eMedicine Specialties > Infectious Diseases > Viral Infections

Smallpox

Author: Aneela Naureen Hussain, MD, FAAFM, Assistant Professor, Department of Family Medicine, State University of New York Downstate Medical Center; Consulting Staff, Department of Family Medicine, University Hospital of Brooklyn
Coauthor(s): Fazal Hussain, MD, MBBS, Director, Clinical Research, King Faisal Cancer Centre; Maqsood Alam, MD, Fellow, Department of Infectious Diseases, State University of New York Downstate Medical Center; Dennis J Cleri, MD, FACP, FAAM, FIDSA, Chairman, Graduate Medical Education Committee, Professor of Medicine, Associate Professor of Infection Disease, Seton Hall University; Director, Internal Medicine Residency Program, St Francis Medical Center
Contributor Information and Disclosures

Updated: Oct 20, 2008

Introduction

Background

Smallpox is an acute contagious disease caused by the variola virus (Poxvirus variolae), a member of the Poxviridae family of the genus Orthopoxvirus. Virologists have speculated that it evolved from an African rodent poxvirus 10 millennia ago. Because of the absence of an animal vector, communities had to reach a critical population (estimated at 200,000 around 3000 BC) before endemic smallpox could be established. The name is derived from the Latin word for "spotted" and refers to the raised bumps on the face and body of the patient.

Poxviridae are linear double-stranded DNA viruses that replicate in the cytoplasm. Poxviridae consist of 2 families: Chordopoxvirinae, which infect vertebrates, and Entomopoxvirinae, which infect insects. Vaccinia virus, monkeypox virus, and cowpox virus are other viruses within the Orthopoxvirus genus that infect humans.

The two classic varieties of smallpox are variola major and variola minor, each of which confers immunity against the other. Variola major is the more severe and common form of smallpox. It causes more extensive rash and fever. Variola major smallpox has 4 subtypes, as follows:

• Ordinary smallpox - The most common form, which accounts for 90% or more of smallpox cases
• Modified smallpox - A mild form that develops in previously vaccinated persons
• Flat smallpox (malignant smallpox) - A severe variety of smallpox in which lesions do not project above the skin surface
• Hemorrhagic smallpox (fulminant smallpox) - A rare, very severe, highly fatal variety of smallpox in which hemorrhages develop in the skin and mucous membranes

Variola minor is less common and much less virulent and was previously found mainly in South Africa, South America, Europe, and Australia.

Variola sine eruptione (variola sine exanthemata) is another less-common form of smallpox. In addition, a pharyngeal form of smallpox develops in immunized individuals; this form presents with a spotty enanthem over the soft palate, uvula, and pharynx. An influenzalike form of smallpox exists but rarely results in a rash. Both of these forms are relatively mild, usually affect individuals who have been previously immunized, and do not cause mortality. A pulmonary form of smallpox characterized by severe symptoms, cyanosis, and bilateral infiltrates has been described in individuals with little or no smallpox immunity. The mortality rate of this type is undetermined.

During the first half of the 20th century, all outbreaks of smallpox in Asia and most in Africa were due to variola major. The case fatality rate was 20% or more in unvaccinated persons. Variola minor carried a case fatality rate of 1% or less and was endemic in some countries in Europe, North America, South America, and many parts of Africa.

Smallpox outbreaks have occurred sporadically for thousands of years, but, after a successful global vaccination program, the disease has now been eradicated. The last case of smallpox in the United States was reported in 1949. The last naturally occurring case in the world was seen in Somalia in 1977. After the disease was eliminated from the world, routine smallpox vaccination was stopped because prevention was no longer necessary. The long-term consequence of eradication is that much of the world's population is now unvaccinated and at risk for smallpox infection.

Pathophysiology

Smallpox is a double-stranded, 135- to 375-kilobase (kb) DNA virus that replicates in the cytoplasm of the host cell and forms B-type inclusion bodies (Guarnieri bodies), unlike herpes viruses, which replicate in the nucleus. The orthopoxviruses are among the largest and most complex of all viruses. The virion is brick-shaped with a diameter of approximately 200 nm.

The smallpox virus is transmitted mainly through the airborne route and adheres via droplet spread of viral particles onto the mucosal surfaces of the oropharyngeal and respiratory tract. This transmission occurs through close personal contact (eg, face-to-face within 6 ft, household contact) for extended periods. Respiratory spread over long distances (eg, from one hospital floor to another) has been reported. Exposure to clothing or blankets contaminated with infected material can also result in disease.

Smallpox has a lower transmission rate than measles, pertussis, and influenza. Transmission through casual and limited contact has been reported in military personnel. Although rare, airborne (ie, suspended viral particles) and fomite transmission can occur. Humans are the only natural hosts of variola; nonhuman animals and insects do not carry the variola virus. Pregnant women with smallpox tend to develop hemorrhagic disease, but intrauterine infection occurs in even the mildest maternal infections, resulting in premature delivery and high fetal and neonatal mortality rates.

Implantation of just a few virions of smallpox into the oropharynx or respiratory tracts can cause infection. The virus infects macrophages during the first 72 hours of the incubation phase. The virus migrates and multiplies in the regional lymph nodes, resulting in asymptomatic viremia by the fourth day. The virus multiplies in the spleen, bone marrow, and lymph nodes, resulting in a symptomatic secondary viremia (ie, fever, toxemia) by the eighth day. Finally, the virus re-enters the blood in leukocytes, producing fever and toxemia, and then passes from leukocytes to adjacent cells in small blood vessels of the dermis and beneath the oropharyngeal mucosa, leading to the initial onset of the enanthem and exanthem, at which point (approximately day 14) the patient becomes infectious.

