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3/15/2017
1
Herpesviruses
Jennifer Babik, MD, PhDAssistant Clinical ProfessorDivision of Infectious Diseases, UCSF
38th Annual Advances in Infectious DiseasesMarch 2017
Disclosures
I have no disclosures.
Learning Objectives
1. To recognize the key clinical features of the most common herpes virus infections seen in the inpatient and outpatient setting.
1. To develop a framework for diagnosis and management of common herpes virus infections
Common Herpesviruses in Clinical Practice
HSV‐1, HSV‐2 VZV
EBV CMV
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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.
1. Throat swab for VZV DFA
1. Throat swab for HSV culture
2. Throat swab for CMV PCR
3. Tonsillar biopsy to r/o lymphoma
The next best test is:
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 symptoms Acyclovir 200mg PO 5x/day (7 days)
Famciclovir 500mg PO bid (7 days)
Valacyclovir 1gm PO bid (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 5th
episode in the last year.
Photo courtesy of Laura Pincus.
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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 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 Famciclvoir 1500mg PO x 1 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 Famciclovir 500mg PO bid Valacyclovir 500‐1000mg PO daily
Cernik et al, Arch Intern Med 2008; 168:1137.
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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
A 22 year old man has fever, lymphadenopathy, and painful blisters at the base of his penis.
He is diagnosed with primary genital herpes. HSV‐2 is detected on culture of one of the lesions.
He wants to know how likely this is to recur in the next 12 months.
Photo courtesy of Laura Pincus.
The likelihood of recurrence in the next 12 mo:
1. 10%
2. 30%
3. 50%
4. >70%
Genital Herpes: Epidemiology and Transmission
HSV‐1 versus HSV‐2:
HSV‐1 now accounts for >50% of 1˚ GH
HSV‐1 = HSV‐2 clinically
But HSV‐2 recurrence rate is
Most transmission occurs from:
People unaware they have GH (<25% know they have it)
Asymptomatic shedding (25% of days)
Bernstein et al, Clin Infect Dis 2013;56:344. Gupta et al, Lancet 2007; 370:2127. Horowitz et al, J Amer Coll Health 2010; 59:69. Mark et al, J Infect Dis 2008; 198:1. Sacks et al, Antiviral Res 2004; 63S1:S19..
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*Another strong predictor of recurrence risk is severity of primary infection
Benedetti et al, Annals Int Med 1994; 121:847. Benedetti et al, Annals Int Med 1999; 131:14. Photo courtesy of Laura Pincus
Recurrent Genital Herpes
HSV primary infection
% with a recurrence within 1 year
# recurrences in 1st year
HSV‐1 20‐50% 1
HSV‐2 70‐90% 4‐5
Classic “scalloped” border
Test Sensitivity Specifcity Important points
Genital HSV: Diagnostics
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.
PCR ~90% overall 99% Most sensitive test if available
DFA Vesicle 70‐90%Ulcer 30%Crusted 10%
99% Rapid (hours)Slight sensitivity c/w culture
Culture Vesicle 70‐90%Ulcer 30‐40%Crusted 20‐30%
100% Moderate sensitivityTakes 1‐2 days
Screening for HSV‐2 By Serology?
New 2016 US Preventative Task Force Recs No!
Why not?
Sensitivity 99% but specificity only 83%
As many false positives as true positives
When might serology be useful?
Recurrent genital symptoms and (‐) HSV cultures/PCR
USPSTF, JAMA 2016, 316:2525.
Treatment Regimens: First episode
Efficacy
duration of symptoms by 2‐4 days
No impact on recurrence rate
Regimens
Acyclovir 400mg PO tid or 200mg PO 5x/day (7‐10 days)
Valacyclovir 1gm PO bid (7‐10 days)
Famciclovir 250mg PO tid (7‐10 days)
CDC, STD Treatment Guidelines 2015. Mertz et al, JAMA 1984; 252:1147.
