Herpesviruses Infectious Diseases in Clinical Practice February 2020 - PDF document

Herpesviruses Infectious Diseases in Clinical Practice February 2020 Jennifer Babik, MD, PhD Associate Clinical Professor Division of Infectious Diseases, UCSF Disclosures  I have no disclosures.

Learning Objectives By the end of this talk, you will be able to: 1. Recognize the key clinical features of the most common herpes virus infections. 1. Describe the important principles of diagnosis and management of common herpes virus infections Roadmap Case ‐ based approach to:  HSV ‐ 1  HSV ‐ 2 (non ‐ genital)  VZV  CMV  EBV

Case #1 A 28 year old man presents with fever and severe sore throat after returning from his honeymoon. He has mild anterior cervical LAN and the oral exam shown. The rest of his exam is normal. Tests for Group A Strep, acute HIV, and EBV are negative. Photo courtesy of Matt Russell. The next best test is: 1. Throat swab for VZV DFA 1. Throat swab for HSV PCR 2. Throat swab for CMV PCR 3. Tonsillar biopsy to r/o lymphoma

Oral HSV: Primary Infection  Children/young adults, HSV ‐ 1  Symptomatic in 10 ‐ 30%:  Gingivostomatitis  Pharyngitis/tonsillitis ‐ may not have vesicles!  Systemic sx (can look like mono)  Duration of symptoms 10 ‐ 14d  Oral antivirals  duration of sx  ACV 200mg PO 5x/day x 7 days  Valacyclovir 1gm PO bid x 7 days Ardino and Porter, J Oral Pathol Med 2008; 37:107. McMillan et al, Pediatr Infect Dis J 1993; 12:280. Ireland, Oxford Dictionary of Dentisty 2010. Cernik et al, Arch Intern Med 2008; 168:1137. Case #2 A 30 year old man presents to clinic complaining of “fever blisters” for the past 24 hours. He has moderate pain but mostly feels a great degree of stress and embarrassment about the lesions. This is his 5 th episode in the last year. Photo courtesy of Laura Pincus.

Oral antivirals 1. Shorten the time for lesions to heal 2. Are effective as suppressive therapy 3. Both #1 and #2 4. Have no treatment effect Recurrent Oral HSV: Herpes Labialis  Almost always HSV ‐ 1  Recurrences in 20 ‐ 40% of HSV ‐ 1 (+)  1.5 recurrences/year  Triggers:  Fever, URI  UV light exposure (sun)  Emotional stress, fatigue  Immunosuppression  Oral/facial surgery or trauma  Menstruation Cernik et al, Arch Intern Med 2008; 1168:1137. Ardino and Porter, J Oral Pathol Med 2008; 37:107.

Oral HSV Reactivation in Immunocompromised HSV: Diagnostics *Oral HSV is often a clinical diagnosis. May need to confirm if immunocompromised, severe, atypical, or not responding to Rx. Test Sensitivity Specifcity Take home points Culture Vesicle 70 ‐ 90% 100% Moderate sensitivity Ulcer 30 ‐ 40% Takes 1 ‐ 2 days Crusted 20 ‐ 30% DFA Vesicle 70 ‐ 90% 99% Rapid (hours) Ulcer 30% Slight  sensitivity c/w culture Crusted 10% PCR ~90% overall 99% Most sensitive test Mosely et al, J Clin Microbiol 1981; 13:913. Wald et al, J Infect Dis 2003; 188:1345. Van Wagoner and Hook, Curr Infect Dis Rep 2012; 14:175. Lafferty et al, J Clin Microbiol 1987; 25:323.

Oral HSV: Treatment Episodic therapy   time to heal by 0.5 ‐ 2.5 days (does not abort lesions)  Antivirals:  Acyclovir 200mg PO 5x/day x 5 days  Valacyclovir 2gm PO bid x 1 day Suppressive therapy   recurrences by 40 ‐ 50% (if ≥ 4 ‐ 6 recurrences/year)  Not known if can  oral HSV ‐ 1 shedding or transmission  Antivirals:  Acyclovir 400mg PO bid  Valacyclovir 500mg or 1000mg PO daily Cernik et al, Arch Intern Med 2008; 168:1137. Oral HSV: Take Home Points  Primary HSV ‐ 1 can be a cause of pharyngitis in young adults (and may not present with vesicles)  HSV PCR of a lesion is the most sensitive diagnostic test for mucocutaneous herpes infections  Oral antivirals have a modest treatment effect: they can shorten healing time and be used as suppressive therapy to prevent recurrences

Case #3 55 year old man is brought in by his neighbor for bizarre behavior for 12 hours. He is found to be febrile and has a witnessed seizure in the ED. MRI is shown. He is started on vancomycin, ceftriaxone, and acyclovir and is tapped 24 h later. Lumbar puncture:  50 WBC (89% lymphs), 50 RBC, protein 80, glucose 78  CSF culture is NGTD  PCR is negative for HSV and VZV What Would You Do With His Antibiotics? 1. Stop acyclovir 2. Change acyclovir to ganciclovir 3. Continue acyclovir

The HSV PCR May Be Negative Because: 1. He got 24 hours of acyclovir 2. It’s not a sensitive test 3. It’s early in the disease course HSV Encephalitis  Epidemiology/Clinical:  Accounts for 10 ‐ 20% of encephalitis  >90% due to HSV ‐ 1, most reactivation (HSV2 rare, in ICH)  Fever, personality change, seizures, focal neuro findings  CSF studies:  WBCs: lymphocytic pleocytosis (median 130 cells) Can be normal in  RBCs: elevated <500 up to 15%  Mildly  protein (median 80 mg/dl), normal glucose Whitley et al, JAMA 1982, 247:312. Whitley et al, JAMA 1989, 262:234. Tang et al, Clin Infect Dis 1999, 29:803. Domingues et al, Clin Infect Dis 1997, 25:86.

