WordNet

a mild form of smallpox caused by a less virulent form of the virus (同)variola_minor, pseudosmallpox, pseudovariola, milk pox, white pox, West Indian smallpox, Cuban itch, Kaffir pox
a type of smallpox virus that has a fatality rate of up to 25 percent (同)variola major virus
relating to small pox (同)variolic, variolous

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2012/09/21 11:29:11」(JST)

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

Smallpox was an infectious disease unique to humans, caused by either of two virus variants, Variola major and Variola minor.^[1] 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 Britain in the 15th century to distinguish variola from the "great pox" (syphilis).^[2] The last naturally occurring case of smallpox (Variola minor) was diagnosed on 26 October 1977.^[3]

Smallpox localizes in small blood vessels of the skin and in the mouth and throat. In the skin it 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.^[4]^[5] Long-term complications of V. major infection include characteristic scars, commonly on the face, which occur in 65–85% of survivors.^[6] 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.^[2] The earliest physical evidence of it is probably the pustular rash on the mummified body of Pharaoh Ramses V of Egypt.^[7] The disease killed an estimated 400,000 Europeans annually during the closing years of the 18th century (including five reigning monarchs),^[8] and was responsible for a third of all blindness.^[4]^[9] Of all those infected, 20–60%—and over 80% of infected children—died from the disease.^[10] Smallpox was responsible for an estimated 300–500 million deaths during the 20th century.^[11]^[12]^[13] 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.^[3]

After vaccination campaigns throughout the 19th and 20th centuries, the WHO certified the eradication of smallpox in 1979.^[3] Smallpox is one of two infectious diseases to have been eradicated, the other being rinderpest, which was declared eradicated in 2011.^[14]^[15]^[16]

1 Classification
2 Signs and symptoms
- 2.1 Ordinary
- 2.2 Modified
- 2.3 Malignant
- 2.4 Hemorrhagic
3 Cause
- 3.1 Transmission
4 Diagnosis
5 Prevention
6 Treatment
7 Prognosis
- 7.1 Complications
8 History
- 8.1 Viral evolution
- 8.2 Human history
- 8.3 Eradication
- 8.4 Post-eradication
9 Society and culture
- 9.1 Biological warfare
- 9.2 Notable cases
- 9.3 Religion and mythology
10 See also
11 References
12 Further reading
13 External links

Classification

There are two clinical forms of smallpox. Variola major is the severe and most common form, with a more extensive rash and higher fever. Variola minor is a less common presentation, and a much less severe disease, with historical death rates of 1% or less.^[17] Subclinical (asymptomatic) infections with variola virus have been noted but are not common.^[18] 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.^[18]

Signs and symptoms

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 major 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 of at least 38.5 °C (101 °F), muscle pain, malaise, headache and prostration. 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.^[5]

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.^[5] At this point variola major infection can take several very different courses, resulting in four types of smallpox disease based on the Rao classification:^[19] ordinary, modified, malignant (or flat), and hemorrhagic. Historically, smallpox has an overall fatality rate of about 30%; however, the malignant and hemorrhagic forms are usually fatal.^[20]

Ordinary

Ninety percent or more of smallpox cases among unvaccinated persons are of the ordinary type.^[18] 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.^[5]

By the sixth or seventh day, all the skin lesions have become pustules. Between seven and ten 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 depigmented scars.^[21]

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. Sometimes, the blisters merge 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%.^[18]

This man is suffering from severe hemorrhagic-type smallpox.

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.^[21] Modified smallpox is rarely, if ever, fatal. This form of variola major is more easily confused with chickenpox.^[18]

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 the ordinary type. It is unknown why some people develop this type. Historically, it accounted for 5%–10% of cases, and the majority (72%) were children.^[22] 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 extensive. Skin lesions mature slowly and by the seventh or eighth day they are flat and appear to be buried in the skin. Unlike ordinary-type smallpox, the vesicles contain little fluid, are soft and velvety to the touch, and may contain hemorrhages. Malignant smallpox is nearly always fatal.^[18]

Hemorrhagic

Hemorrhagic smallpox is a severe form that is accompanied by extensive bleeding into the skin, mucous membranes, and gastrointestinal tract. This form develops in approximately 2% of infections and occurred mostly in adults.^[18] In hemorrhagic smallpox the skin does not blister, but remains smooth. Instead, bleeding occurs under the skin, making it look charred and black,^[18] hence this form of the disease is also known as black pox.^[23]

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.^[18] 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.^[5] This form of smallpox occurs in anywhere from 3 to 25% of fatal cases depending on the virulence of the smallpox strain.^[20] Hemorrhagic smallpox is usually fatal.^[18]

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,^[24] with a single linear double stranded DNA genome 186 kilobase pairs (kbp) in size and containing a hairpin loop at each end.^[25]^[26] The two classic varieties of smallpox are variola major and variola minor.

