Smallpox

Wikipedia

Smallpox is 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 Europe in the 15th century to distinguish variola from the "great pox" (syphilis).[2]

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.[3][4] Long-term complications of V. major infection include characteristic scars, commonly on the face, which occur in 65–85% of survivors.[5] 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 disease killed an estimated 400,000 Europeans each year during the 18th century (including five reigning monarchs), and was responsible for a third of all blindness.[3] Of all those infected, 20–60%—and over 80% of infected children—died from the disease.[6]

During the 20th century, it is estimated that smallpox was responsible for 300–500 million deaths.[7][8][9] In the early 1950s an estimated 50 million cases of smallpox occurred in the world each year.[10] As recently as 1967, the World Health Organization estimated that 15 million people contracted the disease and that two million died in that year.[10] After successful vaccination campaigns throughout the 19th and 20th centuries, the WHO certified the eradication of smallpox in December 1979.[10] To this day, smallpox is the only human infectious disease to have been completely eradicated.[11]

[edit] Cause

Electron micrograph of smallpox.

Smallpox is caused by infection with variola virus, which belongs to the genus Orthopoxvirus, the family Poxviridae, and subfamily chordopoxvirinae. Variola virus is a large brick-shaped virus measuring approximately 302 to 350 nanometers by 244 to 270 nm,[12] with a single linear double stranded DNA genome 186 kilobase pairs (kbp) in size and containing a hairpin loop at each end.[13][14] 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.[15]

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.[13] Infection with either variola major or variola minor confers immunity against the other.[4]

[edit] Evolution

Smallpox appears to have evolved from an African rodent-borne variola-like virus.[16] 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.

[edit] 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.[17] The virus can cross the placenta, but the incidence of congenital smallpox is relatively low.[4] 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.[15] 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.[18]

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.[15] 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.[4] Smallpox is not known to be transmitted by insects or animals and there is no asymptomatic carrier state.[15]

[edit] 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:[19] ordinary, modified, flat, and hemorrhagic. Historically, variola major has an overall fatality rate of about 30%; however, flat and hemorrhagic smallpox are usually fatal.[20] 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.[15]

Variola minor is a less common presentation of smallpox, and a much less severe disease, with historical death rates of 1% or less.[17] Subclinical (asymptomatic) infections with variola virus have also been noted, but are not believed to be common.[15]

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.[4]

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.[4] At this point Variola major infection can take several very different courses.

[edit] Ordinary

Ninety percent or more of smallpox cases among unvaccinated persons are of the ordinary type.[15] 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.[4]

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.[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. 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%.[15]

[edit] 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.[15]

This man is suffering from severe hemorrhagic-type smallpox.

[edit] 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.[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 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.[15]

[edit] 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.[15] 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.[4] This form of smallpox occurs in anywhere from 3–25% of fatal cases depending on the virulence of the smallpox strain.[20] Hemorrhagic smallpox is usually fatal.[15]

[edit] 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 and the absence of Guarnieri bodies cannot be used to rule out smallpox.[23] 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.[4]

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.[24] 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.[25]

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.

[edit] 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.

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.[15] 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.

[edit] 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.[15]

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.[4]

[edit] 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.[26] 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.[27]

[edit] Prevention

Vial containing variolation material (India, early 1970s.)

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,[28] 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.[29] 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.[30] 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.[15]

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.[15]

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.[26] 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.[31]

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 52 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).[26]

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.[32] It is now primarily recommended for laboratory workers at risk for occupational exposure.[15] Mass smallpox vaccination was abandoned in most European countries in the early 1970s as well.[33]

[edit] Eradication

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

Since Jenner demonstrated the effectiveness of cowpox to protect humans from smallpox in 1796, various attempts were made to eliminate smallpox on a regional scale. As early as 1803, the Spanish Crown organized a mission (the Balmis expedition) to transport the vaccine to the Spanish colonies in the Americas and the Philippines, and establish mass vaccination programs there. [34] By about 1817, a very solid state vaccination programme existed in the Dutch East Indies.[35] In British India a program was launched to propagate smallpox vaccination, through Indian vaccinators, under the supervision of European officials.[36] By 1832, the federal government of the United States established a smallpox vaccination program for Native Americans.[37] In 1842, England banned inoculation, later progressing to mandatory vaccination. The British government introduced compulsory smallpox vaccination by an Act of Parliament in 1853.[38] In the United States, from 1843 to 1855 first Massachusetts, and then other states required smallpox vaccination. Although some disliked these measures,[39] coordinated efforts against smallpox went on, and the disease continued to diminish in the wealthy countries. By 1897, smallpox had largely been eliminated from the United States.[40] In Northern Europe a number of countries had eliminated smallpox by 1900, and by 1914, the incidence in most industrialized countries had decreased to comparatively low levels. Vaccination continued in industrialized countries, until the mid to late 1970s as protection against reintroduction. Australia and New Zealand are two notable exceptions; neither experienced endemic smallpox and never vaccinated widely, relying instead on protection by distance and strict quarantines.[41]

