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Smallpox
"Variola" redirects here. For other uses, see Variola (disambiguation).

Smallpox
Classification and external resources

Boy with smallpox

Variola virus (Smallpox) Virus classification Group: Group I (dsDNA) Family: Poxviridae Genus: Orthopoxvirus Species: Variola vera Smallpox is an infectious disease unique to humans, caused by either of two virus variants, Variola major and Variola minor. The disease is also known by the Latin names Variola or Variola vera, which is a derivative of the Latin varius, meaning spotted, or varus, meaning "pimple". The term "smallpox" was first used in Europe in the 15th century to distinguish variola from the "great pox" (syphilis) Smallpox localizes in small blood vessels of the skin and in the mouth and throat. In the skin, this results in a characteristic maculopapular rash, and later, raised fluid-filled blisters. V. major produces a more serious disease and has an overall mortality rate of 30– 35%. V. minor causes a milder form of disease (also known as alastrim, cottonpox, milkpox, whitepox, and Cuban itch) which kills about 1% of its victims.Long-term complications of V. major infection include characteristic scars, commonly on the face, which occur in 65–85% of survivors. Blindness resulting from corneal ulceration and scarring, and limb deformities due to arthritis and osteomyelitis are less common complications, seen in about 2–5% of cases. Smallpox is believed to have emerged in human populations about 10,000 BC.The disease killed an estimated 400,000 Europeans each year during the 18th century (including five monarchs), and was responsible for a third of all blindness.Of all those infected, 20–60%—and over 80% of infected children—died from the disease. During the 20th century, it is estimated that smallpox was responsible for 300–500 million deaths. In the early 1950s an estimated 50 million cases of smallpox occurred in the world each year. As recently as 1967, the World Health Organization (WHO)

estimated that 15 million people contracted the disease and that two million died in that year.After successful vaccination campaigns throughout the 19th and 20th centuries, the WHO certified the eradication of smallpox in December 1979.To this day, smallpox is the only human infectious disease to have been completely eradicated

Cause
Smallpox is caused by infection with variola virus, which belongs to the genus Orthopoxvirus, the family Poxviridae, and subfamily chordopoxvirinae. Variola is a large brick-shaped virus measuring approximately 302 to 350 nanometers by 244 to 270 nm,with a single linear double stranded DNA genome 186 kilobase pairs (kbp) in size and containing a hairpin loop at each end. The two classic varieties of smallpox are variola major and variola minor. The closest viral relative is molluscum contagiosum, which, like smallpox, infects only humans. However, unlike variola species, molluscum infection is benign. Four orthopoxviruses cause infection in humans: variola, vaccinia, cowpox, and monkeypox. Variola virus infects only humans in nature, although primates and other animals have been infected in a laboratory setting. Vaccinia, cowpox, and monkeypox viruses can infect both humans and other animals in nature. The lifecycle of poxviruses is complicated by having multiple infectious forms, with differing mechanisms of cell entry. Poxviruses are unique among DNA viruses in that they replicate in the cytoplasm of the cell rather than in the nucleus. In order to replicate, poxviruses produce a variety of specialized proteins not produced by other DNA viruses, the most important of which is a viral-associated DNA-dependent RNA polymerase. Both enveloped and unenveloped virions are infectious. The viral envelope is made of modified Golgi membranes containing viral-specific polypeptides, including hemagglutinin.] Infection with either variola major or variola minor confers immunity against the other.

Evolution
Smallpox appears to have evolved from an African rodent-borne variola-like virus.The date of this evolution is uncertain at present and estimates vary between 16,000 and 68,000 years ago. The more severe form (variola major) originated in Asia between 400 and 1600 years ago. A second form –alastrim minor– found in West Africa and the Americas is thought to have evolved between 1,400 and 6,300 years ago. This clade gave rise to two subclades that diverged at least 800 years ago.

