Introduction
Background
The history of smallpox is remarkable both because of the spectacular devastation it wreaked upon civilization since the dawn of humankind, as depicted in the image below, and for the astounding achievement of modern medicine, which eradicated this plague through the concerted efforts of global vaccination.
Adult with variola major infection. Hundreds of pustular lesions are centrifugally distributed. Courtesy of the Fitzsimmons Army Medical Center slide file.
The earliest evidence of smallpox comes from ancient Egypt circa 1157 BCE, where the mummified remains of a pockmarked Ramses V were uncovered. International traders spread smallpox throughout the Old World during the 4th-15th centuries CE, while European explorers and conquerors brought the disease to the Western Hemisphere in the early 16th century.
Smallpox directly and profoundly influenced the course of human history. Its tremendous morbidity and mortality led to indiscriminate killing of kings and warlords and tipped the balance of power with regularity in Europe and elsewhere. Whole civilizations, including the Incas and the Aztecs, were destroyed in a single generation, and efforts to ward off the disease indelibly affected the practice of religion and medicine.
Smallpox is the result of infection by the variola virus, which belongs to the genus Orthopoxvirus in the family Poxviridae. The variola virus is a large brick-shaped, double-stranded DNA virus that serologically cross-reacts with other members of the poxvirus family, including ectromelia, cowpox, monkeypox, vaccinia, and camelpox. Unlike other DNA viruses, the variola virus multiplies in the cytoplasm of parasitized host cells. Smallpox infects only humans and does not exist in a carrier state. The virus can survive in the environment for a short period, and it is most stable at low temperatures and low humidity. Variola is spread most efficiently by means of inhalation and less efficiently by means of direct contact with scabs or pustular material from skin lesions.
The 2 predominant variants of variola, major and minor, differ greatly in their mortality rates (30% vs 1%, respectively). Variola major was the predominant endemic strain throughout the world, and, by the end of the 18th century, it was responsible for approximately 400,000 deaths a year in Europe. In patients who recovered from the disease, blindness was common and disfiguring scars were nearly universal.
Intentional inoculation with subvirulent strains of variola to protect against variola major (variolation) began in India sometime before the first millennium CE. This practice spread throughout the Old World and eventually reached Europe in the early 18th century. Although variolation was capable of inducing lifelong immunity in vaccinated individuals, the practice was a risky procedure, and those inoculated had a mortality rate of approximately one tenth that of individuals with naturally occurring disease. Furthermore, treated individuals were capable of transmitting disease to untreated individuals for some time after variolation.
In one of the major accomplishments in modern medicine, Edward Jenner demonstrated in 1796 that an individual could be protected against disease. The skin could be inoculated with pustular material containing the cowpox virus, an orthopoxvirus closely related to variola. Although the heterologous immunity induced by vaccination (from the Latin word vacca, meaning cow) was not lifelong, this approach was significantly safer than variolation, and vaccination quickly spread throughout the world. In subsequent decades, the strain of virus used was sustained by means of arm-to-arm inoculation or maintained as dried material on threads. Over time, the virus mysteriously changed from its original cowpox form to the strain of vaccinia used in current vaccines. In the latter half of the 19th century, the practice of growing virus for vaccines on the flank of calves was adopted to lessen the risk of transmitting other human diseases (eg, syphilis) during vaccination.
In the late 1940s, large-scale production of freeze-dried vaccine enabled mass vaccination campaigns and, eventually, the global eradication of smallpox. In the latter half of the 1960s, the World Health Assembly intensified its efforts in eradicating the disease by using highly potent and stable vaccine, by rapidly identifying outbreaks, and by performing ring vaccination in all contacts of a person who was infected.
The last case of endemic smallpox occurred in Somalia in 1977, and the last recorded case in humans occurred in England in 1978; this case was due to an accidental laboratory infection. In 1980, the World Health Organization officially declared that smallpox had been eradicated. Currently, the only remaining known variola virus isolates are frozen in closely guarded repositories at the US Centers for Disease Control and Prevention (CDC) in the United States and at the Vektor Institute in Russia.
Pathophysiology
Smallpox is most efficiently spread via the respiratory system, although contact with infected skin or fomites also may transmit the disease. The variola virus multiplies in the reticuloendothelial system, and it is clinically silent for approximately 12 days (range, 7-17 d). Viremia then proceeds to the prodromal phase (range, 2-4 d), which is characterized by the sudden onset of fever, severe headache, pharyngitis, nausea, backache, and malaise. During the later part of the prodromal phase, an enanthem may be appreciated on the palate, the tongue, and the pharynx. The virus then enters the skin; this event marks the beginning of the rash phase of the disease.
The skin findings begin on the face and spread centrifugally. Most lesions are in the same stage of development at any given time. Characteristic lesions start as macules and then develop into papules, pustules, and crusts over a period of approximately 17 days. The virus is readily found on the skin, in the oropharynx, and in the reticuloendothelial system throughout the rash phase (a highly infectious period from the appearance of enanthema until day 10 of the rash). Overwhelming toxemia has been the usual cause of death, and typical cases of smallpox had a mortality rate of 30%. The rarer hemorrhagic and flat-type forms of the disease were nearly universally fatal.
Both cellular immunity and humoral immunity are elicited in response to variola infection. Neutralizing antibodies can be detected during the first week of clinical illness, whereas hemagglutination-inhibition and complement-fixation antibodies are found in the second to third weeks. Neutralizing antibodies persist for many years or decades after infection, whereas levels of hemagglutination-inhibition and complement-fixation antibodies generally decrease within a year. Cell-mediated immunity likely plays an important role in controlling disease; virus-specific cytotoxic T cells are detectable in lymphoid organs as early as 4 days after infection. These cytotoxic T cells are believed to limit viral spread by causing lysis of infected cells in the reticuloendothelial system and the skin.