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.^[18]

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.^[25] Infection with either variola major or variola minor confers immunity against the other.^[5]

Transmission

Transmission 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 (1.8 m), 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.^[17] The virus can cross the placenta, but the incidence of congenital smallpox is relatively low.^[5] 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.^[18] 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.^[27]

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.^[18] 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.^[5] Smallpox is not known to be transmitted by insects or animals and there is no asymptomatic carrier state.^[18]

Diagnosis

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.^[18] 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.^[28] 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.^[5]

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.^[29] 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.^[30]

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.^[18]

Smallpox virus lesions on the chorioallantoic membrane of a developing chick.
In contrast to the rash in smallpox, the rash in chickenpox occurs mostly on the torso, spreading less to the limbs.

Prevention

Main article: Smallpox vaccine

Vial containing variolation material (India)

The earliest procedure used to prevent smallpox was inoculation (also known as variolation). Inoculation was possibly practiced in India as early as 1000 BC,^[31] and involved either nasal insufflation of powdered smallpox scabs, or scratching material from a smallpox lesion into the skin. However, the idea that inoculation originated in India has been challenged as few of the ancient Sanskrit medical texts described the process of inoculation.^[32] 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.^[33] 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.^[18]

Lady Mary Wortley Montagu observed smallpox inoculation during her stay in the Ottoman Empire, writing detailed accounts of the practice in her letters, and enthusiastically promoted the procedure in England upon her return in 1718.^[34] In 1721, Cotton Mather and colleagues provoked controversy in Boston by inoculating hundreds. 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.^[18]

Components of a modern smallpox vaccination kit including the diluent, a vial of Dryvax vaccinia vaccine, and a bifurcated needle.

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.^[35]

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.^[36] 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.^[37]

There are side effects and risks associated with the smallpox vaccine. In the past, about 1 out of 1,000 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).^[36]

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, and was abandoned in most European countries in the early 1970s.^[3]^[38] Routine vaccination of health care workers was discontinued in the U.S. in 1976, and among military recruits in 1990 (although military personnel deploying to the Middle East and Korea still receive the vaccination.^[39]) By 1986, routine vaccination had ceased in all countries.^[3] It is now primarily recommended for laboratory workers at risk for occupational exposure.^[18]

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 can offer some protection from disease or may modify the severity of disease.^[36] 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. People with semi-confluent and confluent types of smallpox may have therapeutic issues similar to patients with extensive skin burns.^[40]

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 kidney toxicity.^[41]

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 case-fatality 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.^[21] There is no evidence of chronic or recurrent infection with variola virus.^[21]

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.^[18] 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.^[40]

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.^[18]

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.^[5]

History

Main article: History of smallpox

Viral evolution

Drawing accompanying text in Book XII of the 16th-century Florentine Codex (compiled 1540–1585), showing Nahuas of conquest-era central Mexico suffering from smallpox.

The date of the appearance of smallpox is not settled. It most likely evolved from a rodent virus between 68,000 and 16,000 years ago.^[42]^[43] The wide range of dates is due to the different records used to calibrate the molecular clock. One clade was the variola major strains (the more clinically severe form of smallpox) which spread from Asia between 400 and 1,600 years ago. A second clade included both alastrim minor (a phenotypically mild smallpox) described from the American continents and isolates from West Africa which diverged from an ancestral strain between 1,400 and 6,300 years before present. This clade further diverged into two subclades at least 800 years ago.

A second estimate has placed the separation of variola from Taterapox at 3000–4000 years ago.^[44] This is consistent with archaeological and historical evidence regarding the appearance of smallpox as a human disease which suggests a relatively recent origin. However if the mutation rate is assumed to be similar to that of the herpesviruses the divergence date between variola from Taterapox has been estimated to be 50,000 years ago.^[44] While this is consistent with the other published estimates it suggests that the archaeological and historical evidence is very incomplete. Better estimates of mutation rates in these viruses are needed.

