Smallpox & Other Orthopoxvirus-Associated Infections

Infectious Agent

Smallpox is caused by variola virus, genus Orthopoxvirus . Other members of this genus that cause infection in humans are vaccinia virus, monkeypox virus, and cowpox virus. In 1980, the World Health Organization officially declared smallpox to be eradicated.



Person to person, principally respiratory; less commonly through contact with infectious skin lesions or scabs.


Zoonotic transmission followed by person-to-person, principally respiratory; less commonly through contact with infectious skin lesions or scabs. African rodents and primates may harbor the virus and could infect humans, but the reservoir host is unknown.


Vaccinia virus is the live-virus component of contemporary smallpox vaccines. Rarely, social contacts of people recently vaccinated for smallpox develop infections with vaccinia virus when their skin comes into contact with fluid from the inoculation lesion. Zoonotic infections via contact with infected animals with vaccinialike viruses have been reported in Colombia, Brazil, and India.


Contact with infected animals; transmission between humans has not been observed.



Eradicated globally. A single confirmed case of smallpox would almost certainly be the result of an intentional act (bioterrorism) and would be considered an emergency.


Endemic in tropical forested regions of West and Central Africa, notably the Congo Basin. Rodents imported from West Africa were the source of a 2003 outbreak of human monkeypox in the United States. Monkeypox is endemic in the Democratic Republic of the Congo (DRC) and occurs sporadically in neighboring countries (Republic of the Congo, Central African Republic, Sudan). Refugees and immigrants who have recently left DRC may harbor monkeypox virus infection, but reports of this are rare. Short-term travelers to monkeypox-endemic areas would not generally be at risk.


Infections with wild vaccinialike viruses have been reported among cattle and buffalo herders in India and among dairy workers in southern Brazil and Colombia. Travelers who have direct (hands-on) contact with affected bovines may be at risk for acquiring cutaneous infection.


Human infections with cowpox and cowpoxlike viruses have been reported in Europe and the Caucasus (cowpox and Akhmeta virus in Georgia). Travelers who have direct (hands-on) contact with affected bovines, felines, rodents, or captive exotics (zoo animals) may be at risk for cutaneous infection.

Clinical Presentation


Infections present with acute onset of fever >101°F (38.3°C), malaise, head and body aches, and sometimes vomiting. This phase is followed by a rash characterized by firm, deep-seated vesicles or pustules in the same stage of development. Clinically, the most common rash illness likely to be confused with smallpox is varicella (chickenpox).


Clinically similar to smallpox, with a febrile prodrome followed by a widespread vesiculopustular rash involving the palms and soles. One feature distinctive to monkeypox is marked lymphadenopathy.

Vaccinia and Cowpox

Human infections with vaccinia, wild vaccinialike viruses, cowpox, and cowpoxlike viruses are most often self-limited, characterized by localized pustular (and in cowpox, occasionally ulcerative) lesions. Fever and other constitutional symptoms may occur briefly after lesions first appear. Lesions can be painful and can persist for weeks. People who are immunocompromised or who have exfoliative skin conditions (such as eczema or atopic dermatitis) are at higher risk of severe illness or death.


Orthopoxvirus infection is confirmed by PCR or virus isolation. Health care providers can refer to the CDC smallpox website ( for guidance in the application of a clinical algorithm designed to aid in distinguishing orthopoxvirus infections from other disseminated rash illnesses, namely chickenpox.


Mainly supportive, to include hydration, nutritional supplementation, and prevention of secondary infections. Vaccinia and cowpox lesions should remain covered until the scab detaches to diminish chances of spreading virus to other parts of the body or to another person. Health care providers managing orthopoxvirus infection in a patient who is at high risk for severe outcome (such as a patient who is immunocompromised or has an underlying skin condition) or ocular infections should consult with CDC to explore treatment options (770-488-7100). Investigational use of antivirals could be considered.


Smallpox vaccine is not recommended for international travelers. Smallpox vaccination is recommended only for laboratory workers who handle variola virus (the agent of smallpox) or closely related orthopoxviruses and health care and public health officials who would be designated first responders in the event of an intentional release of variola virus. In addition, members of the US military may be required to receive the vaccine.

For other orthopoxvirus infections, avoid contact with rodents and sick or dead animals, including pets and domestic ruminants (cattle, buffalo), and direct contact with ill humans. For more information about monkeypox and other orthopoxviruses, contact the CDC Poxvirus Inquiry Line (404-639-4129).

CDC websites: and


  1. Baxby D, Bennett M, Getty B. Human cowpox 1969-93: a review based on 54 cases. Br J Dermatol. 1994 Nov;131(5):598–607.  [PMID:7999588]
  2. Levine RS, Peterson AT, Yorita KL, Carroll D, Damon IK, Reynolds MG. Ecological niche and geographic distribution of human monkeypox in Africa. PLoS One. 2007;2(1):e176.  [PMID:17268575]
  3. Nakazawa Y, Emerson GL, Carroll DS, Zhao H, Li Y, Reynolds MG, et al. Phylogenetic and ecologic perspectives of a monkeypox outbreak, southern Sudan, 2005. Emerg Infect Dis. 2013 Feb;19(2):237–45.  [PMID:23347770]
  4. Reynolds MG, Emerson GL, Pukuta E, Karhemere S, Muyembe JJ, Bikindou A, et al. Detection of human monkeypox in the Republic of the Congo following intensive community education. Am J Trop Med Hyg. 2013 May;88(5):982–5.  [PMID:23400570]
  5. Trindade GS, Guedes MI, Drumond BP, Mota BE, Abrahao JS, Lobato ZI, et al. Zoonotic vaccinia virus: clinical and immunological characteristics in a naturally infected patient. Clin Infect Dis. 2009 Feb 1;48(3):e37–40.  [PMID:19115976]


Andrea M. McCollum