3/15/18. Herpesviruses. Disclosures. Learning Objectives. Roadmap. I have no disclosures. 39 th Annual Advances in Infectious Diseases March 2018

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1 Disclosures I have no disclosures. Herpesviruses 39 th Annual Advances in Infectious Diseases March 2018 Jennifer Babik, MD, PhD Associate Clinical Professor Division of Infectious Diseases, UCSF 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 infections) VZV CMV EBV 1

2 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. The next best test is: 1. Throat swab for VZV DFA 1. Throat swab for HSV PCR 2. Throat swab for CMV PCR Tests for Group A Strep, acute HIV, and EBV are negative. 3. Tonsillar biopsy to r/o lymphoma Photo courtesy of Matt Russell. 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 ê duration of sx ACV 200mg PO 5x/day x 7 days Valacyclovir 1gm PO bid x 7 days 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. 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 Cernik et al, Arch Intern Med 2008; 168:1137. Photo courtesy of Laura Pincus. 2

3 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% Ulcer 30-40% Crusted 20-30% DFA Vesicle 70-90% Ulcer 30% Crusted 10% 100% Moderate sensitivity Takes 1-2 days 99% Rapid (hours) Slight ê sensitivity c/w culture 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 Oral HSV: Treatment Episodic therapy ê time to heal by days (does not abort lesions) Antivirals: Acyclovir 200mg PO 5x/day x 5 days Valacyclovir 2gm PO bid x 1 day Suppressive therapy ê recurrences by 40-50% (if 4-6 recurrences/year) Not known if can ê oral HSV-1 shedding or transmission Antivirals: Acyclovir 400mg PO bid Valacyclovir 500mg or 1000mg PO daily 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 Cernik et al, Arch Intern Med 2008; 168:1137. 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. What Would You Do With His Antibiotics? 1. Stop acyclovir 2. Change acyclovir to ganciclovir 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 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) RBCs: elevated <500 Mildly ñ protein (median 80 mg/dl), normal glucose Can be normal in up to 15% 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 à 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 days Can check HSV PCR at d14 to define duration 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 DeBiasi and Tyler, Clin Microbiol Rev 2004, 17:903. Tyler, Herpes 2004, 11 Suppl 2: 57A Tyler, Herpes 2004, 11 Suppl 2: 57A. Aurelius et al, Clin Infect Dis 2012, 54: Berger and Houff, Arch Neurol 2008, 65:596. Noska et al, Clin Infect Dis 2015;60:237. 5

6 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/d for autoimmune hemolytic anemia presents with a painful progressive rash on his left leg in the L4 and L5 dermatomes. 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 ê 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. 6

7 To confirm the dx, the most sensitive test is: 1. VZV DFA 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. 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. Which is the Best Choice to ê the Risk of PHN? 1. Prednisone 2. Valacyclovir 3. Valacyclovir and prednisone Zoster Treatment: Antivirals Benefits of therapy ê duration new lesion formation by 1-2 days ê severity and duration of acute pain and rash ê risk of PHN (inhibits viral replication, neural damage) 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

8 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) 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. Dworkin et al, Clin Infect Dis 2007; 44 (Suppl1): S1. Steroids in Acute Zoster 3 RCTs all show that addition of steroids to ACV: Accelerated healing, reduced pain, improved QOL But no decrease in PHN So when to consider steroids? Moderate to severe pain Facial nerve paralysis No contraindications to steroid use Regimen: Prednisone 60 mg/d then taper over d Case #5 75 y/o man with well controlled HIV presents to clinic with a rash over his R eye in the V1 distribution associated with conjunctival injection. Wood et al, N Eng J Med 1994; 330:896. Whitley et al, Annals Int Med 1996; 125:376. Esmann et al, Lancet 1987; 330:126. Chen et al, Cochrane Database Syst Rev 2010; Issue 12. 8

9 How Would You Treat Him? 1. High dose PO valacyclovir and close follow-up VZV Ophthalmicus Defined as zoster in the V1 distribution 2. Admission and IV acyclovir Without Rx, 50% will develop eye complications Conjunctivitis Anterior uveitis Necrotizing retinitis Keratitis Corneal ulcer Orbital apex syndrome Harding et al, Br J Ophthalmol VZV Ophthalmicus: Management Case #6 Ophtho consult for those with: Eye symptoms Lesions on the tip or side of the nose Immunocompromised Antivirals: Treat all patients irrespective of duration of symptoms Intravenous ACV if immunocompromise or eye involvement Hutchinson s sign A 59 year old man with SLE on cellcept and prednisone (10 mg/day) presents with diffuse vesicular rash. VZV DFA is positive and he is started on high dose acyclovir. He still has new lesions on HD#4. Dworkin et al, Clin Infect Dis 2007; 44 (Suppl1): S1 9