It seems to have emerged in its endemic form in India 2500–3000 years ago.^[45] The variola virus was transferred from West Africa to South America in the 19th century.^{[clarification needed]}

Human history

The earliest credible clinical evidence of smallpox is found in the Egyptian mummy of Ramses V who died over 3000 years ago (1145 BCE).^[7] Historical records from Asia describe evidence of smallpox-like disease in medical writings from ancient India (as early as 1500 BCE)^[46] and China (1122 BCE).^[47] It has been speculated that Egyptian traders brought smallpox to India during the 1st millennium BC, where it remained as an endemic human disease for at least 2000 years. Smallpox was probably introduced in China during the 1st century AD from the southwest, and in the 6th century was carried from China to Japan.^[22] In Japan, the epidemic of 735–737 is believed to have killed up to one-third of the population.^[8]^[48] At least seven religious deities have been specifically dedicated to smallpox, such as the god Sopona in the Yoruba religion. In India, the Hindu goddess of smallpox, Sitala Mata, was worshiped in temples throughout the country.^[49]

The arrival of smallpox in Europe and south-western Asia is less clear. Smallpox is not described in either the Old or New Testaments of the Bible, or in literature of the Greeks and Romans. Scholars agree it is very unlikely such a serious disease as variola major would have escaped a description by Hippocrates if it existed in the Mediterranean region.^[50] While the Antonine Plague that swept through the Roman Empire in 165–180 AD may have been caused by smallpox,^[51] other historians speculate that Arab armies first carried smallpox out of Africa to Southwestern Europe during the 7th and 8th centuries AD.^[22] In the 9th century the Persian physician, Rhazes, provided one of the most definitive observations of smallpox and was the first to differentiate smallpox from measles and chickenpox in his Kitab fi al-jadari wa-al-hasbah (The Book of Smallpox and Measles).^[52] During the Middle Ages, smallpox made periodic incursions into Europe but did not become established there until the population increased and population movement became more active during the time of the Crusades. By the 16th century smallpox was well established over most of Europe.^[22] With its introduction in populated areas in India, China and Europe, smallpox affected mainly children, with periodic epidemics that killed up to 30% of those infected. The appearance of smallpox in Europe is of particular importance, as successive waves of European exploration and colonization served to spread the disease to other parts of the world. By the 16th century it had become an important cause of morbidity and mortality in the known world.^[22]

Smallpox sufferer in the United States, 1912

There are no credible descriptions of smallpox-like disease in the Americas before the westward exploration by Europeans in the 15th century AD.^[43] In 1507 smallpox was introduced into the Caribbean island of Hispaniola and to the mainland in 1520, when Spanish settlers from Hispaniola arriving in Mexico brought smallpox with them. Smallpox devastated the native Amerindian population and was an important factor in the conquest of the Aztecs and the Incas by the Spaniards.^[22] Settlement of the east coast of North America in 1633 in Plymouth, Massachusetts was also accompanied by devastating outbreaks of smallpox among Native American populations,^[53] and subsequently among the native-born colonists.^[54] Some estimates indicate case fatality rates of 80–90% in Native American populations during smallpox epidemics.^[55] Smallpox was introduced into Australia in 1789 and again in 1829.^[22] Although the disease was never endemic on the continent,^[22] it was the principal cause of death in Aboriginal populations between 1780 and 1870.^[56]

By the mid-18th century smallpox was a major endemic disease everywhere in the world except in Australia and in several small islands. In Europe smallpox was a leading cause of death in the 18th century, killing an estimated 400,000 Europeans each year.^[57] Through the century smallpox resulted in the deaths of perhaps 10% of all the infants of Sweden every year,^[8] and the death rate of infants in Russia may have been even higher.^[47] The widespread use of variolation in a few countries, notably Great Britain, its North American colonies, and China, somewhat reduced the impact of smallpox among the wealthy classes during the latter part of the 18th century, but a real reduction in its incidence did not occur until vaccination became a common practice toward the end of the 19th century. Improved vaccines and the practice of re-vaccination led to a substantial reduction in cases in Europe and North America, but smallpox remained almost unchecked everywhere else in the world. In the United States and South Africa a much milder form of smallpox, variola minor, was recognized just before the close of the 19th century. By the mid-20th century variola minor occurred along with variola major, in varying proportions, in many parts of Africa. Patients with variola minor experience only a mild systemic illness, are often ambulant throughout the course of the disease, and are therefore able to more easily spread disease. Infection with v. minor induces immunity against the more deadly variola major form. Thus as v. minor spread all over the USA, into Canada, the South American countries and Great Britain it became the dominant form of smallpox, further reducing mortality rates.^[22]

Eradication

Vaccination during the Smallpox Eradication and Measles Control Program in Niger, February, 1969.