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Efficacy:
Start in prodrome or <1 day of symptoms
Can abort lesions in 20‐30% or symptoms by 1‐2 days
Does not reduce rate of transmission to uninfected partners
Regimens
Acyclovir 400mg PO tid or 800mg PO bid (5 days)
Acyclovir 800mg PO tid (2 days)
Valacyclovir 500mg PO bid (3 days)
Valacyclovir 1gm PO daily (5 days)
Famciclovir (options for 1, 2, 5 days)
Episodic Therapy: Recurrent Episodes
CDC, STD Treatment Guidelines 2015. Strand et al, Sex Transm Infect 2002; 78:435.
Suppressive Therapy for Genital Herpes
Efficacy:
recurrences by 70‐80% and shedding
transmission to negative partner by ~50% (but absolute RR of ~2%)
When to use?
CDC: consider if “frequent” episodes (? ≥ 6) or discordant couples
SF City Clinic: offers to most with a new diagnosis of HSV‐2
Antivirals:
Acyclovir 400mg bid, famciclovir 250mg bid, valacyclovir 500‐1000mg daily
Discuss a trial off therapy qyear
CDC, STD Treatment Guidelines 2015. Corey et al, N Engl J Med 2004; 350:11.
Genital Herpes: Take Home Points
HSV‐1 and HSV‐2 are clinically identical, but HSV‐2 is much more likely to recur
Most transmission occurs in patients who are asymptomatic or are unaware they have genital herpes
HSV culture and DFA are the diagnostic methods of choice
Oral antivirals can shorten symptom duration, abort lesions entirely, and can be used as suppressive therapy to decrease the number of recurrences as well as transmission
Case #4
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
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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)
RBCs: elevated <500
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.
Can be normal in up to 15%
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
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HSV Aseptic Meningitis
1st 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 #5
64 y/o man on prednisone 20mg/d for AIHA 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
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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
Test Sensitivity Specifcity Take home points
Cutaneous VZV: Diagnostics
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.
PCR 95% 99% Most sensitive testNot always available
DFA 90% 95% Rapid if in‐house (hours)Test of choice in most places
Culture 60‐75% 100% Takes 1‐2 weeks to growUsually not done
*Zoster is often a clinical diagnosis (90% accurate?). May need additional diagnostics if immunocompromised, severe/disseminated, atypical, or not responding to Rx.
Review: Diagnosis of HSV vs VZV
Lesion swab HSV VZV
Culture + ‐‐
DFA + +
PCR + +
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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.
Antiviral Options
Drug options: Acyclovir 800 mg PO 5x/day, valacyclovir 1gm PO tid, Famciclovir 500mg 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.
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.
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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 10‐21 d
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.
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 conjunctivalinjection.
How Would You Treat Him?
1. High dose PO valacyclovir and close follow‐up
2. Admission and IV acyclovir
VZV Ophthalmicus
Defined as zoster in the V1 distribution
Without Rx, 50% will develop eye complications
Conjunctivitis
Anterior uveitis
Necrotizing retinitis
Keratitis
Corneal ulcer
Orbital apex syndrome
Harding et al, Br J Ophthalmol 1987.
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VZV Ophthalmicus: Management
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
Use intravenous ACV in immunocompromised or with eye involvement
Dworkin et al, Clin Infect Dis 2007; 44 (Suppl1): S1
Case #6
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.
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
Cohen, NEJM 2013, 369:255. Pergam et al, Am J Transplantation 2013.
Treatment• Total duration 7‐14 days• Use IV for at least 7 days (and until all lesions are crusted)
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VZV Encephalitis
Clinical:
Usually occurs in immunocompromised patients
Rash present in only 2/3 of cases
CSF profile:
Lymphocytic pleocytosis (median 110 cells/mm3)
Elevated protein, glucose normal to slightly low
Positive VZV PCR (sensitivity 80‐100%, specificity 98%)
Positive VZV IgG (more sensitive than PCR, especially if chronic)
Treatment: Acyclovir 10‐15 mg/kg IV q8 h for 10‐14 days
Gilden et al, NEJM 2000. Pahud et al, J Infect Dis 2011, 203:316. Tunkel et al, CID 2008, 47:303.
VZV: Take Home Points
DFA or PCR are the diagnostic methods of choice for cutaneous zoster
Steroids provide no additional benefit to antivirals in risk of PHN
Admit patients for IV acyclovir if they are severely immunocompromised or have disseminated/CNS disease
Case #7
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.
