Varicella-zoster virus

Background

Microbiology

dsDNA virus in the Alphaherpesvirus 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

Normal host

Primary varicella
- Simple VZV infection, start ASAP (<72 hours) after onset of rash if going to treat; or, don't treat
- If higher risk or severe sequelae, more likely to treat
- 5 days in normal host
Zoster
- Start treatment within 72 hours to reduce new lesions (doesn't affect PHN)

Immunocompromised host

Primary varicella: start with IV acyclovir, then step down to oral valacyclovir
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 antiviral with prednisone

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 everyone, 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
- 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
- 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