Varicella-zoster virus

Background

Microbiology

• dsDNA virus in the Alphaherpesvirinae subfamily within the Herpesviridae family, related to HSV
• Key glycoproteins
  • gB II target of neutralizing antibodies like VZIg
  • gC gp IV not essential
  • gE gp I binds Fc IgG
  • gH gp III fusion function
  • gL glycosylation

Epidemiology

• Varicella is more late winter or spring in temperate climates, often corresponds to school year
• Acquired by 5-10 years old in temperate climates
  • In tropical climates, more susceptibility in adults
• Incubation period is 10 to 21 days
• Infectiousness lasts from 24h before rash (around time of fever) to the final crusting
• Transmitted airborne, respiratory secretions; not transmitted on fomites

Pathophysiology

• Transmitted by respiratory route
• Primary viremia infects liver and RES (~14 days)
• Secondary viremia causes dissemination to skin

Clinical Manifestations

Primary Infection (Varicella)

• Primary infection usually benign in childhood
• Primary infection can be severe in adolescents, adults, and immunocompromised hosts
• New vesicle formation stops within 4 days
• Presentation modified by prior vaccination
  • Less severe, fewer vesicles, less classic rash
• Vaccine-associated: can also get infected by the vaccine strain itself

Differential Diagnosis

• Enterovirus
• Staphylococcus aureus
• Drug reactions
• Contact dermatitits
• Eczema herpeticum
• Insect bites

Breakthrough

• 20% of vaccinated children still acquire varicella
• Milder, fewer sequelae

Sequelae

• SSTI caused by secondary bacterial infection with invasive GAS, and can including necrotizing fasciitis
• Hepatitis, especially in immunocompromised, transplant, and advanced HIV (can be severe)
• Diarrhea, pharyngitis, otitis, nephritis, transient arthritis, myocarditis, ...
• Neurologic
  • Acute cerebellar ataxia
  • Diffuse encephalitis
  • Aseptic meningitis, transverse myelitis, strokes
• Reye syndrome: vomiting, excitability, delirium, and coma
  • Secondary to varicella and concomitant aspirin
• Respiratory: pneumonitis can be severe
  • Typically develops days after rash
  • Consider acyclovir ± prednisone

High-Risk Populations

• Certain populations are at higher risk for severe complications
• Pregnancy
  • Spontaneous abortion, IUFD, prematurity
  • Congenital varicella syndrome
    • Highest risk <20 weeks
    • Cutaneous defects, cicatral scarring and limb atrophy
    • Microcephaly, autonomic dysfunction
  • If primary varicella 5 days before to 2 days after delivery, high risk of mortality
• Immune-compromised hosts
  • Can have progressive disease with prolonged lesions and multiorgan infection

Herpes Zoster (Shingles)

• Varicella reactivation from dorsal root ganglia
• Typically a dermatomal distribution
• Herpes ophthalmaticus (CN V1)
• Ramsay-Hunt syndrome
• Post-herpetic neuralgia

Risk Factors

• Rising age predict zoster as well as postherpetic neuralgia
  • 50% by age 85 years
• Post-surgery
• HIV (even with normal CD4)
• Transplant (HSCT > SOT)

Disseminated Zoster

• May become disseminated in immunocompromised patients, typically after transplantation
  • Involvement of visceral organs, or
  • Multidermatomal involving 3 or more dermatomes
• Can become chronic with episodic viremia
• Prophylaxis
  • HSCT: prophylax with valacyclovir for 1+ year following transplant (longer if GVHD)
  • SOT: 3-6 mo after transplant and for duration of lymphodepletion

Diagnosis

• PCR most common, sensitive and specific, can be tissue, serum, CSF, saliva, etc
• Multinucleated giant cells on histology
• Cell culture
• Serology

Management

• Valacyclovir preferred to acyclovir
  • Main side effect of valacylovir is headache
  • Ideally started early, within 72 hours of symptom onset

Immunocompetent Host

• Primary varicella
  • For chickenpox treatment is not necessary but can be considered
  • If higher risk or severe sequelae, more likely to treat
  • If going to treat, start ASAP (<72 hours) after onset of rash
  • Valacyclovir 1 g p.o. three times daily for 5 to 7 days in normal host
• Zoster
  • Start treatment within 72 hours to reduce new lesions (doesn't affect postherpetic neuralgia)
  • Mild to moderate disease: valacyclovir 1 g p.o. three times daily for 7 days
  • Severe disease including neurologic, ocular, or disseminated infections: acyclovir 10 mg/kg IV every 8 hours for 7 to 14 days