Transmission
Transmission of smallpox occurs through inhalation of airborne variola virus, usually droplets expressed from the oral, nasal, or pharyngeal mucosa of an infected person. It is transmitted from one person to another primarily through prolonged face-to-face contact with an infected person, usually within a distance of 6 feet, but can also be spread

through direct contact with infected bodily fluids or contaminated objects (fomites) such as bedding or clothing. Rarely, smallpox has been spread by virus carried in the air in enclosed settings such as buildings, buses, and trains. The virus can cross the placenta, but the incidence of congenital smallpox is relatively low.Smallpox is not notably infectious in the prodromal period and viral shedding is usually delayed until the appearance of the rash, which is often accompanied by lesions in the mouth and pharynx. The virus can be transmitted throughout the course of the illness, but is most frequent during the first week of the rash, when most of the skin lesions are intact.Infectivity wanes in 7 to 10 days when scabs form over the lesions, but the infected person is contagious until the last smallpox scab falls off. Smallpox is highly contagious, but generally spreads more slowly and less widely than some other viral diseases, perhaps because transmission requires close contact and occurs after the onset of the rash. The overall rate of infection is also affected by the short duration of the infectious stage. In temperate areas, the number of smallpox infections were highest during the winter and spring. In tropical areas, seasonal variation was less evident and the disease was present throughout the year.Age distribution of smallpox infections depends on acquired immunity. Vaccination immunity declines over time and is probably lost in all but the most recently vaccinated populations. Smallpox is not known to be transmitted by insects or animals and there is no asymptomatic carrier state.

Signs and symptoms
There are two clinical forms of smallpox. Variola major is the severe and most common form of smallpox, with a more extensive rash and higher fever. There are four types of variola major smallpox based on the Rao classification:ordinary, modified, flat, and hemorrhagic. Historically, variola major has an overall fatality rate of about 30%; however, flat and hemorrhagic smallpox are usually fatal. In addition, a form called variola sine eruptione (smallpox without rash) is seen generally in vaccinated persons. This form is marked by a fever that occurs after the usual incubation period and can be confirmed only by antibody studies or, rarely, by virus isolation. Variola minor is a less common presentation of smallpox, and a much less severe disease, with historical death rates of 1% or less.Subclinical (asymptomatic) infections with variola virus have also been noted, but are not believed to be common.

Child showing rash due to ordinary-type smallpox (variola major) The incubation period between contraction and the first obvious symptoms of the disease is around 12 days. Once inhaled, variola virus invades the oropharyngeal (mouth and throat) or the respiratory mucosa, migrates to regional lymph nodes, and begins to multiply. In the initial growth phase the virus seems to move from cell to cell, but around the 12th day, lysis of many infected cells occurs and the virus is found in the bloodstream in large numbers (this is called viremia), and a second wave of multiplication occurs in the spleen, bone marrow, and lymph nodes. The initial or prodromal symptoms are similar to other viral diseases such as influenza and the common cold: fever (at least 38.5 °C (101 °F)), muscle pain, malaise, headache, prostration, and as the digestive tract is commonly involved, nausea and vomiting and backache often occur. The prodrome, or preeruptive stage, usually lasts 2–4 days. By days 12–15 the first visible lesions—small reddish spots called enanthem—appear on mucous membranes of the mouth, tongue, palate, and throat, and temperature falls to near normal. These lesions rapidly enlarge and rupture, releasing large amounts of virus into the saliva. Smallpox virus preferentially attacks skin cells, causing the characteristic pimples (called macules) associated with the disease. A rash develops on the skin 24 to 48 hours after lesions on the mucous membranes appear. Typically the macules first appear on the forehead, then rapidly spread to the whole face, proximal portions of extremities, the trunk, and lastly to distal portions of extremities. The process takes no more than 24 to 36 hours, after which no new lesions appear.At this point Variola major infection can take several very different courses.

Ordinary
Ninety percent or more of smallpox cases among unvaccinated persons are of the ordinary type. In this form of the disease, by the second day of the rash, the macules become raised papules. By the third or fourth day the papules fill with an opalescent fluid to become vesicles. This fluid becomes opaque and turbid within 24–48 hours, giving

them the appearance of pustules; however, the so-called pustules are filled with tissue debris, not pus. By the sixth or seventh day, all the skin lesions have become pustules. Between 7 and 10 days the pustules mature and reach their maximum size. The pustules are sharply raised, typically round, tense, and firm to the touch. The pustules are deeply embedded in the dermis, giving them the feel of a small bead in the skin. Fluid slowly leaks from the pustules, and by the end of the second week the pustules deflate, and start to dry up, forming crusts (or scabs). By day 16-20 scabs have formed over all the lesions, which have started to flake off, leaving de-pigmented scars. Ordinary smallpox generally produces a discrete rash, in which the pustules stand out on the skin separately. The distribution of the rash is densest on the face; denser on the extremities than on the trunk; and on the extremities, denser on the distal parts than on the proximal. The palms of the hands and soles of the feet are involved in the majority of cases. In some cases, the blisters merge together into sheets, forming a confluent rash, which begin to detach the outer layers of skin from the underlying flesh. Patients with confluent smallpox often remain ill even after scabs have formed over all the lesions. In one case series, the case-fatality rate in confluent smallpox was 62%.

