Lecture 19 Chickenpox + Shingles

Varicella-zoster virus

responsible for chicken pox + shingles
alpha virus

Lifelong latent infection in sensory ganglia neurons

Varicella-zoster vs HSV 1/2

Neural and hematogenous routes are both used during dissemination and pathogenesis for VZV, but not in HSV1/2 (can’t establish viremia in normal ppl, only neurological)

All 3 cause life-long latent infection in neurons of sensory ganglia (sacral/thoracic/dorsal root ganglia + trigeminal ganglia)

Chickenpox clinical name

varicella

shingles clinical name

zoster

Three roots of trigeminal nerve

ophthalmic, maxillary, mandibular

Varicella epidemiology

•Annual incidence of 4 million cases per year in the U.S. before vaccine

•Incidence has declined substantially since vaccine introduction (1995)

Zoster epidemiology

(incidence correlates with aging)

•2.5 cases/1,000 ppl 20-50 years of age

•7.8 cases/1,000 persons >60 years of age

•Incidence continues to rise after age 60

•50% of persons who live to 85 years experience herpes zoster

Varicella Primary Infection Transmission

1. inhalation of respiratory droplets (aerosol transmission)

2. physical contact with infectious vesicles

Pathogenesis

Incubation period from initial infection→ onset of clinical disease is 10-21 days

infection of mucosal epithelial cells of the oropharynx→ infects highly permissive T memory cells found in lymphoid tissues (tonsils)→ Virus-infected T memory cells carry the virus into blood for dissemination (primary viremia)→ Virus-infected T memory cells already programmed for immune surveillance + express skin homing marker = carry virus to skin → Viral skin spread countered by vigorous innate immune responses of epidermal cells→ Replication in epidermal cells→ characteristic rash/vesicles of varicella→ Stronger viremia occurs as virus-infected T cells travel through skin and soft organ tissues (secondary viremia, also has clinical symptoms)→ Viremia + new vesicle formation continue for 3-5 days→  stop due to adaptive immunity (humoral and cellular immunity)→  absorption of vesicular fluid → drying + crusting of lesion

[10-21 day incubation period reflects time needed for virus to overcome vigorous innate immune responses]

Varicella-Zoster Virus Latency

established during primary infection of VZV

•Latent VZV DNA readily detected in human trigeminal ganglia + dorsal root ganglia

•Neurons are primary/exclusive site of virus latency

•Genomes of HSV-1 + VZV detected in the same neuron of a trigeminal ganglion 

Similarities of HSV-1 latency and VZV

Latent VZV genome extrachromosomal episome (non-integrated), possibly in circular/concatameric configuration

-multiple copies of VZV genome per neuron (Less for HSV-1 genomes during latency)

Difference between HSV-1 + VZV latency

•Unlike HSV-1, VZV latency characterized by transcription and translation of multiple genes
>At least 5 ORFs transcribed/translated (IE62 & IE63)
>No homolog to HSV-1 LAT detected during latency [aka no LAT] 

•VZV cannot be induced to reactivate following tissue explant of sensory ganglia

•No asymptomatic shedding of VZV takes place during latency

dermatome

area of skin supplied by sensory neurons that arise from a single sensory ganglion

Herpes Zoster

•Inflammatory changes that occur in sensory ganglion + nerve during VZV reactivation → pain in the corresponding dermatome

•Patients report sensations ranging from mild itching + tingling to severe pain that precedes lesion appearance by 1-5 days (prodrome)

•Vesicles appear in the skin segment innervated by sensory ganglion, they remain unilateral, and do not cross midline
>Thoracic dermatomes involved in 50% of cases
>Cranial nerve dermatomes (trigeminal ganglia) involved in 15% of cases (zoster ophthalmicus, only stays on one side of the face)

Acute phase of herpes zoster 

During acute phase, patients experience dermatomal pain that can be severe (acute neuritis) and described as aching, burning, or stabbing pain

  >headache, photophobia, + malaise, but significant fever is rare
  >CSF is abnormal (pleocytosis and elevated protein) with occasional culture of VZV

VZV/herpes zoster reactivation

VZV reactivation and herpes zoster correlates with aging

VZV reactivation and herpes zoster correlates with dampening of cell-mediated immunity

Antiviral management of VZV

acyclovir

Acyclovir with HSV/VZV thymidine kinase → Acyclovir monophosphate with cellular kinase → acyclovir diphosphate w/ cellular kinase → acyclovir triphosphate [not full, but may ask question on it]

Postherpetic Neuralgia

Most common neurologic complication of herpes zoster, chronic dermatomal pain that persists after cutaneous eruptions of herpes zoster has healed

•Estimated to occur following ~10%-40% of herpes zoster cases

•Incidence correlates directly with patient age with pain persisting more than 1 year in …
>4% of patients younger than 20 years of age
>22% of patients older than 55 years of age
>47% of patients older than 70 years of age

•Within affected dermatome, patients experience variety of sensory abnormalities + neuralgic pain of varying quality/severity

•Microscopic examination of ganglia reveals inflammatory infiltrates often around dying neurons

•Pathogenesis not completely understood
>Involves P/CNS

Varicella Live-Attenuated Vaccine

developed in the 1970s in Japan and approved for use in the United States in 1995 (Varivax)

Live Attenuated Zoster Vaccine

larger-than-normal dose of the varicella vaccine was approved in 2006 (Zostavax) (~70% effectiveness)

Killed (subunit) vaccine [which virus?]

Zoster vaccine consisting of purified VZV glycoprotein E + immune adjuvant approved in 2017 (Shingrix) (~90% effectiveness including postherpetic neuralgia)

•Shingrix requires a second inoculation administered 2-6 months after the first inoculation