Varicella-Zoster Virus/Chickenpox

Varicella-zoster virus (VZV) is a linear, double-stranded DNA virus in the Herpesviridae family. Varicella-zoster infections are highly contagious and transmitted through aerosolized respiratory droplets or contact with infected skin lesions. Chickenpox is the primary infection and occurs most commonly in children. The typical clinical presentation includes prodromal symptoms and a generalized, intensely pruritic vesicular rash. Shingles (also known as herpes zoster) is more common in adults and occurs due to the reactivation of VZV. The diagnosis is primarily clinical. Management is supportive, although antiviral therapy can be used in certain patient populations. Complications can include secondary bacterial infections, encephalitis, or pneumonia. Varicella-zoster vaccine is recommended as a preventive measure in early childhood.

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Classification

DNA virus classification flowchart

Identification of DNA viruses:
Viruses can be classified in many ways. Most viruses, however, will have a genome formed by either DNA or RNA. Viruses with a DNA genome can be further characterized as single or double stranded. “Enveloped” viruses are covered by a thin coat of cell membrane, which is usually taken from the host cell. If the coat is absent, however, the viruses are called “naked” viruses. Some enveloped viruses translate DNA into RNA before incorporating into the genome of the host cell.

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General Characteristics and Epidemiology

Basic features of varicella-zoster virus (VZV)

  • Also known as human herpesvirus 3
  • Taxonomy:
    • Family: Herpesviridae
    • Subfamily: Alphaherpesvirinae
    • Genus: Varicellovirus
  • DNA virus:
    • Linear
    • Double stranded
  • Structural elements:
    • Core (genetic material)
    • Icosahedral protein capsid
    • Tegument (viral proteins and enzymes) 
    • Lipid envelope and glycoprotein spikes
Single varicella zoster virus herpes zoster

Transmission electron microscopic image showing a 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

Associated diseases

Varicella-zoster virus causes 2 distinct syndromes:

  • Chickenpox
  • Shingles (herpes zoster)

Epidemiology

Chickenpox:

  • Prior to routine vaccine use:
    • > 95% of people infected by the age of 20 years
    • Annual incidence in the United States: 4 million cases
    • Approximately 11,000 hospital admissions
    • Approximately 100 deaths
  • Since the vaccine:
    • Decrease in incidence by 90%
    • Substantial decrease in hospitalization and deaths

Shingles:

  • Annual incidence in the United States: 1.2 million cases
  • Approximately 30% of the population will experience herpes zoster during their lifetime.
  • Occurs only in individuals previously affected with chickenpox

Pathogenesis

Reservoir

Humans are the only reservoir for VZV.

Transmission

Infections are highly contagious and the virus may be transmitted through:

  • Inhalation of aerosolized respiratory droplets 
  • Direct contact with the vesicle fluid from skin lesions

Host risk factors

Individuals at higher risk for severe disease and complications:

  • Pregnant women
  • Age extremes:
    • Infants
    • Elderly
  • Immunocompromised patients:
    • HIV/AIDS
    • Organ transplantation
    • Chemotherapy
    • Chronic steroids

Viral replication cycle

  • Virus attaches to receptors on host cells → endocytosis
  • Fuses with the plasma membrane → core is released into the cell’s cytoplasm
  • Moves to nuclear pores → DNA released into the nucleus
  • Viral transcription and replication occurs → assembly
  • Budding from nuclear membrane → provides primary (temporary) envelopment
  • Continued virion assembly and maturation → secondary envelopment → released from the cell

Pathophysiology

Primary infection (chickenpox): 

  • Transmitted through aerosols → targets mucoepithelial cells → replication
  • Viremia → contagious and 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
  • An 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):
Initially, the infection replicates viruses in mucoepithelial cells. The infection 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.

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Pathology

The histology of herpes infections is distinctive.

  • Gross: multiple vesicles (blisters) in clusters showing a snakelike distribution (Gr. herpēs, “to creep”) 
  • Microscopic:
    • Low-power view: intraepidermal blisters (vesicles)
    • Key histologic features: 
      • Acantholysis (loss of intercellular connections) 
      • Solitary keratinocytes within the blister cavity
      • Nuclear changes in keratinocytes: multinucleation, large and pink to purple glassy nuclear inclusions (Cowdry type A inclusions), margination of the nuclear chromatin
      • Intranuclear inclusions consist of viral replication proteins and virions at various stages of assembly that push the host cell chromatin out to the edges of the nucleus. 
      • Multinucleated syncytial cells result from the ability of the herpes virus to promote cell fusion.
      • Vacuolated cytoplasm with swelling (known as ballooning)
      • Inflammatory infiltrates: mixed, predominantly neutrophils and lymphocytes, often with scattered eosinophils

Clinical Presentation

Chickenpox

Chickenpox is caused by a primary infection with VZV and has an incubation period of 10‒21 days after exposure.