The spleen, lymph nodes, kidneys, liver, bone marrow, and other viscera may also contain large amounts of smallpox virus. Incubation periods are typically 10-12 days but can range from 7-17 days. Intrauterine infections rarely occur and usually have shorter incubation periods. Patients exposed to smallpox through routes other than the person-to-person respiratory route also have shorter incubation periods. Prior immunization, vaccinia immune globulin (VIG), and, possibly, antiviral chemotherapy may extend the incubation period.

Patients with smallpox are sometimes contagious upon the onset of fever (prodromal phase) but are most contagious upon rash onset. Infected persons are contagious until the last smallpox scab separates. The highest intensity of viral shedding is during the first 10 days of the rash. Infection rates among close contacts of infected persons have been reported to be between 37% and 88%. Survivors of natural smallpox infection acquire lifelong immunity.

Frequency

United States

The last outbreak of smallpox in the United States was in 1947, when 12 cases were reported in New York City. In the United States, routine vaccination of the civilian population ended in 1972 and in 1990 for the US military.

The most current statistics indicate that approximately 41% of the resident US population is younger than 30 years, most of whom have not been vaccinated against smallpox. The immune status of those who were vaccinated 30 or more years ago has not been satisfactorily established, but some evidence shows residual immunity. Reports from the late 19th century indicate that smallpox vaccination 20-30 years previously may not protect against infection but often prevents death. No conclusive studies have shown whether people with residual immunity can transmit smallpox to nonvaccinated individuals.

International

The last endemic case of variola major was reported in Bangladesh in 1975; the last endemic case of variola minor was reported in Somalia in 1977. In 1979, a laboratory accident in Birmingham, England, resulted in a single case of the disease. Smallpox is authorized to be kept for research purposes only at 2 World Health Organization reference laboratories. One is the US Centers for Disease Control and Prevention (CDC) in Atlanta, Ga, and the other is the State Research Centre of Virology and Biotechnology, also known as the VECTOR Institute, in Koltsovo, Russia. Routine smallpox vaccinations was stopped in 1972 and smallpox was declared eradicated in 1980 after a worldwide vaccination program. In 2002, The Washington Post reported that the Central Intelligence Agency identified possible clandestine smallpox virus stocks in 4 other nations.

Mortality/Morbidity

Variola major infection carries an overall fatality rate of approximately 30% (range, 15-50%) in an unvaccinated population and 3% in a vaccinated population. However, flat smallpox carries a 45.4% mortality rate in patients with discrete lesions who have been immunized. Unimmunized patients with confluent disease have a 99.3% mortality rate. Patients with hemorrhagic smallpox have a mortality rate of more than 96%, regardless of immunization status. Variola minor infection is a less common type of smallpox and a much less severe disease, with a death rate of 1% or less.

Age

The age distribution of smallpox mirrors that of the general population, although residual immunity from previous vaccination could potentially decrease disease in the older population.

Clinical

History

• The incubation period of smallpox ranges from 7-17 days but is usually 10-12 days. During the incubation period, patients are not contagious.
• The initial symptoms of smallpox include fever, malaise, headaches, body aches, and, rarely, vomiting. The fever ranges from 38.8-40°C (101-104°F).
• In this prodromal phase of smallpox, patients are usually too ill to perform normal activities of daily living. The phase may last 2-3 days but may last as long as 5 days.

Physical

• The initial cutaneous lesions of smallpox appear as small red spots on the face, in the mouth and pharynx, and on the forearms. Initially, smallpox lesions are small papules but change into vesicles and pustules within 1-2 days. The rash is typically described as centrifugal. The initial lesions are shotty and do not disappear with pressure. (For additional information on cutaneous manifestations of smallpox, see the eMedicine article Smallpox in the Dermatology volume.)
• These spots develop into sores that break open and spread large amounts of the virus into the mouth and throat. The patient becomes most contagious at this time.
• Around the time the sores in the mouth break down, a rash appears on the skin, starting on the face, spreading to the arms and legs, and progressing to the hands and feet. Usually, the rash spreads to all parts of the body within 24 hours. As the rash appears, the fever reduces and the patient may start to feel better.
• By the third day of the rash, it turns into raised papules.
• By the fourth day, the papules fill with a thick opaque fluid and often have a depression in the center that resembles an umbilicus (bellybutton), which is a major distinguishing characteristic of smallpox. At this time, the fever often rises again and remains high until scabs form over the papules.
• The papules become pustules. The pustules are sharply raised and are usually round and firm to the touch, as if a small round object is present under the skin. The pustules begin to form a crust and then scab.
• By the end of the second week after the rash appears, most of the sores have formed scabs. The scabs begin to separate, leaving marks on the skin that eventually become pitted scars. Most scabs separate by the third week after the rash appears.
• The person is contagious until all of the scabs are gone.
• The smallpox rash has a centrifugal distribution, with more lesions on the arms and legs than on the trunk. Rash on the palms and soles is common. As a comparison, a chickenpox rash has a centripetal distribution, with more lesions on the trunk and with fewer or no lesions on the palms and soles.
• Most patients report severe headaches and spinal pain. Few patients develop neuropsychiatric symptoms (hallucinations, delirium, depression and psychosis, manic depression). Autopsies of patients with smallpox have demonstrated perivenular demyelination.
• Ten to 20% of patients with smallpox develop ophthalmic complications (variola residua). Conjunctivitis is most common, appearing 5 days after rash onset. Some patients develop painful pustules and bulbar conjunctivitis. During epidemics, corneal ulceration was common (complicated by bacterial superinfection and perforation).
• Two to 5% of children develop osteomyelitis (osteomyelitis variolosa) due to viral invasion of the bone rather than to secondary infection. Radiographic surveys in children have found rates as high as 20%.

Causes

• The variola virus causes all forms of smallpox.

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