Herpes Simplex and Varicella-Zoster Virus Infections David Kramer, M.D.HSV Infections Asymptomatic, mucocutaneous, neonatal, CNS, latent Type 1: gingivostomatitis, whitlow, keratoconjunctivitis, encephalitis, eczema herpeticum Type 2: genital HSV, meningitis Classification: primary; non primary, first episode; recurrent, reinfection Latency: sensory or autonomic neurons; LATS Reactivations: trauma, sunlight, stress (despite antibodies) Host: normal vs. immunocompromisedNeonatal HSV Infections Congenital 5%; most HSV 2 (poorer prognosis) Most mothers asymptomatic; antibodies may modify Attack rate after primary maternal infection over 50% (> 10 times than after recurrent infection) Cesarean section controversial in women with recurrent HSV at delivery Culture baby (eye, skin, throat) after 24 hours old Categories, prognosis: skin/eye/mouth, CNS, disseminated Symptoms: skin vesicles, fever, intractable seizures, pneumonia, DIC, conjunctivitis, recurrent skin vesicles after therapyHSV Encephalitis Most common sporadic, focal encephalitis in US. Estimate 1,000 cases yearly in U.S. May be due to 1E or reactivation HSV infection; skin lesions a "red herring" Symptoms: headache, fever, personality change, focal seizures Differential diagnosis: TB meningitis, arbovirus, enterovirus, Mycoplasma, mumps, tumor, toxoplasmosis, aneurysmHSV Infections, Diagnosis Isolate HSV, identify HSV antigen (immunofluorescence) in skin CSF: abnormal; virus isolation + rare (except HSV 2 meningitis) Antibody titers don't differentiate 1 vs. 2 (except g G) Encephalitis: EEG, CT/MR, DNA/PCR, brain biopsy, antigen, antibodyHSV Infections, Therapy: Acyclovir (ACV) PO or IV Resistance: Especially with Repeated Treatment immunocompromised; TK negative (less virulent) foscarnet Indications: neonatal, encephalitis, primary/recurrent in immunosuppressed, primary genital, eczema Questionable efficacy: gingivostomatitis, recurrent infections Keratitis: topical trifluorothymidine + ACV; ophthalmologist Encephalitis: poor outcome if late, in coma, adultMorbidity, Mortality after Neonatal HSV 30 Mg/kg IV Morbidity Mortality Untreated ACV Untreated ACV stage of illness Skin, eye, mouth 2% 2% 0 0 CNS over 80% 60% 40% 15% Disseminated over 80% 40% 70% 60%HSV, Consider Suppressive Therapy Over 6 genital recurrences yearly Recurrent skin lesions in first 6-12 months after neonatal Immunocompromised patient at risk for disseminated, severe HSVNatural History of Varicella-zoster Virus (VZV) Primary infection: varicella Secondary infection: zoster Zoster due to reactivation of VZV: epidemiology, viral DNA & RNA in sensory ganglia (several genes expressed) restriction enzyme studies after varicella and zoster in same patientNatural History of Varicella Normal Host: Usually Mild Infection Immunocompromised Host: May Be Severe or fatal (10% in pre-antiviral era) Highly contagious (80-90% attack rate after household exposure) Major nosocomial problem (95% of adults immune; 75% immune even with no history)Natural History of Zoster Normal hosts: usually self-limited in the young May be presentation of AIDS Immunocompromised hosts: the more immunocompromised, the greater the likelihood of zoster Infectious to susceptibles as varicella (not as zoster) Increased incidence over age 50 (decreased CMI), varicella in uteroVaricella Mainly in children < 10 years old Symptoms: vesicular rash, fever (2 viremias) Complications: hepatitis, streptococcal/staphylococcal superinfection (pneumonia, cellulitis, fasciitis, osteomyelitis) cerebellar ataxia, encephalitis Rare: myocarditis, AGN, Reye's syndrome In immunocompromised: DIC, primary (viral) pneumonia, death Congenital varicella syndrome (2%) scarred rash, hypoplastic limb, eye, CNS damage, early zoster maternal varicella 8th-28th weekVaricella, Epidemiology Airborne spread Incubation period 10-21 days (VZIG may prolong) Contagious 2 days before-3 days after rash onset Immunity: humoral and CMI develop after rash onset 4 million annual cases in US, 9,000 hospitalizations, 100 deaths More severe in adults than children (low CMI) Nosocomial exposures: expensive; nursery transmission rareVaricella, Diagnosis Differential: HSV, scabies, Stevens-Johnson, rickettsial pox, Coxsackie A Laboratory: (usually unnecessary) Test skin lesions (not throat) for VZV culture, PCR, immunofluorescence, in situ hybridization Tzanck smear not specific Antibody titers; IgM; heterologous crossesVaricella, Passive Immunization VZIG within 3-5 days of exposure to varicella or zoster 30-50 x more VZV antibody than IG Criteria for VZIG: intimate exposure and high risk susceptible (immunocompromised, steroids, HIV, malignancy, premature, newborn of mother with varicella) VZIG does not prevent nosocomial spread VZIG not useful for therapy If varicella develops after VZIG, usually not necessary for antiviralsVaricella, Antiviral Therapy ACV interferes with viral DNA synthesis (chain terminator, inhibits polymerase) Immunocompromised patients, primary pneumonia Dose higher than that for HSV Orally to children with chickenpox, shortens course by 1 day poor GI absorption, within 24 hours, no effect on spread Foscarnet if resistant Valacyclovir, famciclovir: no data in childrenVaricella Vaccine "Live" attenuated 90% protection against disease Prevents severe varicella in children, adults Adolescents, adults require 2 doses, 4-8 weeks apart Safe vaccine: adverse effects are fever (10%), mild rash (5%) potential for spread to others (rare) Long term concerns: zoster, waning immunity? (boosting) In leukemics, less zoster if vaccinated Contraindications: pregnancy, immunocompromised, allergy Most American adults who think they are susceptible are immune No problems if inadvertently immunized References Annunziato, P, Gershon, A. Herpes Simplex Virus Infections. Pediatrics in Review 17: 415-423. Arvin, A., Gershon, A. Live attenuated varicella vaccine. Annu. Rev. Microbiol. 1996; 59-100.