MB Track Virology

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MB Virology 5 & 6 Herpesviruses
The Herpesvirus family has a few common characteristics
Ether sensitive envelope
Nucleocapsid is icosahedral
Double-stranded DNA
Herpes Simplex
Type I Type II
Transmission Oral genital practices (which leads to HSV1 on genitals & HSV2 on oral cavity)
Kissing
Contact with oral secretions
o Spread in kindergartens this way
o Causes herpes withlow this way
STD (even in asymptomatic with no lesions)
Perinatally
Epidemiology Common infections transmitted via secretion from carrier
No communal outbreaks
Humans are the only reservoir
Highly contagious & acquired earlier & more frequently than HSV2
Outbreaks occur ever 2-3 years
Devastating in malnourished & AIDS patients
Outbreaks happen more likely in winter & spring
20% of American adults are seropositive
Pathophysiology Enters via skin to replicate in mucous membrane or skin of initial site of infection
Disseminated via lymphatics which may lead to viraemia, depending on immunocompetence
After 1 infection, HSV becomes latent in sensory nerve ganglia which is immunoprivileged, following which it may reactivate due to immunosuppression, menstruation, stress or fever.
CMI is the key suppressor of infection. IgGs are not as effective
Latent in trigeminal ganglia Latent in sacral & lumbar ganglia
Symptoms Vesicular eruptions (virus proliferates in infected cells until they balloon & lyse to fill vesicle with serous fluid of cytoplasmic & viral content)
Grouped vesicles on erythematous base are characteristic of HSV
Acute herpetic gingivostomatitis
o Vesicular eruptions in buccal mucosa
o ulceration of gums wtih grey slough
o Fever, lymphadenopahy
o Fetid breath
Herpes labialis
o Recurrent reactivation of HSV1 in trigeminal ganglion
o Called
o Vesicles at musculocutaneous junction of lips painful ulcers
Herpetic whitlow
o Serous (not purulent as in staphylococcal whitlow) exudates from
lesions in fingers
Keratoconjunctivitis
Herpes progenitalis
o Occurs at perineum i.e. penis, vagina, vulva, cervix
o STD vesiculoulcerative lesions of genitalia
o Fever, malaise, headache
o Itching & pain
o Vaginal, urethral discharge
o Tender inguinal lymphadenopathy
o Recurrent reactivation of HSV2 in lumbar & sacral ganglia causing painful perianal lesions
Recurrent mucocutaneous HSV
o More localized with milder symptoms. Lasts for shorter durations
o Prodromal signs of tingling & shooting pain hr -48 hrs before eruption


MB Track Virology
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CSF & PCR for HSV
Brain biopsy, isolation & using IF
Complications Disseminated herpes in immuno-compromised (e.g. herpes hepatitis)
Eczema herpeticum
o Superinfection of herpes on top of chronic eczematous skin
o Extensive reticulation & significant mortality
o Can lose a lot fluid due to oozing serum
Acute necrotizing encephalitis
o Rare but severe disease
o Must be treated with antivirals early
o Symptoms include sudden fever, confusion,headache, nausea
& temporal lobe necrosis
o Diagnosed via temporal lobe biopsy
Cervical & vulvar carcinoma
o HSV2 may be a hit & run oncogenic virus
o Less impt cause than HPV
Neonatal herpes
o Generalized infections acquired from infected birth canal
o Jaundice, hepatosplenomegaly, thrombocytopaenia
o Prevented by C section, though this is of little use if amniotic sac ruptures
Aseptic meningitis (usually resolved with little sequelae)
May increase chances of HIV acquisition & its rate of progression by increasing the influx of CD4+ into
mucosal surfaces, thus, more targets & host cells for HIV
Sacral radiculopathy (pain & inflammation via sacral nerves)
Extragenital lesions (skin, buttocks, thighs)
Diagnosis Sample Vesicle fluid
Skin swab using viral transport media
Saliva, tears
Corneal scrappings
Brain biopsy (temporal lobe for acute necrotizing encephalitis)
Tissue
Culture
CPE of rounded cells in hamster cell cultures in 48-72 hrs (commonly used) & then identifying by
o IF staining of infected cells
o Detecting virus-specidic glycoproteins using ELISA
Tzanck smear is obtained from skin lesions, where cells from the base of the vesicle are stained with Giemsa stain to reveal multinucleated giant cells. This is a rapid diagnostic
technique that is characteristic for
Antigenic
Detection
IF
ELISA
PCR to detect HSV1 DNA in CSF if acute necrotizing encephalitis is suspected
Serology NT is used to diagnose 1 infections by detecting a raise in AB title but is of little use in diagnosing recurrent infections because many adults already have circulating ABs
Treatment Antivirals Acyclovir
o Administered IV, orally or topically
o Serves as
Treatment for 1 infection by shortening duration of lesions in genital herpes
Treatment for neonatal herpes
Prophylaxis in immunocompromised & for long term administration to prevent recurrence
Little use against recurrence as it has no effect on latent state. But can suppress recurrence
Valaciclovir
o Used to treat genital herpes
o Suppresses recurrence
Vaccine Experimental & little value after 1 infection
Prevention Reducing the no. of sexual partners & sexual debut
C section is done for infected preganant women