Modified
Referring to the character of the eruption and the rapidity of its development, modified smallpox occurs mostly in previously vaccinated people. In this form the prodromal illness still occurs but may be less severe than in the ordinary type. There is usually no fever during evolution of the rash. The skin lesions tend to be fewer and evolve more quickly, are more superficial, and may not show the uniform characteristic of more typical smallpox. Modified smallpox is rarely, if ever, fatal. This form of variola major is more easily confused with chickenpox.

This man is suffering from severe hemorrhagic-type smallpox.

Malignant
In Malignant-type smallpox (also called flat smallpox) the lesions remain almost flush with the skin at the time when raised vesicles form in ordinary-type smallpox. It is unknown why some people develop this type of disease. Historically, malignant smallpox accounted for 5%–10% of cases, and the majority (72%) were in children.Malignant smallpox is accompanied by a severe prodromal phase that lasts 3–4 days, prolonged high fever, and severe symptoms of toxemia. The rash on the tongue and palate is usually extensive. The skin lesions mature very slowly and by the seventh or eighth day the lesions are flat and appear to be buried in the skin. Unlike ordinary-type smallpox, the vesicles contain very little fluid, are soft and velvety to the touch, and may contain hemorrhages. Malignant smallpox is nearly always fatal.

Hemorrhagic
Hemorrhagic smallpox is a severe form of smallpox that is accompanied by extensive bleeding into the skin, mucous membranes, and gastrointestinal tract. This form developed in perhaps 2% of infections and occurred mostly in adults. In hemorrhagic smallpox the skin does not blister, but remains smooth. Instead, bleeding occurs under the skin, making the skin look charred and black, hence this form of the disease is also known as black pox. In the early, or fulminating form, hemorrhaging appears on the second or third day as sub-conjunctival bleeding turns the whites of the eyes deep red. Hemorrhagic smallpox also produces a dusky erythema, petechiae, and hemorrhages in the spleen, kidney, serosa, muscle, and, rarely, the epicardium, liver, testes, ovaries and bladder. Death often occurs suddenly between the fifth and seventh days of illness, when only a few insignificant skin lesions are present. A later form of the disease occurs in patients who survive for 8–10 days. The hemorrhages appear in the early eruptive period, and the rash is flat and does not progress beyond the vesicular stage. Patients in the early stage of disease show a decrease in coagulation factors (e.g. platelets, prothrombin, and globulin) and an increase in circulating antithrombin. Patients in the late stage have significant thrombocytopenia; however, deficiency of coagulation factors is less severe. Some in the late stage also show increased antithrombin.This form of smallpox occurs in anywhere from 3–25% of fatal cases depending on the virulence of the smallpox strain. Hemorrhagic smallpox is usually fatal.

Diagnosis

Smallpox virus pocks on the chorioallantoic membrane of a developing chick. Contrary to the rash in smallpox, the rash in chickenpox occurs mostly on the torso, spreading less to the limbs. The clinical definition of smallpox is an illness with acute onset of fever greater than 101°F (38.3°C) followed by a rash characterized by firm, deep seated vesicles or pustules in the same stage of development without other apparent cause. If a clinical case is observed, smallpox is confirmed using laboratory tests. Microscopically, poxviruses produce characteristic cytoplasmic inclusions, the most important of which are known as Guarnieri bodies, and are the sites of viral replication. Guarnieri bodies are readily identified in skin biopsies stained with hematoxylin and eosin, and appear as pink blobs. They are found in virtually all poxvirus infections but the absence of Guarnieri bodies cannot be used to rule out smallpox. The diagnosis of an orthopoxvirus infection can also be made rapidly by electron microscopic examination of pustular fluid or scabs. However, all orthopoxviruses exhibit identical brick-shaped virions by electron microscopy. Definitive laboratory identification of variola virus involves growing the virus on chorioallantoic membrane (part of a chicken embryo) and examining the resulting pock lesions under defined temperature conditions. Strains may be characterized by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. Serologic tests and enzyme linked immunosorbent assays (ELISA), which measure variola virus-specific immunoglobulin and antigen have also been developed to assist in the diagnosis of infection. Chickenpox was commonly confused with smallpox in the immediate post-eradication era. Chickenpox and smallpox can be distinguished by several methods. Unlike smallpox, chickenpox does not usually affect the palms and soles. Additionally, chickenpox pustules are of varying size due to variations in the timing of pustule eruption: smallpox