  • Prodrome (more common in adolescents and adults):
    • Fever
    • Malaise
    • Pharyngitis
    • Loss of appetite
    • Headache
  • Enanthem:
    • May precede exanthem
    • Small shallow ulcers
    • Can be pruritic or painful
  • Exanthem:
    • Intensely pruritic
    • Evolution: 
      • Small macules → papules → vesicles on red base (“dew drop on a rose petal”)
      • Become pustular → crusted
      • Appear in crops over the course of a few days → lesions will be in different stages of evolution
    • Distribution:
      • Generalized
      • May include the palms and soles

Shingles

Shingles is a reactivation infection that can occur with increasing age or stress and in immunocompromised individuals.

  • Acute neuritis: 
    • Most common symptom (often precedes the rash)
    • Neuropathic pain and hypersensitivity
  • Rash:
    • Unilateral
    • Dermatomal distribution
    • Progression:
      • Erythematous papules → bullae or groups of vesicles 
      • Becomes pustular or hemorrhagic → crust formation 
  • Systemic symptoms (< 20% of cases):
    • Fever
    • Headache
    • Malaise
    • Fatigue

Diagnosis and Management

Diagnosis

The diagnosis of chickenpox is most often clinical. The following tests may be used to diagnose patients with atypical presentations:

  • PCR:
    • A sample from vesicular lesions is used to detect VZV DNA.
    • Most sensitive method
  • Direct fluorescent antibody (DFA) test:
    • To test lesion scrapings
    • Limited sensitivity 
    • Cannot be conducted on crusted lesions
  • Serology
    • To detect IgM or IgG antibodies to VZV
    • Less sensitive than PCR
  • Tzanck smear:
    • Lowest sensitivity and specificity
    • Can confirm a herpetic lesion but cannot differentiate herpes viruses
    • Shows multinucleate giant cells

Management (includes)

Supportive care:

  • Pruritus management:
    • Oatmeal baths
    • Calamine lotion
    • Antihistamines
  • Antipyretics:
    • Acetaminophen
    • Avoid aspirin in children.
  • Avoid scratching skin lesions to prevent:
    • Secondary bacterial infections
    • Permanent scarring

Antiviral therapy:

  • Recommended for patients at risk for severe complications: 
    • Unvaccinated adolescents
    • Children on chronic salicylate therapy
    • Unvaccinated or vaccinated adults
    • Pregnant women
    • Immunocompromised patients
  • Options:
    • Acyclovir
    • Valacyclovir
    • Famciclovir
  • Administer within 24 hours of rash onset.

Prevention

  • Live attenuated vaccine:
    • ↓ Risk of disease by 80% and risk of severe disease by > 99%
    • 2-dose schedule for children:
      • Start at 12‒15 months of age
      • Booster at 4‒6 years of age
    • Contraindications:
      • Immunocompromised patients
      • Pregnant women
  • Infection-control measures for hospitalized patients:
    • Contact and airborne precautions (negative air-flow rooms)
    • Only healthcare workers with immunity should care for affected patients.

Complications (include)

Secondary bacterial skin infections:

  • Often caused by Staphylococcus and Streptococcus spp.
  • Can progress to necrotizing fasciitis or toxic shock syndrome

Neurologic complications:

  • Encephalitis
  • Acute cerebellar ataxia
  • Transverse myelitis

Reye syndrome:

  • Uncommon due to the avoidance of aspirin in children
  • Presents with:
    • Nausea and vomiting
    • Headache
    • Altered mental status

Varicella congenital syndrome (congenital TORCH infection):

  • Intrauterine growth restriction
  • Scarring skin lesions
  • Eye defects: 
    • Cataracts
    • Chorioretinitis
    • Microphthalmus
  • Shortened limbs
  • Neurologic defects:
    • Brain cortical atrophy
    • Seizures
    • Intellectual disability

Other complications:

  • Dehydration
  • Pneumonia
  • Hepatitis
  • Myocarditis
  • Hemorrhagic complications

Comparison of Herpesviruses

The table below compares the 9 herpesviruses considered endemic in humans. There are 115 different total known species of herpesviruses that are grouped into 3 families: 

  • Alpha (infect epithelial cells and produce latent infection in post-mitotic neurons)
  • Beta (infect and produce latent infection in several cell types)
  • Gamma (produce latent infection mainly in lymphoid cells)
Table: Comparison of the 9 herpesviruses considered endemic in humans
HHVCommon namePrimary target cellsLatency siteClinical presentation*
1
(alpha group)
HSV-1 Mucoepithelial cells Dorsal root ganglia
  • Gingivostomatitis
  • Keratitis
  • Herpetic whitlow
  • Meningitis
  • Hepatitis
  • Esophagitis
  • Pneumonitis
2
(alpha group)
HSV-2
  • Genital herpes
  • Meningitis
  • Proctitis
3
(alpha group)
VZV
  • Chickenpox
  • Herpes zoster
4
(gamma group)
EBV
  • Epithelial cells
  • B cells
  • Memory B cells
    • Infectious mononucleosis
    • Hodgkin lymphoma
    • Burkitt lymphoma
    • Oral hairy leukoplakia
    • EBV-associated gastric cancer
    5
    (beta group)
    CMV
    • Monocytes
    • Lymphocytes
    • Epithelial cells
    Hematopoietic progenitor cells in bone marrow
    • CMV mononucleosis
    • CMV retinitis
    • CMV colitis
    • CMV encephalitis
    6A, 6B
    (beta group)
    HHV-6 T cells Monocytes Roseola
    7
    (beta group)
    HHV-7 T cells
    8
    (gamma group)
    KSHV
    • Lymphocytes
    • Epithelial cells
    B cellsKaposi sarcoma
    * Bold in “clinical presentation” column: AIDS-defining illnesses
    CMV: cytomegalovirus
    EBV: Epstein-Barr virus
    HHV: human herpesvirus
    HSV: herpes simplex virus
    KSHV: Kaposi sarcoma-associated herpesvirus
    VZV: varicella-zoster virus