MB Track Virology
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Varicella Zoster Virus
Varicella Zoster
Transmission Aerosol or from saliva
Direct contact with vesicular fluid
Perinatally
Stays latent in dorsal root ganglion following varicella recovery
Re-emerges in adults & immunocompromised
Epidemiology Highly infectious & is an epidemic disease
Can spread before onset of rash via shedding due to 2 viraemia
Not communicable & is not an epidemic disease. Occurs mainly when CMI is
suppressed
VZV stays latent in the dorsal route ganglia & is absent from URT
Pathophysiology Invades URT first
Replicates in regional lymphnodes
It spreads via blood (1 viraemia) to reticuloendothelial system
VZV in cutaneous epithelial cells cause rash (pox) (2 viraemia)
After recovery, virus stays latent in dorsal root ganglia
Zoster disease occurs when CMI is deficient to cause vesicular skin lesions &
nerve pain
Incubation 2-3 wks Long after childhood varicella
Symptoms Prodrome Fever, headache, malaise
Abdominal pain
-
Blisters Papilovesicular, itchy rash appears in crops on trunks to spread to extremities
& head (centripetal distribution)
Evolves from papulesvesicles pustules which eventually crust
Appears for 1-7 days
Each lesion may be in a varying state of evolution in each person (in small
pox, all lesions are in same stage)
Blisters may become pitted scars if scratched
More severe in adults
Clustered, painful vesicles following dermatomal distribution on truck &
head.
Morphologically similar to those in varicella. They rupture & start crusting up
Forms a belt of roses in the thorax where majority of blisters are found
Ophthalmic division involvement can cause iridocyclitis (inflammation of iris
& ciliary body), keratitis & corneal ulceration
Geniculate ganglion involvement causes Ramsay-Hunt syndrome with vesicles
in ext auditory cancer, tympanic membrane, ant tongue & facial nerve palsy
Complications Skin superinfection if skin not kept clean
o Staphylococcus (scalded skin syndrome)
o Streptococcus (flesh eating bact)
Aseptic meningitis, meningoencephalitis & cerebellar ataxia
Post-infectious encephalomyelitis
o Occurs 1 wk after rash
o Can be fatal & more likely to occur in adults
Pneumonia(more in adults & can be fatal)cough/dyspnoea 1-6 days after rash
Haemorrhagic thrombocytopaenia (fulminating varicella) or even DIVC
Regional lymphadenitis & abscesses
Overwhelming varicella in immunosuppressed
o Angry lesions & haemorrhagic
o Needs aggressive treatment
Reyes Syndrome
o Encephalopathy & liver degeneration
o Occurs if children infected with VZV or Influenza B are given aspirin
Chicken pox during pregnancy
o Intrauterine death may occur
o Congenital varicella syndrome
Occurs in 1
st
or 2
nd
trimester
Encephalomyelitis
Post-herpetic neuralgia
o Occurs in elderly after zoster rash has disappeared
o Very painful phantom nerve pain
o Can drive elderly to suicide!
Disseminated zoster in the immunosuppressed or elderly
Pneumonia in immunocompromised


