Clin Med II Infectious Disease Lecture II—Viral Diseases, part 2/3

Herpes Simplex Virus

What’s with all the numbers? Human Herpesviruses HHV 1—Herpes Simplex Virus type 1 HHV 2—Herpes Simplex Virus type 2 HHV 3—Varicella Zoster Virus HHV 4—Epstein-Barr Virus HHV 5—Cytomegalovirus HHV 6—Roseola Infantum HHV 7—”The Multitasker” Roseola, Seizures, Encephalitis, “helps” CMV in renal transplants HHV 8—Kaposi sarcoma/primary effusion lymphoma

Herpes Simplex Virus HSV-1—oral HSV-2—genital Risks—in text—black race, female gender, lower socioeconomic status, and high-risk sexual history Asymptomatic shedding HSV-2 and HIV—linked HSV-2 increases risk of HIV HSV-2 reactivates more often in advanced HIV HSV-2 suppression can decrease HIV-1 plasma level and genital tract shedding

Mucocutaneous HSV-1 HSV-1—mouth and oral cavity ”herpes labialis” or “gingivostomatitis” Herpetic whitlow—painful digital lesions Herpes gladiatorum—painful rash transmitted classically by sports contact Frequent asymptomatic shedding—monthly or more Vesiclesulcers (1-2 days)epithelialization (1-2 wks) Recurrences--fewer lesions, labial, heal faster Triggers—stress, fever, infection, sunlight, chemo, ???

Mucocutaneous HSV-1

Mucocutaneous HSV-1

Mucocutaneous HSV-1

Mucocutaneous HSV-2 Primarily involves genital tract May affect perianal region, buttocks, upper thighs Multiple, painful, small, grouped, vesicular lesions Dysuria, cervicitis, urinary retention Increased HSV-2 lesion rates—postpartum period and among women who have sex with women HIV patients—proctitis and sacral lesions extensive, ulcerating, weeping lesions Drug-resistant isolates—large ulcerations, atypical lesions

Mucocutaneous HSV-2

Mucocutaneous HSV-2

Mucocutaneous HSV-2

Mucocutaneous HSV Diagnosis Clinical Standard—viral cultures of vesicular fluid or direct immunofluorescent antibody staining of lesions Intranuclear inclusion bodies Multinucleated giant cells on Tzanck smear or Calcofluor prep

Mucocutaneous HSV Treatment often not necessary in immunocompetent pts Genital infection—oral agents—acyclovir, valacycloivr, famiciclovir Primary—7-10 days and higher doses; Recurrent—1-3 days Primary herpes labialis—oral antivirals as for primary genital Recurrent herpes labialis—topical acyclovir and hyrocortisone, topical penciclovir, or oral antivirals Immunocompromised—consider IV antivirals Atypical isolates, large ulcerations, new lesions, poor response Secondary prophylaxis—recurrent infections—daily oral antivirals

Ocular HSV Keratitis, Blepharitis, Keratoconjuncitvits If epithelial—heal without vision impairment If stroma involved— uveitis, scarring, blindness Frequent recurrence Second most common cause of acute retinal necrosis

Ocular HSV Branching (dendritic) ulcers on fluorescein stain Treat with topical antivirals Acute retinal necrosis—IV acyclovir or oral famciclovir Topical steroids—may exacerbate Long term treatment can reduce recurrences

Congenital/Neonatal HSV HSV-1 and HSV-2 Congenital—organomegaly, bleeding, CNS abnormalities Neonatal is more common than congenital Highest risk—maternal infection in 3rd trimester 70% of infections are asymptomatic or unrecognized

Congenital/Neonatal HSV Treat disseminated lesions with IV acyclovir for 2-3 weeks Counseling with serologic screening should be offered to pregnant mothers Maternal antenatal suppressive therapy with acyclovir at 36 weeks gestation C-section for pregnant women with active genital lesions or prodromal symptoms

HSV and CNS Disease HSV-1: HSV Encephalitis, may enhance Alzheimer disease Encephalitis symptoms: flu-like prodrome, headache, fever, behavioral or speech disturbances, seizures High mortality rate—untreated, presentation with coma Does not occur disproportionately among immunocompromised HSV-2: Meningitis (primary or recurrent) Both HSV-1 and HSV-2: benign recurrent lymphocytic meningitis; mild, nonspecific neurologic symptoms

HSV Encephalitis and Recurrent Meningitis CSF Pleocytosis common HSV DNA PCR of CSF— rapid, sensitive, specific but can have up to 25% false negatives MRI scanning—increased signal in temporal and frontal lobes IV acyclovir q 8 hours for 10+ days if suspected HSV encephalitis Long term neurologic sequelae are common

HSV Encephalitis

Other HSV Manifestations Disseminated—immunosuppression, pregnancy Bell’s Palsy—associated with HSV-1 Esophagitis—HSV-1; immunocompromised Proctitis—primarily in men who have sex with men Erythema multiforme—leading association with EM and SJS (along with medications) Acute liver failure—1% of cases but 75% mortality Lower respiratory tract—mechanically ventilated pts HSV-1—perinephric abscess, febrile neutropenia, chronic urticaria, SLE-related esophagitis and enteritis, H. pylori- negative upper GI ulcers, atrial myxoma

HSV Prevention Antiviral suppressive therapy Counseling Barrier precautions Disclosure of partner status—50% decrease in HSV-2 transmission Hand washing and glove/gown precautions HSV-2 glycoprotein D vaccine is under development

Varicella Zoster Virus

Varicella Zoster Virus Manifests as chickenpox (varicella) and shingles (zoster) Varicella—typically in childhood; incubates 10- 20 days Highly contagious— droplet inhalation or lesion contact Zoster—up to 25% of population; increases with age