Post-eradication

Three former directors of the Global Smallpox Eradication Program read the news that smallpox had been globally eradicated, 1980

The last cases of smallpox in the world occurred in an outbreak of two cases (one of which was fatal) in Birmingham, UK in 1978. A medical photographer, Janet Parker, contracted the disease at the University of Birmingham Medical School and died on September 11, 1978,^[75] after which the scientist responsible for smallpox research at the university, Professor Henry Bedson, committed suicide.^[2] In light of this incident, all known stocks of smallpox were destroyed or transferred to one of two WHO reference laboratories which had BSL-4 facilities; the Centers for Disease Control and Prevention (CDC) in the United States and the State Research Center of Virology and Biotechnology VECTOR in Koltsovo, Russia.^[76]

In 1986, the World Health Organization first recommended destruction of the virus, and later set the date of destruction to be 30 December 1993. This was postponed to 30 June 1999.^[77] Due to resistance from the US and Russia, in 2002 the World Health Assembly agreed to permit the temporary retention of the virus stocks for specific research purposes.^[78] Destroying existing stocks would reduce the risk involved with ongoing smallpox research; the stocks are not needed to respond to a smallpox outbreak.^[79] Some scientists have argued that the stocks may be useful in developing new vaccines, antiviral drugs, and diagnostic tests,^[80] however, a 2010 review by a team of public health experts appointed by the World Health Organization concluded that no essential public health purpose is served by the US and Russia continuing to retain virus stocks.^[81] The latter view is frequently supported in the scientific community, particularly among veterans of the WHO Smallpox Eradication Program.^[82]

In March 2004 smallpox scabs were found tucked inside an envelope in a book on Civil War medicine in Santa Fe, New Mexico.^[83] The envelope was labeled as containing scabs from a vaccination and gave scientists at the Centers for Disease Control and Prevention an opportunity to study the history of smallpox vaccination in the US.

Society and culture

Biological warfare

The British at least considered using smallpox as a biological warfare agent at the Siege of Fort Pitt during the French and Indian Wars (1754–63) against France and its Native American allies.^[84]^[85] Although it is not clear whether the actual use of smallpox had official sanction, on June 24, 1763, William Trent, a local trader, wrote, "Out of our regard for them [sc. representatives of the besieging Delawares], we gave them two Blankets and an Handkerchief out of the Small Pox Hospital. I hope it will have the desired effect."^[86]^[87] Historians do not agree on whether this effort to broadcast the disease was successful. It has also been alleged that smallpox was used as a weapon during the American Revolutionary War (1775–83).^[88]^[89]

During World War II, scientists from the United Kingdom, United States and Japan were involved in research into producing a biological weapon from smallpox.^[90] Plans of large scale production were never carried through as they considered that the weapon would not be very effective due to the wide-scale availability of a vaccine.^[91]

In 1947 the Soviet Union established a smallpox weapons factory in the city of Zagorsk, 75 km to the northeast of Moscow.^[92] An outbreak of weaponized smallpox occurred during testing at a facility on an island in the Aral Sea in 1971. General Prof. Peter Burgasov, former Chief Sanitary Physician of the Soviet Army and a senior researcher within the Soviet program of biological weapons, described the incident:

On Vozrozhdeniya Island in the Aral Sea, the strongest recipes of smallpox were tested. Suddenly I was informed that there were mysterious cases of mortalities in Aralsk. A research ship of the Aral fleet came to within 15 km of the island (it was forbidden to come any closer than 40 km). The lab technician of this ship took samples of plankton twice a day from the top deck. The smallpox formulation—400 gr. of which was exploded on the island—”got her” and she became infected. After returning home to Aralsk, she infected several people including children. All of them died. I suspected the reason for this and called the Chief of General Staff of Ministry of Defense and requested to forbid the stop of the Alma-Ata—Moscow train in Aralsk. As a result, the epidemic around the country was prevented. I called Andropov, who at that time was Chief of KGB, and informed him of the exclusive recipe of smallpox obtained on Vozrazhdenie Island.^[93]^[94]