10 What Would You Do? 1. Continue ACV and monitor for visceral involvement 2. Change to foscarnet given concern for resistance Disseminated VZV = lesions outside the primary or adjacent dermatomes Usually immunocompromised, occurs by viremic spread to skin Patients may have new lesions for up to 2 weeks Patients are at high risk for pneumonitis, hepatitis, DIC Treatment Total duration 7-14 days Use IV at least 7 days and until all lesions are crusted Cohen, NEJM 2013, 369:255. Pergam et al, Am J Transplantation Another Complication of VZV: Encephalitis Usually occurs in immunocompromised patients Clinical: HA, fever, AMS, seizures Rash present in only 2/3 of cases CSF profile: Lymphocytic pleocytosis (median 110 cells/mm 3 ) Elevated protein, glucose normal to slightly low Positive VZV PCR (sensitivity %, specificity 98%) Positive VZV IgG (more sensitive than PCR, especially if chronic) VZV: Take Home Points DFA or PCR are the diagnostic methods of choice for cutaneous zoster Steroids provide no additional benefit to antivirals in ê risk of PHN Admit patients for IV acyclovir if they are severely immunocompromised or have disseminated/cns disease Treatment: Acyclovir mg/kg IV q8 h for days Gilden et al, NEJM Pahud et al, J Infect Dis 2011, 203:316. Tunkel et al, CID 2008, 47:

11 Case #7 What Antibiotics Should You Start? 47 year old M with no PMH is admitted with fever and respiratory distress. CT shows prominent GGO. HIV Ab test is positive and CD4 is 56. BAL is performed and is positive for PCP. BAL is also positive for CMV culture. Plasma CMV PCR is positive at 970 IU/mL. 1. TMP-SMX alone 2. TMP-SMX plus ganciclovir 3. TMP-SMX plus acyclovir 4. TMP-SMX plus IVIG Approach to CMV Infections Symptomatic CMV in Immunocompetent Patients Define the Host Clinical: viral syndrome, abnormal LFTs Immunocompetent Primary infection Asymptomatic or heterophile (-) mononucleosis Diagnosis by serology Supportive Rx only Immunocompromised Primary or reactivation Asymptomatic viremia CMV syndrome End-organ disease Diagnosis by tissue biopsy, blood PCR, culture Usually anti-cmv therapy Diagnosis (if testing is done): Positive CMV IgM (but beware false positives) Can be elevated for > 4-12 mo after infection, during reactivation, or polyclonal stimulation (e.g. during acute EBV infection) Negative or low avidity IgG Treatment: supportive Navalpotro et al, J Clin Virol 2006; 35:193. Wreghitt et al, Clin Infect Dis 2003; 37:1603. Wreghitt et al, Clin Infect Dis 2003; 37:

12 CMV Infection in Immunocompromised Patients CMV End-Organ Disease: Examples CMV Infection CMV Colitis Fever, diarrhea (+/- bloody), abdominal pain Asymptomatic Viremia CMV Syndrome End-Organ Disease Asymptomatic Plasma CMV PCR (+) Treatment depends on host Fever plus bone marrow suppression (leukopenia and/or thrombocytopenia) Plasma CMV PCR (+) Treat all patients Neuro: Encephalitis, Retinitis Pneumonitis GI: Colitis>Esophagitis Others: hepatitis, nephritis, myocarditis, pancreatitis Plasma CMV PCR (+) (GI can be compartmentalized) Treat all patients CMV Pneumonitis Fever, mild to severe respiratory failure CMV in HIV+ Patients Asymptomatic viremia in up to 35% pts w/cd4<200 Most common end-organ disease: Retinitis GI (colitis > esophagitis) Pneumonitis is rare: BAL+ for CMV in ~50% of patients (without CMV pneumonitis) CMV Treatment IV vs PO? IV ganciclovir if severe infection, high viral load (e.g., >1 million copies/ml), poor oral absorption PO valganciclovir okay for mild-moderate disease How long to treat? 2-3 weeks and until PCR negative (check weekly) May consider secondary prophylaxis in selected patients Durier et al, Clin Infect Dis 2013;57:147. Deayton et al, Lancet 2004; 363: Hayner et al, Chest 1995;107;735. Miles et al, Chest 1990;97;1072. CDC/NIH/HIVMA Guidelines for the prevention and treatment of OIs in HIV-infected adults, Razonable et al, Am J Transplant 2013; 13:93. Asberg et al (VICTOR study group), Am J Transplant 2007; 7:

13 Case #8 57 year old woman s/p renal transplant 4 months prior who has been off her CMV prophylaxis (valganciclovir) due to leukopenia. She presents to clinic with fatigue and fever to 39.1 and is found to have pancytopenia. She has no other localizing signs/symptoms. Review Question: What is the Diagnosis? 1. Asymptomatic CMV viremia 2. CMV syndrome 3. CMV end-organ disease Labs: WBC 1.0 (previously 2.5) Platelets 81 (previously normal) CMV viral load in the plasma is 56,000 IU/mL CMV: Take-Home Points Define your host: immunocompetent or immunocompromised (HIV vs transplant/other) Determine which type of CMV infection your patient has: Asymptomatic viremia CMV syndrome End-organ disease Case #9 22 y/o woman presents with fever, sore throat, and cervical lymphadenopathy for 2 days. Heterophile antibody test is negative. HIV+ patients are a special category: Commonly have asymptomatic viremia Can have severe end-organ disease (retinitis, GI most common) Rarely have pneumonitis despite frequent +BAL for CMV 13

14 The Sensitivity of Heterophile Ab in 1 st Week is: 1. 25% 2. 50% Case #10 A 28 year old man with no PMH is admitted with fever to 39.6, diffuse lymphadenopathy, and pancytopenia. 10 days prior he had a sore throat (now resolved) for which he was prescribed azithromycin % 4. >90% His EBV testing is as follows: - Monospot positive - EBV IgM negative, IgG positive - EBV PCR negative The Most Likely Diagnosis is: 1. Acute EBV infection (Mononucleosis) EBV 75% of US is seropositive by age Prior EBV infection and a different acute process Clinical: Incubation period 4-6 weeks <18 y/o: Most are asymptomatic or nonspecific illness >18 y/o: Most are symptomatic Infectious mononucleosis = classic triad of sore throat, cervical lymphadenopathy, fever Balfour et al, J Infect Dis 2013; 207:80. 14

15 Diagnosis of IM: Heterophile Antibody (Monospot) Diagnosis of IM: EBV Serologies + X-reactivity EBV IgM (VCA) EBV IgG (VCA) Acute Infection IgM VCA IgG VCA IgG EBNA + +/ Patient s blood: IgM against viral antigens Sheep or horse RBCs Agglutination EBV IgG (EBNA) Prior Infection + + Sensitivity: 90-95% after 1 st week, but only 75% in the 1 st week Specificity: 94%. False (+): infections (CMV, Toxo, acute HIV), malignancy, autoimmune (SLE) *No longer recommended by the CDC given false (+) and ( )* Weeks Sensitivity 85-90% Specificity >95% Luzuriaga and Sullivan, N Engl J Med 2010; 362:21. Luzuriaga and Sullivan, N Engl J Med 2010; 362:21. Diagnosis of IM: EBV PCR Not a lot of data Positive early on, usually undetectable by week meta-analysis of 4 small studies in kids/young adults: Pooled sensitivity: 80% Pooled specificity: 95% Diagnosis of IM: CBC with Differential Absolute lymph count > 4,000 x 10 6 /L Sensitivity 84% Specificity 94% Atypical lymphs >10% Sensitivity 75% Specificity 92% May be helpful when other tests are inconclusive Jiang et al, J Med Virol 2016; 88:871. Berth et al, J Clin Virol 2011; 50:184. Bauer et al, J Med Virol 2005; 75:54. Luzuriaga and Sullivan, N Engl J Med 2010; 362:21. Vouloumanou et al, Curr Opin Hematol 2012; 19:14. Biggs et al, Laryngoscope 2013, 123:

16 Complications of EBV Infection Mononucleosis: Treatment Hematologic 25-50% Hemolytic anemia Thrombocytopenia Aplastic anemia TTP/HUS DIC Trigger for HLH Splenic rupture Neurologic 1-5% Guillain Barre syndrome Facial paralysis Aseptic meningitis Encephalitis Transverse myelitis Peripheral neuritis Optic neuritis Steroids? à Not for all, maybe in select cases Cochrane review 2015: insufficient evidence to the efficacy of steroids for symptom control lack of research on the side effects and long-term complications Consider short course to treat severe complications (e.g., upper-airway obstruction) Antivirals? à NO, multiple RCTs show no benefit Luzuriaga and Sullivan, N Engl J Med 2010; 362:21. Luzuriaga and Sullivan, N Engl J Med 2010; 362:21. Rezk et al, Cochrane Database Syst Rev 2015, issue 11. Balfour et al, J Clin Virol 2007; 39:16. EBV Take Home Points Thank You! Monospot testing can lead to false negatives and false positives and is no longer a recommended test Questions? Serology is 85-90% sensitive PCR is positive early on with overall 80% sensitivity Lymphocytosis and atypical lymphs can be an important clue to diagnosis 16