The first hemisphere-wide effort to eradicate smallpox was made in 1950 by the Pan American Health Organization.[42] The campaign was successful in eliminating smallpox from all American countries except Argentina, Brazil, Colombia, and Ecuador.[41] In 1958 Professor Viktor Zhdanov, Deputy Minister of Health for the USSR, called on the World Health Assembly to undertake a global initiative to eradicate smallpox. The proposal (Resolution WHA11.54) was accepted in 1959.[43] At this point, 2 million people were dying every year. Overall, however, progress towards eradication was disappointing, especially in Africa and in the Indian subcontinent. In 1967, the World Health Organization intensified the global smallpox eradication by contributing $2.4 million annually to the effort. An international team, the Smallpox Eradication unit, was formed under the leadership of an American, Donald Henderson.[44]

To eradicate smallpox, each outbreak had to be stopped from spreading, by isolation of cases and vaccination of everyone who lived close by. This process is known as "ring vaccination". The key to this strategy was monitoring of cases in a community (known as surveillance) and containment. The initial problem the WHO team faced was inadequate reporting of smallpox cases, as many cases did not come to the attention of the authorities. The fact that humans are the only reservoir for smallpox infection, and that carriers did not exist, played a significant role in the eradication of smallpox. The WHO established a network of consultants who assisted countries in setting up surveillance and containment activities. Early on donations of vaccine were provided primarily by the Soviet Union and the United States, but by 1973, more than 80% of all vaccine was produced in developing countries.[41]

This 1980 photograph, taken at the CDC, shows three former directors of the Global Smallpox Eradication Program as they read the news that smallpox had been globally eradicated.

The last major European outbreak of smallpox was in 1972 in Yugoslavia, after a pilgrim from Kosovo returned from the Middle East, where he had contracted the virus. The epidemic infected 175 people, causing 35 deaths. Authorities declared martial law, enforced quarantine, and undertook massive re-vaccination of the population, enlisting the help of the WHO. In two months, the outbreak was over.[45] Prior to this, there had been a smallpox outbreak in May–July 1963 in Stockholm, Sweden, brought from the Far East by a Swedish sailor; this had been dealt with by quarantine measures and vaccination of the local population.[46]

By the end of 1975, smallpox persisted only in the Horn of Africa. Conditions were very difficult in Ethiopia and Somalia, where there were few roads. Civil war, famine, and refugees made the task even more difficult. An intensive surveillance and containment and vaccination program was undertaken in the spring and summer of 1977. The last naturally occurring case of indigenous smallpox (Variola minor) was diagnosed in Ali Maow Maalin, a hospital cook in Merca, Somalia, on 26 October 1977.[15] The last naturally occurring case of the more deadly Variola major had been detected in October 1975 in a two-year-old Bangladeshi girl, Rahima Banu.[47]

The global eradication of smallpox was certified, based on intense verification activities in countries, by a commission of eminent scientists on 9 December 1979 and subsequently endorsed by the World Health Assembly on 8 May 1980[10][48] as Resolution WHA33.3. The first two sentences of the resolution read: "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."[49]

[edit] Post-eradication

The last cases of smallpox in the world occurred in an outbreak of two cases (one of which was fatal) in Birmingham, England in 1978. A medical photographer, Janet Parker, contracted the disease at the University of Birmingham Medical School and died on 11 September 1978,[49] after which the scientist responsible for smallpox research at the university, Professor Henry Bedson, committed suicide.[2] In light of this accident, all known stocks of smallpox were destroyed or transferred to one of two WHO reference laboratories; 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 where a regiment of troops guard it.[50] In 1986, the World Health Organization recommended destruction of the virus, and later set the date of destruction to be 30 December 1993. This was postponed to 30 June 1995.[51] In 2002 the policy of the WHO changed to be against its final destruction.[52] Destroying existing stocks would reduce the risk involved with ongoing smallpox research; the stocks are not needed to respond to a smallpox outbreak.[53] However, the stocks may be useful in developing new vaccines, antiviral drugs, and diagnostic tests.[54]

In March 2004 smallpox scabs were found tucked inside an envelope in a book on Civil War medicine in Santa Fe, New Mexico.[55] 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.