What Antibiotics Should You Start?
1. TMP‐SMX alone
2. TMP‐SMX plus ganciclovir
3. TMP‐SMX plus acyclovir
4. TMP‐SMX plus IVIG
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Approach to CMV Infections
Immunocompetent
Primary infection
Asymptomatic or heterophile(‐) mononucleosis
Diagnosis by serology
Supportive Rx only
Navalpotro et al, J Clin Virol 2006; 35:193. Wreghitt et al, Clin Infect Dis 2003; 37:1603.
Immunocompromised
Primary or reactivation
• Asymptomatic viremia• CMV syndrome• End‐organ disease
Diagnosis by tissue biopsy,blood PCR, culture
Usually anti‐CMV therapy
Define the Host
CMV Infection in Immunocompromised Patients
Asymptomatic Viremia
Asymptomatic
Plasma CMV PCR (+)
Treatment depends on host
CMV Syndrome
Fever plus bone marrow suppression (leukopenia and/or thrombocytopenia)
Plasma CMV PCR (+)
Treat all patients
End‐Organ Disease
•Neuro: Encephalitis, Retinitis• Pneumonitis •GI: Colitis>Esophagitis•Others: hepatitis, nephritis,myocarditis, pancreatitis
Plasma CMV PCR (+) (GI can be compartmentalized)
Treat all patients
CMV Infection
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)
Durier et al, Clin Infect Dis 2013;57:147. Deayton et al, Lancet 2004; 363: 2116. 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, 2015.
CMV End‐Organ Disease
CMV Colitis• Fever, diarrhea (+/‐ bloody), abd pain• Dx by colonoscopy with path, IHC• Blood PCR can be negative
CMV Pneumonitis• Fever, mild to severe resp failure• CT shows diffuse bilateral GGO• Dx by BAL: culture, path• Blood PCR usually positive
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CMV Treatment
IV vs PO?
IV ganciclovir if severe, viral load >1 million copies/mL, poor oral absorption
PO valganciclovir okay for mild‐moderate disease
IVIG?
Case‐by‐case basis for severe pneumonitis
How long to treat?
2‐3 weeks and until PCR negative
Consider secondary prophylaxis in selected patients
Razonable et al, Am J Transplant 2013; 13:93. Asberg et al (VICTOR study group), Am J Transplant 2007; 7:2106.
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
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
Case #8
22 y/o woman presents with fever, sore throat, and cervical lymphadenopathy for 2 days. Heterophileantibody test is negative.
The Sensitivity of Heterophile Ab in 1st Week is:
1. 25%
2. 50%
3. 75%
4. >90%
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EBV
75% of US is seropositive by age 18
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.
Diagnosis of IM: CBC with Differential
Absolute lymph count > 4,000 x 106/L
Sensitivity 84%
Specificity 94%
Atypical lymphs >10%
Sensitivity 75%
Specificity 92%
Luzuriaga and Sullivan, N Engl J Med 2010; 362:21. Vouloumanou et al, Curr Opin Hematol 2012; 19:14. Biggs et al, Laryngoscope 2013, 123:2401.
Diagnosis of IM: Heterophile Antibody (Monospot)
Patient’s blood: IgM against viral antigens
+
Sheep or horse RBCs
Agglutination
X‐reactivity
Sensitivity: 90‐95% after 1st week, but only 75% in the 1st week
Specificity: 94%
*No longer recommended by the CDC given false (+) and (–)*
Luzuriaga and Sullivan, N Engl J Med 2010; 362:21.
Diagnosis of IM: EBV Serologies
Luzuriaga and Sullivan, N Engl J Med 2010; 362:21.
IgM VCA
IgG VCA
IgGEBNA
Acute Infection
+ +/− −
Prior Infection
− + +
• Sensitivity 85‐90%
• Specificity >95%
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Mononucleosis: Treatment
Steroids? 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? NO, multiple RCTs show no benefit
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
Diagnosis of IM:
Usually a clinical diagnosis
Elevated ALC and atypical lymphs can be an important clue to diagnosis
Monospot testing is only 75% sensitive in the 1st week and is no longer a recommended test
Serology is 85‐90% sensitive
Treatment is supportive in most cases
Thank You!
Questions?