Immunocompromised Host

• Primary varicella: start with IV acyclovir, then step down to oral valacyclovir
• Herpes zoster: start with IV acyclovir, then PO with close followup, until no new lesions for 2 days (minimum 7 days)
• Pregnancy: treat zoster if more than 50 lesions
• Ophthalmic zoster should be treated (involve Ophtho)
• Acute retinal necrosis: IV acyclovir for 10 to 14 days, with steroids (involve Ophtho)
• Ramsay Hunt syndrome: PO acyclovir or valacyclovir, with prednisone
• CNS disease: IV acyclovir for 10 to 14 days
  • Consider oral valacyclovir up to 2 g p.o. q6h1

Prevention

Infection Prevention and Control

• Airborne isolation required for primary varicella and disseminated zoster

Post-Exposure Management

• Identify contacts: very long list, includes anyone with 5 minutes of face-to-face time, adjacent rooms or beds, ...
  • Infectious 1-2 days before onset of rash
• Isolation of contacts
  • Exposed patients without evidence of immunity should be discharge as soon as possible
  • If not discharged, isolate them starting 8 days from first exposure (in airborne)
  • Duration of isolation 21 days; if VZIg (or IVIg), extend duration of isolation to 28 days
  • i.e. day 8 to 21 if no VZIg, day 8 to 28 if VZIg
• Post-exposure vaccination
  • Recommended for all susceptible exposed individuals, assuming that there is no documented immunity and there is no contraindication
  • Within 3-5 days post-exposure to prevent disease (or any time because they need vaccination anyway)
• VZIg (or IVIg, if VZIg not available)
  • Indicated only for susceptible individuals with significant exposure who are at high risk of poor outcome and have a contraindication to vaccination
    • That is, anyone who is already fully vaccinated or is eligible for vaccination is ineligible for VZIg
    • If their serostatus is unknown and can be checked within 96 hours, then do that first (except for patients with HSCT, who get immunized regardless)
  • High risk groups include:
    • Neonates exposed to mother who had onset of varicella 5 days before to 2 days after delivery
    • Infant in NICU who is preterm <28 weeks or weighs <1000 g, regardless of maternal immunity
    • Pregnancy (again, only if susceptible)
    • Immunocompromised individuals, including HIV with CD4 <200 or <15%
    • HSCT who have not completed their vaccines post-transplant, regardless of prior immunity
  • Significant contact includes:
    • Continuous household contact
    • Indoors for more than 1 hour, including same hospital room
    • 15 minutes face-to-face contact
    • Touch lesions, clothes, or bedsheets
  • Start within 4 days of exposure to prevent disease, or within 10 days of exposure to attenuate it

Vaccination

Varicella

• Live attenuated varicella vaccine at 12 months then again at 4 to 6 years
• Can use for PEP if within 3 days of exposure to reduce severity and duration
• Live vaccine, so must be at least 12 months
• Two doses 90% effective, though can wane over time
• Adverse effects
  • Injection site reaction 20%
  • Rash with 2-5 lesions (1-3%) or generalized within 1 month (3-5%); it is infectious
  • Febrile seizures: MMR + VZV at 12 months has higher risk of febrile seizures
  • Disseminated, including meningitis
• See the Canadian Immunization Guide

Zoster

• Vaccination prevents episodes of herpes zoster (HZ) as well as decreasing post-herpetic neuralgia (PHN)
• Indicated in all people ≥50 years old to reduce risk of zoster and PHN
  • History of VZV or vaccination doesn't matter, everyone should get it
• In Canada, preferentially use Shingrix, as it is more effective than the live vaccine
  • If received Zostavax, wait at least 1 year before giving a booster with Shingrix
  • If recent episode of HZ, wait at least 1 year before vaccinating
• See the Canadian Immunization Guide

	Recombinant	Live Attenuated
Brand Name	Shingrix	Zostavax II
Schedule	2 doses, 2-6 months apart	1 dose
Effectiveness	>90% for HZ and PHN, and persists over time	50-70% for HZ and 70% for PHL, but decreases significantly by 5 years

Antiviral Prophylaxis

• Acyclovir 400 mg p.o. twice daily (though range is 200 mg once daily to 300 mg three ties daily)
• Valacyclovir 500 mg p.o. daily (or 250 mg daily)
• Famciclovir 500 mg p.o. daily