[edit] Biological warfare

The British may have used smallpox as a biological warfare agent during the French and Indian Wars (1754–63), against France and its Native American allies at the Siege of Fort Pitt. It has been alleged that smallpox was also used as a weapon during the American Revolutionary War (1775–83).[56]

During World War II, scientists from the United Kingdom, United States and Japan were involved in research into producing a biological weapon from smallpox.[57] 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.[56] The Soviet Union established a smallpox weapons factory in 1947 in the city of Zagorsk, 75 km to the northeast of Moscow.[58]

An outbreak of weaponized smallpox possibly occurred during testing in the 1970s. 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.”[59][60]

Others contend that the first patient may have contracted the disease while visiting Uyaly or Komsomolsk, two cities where the boat docked.[61]

[edit] History

Aztecs dying of smallpox, (“The Florentine Codex” 1540-1585)

Smallpox likely diverged from an ancestral African rodent-borne variola-like virus between 16,000 and 68,000 years ago.[16] However, the precise origins of smallpox are unknown, and most early references to it are unreliable. Historical records from Asia describe evidence of smallpox-like disease in medical writings from ancient China (1122 B.C.) and India (as early as 1500 B.C.)[39] The earliest credible clinical evidence of smallpox is found in the Egyptian mummies of persons who died some 3000 years ago. 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. Unmistakable descriptions of smallpox first appeared in the 4th century AD in China and the 7th century in India. Smallpox was likely introduced in China during the 1st century AD from the southwest, and in the 6th century was carried from China to Japan.[22]

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.[62] While the Antonine Plague that swept through the Roman Empire in 165–180 AD may have been caused by smallpox,[63] 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).[64] 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: Illinois, 1912

There are no credible descriptions of smallpox-like disease in the Americas before the westward exploration in the 15th century AD.[16] 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, and subsequently among the native-born colonists.[65] Smallpox was introduced into Australia in 1789 and again in 1829 and caused devastation among the aborigines, but quickly died out on both occasions.[22]

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, including five reigning European monarchs.[66] In Russia every 7th child born died from smallpox.[10] The widespread use of variolation in a few countries, notably Great Britain and its North American colonies, 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. Additionally, 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 would become the dominant form of smallpox, further reducing mortality rates.[22]

[edit] Famous sufferers and survivors

Famous historical figures who contracted smallpox include Lakota Chief Sitting Bull, Ramses V of Egypt,[48] 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 1744,[67] and Maximilian III Joseph, Elector of Bavaria in 1777. Maharaja Ranjit Singh, the Lion of the Punjab, lost sight in his left eye due to an attack of smallpox during his childhood.[68]

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 daughter, Elizabeth I of England in 1562 (as an adult she would often try to disguise the pockmarks with heavy makeup). A more distant relative, Mary, Queen of Scots, contracted the disease as a child but had no visible scarring.

In Europe, deaths from smallpox often changed dynastic succession. 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. The only surviving son of Henry VIII, Edward VI, likely died from complications shortly after apparently recovering from the disease, thereby rendering his sire's infamous efforts to provide England with a male heir moot. (His immediate successors were all females.) 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.

Mozart and Beethoven contracted and survived the disease as children; both had visible pockmark scars on their faces.

Both George Washington and Abraham Lincoln, Presidents of the United States, contracted and recovered from the disease. Joseph Stalin, who was badly scarred by the disease early in life, often had photographs retouched to make his pockmarks less apparent[citation needed].

Andrew Jackson and his older brother, Robert, contracted smallpox in his youth while imprisoned by the British during the American Revolutionary War. While Robert died from the disease, Andrew survived it and eventually served as the 7th President of the United States.

Crime figure Lucky Luciano contracted the disease in 1907 at the age of ten, upon coming to New York from Sicily.

Indian actress Geeta Bali died of smallpox in 1965.

Turkish poet Aşık Veysel Şatıroğlu was blinded by smallpox at the age of seven.

Hungarian poet Ferenc Kölcsey, who wrote the Hungarian anthem, lost his right eye to smallpox.

