Orthopoxvirus is a genus of large, brick-shaped, double-stranded DNA viruses. Several clinically relevant species exist, including variola virus (the cause of smallpox), monkeypox virus, vaccinia virus, and cowpox virus. Transmission varies depending on the species but can be through contact with infected bodily secretions, skin lesions, or fomites. Smallpox is the most severe disease, presenting with constitutional symptoms and a diffuse, well-circumscribed maculopapular rash that progresses through an evolutionary process that results in scarring. Smallpox is associated with a high mortality rate. Monkeypox presents similarly but has lower mortality and is associated with lymphadenopathy. Vaccinia and cowpox produce milder disease with localized lesions acquired from direct skin-to-skin contact. These infections are diagnosed with the aid of PCR, serology, viral culture, and/or electron microscopy. There are no known treatments for these diseases, and management is generally supportive. Vaccination has led to the eradication of smallpox.

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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 orthopoxviruses

  • Largest and most complex viruses
  • Taxonomy:
    • Family: Poxviridae
    • Genus: Orthopoxvirus
  • DNA virus:
    • Double-stranded
    • Linear
  • Structure:
    • Nucleosome (instead of a capsid)
    • Proteolipid envelope
    • Oval or brick-shaped

Clinically relevant species

Notable orthopoxviruses that infect humans include:

  • Variola virus (smallpox)
  • Monkeypox virus
  • Vaccinia virus (used in the smallpox vaccine)
  • Cowpox virus


  • Orthopoxvirus infections are rare events.
  • Smallpox:
    • The last case of naturally occurring smallpox was in the 1970s.
    • Considered eradicated in 1980
    • Mortality had been as high as 25%–30%.
  • Monkeypox:
    • Sporadic epidemics have occurred in Africa
    • Mortality can be as high as 17%.
  • Cowpox:
    • < 150 cases reported
    • Most cases occur in individuals < 18 years of age



Table: Transmission of Orthopoxviridae
  • Respiratory aerosols
  • Contact with lesions
  • Fomites
MonkeypoxUnknown (maybe small rodents)
  • Respiratory aerosols
  • Contact with infected bodily fluids
  • Contact with lesions
  • Fomites
VacciniaUnknownSkin-to-skin contact (often from those recently vaccinated)
CowpoxRodentsDirect contact with infected animals (often cows)

Host risk factors

More severe disease tends to occur in:

  • Immunosuppressed patients
  • Certain skin conditions (e.g., eczema)

Viral replication cycle

  • Unlike many other viruses:
    • Viral replication is cytoplasmic.
    • No cell receptor or specific protein is targeted by the virus to gain entry into the cell.
  • Entry into a host cell is mediated by endocytosis → viral core is released into the cytoplasm
  • Intermediate genes are expressed → DNA replication
  • Progeny virions are assembled → mature virions are released from the cell upon cellular lysis


  • Smallpox:
    • Inhaled secretions and virus → entry into the respiratory tract
    • Viral replication → spread to regional lymphatic tissue → replication → viremia
    • Dissemination to lymphoid organs → secondary viremia → symptoms
    • Virus localizes in dermal blood vessels → endothelial swelling
    • Infection of epidermal cells → cutaneous manifestations
  • Vaccinia: virus replicates at the site of inoculation → localized cutaneous manifestations

Clinical Presentation

The following table summarizes notable clinical diseases caused by orthopoxviruses:

Table: Clinical diseases caused by orthopoxviruses
DiseaseIncubationConstitutional symptomsRash
Smallpox7–19 days
  • Fever
  • Malaise
  • Headache
  • Backache
  • Starts on mucous membranes → cutaneous lesions
  • Centrifugal spread
  • Can involve palms and soles
  • Papules → vesicles → pustules → crusts
  • Deep-seated
  • Firm
  • Round
  • Well-circumscribed
  • Results in scarring
Monkeypox5–17 days
  • Fever
  • Malaise
  • Headache
  • Myalgias
  • Lymphadenopathy
  • Similar to smallpox
  • Lesions occur in crops
Vaccinia2–4 days
  • Fever
  • Lymphadenopathy
  • Localized lesions
  • Can occur from vaccination
  • Can disseminate (severe)
Cowpox2–4 days
  • Fever
  • Lymphadenopathy
  • Localized lesions
  • Similar to vaccinia

Diagnosis and Management


The diagnosis can be supported with the following testing:

  • PCR for viral DNA from lesion specimens
  • Serology (not specific for individual viruses)
  • Viral culture
  • Electron microscopy of lesion specimens


  • There is no known treatment for these diseases.
  • Management is supportive.
  • Potential antiviral treatments:
    • Tecovirimat
      • FDA-approved for the treatment of smallpox infection
      • Effectiveness is unknown
    • Cidofovir 
      • Has in vitro activity against orthopoxviruses
      • No clinical data in humans


The smallpox vaccine is not only responsible for the eradication of smallpox but also appears to:

  • Confer protection against some other orthopoxviruses, such as monkeypox
  • Blunt the clinical course of smallpox if given after exposure

Differential Diagnosis

  • Chickenpox: primary infection caused by the varicella–zoster virus. The typical clinical presentation includes prodromal symptoms, an oral enanthem, and a generalized, intensely pruritic vesicular rash. These lesions appear in crops and will be in varying stages of evolution. The diagnosis is primarily clinical. Management is supportive, though antiviral therapy can be used in certain patient populations. 
  • Molluscum contagiosum (MC): viral infection limited to the epidermis. Molluscum contagiosum is mainly 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. Diagnosis is usually clinical. This infection is highly transmissible, and patient education is key in management. Cryotherapy with liquid nitrogen is the 1st-line therapy in patients who require it.
  • Hand, foot, and mouth disease: mild, self-limited disease caused by coxsackie group A virus. Patients may have fever, mouth pain, and pharyngitis. An oral enanthem may occur. Skin lesions can be macular, papular, or vesicular and often include the palms, soles, and buttocks. Diagnosis is usually clinical. Management is supportive.
  • Bacillary angiomatosis: condition seen in HIV/AIDs patients that results in angiomatous skin lesions due to Bartonella infection. The skin lesions are usually protuberant, red papules or nodules that are friable. Painful osteolytic bone lesions can also occur. Diagnosis can be made with biopsy, cultures, and PCR. Management includes antibiotics and antiretroviral therapy for HIV.


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