Clin Med II Infectious Disease

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

2. Herpes Simplex Virus

3. 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—RoseolaInfantum • HHV 7—”The Multitasker” • Roseola, Seizures, Encephalitis, “helps” CMV in renal transplants • HHV 8—Kaposi sarcoma/primary effusion lymphoma

4. 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

5. 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, ???

6. Mucocutaneous HSV-1

7. Mucocutaneous HSV-1

8. Mucocutaneous HSV-1

9. 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

10. Mucocutaneous HSV-2

11. Mucocutaneous HSV-2

12. Mucocutaneous HSV-2

13. 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

14. Mucocutaneous HSV • Treatment often not necessary in immunocompetentpts • 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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

21. HSV Encephalitis

22. 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

23. 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

24. Varicella Zoster Virus

25. 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

26. 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

27. 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

28. Herpes Zoster Ophthalmicus

29. Herpes Zoster Oticus

30. 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

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

32. 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

33. VZV Encephalitis

34. 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

35. 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

36. 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 immunocompromisedpts (see text) • Varicella incidence decreased 67%-87% due to vaccination • Postexposurevaccination recommended for unvaccinated persons without other evidence of immunity • Varicella Zoster immunoglobulin—consider for susceptible pts who cannot receive vaccine

37. 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

38. Rabies

39. 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

40. 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

41. 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

42. Rabies Treatment • Intensive care—airway, oxygenation, seizure control • Universal precautions • Postexposureprophlaxis 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

43. 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

44. Questions?