Smallpox Prognosis

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Smallpox is a highly infectious disease caused by the variola virus, an orthopoxvirus. Humans are the only known reservoir of this virus, thus no known animal or insect reservoirs have been identified. As routine vaccination is no longer undertaken, exposure to variola virus has the potential to cause high rates of morbidity and mortality in human population.

Following an incubation period, infected individuals manifest with prodromal symptoms that include high fever, malaise, back pain and prostration. The eruptive stage is characterized by maculopapular rash that progresses to papules, then vesicles, and finally pustules and scab lesions. Prognosis can vary according to the disease type and patient status.

Disease prognosis

Mortality rates varied with the type of smallpox, but were also partially dependent on prior vaccination status, as well as the patient’s immune system. The hemorrhagic form of the disease was uniformly fatal, whereas flat smallpox resulted in death in the majority of cases.

The death of patients with smallpox was often attributed to “toxemia”, which is a conclusion consistent with modern concepts of sepsis and septic shock. Most deaths were occurring during the second week of illness, and disseminated intravascular coagulation was the most likely culprit of the hemorrhagic diathesis in hemorrhagic smallpox.

Typical disease in individuals who were not previously vaccinated carried a mortality frequency as high as 30%. Successful vaccination resulted in a solid immunity against the disease for several years, and likely conferred certain degree of protection for much longer period.

Death rate from smallpox among pregnant women was extraordinarily high. Pregnant women also had a higher rate of hemorrhagic disease in comparison with other adults. The case-fatality rate in unvaccinated pregnant women approached 70%, while fetal wastage was approximately 80%.

Research of cases imported into Europe over a 20-year period found a mortality rate of 52% in those never vaccinated, compared to 11% in those vaccinated more than 20 years before contracting a disease. Still, it must be noted that all experience with smallpox predated the advent of modern critical care medicine, thus mortality would conceivably be lower than in the past.

Treatment of smallpox

Throughout history, management of smallpox was strictly supportive. No effective treatment for smallpox had been found by the time of eradication and there is no treatment approved by the Food and Drug Administration (FDA) for orthopoxviruses.  Antimicrobial agents were used if smallpox lesions got infected, or if the eruption was very dense and widespread.

The appropriate care and management of smallpox patients requires hospitalization. Today, any suspect case of smallpox should be managed in a negative-pressure room and the patient should be vaccinated, particularly if the illness is in an early stage. Strict airborne and contact isolation precautions should be followed.

The patient should be isolated until all scabs have fallen off in order to prevent transmission of variola virus to nonimmune individuals. As substantial amounts of fluid and protein can be lost by febrile individuals with pox lesions, patients require appropriate hydration and nutrition.

Recent research endeavors to develop antiviral therapies have targeted the poxviral DNA polymerase. Nucleotide analogue cidofovir, which is currently licensed for the treatment of cytomegalovirus retinitis, targets the viral enzyme much more efficiently than its cellular counterpart. Still, this drug is still investigational and may cause a number of serious side effects.


  7. Petersen BW, Damon IK. Orthopoxviruses: Vaccinia (Smallpox Vaccine), Variola (Smallpox), Monkeypox, and Cowpox. In: Bennett JE, Dolin R, Blaser MJ. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. Elsevier Health Sciences, 2014; pp. 1694-1702.

Further Reading

Last Updated: Jul 6, 2023

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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