Others contend that the first patient may have contracted the disease while visiting Uyaly or Komsomolsk-on-Ustyurt, two cities where the boat docked.^[95]^[96]

Responding to international pressures, in 1991 the Soviet government allowed a joint US-British inspection team to tour four of its main weapons facilities at Biopreparat. The inspectors were met with evasion and denials from the Soviet scientists, and were eventually ordered out of the facility.^[97] In 1992 Soviet defector Ken Alibek alleged that the Soviet bioweapons program at Zagorsk had produced a large stockpile—as much as twenty tons—of weaponized smallpox (possibly engineered to resist vaccines, Alibek further alleged), along with refrigerated warheads to deliver it. Alibek's stories about the former Soviet program's smallpox activities have never been independently verified.

In 1997, the Russian government announced that all of its remaining smallpox samples would be moved to the Vector Institute in Koltsovo.^[97] With the breakup of the Soviet Union and unemployment of many of the weapons program's scientists, US government officials have expressed concern that smallpox and the expertise to weaponize it may have become available to other governments or terrorist groups who might wish to use virus as means of biological warfare.^[98] Specific allegations made against Iraq in this respect, however, proved to be false.^[99]

Concern has been expressed by some that artificial gene synthesis could be used to recreate the virus from existing digital genomes, for use in biological warfare.^[100] Insertion of the synthesized smallpox DNA into existing related pox viruses could theoretically be used to recreate the virus.^[100] The first step to mitigating this risk, it has been suggested, should be to destroy the remaining virus stocks so as to enable unequivocal criminalization of any possession of the virus.^[101]

Notable cases

Famous historical figures who contracted smallpox include Lakota Chief Sitting Bull, Ramses V of Egypt,^[102] the Kangxi Emperor (survived), Shunzhi Emperor and Tongzhi Emperor (refer to the official history) of China, Date Masamune of Japan (who lost an eye to the disease). Cuitláhuac, the 10th tlatoani (ruler) of the Aztec city of Tenochtitlan, died of smallpox in 1520, shortly after its introduction to the Americas, and the Incan emperor Huayna Capac died of it in 1527. More recent public figures include Guru Har Krishan, 8th Guru of the Sikhs, in 1664, Peter II of Russia in 1730 (died),^[103] George Washington (survived), king Louis XV in 1774 (died) and Maximilian III Joseph, Elector of Bavaria in 1777.

Prominent families throughout the world often had several people infected by and/or perish from the disease. For example, several relatives of Henry VIII survived the disease but were scarred by it. These include his sister Margaret, Queen of Scotland, his fourth wife, Anne of Cleves, and his two daughters: Mary I of England in 1527 and Elizabeth I of England in 1562 (as an adult she would often try to disguise the pockmarks with heavy makeup). His great-niece, Mary, Queen of Scots, contracted the disease as a child but had no visible scarring.

In Europe, deaths from smallpox often changed dynastic succession. The only surviving son of Henry VIII, Edward VI, died from complications shortly after apparently recovering from the disease, thereby nullifying Henry's efforts to ensure a male successor to the throne (his immediate successors were all females). Louis XV of France succeeded his great-grandfather Louis XIV through a series of deaths of smallpox or measles among those earlier in the succession line. He himself died of the disease in 1774. William III lost his mother to the disease when he was only ten years old in 1660, and named his uncle Charles as legal guardian: her death from smallpox would indirectly spark a chain of events that would eventually lead to the permanent ousting of the Stuart line from the British throne. William III's wife, Mary II of England, died from smallpox as well.

In China, the Qing Dynasty had extensive protocols to protect Manchus from the Peking's endemic smallpox.

