What is Smallpox?

Smallpox is an acute contagious viral disease that has a relatively high fatality rate in immunologically naive populations. It is caused by variola virus, which is a member of a larger pox family of viruses. Smallpox can manifest itself in two clinical forms (variola major and variola minor) and it can be transmitted from person to person. There is no specific treatment for this disease other than the management of symptoms.

It is believed that smallpox originated 10 thousand years B.C. in Africa and subsequently spread to India and Egypt. Due to its high mortality rate, outbreaks of this disease had a significant impact on the course of history. During the twentieth century alone, smallpox is estimated to have caused over 500 million human deaths around the world.

The term “smallpox” was initially introduced in Europe in the 15th century in order to distingusih variola from the “great pox” (which was a historic name for syphilis). The disease is also known by the Latin names “Variola” or “Variola vera”, derived from Latin words varius (“stained”) or varus (“mark on the skin”). The word poc or pocca – a bag or pouch – describes an exanthematous disease, i.e. a disease accompanied by skin eruption.

Pathogenesis of the disease

The inhalation of virus initiates foci of mucosal infection in the upper airway without causing symptoms or apparent lesions. According to the mousepox model, replication at the point of entry is followed by infection of mononuclear phagocytic cells in regional lymph nodes, with possible further spread through the bloodstream to similar cells in the liver, spleen and other tissues.

After reaching the skin, the virus spreads in the middle and basal layers, causing expanding zones of necrosis that form vesicles. In the nonkeratinized squamous epithelium of the oropharynx, the same process is responsible for the formation of ulcerated lesions.

Pustules with surrounding edema and erythema are produced as a result of increased permeability of local blood vessels and the subsequent infiltration of neutrophils, lymphocytes and macrophages. Cell-mediated immune response is a prerequisite for lesion resolution.

Two concepts are used to explain the clinical manifestations of most forms of smallpox. First, the ability of host responses to limit viral replication during the incubation period is in direct correlation with disease severity. Second, once viral dissemination has occurred, manifestations of severe illness (including hypotension and coagulopathy) arise as a result of host inflammatory responses.

Differences in host responses are therefore responsible for a spectrum of disease, ranging from mild illness with a handful or no lesions in persons with partial immunity, to extremely fatal hemorrhagic disease when failure to control replication leads to high viremia, coagulopathy and shock. Ordinary smallpox can be found between those two extreme scenarios.

Establishing a diagnosis

In December 1979, a scientific commission concluded that smallpox had been globally eradicated and the World Health Assembly endorsed its findings in 1980. Nevertheless, a future outbreak of smallpox due to the release of variola virus – whether accidental or deliberate – cannot be fully excluded.

Due to the serious consequences of a diagnosis or misdiagnosis of smallpox, it is of utter most importance to reliably and unambiguously identify smallpox, as well as to differentiate it from other similar clinical entities. Although there are other causes of rash that present as vesicles and pustules, smallpox can be distinguished by severe prodrome and its course.

Clinical case definition of smallpox states that this disease presents with acute onset of fever greater than 101 °F (or 38.3 °C), followed by a rash characterized by firm, deep seated vesicles or pustules in the same stage of development without any other apparent cause.

Laboratory criteria for confirmation include identification of variola DNA in clinical specimens with polymerase chain reaction (PCR) or isolation of the virus from a clinical specimen in a BSL4 laboratory (i.e. laboratory with the most stringent biosafety level and with appropriate capabilities). Electron microscopy can also be employed for diagnostic purposes.

Other zoonotic poxviruses could also emerge as a variola-like virus of humans. Taking everything into account, the availability of rapid, sensitive and specific diagnostic tools and procedures for identification and differentiation of variola virus is of critical importance.


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Further Reading

Last Updated: Aug 23, 2018

Dr. Tomislav Meštrović

Written by

Dr. Tomislav Meštrović

Dr. Tomislav Meštrović is a medical doctor (MD) with a Ph.D. in biomedical and health sciences, specialist in the field of clinical microbiology, and an Assistant Professor at Croatia's youngest university - University North. In addition to his interest in clinical, research and lecturing activities, his immense passion for medical writing and scientific communication goes back to his student days. He enjoys contributing back to the community. In his spare time, Tomislav is a movie buff and an avid traveler.


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  1. Sabrina Silva Sabrina Silva Brazil says:

    major ou maior?

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
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