Herpes Zoster (Shingles)

Herpes zoster (also known as shingles) is a viral, reactivation infection caused by the varicella-zoster virus (VZV). Latent VZV remains dormant in the dorsal root ganglion after the primary infection phase of varicella (chickenpox). Age, stress, or immunocompromised states can trigger the reactivation of the virus. Herpes zoster clinically presents in a single, dermatomal distribution as a painful, unilateral rash. The diagnosis is primarily made from the history and physical examination. However, laboratory testing (such as PCR) can be performed if the diagnosis is unclear. Management includes antiviral therapy and symptomatic treatment.

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Overview

Definition

Herpes zoster (also known as shingles) is a viral, reactivation infection caused by the varicella-zoster virus (VZV) manifesting as a unilateral, dermatomal, painful, vesicular eruption.

Epidemiology

  • Annual incidence in the United States: 1.2 million people
  • Approximately 30% of the population will experience herpes zoster during their lifetime.
  • More common in:
    • Older age
    • Immunocompromised
    • Women
  • Only individuals previously affected with chickenpox

Etiology

Causative organism: VZV

  • Also known as human herpesvirus 3
  • Enveloped, double-stranded DNA virus
  • Belongs to the herpesviridae family

Transmission: 

  • Direct contact with blisters
  • Respiratory droplets (from individuals with disseminated disease)
  • Causes chickenpox in exposed individuals without immunity
Single varicella zoster virus herpes zoster

Transmission electron microscopic image showing the single varicella-zoster virus (VZV), also known as human herpesvirus 3, which causes chickenpox

Image: “Ultrastructural features exhibited by a single varicella-zoster virus (VZV), also known as human herpesvirus 3 (HHV-3), the cause of chickenpox.” by CDC. License: Public Domain

Risk factors

  • Immunocompromised patient:
    • Transplant
    • Immunosuppressive therapy
    • Human immunodeficiency virus (HIV)
    • Autoimmune disorder
  • Active or chronic illness
  • Physical trauma
  • Family history
  • Age
  • Stress

Pathophysiology

Varicella-zoster virus causes 2 distinct syndromes:

Primary infection (chickenpox): 

  • Transmitted through aerosol → targets mucoepithelial cells
  • Viremia → contagious, febrile illness occurs
  • After resolution, viral particles remain in the dorsal root ganglia or other sensory ganglia.
  • Host immune system suppresses replication of the virus → lays dormant for years to decades (latency period)

Secondary infection (shingles):

  • Host immune system fails to contain the virus → VZV reactivates
  • Spreads down the sensory nerve → skin → rash
  • Inflammatory response in the sensory ganglia: 
    • Involves plasma cells and T lymphocytes
    • Can result in neuronal damage → neuropathic pain
Pathogenesis of varicella-zoster virus Herpes zoster

Pathogenesis of varicella-zoster virus (VZV):
The infection replicates viruses in mucoepithelial cells then spreads throughout the reticuloendothelial (RE) system and bloodstream, causing flu-like symptoms and chickenpox. After resolution of the primary infection, a latency period occurs and the virus remains dormant in the dorsal root ganglia. Reactivation of the infection results in shingles.

Image by Lecturio.

Clinical Presentation and Complications

Common presentation

Acute neuritis: 

  • Most common symptom (often precedes the rash)
  • Neuropathic pain:
    • Burning
    • Stabbing
    • Throbbing
    • Constant or intermittent
  • Hypersensitivity
  • Allodynia

Rash:

  • Unilateral
  • Dermatomal distribution
  • Initially appears as erythematous papules 
  • Progresses into bullae or groups of vesicles
  • Becomes pustular or hemorrhagic within 3–4 days
  • Lesions start to crust in 7–10 days (no longer infectious). 
  • Scarring and hypo- or hyperpigmentation may occur.

