Herpes Viruses

E. McNamara.

History

• 1900. Epidemiological linkage of varicella and zoster.

• 1943. EM of vesicle fluid

• 1953. Isolation of virus.

• 1986. DNA sequence published.

Taxonomy

• Family, Herpesviridae

• Sub families,

• Alpha

• HHV-1, HSV1

• HHV-2, HSV2

• HHV-3, VZV

• Gamma

• HHV-4, EBV

• HHV-8

• Beta• HHV-5, CMV• HHV-6, • HHV-7

Alpha. Rapid, Neuron

Gamma. Lymphotrophic

Beta. Slow, Mesothelial

Structure

• ds DNA core

• Capsid enveloped (glycopeptide)

• Capsid enveloped 150mm diameter

Herpes Simplex

2 Serotypes - HSV-1, HSV-2

• Primary, muco-cutanens

• Latent infection in Neuronal cells, dorsal root ganglia

• Viral reactivation

• Transmission, direct contact

• Cross immunity, HSV-1 and HSV-2

H. Simplex - I• Primary HS I

– Gingivostomatitis / asymptomatic

– Lesions, vesicle, ulcer, crust

• Reactivation– Orolabial infections (gential infection)

– Conjunctivitis

– Deratitis

– Herpetic whitlow

– Encephalitis (untreated mortility of 70%)

H. Simplex 2• Primary HS-2

– Genital Herpes (85%), recurrent/asymptomatic

• Complications – neonatal infections– Skin– Eyes– Mucosa– CNS– Disseminated (mortality untreated > 70%)

H. Simplex in immunocompromised

• Primary or reactivation– Severe– Locally invasive– Dessiminate

• Oesphagitis• Proctitis• Meningo-encephalitis• Pneumonitis• Hepatitis• Coagulopathy• Secondary bacterial infections

H. Simplex - Diagnosis

• Early dx, rapid rx.

• Samples– Swabs– Vesicle fluid– CSF– Tissue– Serum

H. Simplex – Diagnosis contd./

• Direct microscopy – E.M.

• Culture, CPE, typing

• Serology• Paired sera (Ab)

– Cross reactivity, HS1, HS2

• Antigen

Varicella Zoster (VZV)

• Varicella – Chickenpox, Primary

• Zoster – Shingles, Reactivation (sensory ganglia)

• Same agent

Varicella, Chicken Pox

• Transmission – respiratory, vertical, contact• Incubation, 2 weeks• Prodromal, flu like symptoms, 1º viraemia• Rash, fever (centripetal), 2º viraemia• Crops macules, papules, vesicles, crusts• Infectious, 2 days pre-rash to 3-5 days post-rash

eruption• Secondary attack rates of 85%

Varicella, Chicken Pox contd./

• Complications– Secondary bacterial infections

– Haemorrhagic chicken pox

– Pneumonia

– Encephaliis

• Immunocompromised/Impaired cell mediated immunity/have increased mortality

• Adults more severe disease

Varicella Chicken Pox contd./

• Epidemiology– Increase winter/early spring– Highest rate in 4-10 year olds– Life long immunity to exogenous infection

Varicella in Pregnancy

Early (20 weeks) (sero-negative mother)• Congenital varicella syndrome

– Very rare (3% those infected)– Cortical atrophy– Chorioretinitis– Hypoplasia of limbs– Muscular atrophy– <50% survive beyond 20 months

Varicella in Pregnancy contd./

Late Varicella

• Varicella onset 8 days or more pre-delivery– Maternal ab. Present– Mild/asymptomatic infection in-intero

• Varicella onset 7 days or less pre-delivery– No maternal ab.– Risk of severe dessiminated neonatal disease.

Varicella – Infection Control

• Sero Prevalance, HCW

• Vaccine

• Air/contact precautions

Diagnosis VZV

• Microscopy– EM– Immunoflurescence

• Culture, CPE – cell line specific

• Serology

• PCR - CSF

Herpes Zoster, Shingles

• Reactivation latent virus > 50 years old• Single dermatome (very painful)

– Trigeminal – opthalmic branch– Sacral ganglia – acute retention– Facial nerve – Ramsey Hunt

• Complications– 2º bacterial infections– Neuralgia– Encephalitis (rare)– Ocular defects

Zoster, Shingles contd./

• DX– EM– Culture– Serology

EBV (Epstein Barr Virus)

• Primary Infection– Children – asymptomtic– Young adults – infectious mononucleosis (mild

– severe)