HSV Encephalitis: Diagnosis and Rx  CSF PCR:  96% sensitive, 99% specific  May have false ( ‐ ) in the first 3d  if suspicion is high re ‐ tap  ACV has little effect on PCR (+) within the first 5 days of therapy  MRI: temporal/frontal lobe involvement in 90%  Treatment:  ACV 10mg/kg IV q8h x 14 ‐ 21 days  Can check HSV PCR at d14 to define duration DeBiasi and Tyler, Clin Microbiol Rev 2004, 17:903. Tyler, Herpes 2004, 11 Suppl 2: 57A HSV Aseptic Meningitis  1 st episode in primary genital HSV ‐ 2 (women>men)  Recurrences:  20 ‐ 30% of patients will have at least 1 recurrence  Mollaret’s = repeated self ‐ limited episodes +/ ‐ skin lesions  Antivirals needed?  Consider ACV 10 mg/kg q8h or valacyclovir 1gm PO tid x 7 ‐ 14d (some data for benefit in immunocompromised)  Suppressive therapy not effective to prevent recurrences Tyler, Herpes 2004, 11 Suppl 2: 57A. Aurelius et al, Clin Infect Dis 2012, 54: 1304. Berger and Houff, Arch Neurol 2008, 65:596. Noska et al, Clin Infect Dis 2015;60:237.

HSV Neuro Complications: Take ‐ Home  HSV encephalitis is usually caused by HSV ‐ 1 and affects the frontal/temporal lobes  CSF HSV PCR is very sensitive for HSV encephalitis:  There can be false ( ‐ ) within the first 3 days of symptoms  ACV has little effect on sensitivity within the first 5 days  HSV meningitis is a complication of primary genital herpes from HSV ‐ 2 and can be recurrent Case #4 64 y/o man on prednisone 20mg/day for autoimmune hemolytic anemia presents with a painful progressive rash on his abdomen in the T8/T9 distribution. He is admitted with concern for disseminated zoster. Acyclovir is started but he still has new lesions on day 2

The Most Likely Diagnosis Is: 1. Disseminated zoster 2. Resistant zoster 3. Uncomplicated localized zoster 4. Herpetic whitlow Zoster: Key Clinical Features  80% have prodrome (lasts 2 ‐ 3 days)  New vesicles appear for 2 ‐ 4 days (antivirals  new lesions by 1 ‐ 2 days)  Overlap into adjacent dermatomes in 20% (normal variation in innervation)  PHN: pain lasting >3 months after zoster episode, occurs in 10 ‐ 20% Dworkin et al, Clin Infect Dis 2007; 44 (Suppl1): S1.

To confirm the dx, the most sensitive test is: 1. VZV DFA 2. VZV culture Cutaneous VZV: Diagnostics • Zoster is often a clinical diagnosis (~90% accurate). • May need to confirm if immunocompromised, severe/disseminated (e.g., hospitalized), atypical, or not responding to Rx. Test Sensitivity Specifcity Take home points Culture 60 ‐ 75% 100% Takes 1 ‐ 2 weeks to grow Usually not done DFA 90% 95% Rapid if in ‐ house (hours) PCR 95% 99% Most sensitive test Not always available Dworkin et al, CID 2007; 44 (Suppl1): S1. Helgason et al, Eur J Gen Pract 1996; 2:12 . Kalman and Laskin, Am J Med 1986, 81:775.

Which is the Best Choice to  the Risk of PHN? 1. Prednisone 2. Valacyclovir 3. Valacyclovir and prednisone Zoster Treatment: Antivirals  Benefits of therapy   duration new lesion formation by 1 ‐ 2 days   severity and duration of acute pain and rash   risk of PHN (inhibits viral replication, neural damage)  Who to Treat?  ≥ 50 years, mod ‐ severe pain/rash, immunocompromised  Consider in all as benefit (  PHN) likely outweighs risk Dworkin et al, Clin Infect Dis 2007; 44 (Suppl1): S1. Chen et al, Cochrane Database Syst Rev 2010; Issue 12.

Timing of Therapy  Timing :  All RCTs initiate therapy within 72 hours  Starting at >72h hasn’t been well studied (?benefit up to 7d)  If a patient presents at >72 hrs, would still treat if:  Presence of new vesicles (indicates ongoing viral replication)  Cutaneous, motor, ocular, neurologic complications  Advanced age, severe pain (since these are risks for PHN)  Immunocompromised  V1 zoster (VZV ophthalmicus) Dworkin et al, Clin Infect Dis 2007; 44 (Suppl1): S1. Antiviral Options  Drug options:  Acyclovir 800 mg PO 5x/day, valacyclovir 1gm PO tid  Duration 7 ‐ 10 days  Immunocompromised: treat until all lesions crusted given risk of relapse  When to admit patients for IV acyclovir?  Disseminated disease or CNS/eye complications  Severely immunocompromised patients with localized disease (to prevent dissemination)  Consider in VZV ophthalmicus (V1 zoster) Dworkin et al, Clin Infect Dis 2007; 44 (Suppl1): S1.