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Rare transplacental infection
Skin lesions, limb hypoplasia, eye disease & neurological defects
o Neonatal varicella
Contracted nearer full term
High mortality (35%)
Diagnosis Sample Vesicles
Tissue Culture Multinucleated cells seen in Tzanck smear (like in HSV)
Focal CPE in human fibroblast cultures
Antigenic
Detection
IF (most useful)
Serology Rise in AB titre Rise in AB titre is less useful as the AB will already be there
Treatment Symptomatic
o Antipyretics
o Antipruritics (to stop scratching)
Vaccination
o Varicella-zoster immune globulin prophylaxis given to
immunocompromised & pregnant
o Live attenuated vaccine but does not eliminate latent state
Antivirals
o Acyclovir: severe varicella pneumonia, haemorrhagic varicella &
immunocompromised.
o Foscarnet given if resistant
o Antivirals can speed up healing though not required
Acyclovir given to immunocompromised or to limit extent of progression.
Cannot treat latent state
VZIG given as prophylaxis




MB Track Virology
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Epstein-Barr Virus Cytomegalovirus
Transmission Saliva
Kissing
Intimate contact
Still not fully understood
Saliva
Urine-hand-mouth & semen/cervical secretions
Blood transfusion or organ transplantation (due to immunosuppressants following
organ transplant)
Transplacentally along birth canal or via breast milk
Epidemiology Very common infection with worldwide in distribution. 90% of world population infected
Subclinical in children
Infects primates & humans (natural host)
Transmission is not fully understood
Is not an epidemic disease. No good epidemic has been describes
EBV can be shed up to 18 mths after recovery from infectious mononucleosis
Humans are the natural host
Aymptomatic in healthy hosts but can cause inclusion diseases that cause congenital
abnormalities
50% of adults have CMV ABs
Induces lifelong latency in hosts. Thus, very successful infectious agent
Infection is common but actual infection is uncommon. However, most problematic
for pregnancies as it can affect foetus
Pathophysiology First infects oropharynx
Spreads by blood to infect B lymphocytes where they remain latent
Some may incorporate DNA into cell genome
Viral capsid antigen is the target of Abs
Assembly of MHC Class I viral peptide complex is unstable in infected cells thus
allowing evasion of immune system
CMI still occurs & is more important that ABs
Incubation 4-7 wks -
Symptoms Infectious mononucleosis (IMS)
Fever (up to 40C for up to 14 days)
Lymphadenopathy (classically cervical but may be axillary & inguinal)
More mononuclear cells & atypical lymphocytes can be seen in blood smear
Lethargy & anorexia
Pharyngitis, exudative tonsillitis (characteristic)
Hepatosplenomegaly
Rashes may form if ampicilin is used
Differential diagnosis includes
o Steptococcal pharyngitis (no mononuclear cells detected)
o HIV or CMV infection
o Acute toxoplasmosis
Congenital CMV infection
o Foetal infection following maternal viraemia
o Usually mild but severe in 20% esp during 1
st
trimester
o Neurologic sequelae mostly like microcephaly, chorioretinitis, optic atrophy,
mental retardation, spasticity & epilepsy
Cytomegalic inclusion disease
o If mother has a 1 infection & there are no ABs, it will infect foetus
o Rare but severe
o Causes
Jaundice & hepatosplenomegaly
interstitial pneumonitis
thrombocytopaenia & haemolytic anaemia
o Enlarged cells in organs with large intranuclear owls eye inclusions with
syncytial formations
Perinatal hepatitis causing hepatomegaly & jaundice
Infectious mononucleosis
o Often post-perfusion or after open heart surgery
o Similar to that in EBV but no heterophile antibodies
Complications Complications of IMS
o Splenic rupture (spleen is extremely fragile & may rupture on palpation)
o Haemolytic anaemia & thrombocytopaenia
o Hepatitis with jaundice
o Neurologic (rare) i.e. Meningitis, cerebellitis, encephalitis, cranial nerve palsies
Pneumonitis
African Burkitts Lymphoma
o Occurs where there is endemic malaria. Thus the name
Guillain-Barre Syndrome
Myocarditis in heart transplant
Disseminated CMV in AIDS (most severe)
o Fever
o Leukopaenia
o Pneumonitis
o Hepatitis
o Retinitis (in AIDS)