U.S. Presidents George Washington, Andrew Jackson, and Abraham Lincoln all contracted and recovered from the disease. Washington became infected with smallpox on a visit to Barbados in 1751.^[104] Jackson developed the illness after being taken prisoner by the British during the American Revolution, and though he recovered, his brother Robert did not.^[104] Lincoln contracted the disease during his Presidency, possibly from his son Tad, and was quarantined shortly after giving the Gettysburg address in 1863.^[104]

Famous theologian Jonathan Edwards died of smallpox in 1758 following an inoculation.^[105]

Soviet leader Joseph Stalin fell ill with smallpox at the age of seven. His face was badly scarred by the disease. He later had photographs retouched to make his pockmarks less apparent.^[106]

Hungarian poet Ferenc Kölcsey, who wrote the Hungarian national anthem, lost his right eye to smallpox.^[107]

Religion and mythology

As a reaction to the devastation of smallpox, smallpox gods and goddesses were invented as a mechanism to cope with the disease. Two examples of this occurred in China and India. In China, the smallpox goddess was referred to as T’ou-Shen Niang-Niang.^[108] The Chinese actively worked to please the goddess and thus keep the disease at bay. For example, the Chinese referred to the smallpox pustules as “beautiful flowers”; this was an attempt to not offend the goddess and keep her happy.^[109] The Chinese also took great measure to protect children from the dangers of smallpox by tricking their smallpox goddess. It was believed that the goddess enjoyed passing the disease to attractive children. This transmission was most likely to occur on the last night of the year, so children wore ugly masks to bed to trick the goddess into passing over them.^[109] If infection of smallpox did occur, shrines were set up in the homes of the victims. These shrines were worshipped and made offerings too while the victim was sick. If the victim recovered, the shrines were taken away from the home in a special handmade paper chair or boat and burned. If the patient did not recover, the shrine was destroyed and curses were used to remove the goddess from the house.^[108]

India’s first records of smallpox can be found in a medical book that dates back to A.D. 400. This book describes a disease that sounds exceptionally like smallpox.^[109] India, like China, created a goddess in response to its exposure to smallpox. Shitala Mata was both worshipped and feared during her reign. It was believed that this goddess was both evil and kind and had the ability to inflict victims when angered, as well as calm the fevers of the already afflicted.^[110] Portraits of the goddess show her holding a broom in her right hand to continue to move the disease and a pot of cool water in the other hand in an attempt to soothe victims.^[109] Shrines were created where many India natives, both healthy and not, went to worship and attempt to protect themselves from this disease. Some Indian women, in an attempt to ward off Shitala Mata, placed plates of cooling foods and pots of water on the roofs of their homes.^[111]

In medieval times, several countries held a belief in the smallpox demon, who was blamed for the disease. Such beliefs were prominent in Japan, Europe, Africa, and other parts of the world. Nearly all cultures who believed in the demon also believed that it was afraid of the color red, and people would often dress in red hoping to scare off the demon and cure smallpox. The belief in the color red's ability to treat smallpox persisted until the 1930s.

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External links

Wikimedia Commons has media related to: Smallpox

Smallpox Biosafety: A Website About Destruction of Smallpox Virus Stocks
Detailed CIDRAP Smallpox overview
Agent Fact Sheet: Smallpox, Center for Biosecurity
Photographs of eye damage due to smallpox
Smallpox Images and Diagnosis Synopsis
Variola Virus Genomes database search results from the Poxvirus Bioinformatics Resource Center
Virus Pathogen Database and Analysis Resource (ViPR): Poxviridae

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. 痘瘡の疫学、病因、および臨床症状 the epidemiology pathogenesis and clinical manifestations of smallpox
2. 痘瘡ワクチンとしてのワクシニアウイルス vaccinia virus as the smallpox vaccine
3. サル痘 monkeypox
4. 生物テロの犠牲者の身元確認および管理 identifying and managing casualties of biological terrorism
5. 妊娠中の予防接種 immunizations during pregnancy

English Journal

Preventing the return of smallpox: molecular modeling studies on thymidylate kinase from Variola virus.

Guimarães AP1, Ramalho TC, França TC.
Journal of biomolecular structure & dynamics.J Biomol Struct Dyn.2014 Oct;32(10):1601-12. doi: 10.1080/07391102.2013.830578. Epub 2013 Sep 2.
Smallpox was one of the most devastating diseases in the human history and still represents a serious menace today due to its potential use by bioterrorists. Considering this threat and the non-existence of effective chemotherapy, we propose the enzyme thymidylate kinase from Variola virus (VarTMPK)
PMID 23998201

Studying the immune response to human viral infections using zebrafish.

