNA but forms
circular episomes which reside in the
nucleus.
• The genome is large enough to code for
100 - 200 ​proteins but only a few have been
identified.

Epidemiology
• Two epidemiological patterns are
seen with EBV.
• In developed countries, 2 peaks of

infection are ​seen : the first in very

young preschool children ​aged 1 - 6

and the second in adolescents and

young adults aged 14 - 20 Eventually

80-90% of adults are infected.
• In developing countries, infection

occurs at a ​much earlier age so that

by the age of two, 90% of children

are seropositive.
• The virus is transmitted by contact

with saliva, in ​particularly through

kissing.
Pathogenesis
• Once infected, a lifelong carrier state
develops whereby a ​low grade infection is
kept in check by the immune ​defenses.
• Low grade virus replication and shedding
can be ​demonstrated in the epithelial cells
of the pharynx of all ​seropositive
individuals.
• EBV is able to immortalize B-lymphocytes
in vitro and in ​vivo
• Furthermore a few EBV-immortalized
B-cells can be demonstrated in the
circulation which are continually cleared by
immune surveillance mechanisms.
• EBV is associated with several very
different diseases where it may act directly
or one of several co-factors.

Disease Association
1. ​Infectious Mononucleosis ​2.
Burkitt's lymphoma 3.
Nasopharyngeal carcinoma 4.
Lymphoproliferative disease and
lymphoma in the ​immunosuppressed.
5. X-linked lymphoproliferative
syndrome ​6. Chronic infectious
mononucleosis 7. Oral leukoplakia in
AIDS patients 8. Chronic interstitial
pneumonitis in AIDS patients.
Infectious
Mononuclosis
• Primary EBV infection is usually subclinical in

childhood. However in ​adolescents and adults, there

is a 50% chance that the syndrome of infectious

mononucleosis (IM) will develop.

• IM is usually a self-limited disease which consists

of fever, ​lymphadenopathy and splenomegaly. In

some patients jaundice may be ​seen which is due to

hepatitis. Atypical lymphocytes are present in the

blood.
• Complications occur rarely but may be serious e.g.

splenic rupture, ​meningoencephalitis, and

pharyngeal obstruction.
• In some patients, chronic IM may occur where

eventually the patient ​dies of lymphoproliferative

disease or lymphoma.
• Diagnosis of IM is usually made by the heterophil

antibody test and/or ​detection of EBV IgM.

• There is no specific treatment.

Burkitt’s Lymphoma (1)

• Burkitt's lymphoma (BL) occurs
endemically in parts of Africa (where it is
the commonest childhood tumour) and
Papua New Guinea. It usually occurs in
children aged 3- ​14 years. It respond
favorably to chemotherapy.
• It is restricted to areas with holoendemic
malaria. Therefore it appears that malaria
infection is a cofactor.
• Multiple copies of EBV genome and some
EBV antigens ​can be found in BL cells and
patients with BL have high titres of
antibodies against various EBV antigens.

Burkitt’s Lymphoma (2)

• BL cells show a reciprocal translocation between
the long arm of ​chromosome 8 and chromosomes
14, 2 or 22.
• This translocation result in the c-myc oncogene
being transferred to ​the Immunoglobulin gene
regions. This results in the deregulation of ​the
c-myc gene. It is thought that this translocation is
probably already present by the time of EBV
infection and is not caused by EBV.
• Sporadic cases of BL occur, especially in AIDS
patients which may ​or may not be associated with
EBV.
• In theory BL can be controlled by the eradication
of malaria (as has ​happened in Papua New
Guinea) or vaccination against EBV.

Nasopharyngeal
Carcinoma
• Nasopharyngeal carcinoma (NPC) is a malignant

tumour of the ​squamous epithelium of the

nasopharynx. It is very prevalent in S. China, where

it is the commonest tumour in men and the second

commonest in women.
• The tumour is rare in most parts of the world,

though pockets occur in ​N. and C. Africa, Malaysia,

Alaska, and Iceland.
• Multiple copies of EBV genome and EBV EBNA-1

antigen can be ​found in cells of undifferentiated

NPC. Patients with NPC have high ​titres of

antibodies against various EBV antigens.

• Besides EBV there appears to be a number of

environmental and ​genetic cofactors in NPC.

• NPC usually presents late and thus the prognosis
is poor.
• In theory NPC can be prevented by vaccination.