pustules are all very nearly the same size since the viral effect progresses more uniformly. A variety of laboratory methods are available for detecting chickenpox in evaluation of suspected smallpox cases.

Prognosis
The overall case-fatality rate for ordinary-type smallpox is about 30%, but varies by pock distribution: ordinary type-confluent is fatal about 50–75% of the time, ordinary-type semi-confluent about 25–50% of the time, in cases where the rash is discrete the casefatality rate is less than 10%. The overall fatality rate for children younger than 1 year of age is 40%–50%. Hemorrhagic and flat types have the highest fatality rates. The fatality rate for flat-type is 90% or greater and nearly 100% is observed in cases of hemorrhagic smallpox. The case-fatality rate for variola minor is 1% or less. There is no evidence of chronic or recurrent infection with variola virus. In fatal cases of ordinary smallpox, death usually occurs between the tenth and sixteenth days of the illness. The cause of death from smallpox is not clear, but the infection is now known to involve multiple organs. Circulating immune complexes, overwhelming viremia, or an uncontrolled immune response may be contributing factors.In early hemorrhagic smallpox, death occurs suddenly about six days after the fever develops. Cause of death in hemorrhagic cases involved heart failure, sometimes accompanied by pulmonary edema. In late hemorrhagic cases, high and sustained viremia, severe platelet loss and poor immune response were often cited as causes of death.[22] In flat smallpox modes of death are similar to those in burns, with loss of fluid, protein and electrolytes beyond the capacity of the body to replace or acquire, and fulminating sepsis.

Complications
Complications of smallpox arise most commonly in the respiratory system and range from simple bronchitis to fatal pneumonia. Respiratory complications tend to develop on about the eighth day of the illness and can be either viral or bacterial in origin. Secondary bacterial infection of the skin is a relatively uncommon complication of smallpox. When this occurs, the fever usually remains elevated Other complications include encephalitis (1 in 500 patients), which is more common in adults and may cause temporary disability; permanent pitted scars, most notably on the face; and complications involving the eyes (2% of all cases). Pustules can form on the eyelid, conjunctiva, and cornea, leading to complications such as conjunctivitis, keratitis, corneal ulcer, iritis, iridocyclitis, and optic atrophy. Blindness results in approximately 35% to 40% of eyes affected with keratitis and corneal ulcer. Hemorrhagic smallpox can cause subconjunctival and retinal hemorrhages. In 2% to 5% of young children with smallpox, virions reach the joints and bone, causing osteomyelitis variolosa. Lesions are symmetrical, most common in the elbows, tibia, and fibula, and characteristically cause separation of an epiphysis and marked periosteal reactions. Swollen joints limit movement, and arthritis may lead to limb deformities, ankylosis, malformed bones, flail joints, and stubby fingers.

Treatment
Smallpox vaccination within three days of exposure will prevent or significantly lessen the severity of smallpox symptoms in the vast majority of people. Vaccination four to seven days after exposure likely offers some protection from disease or may modify the severity of disease.Other than vaccination, treatment of smallpox is primarily supportive, such as wound care and infection control, fluid therapy, and possible ventilator assistance. Flat and hemorrhagic types of smallpox are treated with the same therapies used to treat shock, such as fluid resuscitation. Patients with semi-confluent and confluent types of smallpox may have therapeutic issues similar to patients with extensive skin burns. No drug is currently approved for the treatment of smallpox. However, antiviral treatments have improved since the last large smallpox epidemics, and studies suggest that the antiviral drug cidofovir might be useful as a therapeutic agent. The drug must be administered intravenously, however, and may cause serious renal toxicity