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o Persistant malarial infestation causes immunosuppressive effect on CTL surveillance
of EBV transformed cells
Nasopharyngeal cancer is strongly associated to EBV
Hairy leukoplasia in AIDS patients with EBV. Whitish lesions on tongue
Immunoblastic lymphoma
o Occurs in children with X-linked lymphoproliferative syndrome
o Gene is needed for signal transduction proteins in T & NK cells
o Mortality rate is 75% by 10 yrs of age
o Polyclonal immunoblastic proliferation followed by monoclonal neoplasia
Chronic fatigue syndrome
o Extreme fatigue
o Fever, sore throat
o Painful lymphadenopaty
o Muscle weakness & memory loss
o Thought to be reactivation of latent EBV
o Colitis (in AIDS)
Diagnosis Sample Blood sample
Biopsy (EBV genome may be found in Burkitts Lymphoma & nasopharyngeal cancer)
Desquamated cells in urinary sediment
Throat swab
Tissue
Culture
Atypical mononuclear cells seen in peripheral blood film. Pleomorphic with diff shapes/sizes/
staining
Owls Eye intranuclear inclusions CPE in human embryo lung cultures after 2-3 wks
Antigenic
Detection
Formation of haemagluttinating ABs that agglutinate sheep or horse RBC. They are heterophile
ABs i.e. ABs that do not have affinity for any antigen produced by EBV. Called a monospot test.
PCR to detect viral nucleic acids
IF is also used
Serology 90% of healthy adults have EBV ABs
High IgMs confirm for recent IMS
IgG can detect previous infection. However they are high from the start
AB to early antigen
o Anti-D (peaks 3-4 wks after onset. +ive in NPC)
o Anti-R (uncommon in IMS, +ive in Burkitts Lymphoma)
4-fold increase in IgM implies recent infection using ELISA
Treatment Symptomatic
Avoid ampicillin as it causes rash in IMS
EBV vaccine under trial
Ganciclovir for life-threatening CMV infections like retinitis, colitis & pneomonitis
Isolation of neonates with severe CMV
Screening of blood & organ donors
CMVIG for prophylaxis in CMV-seronegative organ receipients receiving from CMV-
seropositive donor
Live CMV vaccine under trial



MB Track Virology
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Other Herpesviruses
HHV6
o Human B-lymphotropic virus
o Can stay asymptomatic in healthy individuals
o Associated with exanthema subitum
Mild disease of children btw 6mths & 3 yrs of age occasionally confused with rubella
Incubation of 1-2 wks
Abrupt onset with high pyrexia, lympahdenopathy & convulsions
Rubelliform rash appears after fever disappears except on face
Leukopaenia with relative lymphocytosis
Spontaneous recovery
HHV7
o Not associated with any human disease so far
o Virus persists in saliva of 75% of normal adults
o Seroconversion in most children
HHV8
o Kaposis Sarcoma-associated herpesvirus
o Malignancy of vascular endothelial cells which manifests as purple lesions in skin, oral cavity, GIT & lungs in AIDS patients
o Transmitted sexually
o No antivirals or vaccines available