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

Blood

Adapted from Kimberlin and Whitley NEJM 2007 VZV DNA is Present In Neurons in Ganglia Years After Chickenpox

Ganglia latently infected with VZV

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

Wang et al J Virol 2005 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 III, VII VZV 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

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

Harpaz et al MMWR 2008 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 Rates of Zoster and Postherpetic Neuralgia by Age in the US

Harpaz et al MMWR 2009 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 Taguchi J Infect 2011 • Meningitis, Guillain-Barre, transverse myelitis • Stroke or TIAs (vasculitis of cranial arteries) during zoster, or months later

Gilden et al NEJM 2002 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 Shaikh et al AFP 2002 – If eye involved, important to have ophthalmology consultation to determine if ocular therapy is needed 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 Zoster Symptoms: Persons with Impaired Cellular Immunity

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

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 Cell Mediated Immunity to VZV Declines Over Time

Gershon et al. Nature Reviews: Disease Primers 2015 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