• Reactivations – intermittent (B. lymphocyte)

EBV (Epstein Barr Virus) contd./

Infectious mononucleosis• Triad. Fever, phargngitis, cervical

lymphadenopathy• Duration 1-4 weeks• Complications

– Spleenomegaly– Hepatitis– Pericarditis– CNS, meningo-encephalitis– Guillam-Barre Syndrome

EBV (Epstein Barr Virus) contd./

– Neoplasia• Burkitts lymphoma

• Nasopharyngeal carcinoma

• B. cell lymphtomas, Tx., HIV

• Oral hairy leucoplakia

EBV (Epstein Barr Virus) contd./

• Diagnosis– Blood film – atypical lymphocytes– Monospot– LFT’s– Microscopy – immunofluorescence– Culture– Serology

CMV - Cytomegalovirus

• CMV Infection– Primary– Reactivation– Majority is asymptomatic (21% Infect.Mono.)

• Significant symptomatic infection– Congenital / perinatal– Immunosuppressed (Tx. HIV)

CMV – Cytomegalovirus contd./Congenital CMV• 1º infection in pregnancy – 55% risk• Timing in pregnancy (1st 20 weeks)• Sero positive minimum – low transmission• Symptoms, mild – severe

– Intra uterine growth retardation– Jaundice/Hepathospleenomegaly– CNS – neurological damage– Chorioretinitis– Early asymptomatic – later, hearing and vision

impairment

CMV – Cytomegalovirus contd./

Perinatal

• Generally asymptomatic

• Excrete virus, 3 months

Immunosuppressed and CMV:

• Transplant, AIDS

• Primary - more severe (Blood, Graft)

• Reactiviation - majority

CMV – TX• Type of Transplant• Mismatch, Donor (+ve), recipient (-ve)• Duration immunosuppression Rx.• Symptoms

– Fever– Leucopenia– Pneumonitis– Hepatitis– Retinitis– Encephalitis– Super infections / mortality

CMV – TX contd./

• Prevention– Prophylaxis– Screen blood products– Aggressive Rx.

CMV – HIV

• CD4 < 100

• Retinitis

• Gastritis

• CNS

CMV – Diagnosis

• Microscopy, Histology– Nuclear inclusions “owls eye”– Immunofluorescence – Tissue

• Culture– Urine, saliva, Buffy coat, BAL, swabs– Tissue culture 1-4 weeks – inclusions– Shell vials+ MAb, Rapid 1-2 days “Deaff” test.

CMV – Diagnosis contd./

• Serology– Paired sera

– Igm

• Viral antigen in neutrophils– CMV viraemia

– Quantitative, rapid, monitor pre-symtoms

– Use MAb against the phospho protein PP65

– But neutropaenic, may not have sufficient leucocytes

CMV – Diagnosis contd./

• PCR– Primers CMV early Ag– Detects small amount of CMV DNA– V. sensitive

• Specificity – problematic (false positives)

CMV – Diagnosis contd./

SUMMARY

• Dx. Acute CMV difficult– Infection common in population – Positive culture normal from cervical, semen

specimens– Congenital infections – culture

• Positive in the 1st 3 weeks of life

– PCR – CMV in many body fluids

Novel Human Herpes Viruses

• HHV 6, 1986 (T. cells)

• HHV 7, 1990 (T. cells)

• HHV 8, 1994 Kaposis sarcoma associated Herpes (B. cells)

Novel Human Herpes Viruses contd./• HHV 6

– Ubiquitous, childhood (6 months to 3 years old)– Roseola (exauthem subitum)

• Fever 40º• Erythematous maculopapular rash (1-3 days)• Irritability and drowsiness• Self limiting• Neuro complications – rare

– Transmission• Saliva• Perinatal (cervical secretions)

Novel Human Herpes Viruses contd./

• Dx.– Culture of blood mononuclear cells– PCR – blood cells– Serology – ab. Paired sera– Cross reactivity with CMV, HHV 7.

Novel Human Herpes Viruses contd./

• HHV 7– 40% homology with HHV 6 genome– No clinical human disease– Co factor with HIV?– 90% adults – seropositive– Transmission – saliva– Dx. – Culture, PCR

Novel Human Herpes Viruses contd./

• HHV 8– Discovered by comparing DNA sequences of Kaposi’s

sarcoma lesions and normal skin.– Causative role in

• KS questioned (association v causation)• B. cell lymphomas

– Unknown • Prevalence in general population• Transmission• Disease pathogenesis

– Dx. - PCR