Prevention
Main articles: Inoculation and Smallpox vaccine

Vial containing variolation material (India) The earliest procedure used to prevent smallpox was inoculation (also known as variolation). Inoculation was allegedly first practiced in India as early as 1000 BC, and involved either nasal insufflation of powdered smallpox scabs, or scratching material from a smallpox lesion into the skin. However, this idea has been challenged as few of the ancient Sanskrit medical texts of India described the process of inoculation. Accounts of inoculation against smallpox in China can be found as early as the late 10th century, and the procedure was widely practiced by the 16th century, during the Ming Dynasty. If successful, inoculation produced lasting immunity to smallpox. However, because the person was infected with variola virus, a severe infection could result, and the person could transmit smallpox to others. Variolation had a 0.5–2% mortality rate; considerably less than the 20–30% mortality rate of the disease itself.

In 1796 Edward Jenner, a doctor in Berkeley, Gloucestershire, rural England, discovered that immunity to smallpox could be produced by inoculating a person with material from a cowpox lesion. Cowpox is a poxvirus in the same family as variola. Jenner called the material used for inoculation vaccine, from the root word vacca, which is Latin for cow. The procedure was much safer than variolation, and did not involve a risk of smallpox transmission. Vaccination to prevent smallpox was soon practiced all over the world. During the 19th century, the cowpox virus used for smallpox vaccination was replaced by vaccinia virus. Vaccinia is in the same family as cowpox and variola but is genetically distinct from both. The origin of vaccinia virus and how it came to be in the vaccine are not known. The current formulation of smallpox vaccine is a live virus preparation of infectious vaccinia virus. The vaccine is given using a bifurcated (two-pronged) needle that is dipped into the vaccine solution. The needle is used to prick the skin (usually the upper arm) a number of times in a few seconds. If successful, a red and itchy bump develops at the vaccine site in three or four days. In the first week, the bump becomes a large blister (called a “Jennerian vesicle”) which fills with pus, and begins to drain. During the second week, the blister begins to dry up and a scab forms. The scab falls off in the third week, leaving a small scar.

Components of a modern smallpox vaccination kit including the diluent, a vial of Dryvax vaccinia vaccine, and a bifurcated needle. The antibodies induced by vaccinia vaccine are cross-protective for other orthopoxviruses (such as monkeypox, cowpox, and variola (smallpox) viruses). Neutralizing antibodies are detectable 10 days after first-time vaccination, and seven days after revaccination. Historically, the vaccine has been effective in preventing smallpox infection in 95% of those vaccinated.Smallpox vaccination provides a high level of immunity for three to five years and decreasing immunity thereafter. If a person is vaccinated again later, immunity lasts even longer. Studies of smallpox cases in Europe in the 1950s and 1960s demonstrated that the fatality rate among persons vaccinated less than 10 years before exposure was 1.3%; it was 7% among those vaccinated 11 to 20 years prior, and 11% among those vaccinated 20 or more years prior to infection. By contrast, 52% of unvaccinated persons died. There are side effects and risks associated with the smallpox vaccine. In the past, about 1,000 people for every 1 million people vaccinated for the first time experienced serious, but non-life-threatening, reactions including toxic or allergic reaction at the site of the vaccination (erythema multiforme), spread of the vaccinia virus to other parts of the body, and to other individuals. Potentially life-threatening reactions occurred in 14 to 500

people out of every 1 million people vaccinated for the first time. Based on past experience, it is estimated that 1 or 2 people in 1 million (0.000198%) who receive the vaccine may die as a result, most often the result of postvaccinial encephalitis or severe necrosis in the area of vaccination (called progressive vaccinia). Given these risks, as smallpox became effectively eradicated and the number of naturally-occurring cases fell below the number of vaccine-induced illnesses and deaths, routine childhood vaccination was discontinued in the United States in 1972. Routine vaccination of healthcare workers was discontinued in 1976, and among military recruits in 1990. Military members deploying to the Middle East and Korea still receive the vaccination.It is now primarily recommended for laboratory workers at risk for occupational exposure.Mass smallpox vaccination was abandoned in most European countries in the early 1970s as well.

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