Varicella Fever and malaise Pruritic rash Maculopapulesvesicles pustulescrusts Multiple stages of eruption usually present simultaneously “dew drop on rose petal” Complications—secondary bacterial infection, pneumonitis, encephalitis—in 1% More severe in older pts and immunocompromised

Zoster Mostly among adults Pain—severe—often precedes rash Varicella-like lesions—usually in dermatomal distribution Herpes Zoster Ophthalmicus—lesions on tip of nose, inner corner of eye, and root and side of the nose (Hutchinson sign) Herpes Zoster Oticus—facial palsy, lesions of ear +/- TM involvement, vertigo, tinnitus, deafness (Ramsay Hunt syndrome) Contact with varicella patients—not a risk factor

Herpes Zoster Ophthalmicus

Herpes Zoster Oticus

Varicella Zoster Virus Diagnosis—usually clinical Confirm with direct immunofluorescent antibody staining or PCR of scrapings from lesions Multinucleated giant cells on Tzanck smear Leukopenia and subclinical AST/ALT elevation Thrombocytopenia Varicella skin test and ELISPOT—VZV susceptibility

Varicella Complications Secondary bacterial skin superinfections Interstital VZV pneumonia Neuro—cerebellar ataxia, encephalitis Purpura fulminans—extremely rare Liver—hepatitis, Reye’s syndrome Pregnancy— 1st or 2nd trimesters, small risk of congenital malformations 3rd trimester, risk of disseminated disease

Zoster Complications Postherpetic neuralgia—60-70% of pts >60 years old Bacterial skin superinfections Herpes zoster ophthalmicus or unilateral ophthalmoplegia Cranial nerve involvement Aseptic meningitis Peripheral motor neuropathy Transverse myelitis Encephalitis Acute cerebellitis Stroke or vasculopathy Acute retinal necrosis or progressive outer retinal necrosis

VZV Encephalitis

VZV—Treatment General treatment measures—initial isolation; bed rest till afebrile; control of pruritis Antivirals—Acyclovir within 24 hours after rash onset Consider—patients over 12 years old, secondary contacts, patients with chronic cutaneous and cardiopulmonary disease, and children on long-term salicylate therapy High dose IV antivirals—for immunocompromised patients, pregnancy (3rd trimester), extracutaneous disease Prophylaxis for profoundly immunosuppresed patients Postherpetic neuralgia—gabapentin, lidocaine patches Tricyclic antidepressants, opioids, capsaicin cream Epidural injection of steroids and anesthetics

VZV—Prognosis and Prevention Varicella—duration usually 2 weeks or less; fatalites rare Zoster—2-6 weeks; greater antibody response Ophthalmic involvement—periodic exams Screen healthcare workers and vaccinate if negative Workers with zoster should receive antiviral agents during 1st 72 hours of disease and stay away from work until lesions are crusted Isolate patients with active VZV from negative contacts

Varicella Vaccination Universal childhood vaccination against varicella—98.1% effective when given after 13 months of age 1st dose 12-15 months, 2nd dose 4-6 years Avoid aspirin for at least 6 weeks Seronegative individuals over 13 years old—2 doses of varicella vaccine 4-8 weeks apart Consider vaccination for HIV + adolescents and adults with CD4 200 cells/mcL or higher Also other selected immunocompromised pts (see text) Varicella incidence decreased 67%-87% due to vaccination Postexposure vaccination recommended for unvaccinated persons without other evidence of immunity Varicella Zoster immunoglobulin—consider for susceptible pts who cannot receive vaccine

Zoster Vaccination Live attenuated VZV vaccine—for patients 60 and older Reduces incidence of postherpetic neuralgia by 67% Reduces incidence of herpes zoster by 51% Should not co-administer with pneumonia vaccine

Rabies

Rabies Viral encephalitis transmitted by infected saliva 50,000-100,000 deaths/year globally In US—dog rabies has almost disappeared, but wildlife rabies has greatly increased Incubation—10 days to years (usually 3-7 weeks) Inoculation site  nerves  brain  efferent nerves  salivary glands Forms cytoplasmic inclusion bodies Almost uniformly fatal

Rabies Symptoms History of animal bite (may not notice bat bite) Pain (at bite location), fever, malaise, headache, nausea, vomiting Aerophobia and sensitivity to temperature change Percussion myoedema 10 days after prodrome—CNS stage Encephalitic—”furious”—80%--classic rabies symptoms Paralytic—”dumb”—20%--acute ascending paralysis Progresses to coma, ANS dysfunction, and death

Rabies Diagnosis Bitten animals that appear well—quarantine 10 days Ill or dead animals—test for rabies If animal cannot be examined—presume that raccoons, skunks, bats, foxes, bats and foxes are rabid Direct fluoroscent antibody testing—skin material from posterior neck—60-80% sensitivity Definitive diagnostic assays— RT-PCR nucleic acid sequence-based amplification direct rapid immunohistochemical test viral isolation from CSF or saliva

Rabies Treatment Intensive care—airway, oxygenation, seizure control Universal precautions Postexposure prophlaxis given prior to symptoms—nearly 100% successful in disease prevention Once symptoms have appeared, death almost inevitably occurs after 7 days, usually from respiratory failure

Rabies—Prevention Immunization of household dogs, cats, and patients with significant animal exposure Cleansing, debridement, and flushing of wounds Do not suture animal bite wounds Decision to treat with immune globulin or antiserum— varies with circumstances of bite Consult with state and local health departments Give treatment as promptly as possible if indicated Read—when to admit, when to refer

Questions?