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2/21/19 Disclosures I have no disclosures. Herpesviruses Infectious Diseases in Clinical Practice February 2019 Jennifer Babik, MD, PhD Associate Clinical Professor Division of Infectious Diseases, UCSF Learning Objectives Roadmap By

  1. 2/21/19 Disclosures § I have no disclosures. Herpesviruses Infectious Diseases in Clinical Practice February 2019 Jennifer Babik, MD, PhD Associate Clinical Professor Division of Infectious Diseases, UCSF Learning Objectives Roadmap By the end of this talk, you will be able to: Case-based approach to: § HSV-1 1. Recognize the key clinical features of the most common herpes virus infections. § HSV-2 (non-genital infections) § VZV 1. Describe the important principles of diagnosis and § CMV management of common herpes virus infections § EBV 1

  2. 2/21/19 Case #1 The next best test is: A 28 year old man presents 1. Throat swab for VZV DFA with fever and severe sore throat after returning from his honeymoon. He has mild 1. Throat swab for HSV PCR anterior cervical LAN and the oral exam shown. The 2. Throat swab for CMV PCR rest of his exam is normal. Tests for Group A Strep, 3. Tonsillar biopsy to r/o lymphoma acute HIV, and EBV are negative. Photo courtesy of Matt Russell. Oral HSV: Primary Infection Case #2 § Children/young adults, HSV-1 A 30 year old man presents to clinic complaining of “fever § Symptomatic in 10-30%: blisters” for the past 24 hours. He has moderate pain but § Gingivostomatitis § Pharyngitis/tonsillitis - may not have vesicles! mostly feels a great degree of § Systemic sx (can look like mono) stress and embarrassment § Duration of symptoms 10-14d about the lesions. This is his 5 th episode in the last year. § Oral antivirals ê 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. Photo courtesy of Laura Pincus. 2

  3. 2/21/19 Oral antivirals Recurrent Oral HSV: Herpes Labialis § Almost always HSV-1 1. Shorten the time for lesions to heal § Recurrences in 20-40% of HSV-1 (+) 2. Are effective as suppressive therapy § 1.5 recurrences/year § Triggers: 3. Both #1 and #2 § Fever, URI § UV light exposure (sun) 4. Have no treatment effect § 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 ê 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. 3

  4. 2/21/19 Oral HSV: Treatment Oral HSV: Take Home Points Episodic therapy § Primary HSV-1 can be a cause of pharyngitis in young § ê time to heal by 0.5-2.5 days (does not abort lesions) adults (and may not present with vesicles) § Antivirals: § Acyclovir 200mg PO 5x/day x 5 days § HSV PCR of a lesion is the most sensitive diagnostic § Valacyclovir 2gm PO bid x 1 day test for mucocutaneous herpes infections Suppressive therapy § Oral antivirals have a modest treatment effect: they § ê recurrences by 40-50% (if ≥4-6 recurrences/year) can shorten healing time and be used as suppressive § Not known if can ê oral HSV-1 shedding or transmission therapy to prevent recurrences § Antivirals: § Acyclovir 400mg PO bid § Valacyclovir 500mg or 1000mg PO daily Cernik et al, Arch Intern Med 2008; 168:1137. Case #3 What Would You Do With His Antibiotics? 55 year old man is brought in by his 1. Stop acyclovir neighbor for bizarre behavior for 12 hours. He is found to be febrile and has a witnessed seizure in the ED. 2. Change acyclovir to ganciclovir MRI is shown. He is started on vancomycin, ceftriaxone, and acyclovir and is tapped 24 h later. 3. Continue acyclovir Lumbar puncture: § 50 WBC (89% lymphs), 50 RBC, protein 80, glucose 78 § CSF culture is NGTD § PCR is negative for HSV and VZV 4