Goody MF1, Sullivan C2, Kim CH3.
Developmental and comparative immunology.Dev Comp Immunol.2014 Sep;46(1):84-95. doi: 10.1016/j.dci.2014.03.025. Epub 2014 Apr 6.
Humans and viruses have a long co-evolutionary history. Viral illnesses have and will continue to shape human history: from smallpox, to influenza, to HIV, and beyond. Animal models of human viral illnesses are needed in order to generate safe and effective antiviral medicines, adjuvant therapies, a
PMID 24718256

New York City's Innovative Epidemiologist: The Life and Career of Morris Greenberg.

Imperato PJ1, Imperato GH.
Journal of community health.J Community Health.2014 Aug;39(4):682-7. doi: 10.1007/s10900-014-9882-2.
Dr Morris Greenberg was an eminent American epidemiologist who served with the New York City Department of Health for a 40 year period, from 1920 until his passing in 1960. In 1946, he became Director of the department's Bureau of Preventable Diseases. In this role, he set very high standards for o
PMID 24838855

Japanese Journal

Lipid Characteristics of Five Epinephelinae Fishes, Epinephelus fasciatus, Epinephelus retouti, Cephalopholis aurantia, Cephalopholis miniatus, and Variola louti, in the Coral Reef

Journal of Oleo Science 63(5), 471-484, 2014
NAID 130003391389

29aRC-5 リニアコライダーのための結晶-非結晶複合標的による陽電子源開発III(29aRC 素粒子実験領域,ビーム物理領域合同 SuperKEKB/Belle II,ILC/ILD,素粒子実験領域)

日本物理学会講演概要集 68(1-1), 39, 2013-03-26
NAID 110009642565

奄美大島・加計呂麻島におけるシガテラ原因魚の毒組成解析

食品衛生学雑誌 54(6), 385-391, 2013
NAID 130003384690

Related Pictures

★リンクテーブル★

リンク元	「痘瘡」「alastrim」
拡張検索	「variola minor」「variola virus」「vaccinum variolae」

「痘瘡」

Variola virus (Smallpox)
	This transmission electron micrograph depicts a number of smallpox virions. The “dumbbell-shaped” structure inside the virion is the viral core, which contains the viral DNA; Mag. = ~370,000x
Virus classification
Group:	Group I (dsDNA)
Order:	Unassigned
Family:	Poxviridae
Subfamily:	Chordopoxvirinae
Genus:	Orthopoxvirus
Type species
	Vaccinia virus;
Species
	Variola virus

Smallpox
	Classification and external resources
	; Girl infected with smallpox. Bangladesh, 1973. In ordinary type smallpox the bumps are filled with a thick, opaque fluid and often have a depression or dimple in the center. This is a major distinguishing characteristic of smallpox.
ICD-10	B03
ICD-9	050
DiseasesDB	12219
MedlinePlus	001356
eMedicine	emerg/885
MeSH	D012899

　　[★]

英: smallpox, variola major
ラ: variola
同: 天然痘、疱瘡
関: smallpox

こっちの方がややメジャー？

「alastrim」

　　[★]

痘瘡、乳痘、白痘

関: smallpox、variola、variola minor

「variola minor」

　　[★]

小痘瘡

関: alastrim、smallpox、variola

「variola virus」

　　[★]

痘瘡ウイルス

関: smallpox virus

「vaccinum variolae」

　　[★] ワクシニアウイルス

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Smallpox
Classification and external resources
Girl infected with smallpox. Bangladesh, 1973. In ordinary type smallpox the bumps are filled with a thick, opaque fluid and often have a depression or dimple in the center. This is a major distinguishing characteristic of smallpox.
ICD-10	B03
ICD-9	050
DiseasesDB	12219
MedlinePlus	001356
eMedicine	emerg/885
MeSH	D012899

“	Having considered the development and results of the global program on smallpox eradication initiated by WHO in 1958 and intensified since 1967 … Declares solemnly that the world and its peoples have won freedom from smallpox, which was a most devastating disease sweeping in epidemic form through many countries since earliest time, leaving death, blindness and disfigurement in its wake and which only a decade ago was rampant in Africa, Asia and South America."	”
—World Health Organization, Resolution WHA33.3^[75]

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variola