The relative importance of the cellular immune response against smallpox has been demonstrated in animals. Studies show that mice with defective T cells are able to generate normal humoral responses to a viral challenge, yet they die when exposed to orthopoxvirus concentrations that are sublethal in healthy mice. Studies in rodents and sheep have demonstrated memory in the form of virus-specific, cytotoxic lymphocyte immune responses that occur long after the initial variola infection.
Currently, nearly half the US population has not been vaccinated and has no immunity to vaccinia or variola. The remainder of the population was vaccinated 30 or more years ago and may retain partial protection from the disease.
Frequency
International
Since 1978, no cases of smallpox have been reported in the world.
Mortality/Morbidity
Morbidity was commonly associated with smallpox (see Complications).- Typical variola major smallpox in individuals who were not immune was associated with a mortality rate of 30%. A minority of cases were the hemorrhagic and flat-type forms of smallpox (3% and 7%, respectively); each had a mortality rate of close to 100% in individuals who were not immune.
- Variola minor had an associated case-fatality rate of 0.1-2%. In all cases, higher mortality rates occurred in individuals who were immunocompromised, young children, elderly individuals, or pregnant women.
- Congenital infection resulted in a stillbirth rate of 35%, and 50% of neonates died within their first few days of life.
Race
No racial predilection is known for smallpox.
Sex
Pregnant women were at risk for severe smallpox.
Age
Historically, young or old individuals are more susceptible to severe smallpox.
Clinical
History
For additional information, see Evaluating Patients for Smallpox.
- The incubation period of smallpox is 7-17 days.
- The prodromal phase of smallpox lasts 2-4 days and is characterized by the following:
- Fever (temperature >40°C)
- Severe headache
- Backache
- Pharyngitis
- Nausea
- Vomiting
- Prostration
- Enanthema on the mucous membranes of the tongue and the oropharynx
- As many as 10% of fair-skinned individuals with smallpox may also present with a fine, erythematous, macular rash during the prodromal phase.
- Virus shedding and subsequent infectivity are maximal at the beginning of the enanthema, and they last until scab separation of the skin lesions.
- For a few days, the virus can be found in respiratory secretions, skin lesions, and contaminated objects.
- Respiratory infectivity occurs with face-to-face contact, although reports of infection due to viral spread through ventilation systems are well documented.
Physical
- The characteristic rash of smallpox begins after the prodromal phase.
- Small, red macules first appear on the face and then spread to the extremities and the trunk.
- Over 1-2 days, the macules develop into 2- to 3-mm, firm papules.
- Within 1-2 more days, the papules evolve into 2- to 5-mm vesicles, as see in the image below.
Unvaccinated infant with centrifugally distributed umbilicated pustules on day 3 after exposure to the ordinary form of the variola major strain of smallpox. Reprinted with permission from Smallpox and Its Eradication. Copyright 1988, World Health Organization.
- By days 4-7 after the appearance of the rash, the lesions develop into 4- to 6-mm pustules, many of which become confluent, particularly on the face, as seen in the images below. In the past these pustules have been described as deep-seated, particularly on the palms and soles, however this is likely due to thick stratum corneum at those sites.
Unvaccinated infant with centrifugally distributed umbilicated pustules on day 5 after exposure to the ordinary form of the variola major strain of smallpox. Reprinted with permission from Smallpox and Its Eradication. Copyright 1988, World Health Organization.
Unvaccinated infant with centrifugally distributed umbilicated pustules on day 7 after exposure to the ordinary form of the variola major strain of smallpox. Reprinted with permission from Smallpox and Its Eradication. Copyright 1988, World Health Organization.
- The pustules reach their maximal size by day 10.
- By day 17, the pustules become pitted and are covered with a scab.
- All skin lesions tend to be in the same stage of development at any given time in the course of the infection.
- Compared with unvaccinated persons, vaccinated individuals who contract smallpox tend to have less severe toxemia; fewer constitutional symptoms; and smaller and fewer numbers of lesions, which tend to be more superficial and mimic those of chickenpox.
- The rash of chickenpox was frequently mistaken for that of smallpox during the days of natural infection.
- Both conditions could result in pustular scarring lesions that involved the face.
- Varicella typically does not have a prodromal phase, and the evolution of the rash from its appearance to scab separation takes approximately 7 days in varicella.
- Often, individuals who were previously vaccinated had only a mild prodrome without any rash.
- Hemorrhagic smallpox, as seen in the image below, develops fulminantly and was most often confused with meningococcemia or severe acute leukemia.
Hemorrhagic-type variola major lesions. Death usually ensues before typical pustules develop. Reprinted with permission from Smallpox and Its Eradication. Copyright 1988, World Health Organization.
- Contact dermatitis, although often vesicular, would be distinguishable from smallpox lesions because contact dermatitis is pruritic and is not accompanied by fever or constitutional symptoms.
- Flat-type smallpox was slower to evolve, but it resulted in confluent velvety macular lesions and was associated with severe prostration.
- Variola minor was characterized by constitutional symptoms, with fewer and smaller skin lesions than variola major.
- The fever and vesicular rash of chickenpox, herpes zoster, and erythema multiforme were often confused with those of variola major.
Causes
Smallpox is caused by infection with the variola virus.
More on Smallpox |
 Overview: Smallpox |
| Differential Diagnoses & Workup: Smallpox |
| Treatment & Medication: Smallpox |
| Follow-up: Smallpox |
| Multimedia: Smallpox |
| References |
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Further Reading
Keywords
smallpox, variola virus, variola major, variola minor, variola infection, vaccinia, Orthopoxvirus, Poxviridae, poxvirus, hemorrhagic smallpox, flat-type smallpox