  5. 2/21/19 The HSV PCR May Be Negative Because: HSV Encephalitis 1. He got 24 hours of acyclovir § Epidemiology/Clinical: § Accounts for 10-20% of encephalitis § >90% due to HSV-1, most reactivation (HSV2 rare, in ICH) 2. It’s not a sensitive test § Fever, personality change, seizures, focal neuro findings 3. It’s early in the disease course § CSF studies: § WBCs: lymphocytic pleocytosis (median 130 cells) Can be normal in § RBCs: elevated <500 up to 15% § Mildly ñ 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 HSV Aseptic Meningitis § 1 st episode in primary genital HSV-2 (women>men) § CSF PCR: § 96% sensitive, 99% specific § Recurrences: § May have false (-) in the first 3d à if suspicion is high re-tap § ACV has little effect on PCR (+) within the first 5 days of therapy § 20-30% of patients will have at least 1 recurrence § Mollaret’s = repeated self-limited episodes +/- skin lesions § MRI: temporal/frontal lobe involvement in 90% § Antivirals needed? § Consider ACV 10 mg/kg q8h or valacyclovir 1gm PO tid x 7- § Treatment: 14d (some data for benefit in immunocompromised) § ACV 10mg/kg IV q8h x 14-21 days § Suppressive therapy not effective to prevent recurrences § Can check HSV PCR at d14 to define duration Tyler, Herpes 2004, 11 Suppl 2: 57A. Aurelius et al, Clin Infect Dis 2012, 54: 1304. Berger and Houff, Arch Neurol 2008, 65:596. DeBiasi and Tyler, Clin Microbiol Rev 2004, 17:903. Tyler, Herpes 2004, 11 Suppl 2: 57A Noska et al, Clin Infect Dis 2015;60:237. 5

  6. 2/21/19 HSV Neuro Complications: Take-Home Case #4 § HSV encephalitis is usually caused by HSV-1 and 64 y/o man on prednisone 20mg/d for autoimmune affects the frontal/temporal lobes hemolytic anemia presents with a painful progressive rash § CSF HSV PCR is very sensitive for HSV encephalitis: on his left leg in the L4 and L5 dermatomes. § There can be false (-) within the first 3 days of symptoms § ACV has little effect on sensitivity within the first 5 days He is admitted with concern for disseminated zoster. § HSV meningitis is a complication of primary genital herpes from HSV-2 and can be recurrent Acyclovir is started but he still has new lesions on day 2 The Most Likely Diagnosis Is: Zoster: Key Clinical Features § 80% have prodrome (lasts 2-3 days) 1. Disseminated zoster § New vesicles appear for 2-4 days 2. Resistant zoster (antivirals ê new lesions by 1-2 days) 3. Uncomplicated localized zoster § Overlap into adjacent dermatomes in 20% (normal variation in innervation) 4. Herpetic whitlow § PHN: pain lasting >3 months after zoster episode, occurs in 10-20% Dworkin et al, Clin Infect Dis 2007; 44 (Suppl1): S1. 6

  7. 2/21/19 To confirm the dx, the most sensitive test is: Cutaneous VZV: Diagnostics • Zoster is often a clinical diagnosis (~90% accurate). 1. VZV DFA • May need to confirm if immunocompromised, severe/disseminated (e.g., hospitalized), atypical, or not responding to Rx. 2. VZV culture 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. Zoster Treatment: Antivirals Which is the Best Choice to ê the Risk of PHN? 1. Prednisone § Benefits of therapy § ê duration new lesion formation by 1-2 days § ê severity and duration of acute pain and rash 2. Valacyclovir § ê risk of PHN (inhibits viral replication, neural damage) 3. Valacyclovir and prednisone § Who to Treat? § ≥50 years, mod-severe pain/rash, immunocompromised § Consider in all as benefit ( ê PHN) likely outweighs risk Dworkin et al, Clin Infect Dis 2007; 44 (Suppl1): S1. Chen et al, Cochrane Database Syst Rev 2010; Issue 12. 7

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