    Differential Diagnosis

    • Acute or chronic urticaria: a reaction pattern representing cutaneous mast cell degranulation, resulting in the release of histamine and other vasoactive substances. Patients with acute or chronic urticaria will have erythematous wheals, edema, and severe pruritus. Diagnosis is clinical and supported with allergy testing. Management includes antihistamines and avoidance of triggers.
    • Hand, foot, and mouth disease: an infection caused by coxsackievirus. Patients may present with fever, oral vesicular lesions, and skin lesions on the hands and feet. Hand, foot, and mouth disease may be accompanied by fever and pharyngitis. Diagnosis is usually clinical, and the management is supportive.
    • Stevens-Johnson syndrome: a cutaneous, immune-mediated hypersensitivity reaction commonly triggered by medications, including antiepileptic drugs and antibiotics. Patients may present with fever, pharyngitis, and fatigue. A macular rash will occur and progress to bullae formation and desquamation. Diagnosis is clinical, and withdrawal of the offending agent is necessary. Patients require hospitalization for supportive therapy and monitoring for superinfection.
    • Kawasaki disease: necrotizing vasculitis of medium-sized vessels. Children often present with fever, erythema of the oral mucous membranes (“strawberry tongue”), and lymphadenopathy. Patients can also have a macular skin rash with desquamation on the hands, feet, and genital area. Diagnosis is clinical and supported with diagnostic criteria. Management is supportive and may include IV immunoglobulins and aspirin.
    • Impetigo: a superficial bacterial infection caused by S. aureus and S. pyogenes. Children may present with papules or vesicles that eventually form “honey-colored” crusts. The diagnosis is clinical and the management includes topical or systemic antibiotics.
    • Measles: a viral infection caused by the measles virus. Patients may present with a prodrome of fever followed by a rash. Unlike chickenpox, measles is associated with cough, conjunctivitis, and mucosal lesions (Koplik’s spots). Diagnosis is clinical and confirmed based on serology or PCR. Management is supportive.
    • Rubella: a viral infection caused by the rubella virus. Patients present with constitutional symptoms and a fine, macular viral exanthem that affects the face and spreads to the trunk and limbs. The rash is associated with red papules that are seen on the soft palate. The papules are not vesicular, unlike those seen in chickenpox. Diagnosis is clinical and supported based on serology or PCR. Management is supportive.

    References

    1. CDC. (2021). Chickenpox (Varicella). Retrieved May 19, 2021, from https://www.cdc.gov/chickenpox/hcp/index.html
    2. Albrecht, M.A. (2019). Epidemiology of varicella-zoster virus infection: Chickenpox. UpToDate. Retrieved May 18, 2021, from https://www.uptodate.com/contents/epidemiology-of-varicella-zoster-virus-infection-chickenpox
    3. Albrecht, M.A. (2019). Clinical features of varicella-zoster virus infection: Chickenpox. UpToDate. Retrieved May 21, 2021, from https://www.uptodate.com/contents/clinical-features-of-varicella-zoster-virus-infection-chickenpox
    4. Albrecht, M.A. (2020). Treatment of varicella (chickenpox) infection. UpToDate. Retrieved May 21, 2021, from https://www.uptodate.com/contents/clinical-features-of-varicella-zoster-virus-infection-chickenpox
    5. Albrecht, M.A. (2021). Vaccination for the prevention of chickenpox (primary varicella infection). UpToDate. Retrieved May 18, 2021, from https://www.uptodate.com/contents/vaccination-for-the-prevention-of-chickenpox-primary-varicella-infection
    6. Kaye, K.M. (2019). Chickenpox. [online] MSD Manual Professional Version. Retrieved May 21, 2021, from https://www.msdmanuals.com/professional/infectious-diseases/herpesviruses/chickenpox
    7. Ayoade, F., Kuman, S. (2020). Varicella zoster. [online] StatPearls. Retrieved May 21, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK448191/
    8. Anderson, W.E. (2019). Varicella-zoster virus (VZV). Medscape. Retrieved May 21, 2021, from https://emedicine.medscape.com/article/231927-overview

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