Herpes Zoster

Lesia Dropulic Jeffrey Cohen

Laboratory of Infectious

Diseases, NIAID

Varicella (Chickenpox)

Centers for Disease Control and Prevention

Zoster (Shingles)

Centers for Disease Control and Prevention

Zoster is Due to Reactivation of Varicella from the Nervous System

Adapted from Kimberlin and Whitley NEJM 2007

Blood

VZV DNA is Present In Neurons in Ganglia Years After Chickenpox

Wang et al J Virol 2005

Subject No. Neurons No. (%) neurons Median VZV DNA Number Tested positive for VZV copies/positive cell

Ganglia latently infected with VZV

History of Zoster

•  Zoster: Greek for girdle

•  Shingles: Latin (cingere) girdle Partial encircling of the trunk with rash

First Cell Culture of Varicella-Zoster Virus (March 19, 1949)

Thomas Weller in Varicella-Zoster Virus, Cambridge Press 2000

Varicella-Zoster Virus

Straus et al. Ann Intern Med 1988

Epidemiology of Zoster

•  About 99% of adults >40 yo infected with varicella-zoster, thus all older adults at risk

•  About 1 million cases in the US each year •  Rates appear to be increasing •  50% of persons of live to age 85 will develop

zoster, 5% may get a second case

Risk Factors for Zoster

•  Age- the major risk factor for healthy persons (long duration since exposure to virus)

•  Immune compromise- T cell immunity: transplant recipients, leukemia, lymphoma; HIV increases the risk up to 50 fold

•  Age and immune compromise- reduced VZV-specific T cell immunity

Varicella-Zoster Virus: Site of Latency

•  Varicella-zoster virus is latent in dorsal root ganglia (along the spine) or cranial nerve ganglia and reactivates spreading along the nerve to the skin

Dorsal root ganglia with VZV

III, VII cranial nerves

Map of Dermatomes Trigeminal, thoracic, & cervical dermatomes most often affected by zoster

Thoracic Zoster: T1-T2

Cervical Zoster: C5-C6

Dworkin Clin Infect Dis 2007

Zoster Involving the V1 Dermatome of the Trigeminal Ganglia

Vallejo-Garcia Clev Clin 2009

Zoster Symptoms- Rash: Healthy Persons

•  Vesicular rash in a dermatomal pattern that does not cross the midline (dermatome=area of the skin innervated by sensory nerve from one nerve root)

•  Can have a few lesions outside the dermatome(s) •  Duration of rash

New lesions over 5-7 days Papules>vesicles>pustules Crusting over 7-10 days

•  Some patients do not have rash (zoster sine herpete)

Zoster Symptoms- Pain: Healthy Persons

•  Increased sensation 1-5 days before rash: tingling or itching leading to pain (initially difficult to diagnose zoster without rash)

•  Abdominal or chest pain can be confused with appendicitis or heart attack

•  Pain ranges from aching, burning, stabbing, excruciating; continuous or episodic

•  Up to 10% of patients do not have pain (more common in younger patients)

Duration of Pain after Onset of Zoster

Johnson and Rice NEJM 2014

Duration of Pain after Onset of Zoster

Mean age of patients 66 yo Johnson and Rice NEJM 2014

Postherpetic Neuralgia

•  Pain persisting for 90 days (definitions vary) after onset of the rash is termed postherpetic neuralgia (PHN)

•  Pain may persists for months to years •  Pain is due to nerve damage (from skin to spinal cord)

during zoster •  More common in persons >50 years old •  Allodynia (sensation of pain after nonpainful stimuli) •  Paresthesias (burning, tingling) •  Dysesthesias (impaired sensation) •  Continuous neuropathic pain

Harpaz et al MMWR 2008

Impact of Acute Herpes Zoster and Postherpetic Neuralgia on Quality of Life

Risk Factors for Postherpetic Neuralgia

•  Age: - PHN occurs in 25-50% of persons >50 yo - PHN rare in patients <40 yo

•  Severe pain or severe rash at onset of zoster

•  Immune compromise is not a risk factor for PHN

Epidemiology of Postherpetic Neuralgia

•  100,000 to 200,000 cases of PHN per year •  10% of zoster patients have >90 days of

pain •  18% of zoster patients have >30 days of

pain

Harpaz et al MMWR 2009

Rates of Zoster and Postherpetic Neuralgia by Age in the US

50% of persons reaching 85 yo will have zoster

Neurologic Complications of Zoster

•  Bell’s palsy: unilateral facial paralysis (reactivation in the VII cranial nerve)

•  Ramsay-Hunt syndrome: pain and vesicles in the ear, numbness of the anterior tongue, and facial palsy (reactivation in the geniculate ganglion of the VII N)

•  Hearing impairment •  Meningitis, Guillain-Barre, transverse

myelitis •  Stroke or TIAs (vasculitis of cranial

arteries) during zoster, or months later

Gilden et al NEJM 2002

Taguchi J Infect 2011

Ocular Complications of Zoster

Eye disease involving any part of the eye (reactivation in the VI branch trigeminal ganglia):

–  15% of zoster cases involve the eye –  Keratitis, uveitis, retinitis, glaucoma –  If eye involved, important to have

ophthalmology consultation to determine if ocular therapy is needed

Shaikh et al AFP 2002

Other Complications of Zoster

•  Bacterial superinfection

•  Post-herpetic pruritis

•  3% of patients with zoster are hospitalized

•  Transmission of VZV to susceptible children, causing varicella: zoster is ~20% as contagious as varicella

Zoster: Reactivation of Latent VZV from Dorsal Root or Cranial Nerve Ganglia

Viremia in Immunosuppressed Persons

Gilden et al NEJM 2000

Zoster in Persons with Impaired Cellular Immunity

•  New lesion formation continues for up to 2 weeks

•  Healing may require 3 to 4 weeks

•  Disseminated zoster: -Generalized rash -Visceral disease: Pneumonia Hepatitis Encephalitis Dworkin et al CID 2007

HIV patients: •  Verrucous lesions •  Acute retinal necrosis •  Chronic zoster

Stem cell transplant patients •  Reactivation from celiac ganglia

with pancreatitis, abdominal pain •  May be fatal, if delayed diagnosis

Cohen et al. , Fields Virology Lippincott 2007

Zoster Symptoms: Persons with Impaired Cellular Immunity

HIV Patient with Chorioretinitis and Multifocal CNS Vasculitis

Immunology of Zoster

Zoster patients have: •  normal levels of antibody to VZV •  reduced T cell immunity to VZV Zoster is due to reduced cellular immunity

(T cells) specific for VZV

Cell-Mediated Immunity Declines with Age

From Plotkin et al Vaccines 2008; Data from Burke et al Arch Intern Med 1982

Gershon et al. Nature Reviews: Disease Primers 2015

Cell Mediated Immunity to VZV Declines Over Time

Diagnosis of Zoster

•  Usually clinical diagnosis in setting of a dermatomal, unilateral vesicular rash with pain

•  PCR for VZV DNA of skin lesion fluid

(or PCR of cerebrospinal fluid for CNS disease) •  Rash may be confused with herpes simplex

which is more likely to recur often