Systemic symptoms (< 20% of cases):

  • Fever
  • Headache
  • Malaise
  • Fatigue

Disseminated herpes zoster

The following are severe presentations, which may occur in immunocompromised patients:

Cutaneous dissemination:

  • Vesicular lesions are in a generalized distribution.
  • May be accompanied by visceral involvement
  • Associated with ↑ risk of transmission

Visceral organ involvement:

  • Pneumonia
  • Hepatitis
  • Encephalitis
  • May occur with or without a rash

Other presentations

Herpes zoster ophthalmicus:

  • Involves the ophthalmic division of the 5th cranial nerve
  • Symptoms:
    • Unilateral pain
    • Hypesthesia
    • Headache
    • Malaise
    • Fever
  • Progression to: 
    • Conjunctivitis
    • Uveitis
    • Episcleritis
    • Keratitis
    • Vision loss

Ramsay Hunt syndrome (herpes zoster oticus):

  • Involves the geniculate ganglion and 8th cranial nerve
  • Triad of symptoms: 
    • Ipsilateral facial paralysis
    • Ear pain
    • Vesicles in the auditory canal or auricle
  • Additional features: 
    • Dysgeusia
    • Hearing abnormalities
    • Lacrimation
Herpes zoster ophthalmicus

Herpes zoster ophthalmicus with involvement of the left eye

Image: “External photograph showing herpes zoster ophthalmicus” by Sudharshan S et al. License: CC BY 2.0

Complications

Postherpetic neuralgia: 

  • Most common complication 
  • Persistence of significant pain for 90 days after rash development
  • Other symptoms: 
    • Numbness
    • Dysesthesias
    • Pruritus
    • Allodynia

Acute retinal necrosis: 

  • Features: 
    • Acute iridocyclitis
    • Vitritis 
    • Necrotizing retinitis
    • Occlusive retinal vasculitis
  • Complications: 
    • Rapid loss of vision 
    • Retinal detachment

Other complications: 

  • Secondary bacterial infections of the skin
  • Aseptic meningitis
  • Peripheral motor neuropathy
  • Guillain-Barré syndrome
  • Stroke syndromes

Diagnosis

Shingles diagnosis is primarily based on clinical presentation. In patients with atypical presentations, the following can be used:

  • PCR:
    • Utilizes a sample from vesicular lesions to detect VZV DNA
    • Preferred method of testing due to high sensitivity
    • More rapid than other methods of testing
    • Can be used in all stages of the disease 
  • Direct fluorescent antibody (DFA):
    • Tests lesion scrapings
    • Limited sensitivity 
    • Cannot be conducted on crusted lesions
  • Tzanck smear:
    • Lowest sensitivity and specificity
    • Confirms a herpetic lesion, but does not differentiate herpes viruses
    • Shows multinucleated giant cells
Tzanck smear Herpes zoster

Tzanck smear with 3 multinucleated giant cells

Image: “Positive Tzanck test, showing three multinucleated giant cells in center” by NIAID. License: Public Domain

Management and Prevention

Antiviral therapy

  • Antiviral therapy aims to:
    • ↓ Severity and duration of pain
    • Aid in rapid healing of the lesions
    • Prevent the formation of new lesions
    • ↓ Viral shedding
    • Prevent complications 
  • Options:
    • Acyclovir
    • Valacyclovir
    • Famciclovir
  • Treatment should be administered:
    •  ≤ 72 hours after symptom onset
    • During the eruption of new lesions
    • In all immunocompromised patients

Supportive care

  • Analgesics:
    • Acetaminophen 
    • NSAID
    • Tricyclic antidepressants (TCAs) 
    • Gabapentinoids: 
      • Gabapentin
      • Pregabalin
  • Corticosteroids (e.g., prednisone) for severe pain or neurologic complications
  • Antibiotics: 
    • For suspected secondary bacterial infection
    • Provide staphylococcal and streptococcal coverage

Management of complicated disease

  • Postherpetic neuralgia:
    • TCAs and gabapentinoids are the 1st-line therapy
    • Topical drugs (capsaicin) to control mild-to-moderate pain
    • Opioids or intrathecal glucocorticoids only if other measures fail
  • Herpes zoster ophthalmicus:
    • Immunocompetent patients: oral antivirals
    • Immunocompromised patients: IV acyclovir 
    • Strongly consider early ophthalmologic referral.
  • Acute retinal necrosis:
    • Initial: IV acyclovir 
    • Followed by: oral valacyclovir 
    • ↓ Visual acuity: glucocorticoids
  • Ramsay Hunt syndrome: 
    • Oral valacyclovir and prednisone
    • Severe symptoms: IV antiviral therapy

Prevention

Measures to prevent transmission:

  • Cover the rash.
  • Avoid contact with:
    • Nonimmune pregnant women
    • Premature infants
    • Immunocompromised patients

Vaccines:

  • Indicated in adults ≥ 50 years of age
  • Types of vaccines:
    • Zoster vaccine live (live-attenuated vaccine):
      • No longer available in the United States, but used in other countries 
      • Contraindicated in immunocompromised patients
    • Recombinant zoster vaccine (recombinant glycoprotein E vaccine)

Differential Diagnosis

  • Herpes simplex: caused by the herpes simplex virus and spreads via direct contact with herpetic lesions or mucosal surfaces. The primary infection often presents with systemic, prodromal symptoms followed by dysuria, painful lymphadenopathy, and clusters of painful, fluid-filled vesicles on an erythematous base. Diagnosis is confirmed with laboratory testing, such as PCR and DFA. Treatment includes antiviral therapy.
  • Cellulitis: a common bacterial skin infection affecting the deeper layers of the dermis and subcutaneous tissue. The condition is most commonly caused by Staphylococcus aureus and Staphylococcus pyogenes. Cellulitis presents as an erythematous, edematous area, which is warm and tender to the touch. Diagnosis is clinical and management involves antibiotics tailored to the suspected organism.
  • Folliculitis: inflammation of the hair follicles caused by a bacterial or fungal infection. Patients may present with itchy, sore, erythematous papules/pustules around the hair follicles. The diagnosis is clinical. Management is usually supportive, but topical or oral antibiotic therapy may be required for severe cases.
  • Allergic contact dermatitis: inflammation of the skin due to contact with an allergen. Patients commonly present with a local, red, pruritic rash and blistering may occur. Diagnosis is made through history and examination, but skin patch testing can be used to determine a trigger. Management includes topical corticosteroids and allergen avoidance.
  • Molluscum contagiosum: a viral skin infection caused by a poxvirus typically seen in children < 5 years of age. Lesions are grouped, flesh-colored, dome-shaped papules with central umbilication. The disease is mild in immunocompetent patients and self-resolves within months. An immunocompromised patient may present with extensive lesions and systemic disease requiring treatment. The diagnosis is clinical. Cryotherapy with liquid nitrogen is the 1st-line in patients requiring therapy.

References

  1. Albrecht, M.A., and Levin, M.J. (2021). Epidemiology, clinical manifestations, and diagnosis of herpes zoster. In, Mitty, J. (Ed.), UpToDate. Retrieved April 18, 2021, from https://www.uptodate.com/contents/epidemiology-clinical-manifestations-and-diagnosis-of-herpes-zoster
  2. Albrecht, M.A. (2020). Diagnosis of varicella zoster virus infection. In Mitty, J. (Ed.), UpToDate. Retrieved April 18, 2021, from https://www.uptodate.com/contents/diagnosis-of-varicella-zoster-virus-infection
  3. Albrecht, M.A. (2020). Treatment of herpes zoster in the immunocompetent host. In Mitty, J. (Ed.), UpToDate. Retrieved April 18, 2021, from https://www.uptodate.com/contents/treatment-of-herpes-zoster-in-the-immunocompetent-host
  4. Albrecht, M.A., and Levin, M.J. (2020). Vaccination for the prevention of shingles (herpes zoster). In Mitty, J. (Ed.), UpToDate. Retrieved April 18, 2021, from https://www.uptodate.com/contents/vaccination-for-the-prevention-of-shingles-herpes-zoster
  5. Janniger, C.J., and Eastern, J.S. (2021). Herpes zoster. In Elston, D.M. (Ed.), Medscape. Retrieved April 18, 2021, from https://emedicine.medscape.com/article/1132465-overview#a4
  6. Center for Disease Control and Prevention (2019). Shingles (herpes zoster). Retrieved April 18, 2021, from https://www.cdc.gov/shingles/hcp/diagnosis-testing.html
  7. Kaye, K.M. (2019). Herpes zoster. [online] MSD Manual Professional Version. Retrieved April 18, 2021, from https://www.msdmanuals.com/professional/infectious-diseases/herpesviruses/herpes-zoster
  8. Nair, P.A., and Patel, B.C. (2021). Herpes zoster. [online] StatPearls. Retrieved April 18, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK441824/

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