[edit] See also

[edit] References

[edit] Further reading

[edit] External links

• Smallpox Biosafety The Genetic Engineering of Smallpox: WHO’s Retreat from the Eradication of Smallpox Virus
• 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

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Annotations

• N steve h on Fri 7 Mar 2003, 03:36am. Flag this

  Smallpox was the major epidemic disease in Europe in the 17th century, when it really took off. It was a major problem in London in this period, with what seem to be a new series of epidemics from 1659 onward. Demographers believe that factors promoting the worst outbreaks smallpox in England included low temperatures in winter, low rainfall in autumn, crowding in the city, and malnutrition. Living in London was bad for your health.

• N vincent on Sun 21 Dec 2003, 04:38am. Flag this

  who discouvered the cure first:
  The Introduction of Inoculation to the West
  http://www.foundersofscience.net/lady_mary_montagu.htm
  from letter by Letter of Lady Montegu: …… To Sarah Chiswell …….. Adrianople 1, April 1717
  They make parties for this purpose, and when they are met (commonly fifteen or sixteen together) the old woman comes with a nutshell full of the matter of the best sort of smallpox and asks what veins you please to have opened. She immediately {ug}
  other leads [cowx-smallpox google]
  Edward Jenner learned early in his medical career of the farm worker’s’ belief that if at one time one had cowpox, one would not get smallpox

  http://www.foundersofscience.net/jenner.htm
  then man at his most ….
  An early BW attack took place in the Black Sea port of Kaffa (now Feodossia, Ukraine) in 1346. Rats and their fleas carried the disease to attacking Tatar soldiers. In spite, the Tatars catapulted the bodies of victims at the defending Genoese who contracted plague and left Kaffa. The same rats afflicting the Tatars likely brought disease to the Genoese.[5]
  Another attempted use of biological warfare occurred between 1754 and 1767 when the British infiltrated smallpox-infested blankets to unsuspecting American Indians during the French and Indian war. Smallpox decimated the Indians, but it is unclear if the contaminated blankets or endemic disease brought by the Europeans caused these epidemics.[92]
  http://www.toxicmold.org/documents/0376.html
  

• N vicente on Mon 16 Aug 2004, 03:04am. Flag this

  leads for those of enquiring mind :
  More on smallpox and who dun it first. It appears not one of the begowned ones.At the time, Reverend Cotton Mather lived in Boston had known of the practice of inoculation since 1706. A slave, Onesimus, had explained to him how he had been inoculated as a child in Africa. The practice was an ancient one, and Mather was fascinated by the idea. He encouraged physicians to try it, without success. Then, at Mather’s urging, one doctor, Zabdiel Boylston, was courageous enough to use the procedure.
  ………………….
  Around the fifteenth century, a practice of applying powdered smallpox “crusts” and inserting them with a pin or

• N dirk on Mon 16 Aug 2004, 07:13pm. Flag this

  Lady Mary Mortley Montagu

  Vincent, is she in any way related to “my Lord” - just curiosity. (I know it killed the cat!)
  

• N vicente on Mon 16 Aug 2004, 08:44pm. Flag this

  interesting: she married Wortley:
  here not sorted:
  Lady Mary Wortley Montagu (1689-1762)
  Her father, Evelyn Pierrepont, was connected with the Evelyns of Wootton, and married Mary Feilding, daughter of the earl of Denbigh, from one of whose brothers Henry Fielding the novelist descended. Mary was born in May, 1689; a year later, her father became earl of Kingston and, at the whig triumph of 1715, duke of Kingston; she was brought up, carelessly enough, in a library….One of her girl friends was Anne Wortley Montagu, a granddaughter of the first earl of Sandwich (Pepys

• N vicente on Mon 16 Aug 2004, 09:04pm. Flag this

  “Evelyn Pierrepont” Evelyns Diary: Evelyn, grand pa had 16 sons and * daughters. One daughter became mother of the ‘present’ Evelyn, Earle of Kinston and son of William Perpoint: interesting read, page 2 of DeBeers version of Kalendarium by J.E..
  Evelyn fortune was derived from Powder workes.

• N Sjoerd on Tue 17 Aug 2004, 01:19pm. Flag this

  So to answer Dirk’s question:

  Yes, by marriage:
  This Lady Mary Wortley (not Mortley) Montagu was married to Edward Wortley Montagu, son of Edward Montagu, who adopted his wife’s name Wortley.

  This Edward Wortley Montagu was the second son of the 1st Earl of Sandwich, “Mylord”.

  See http://www.twickenham-museum.org.uk/detail.asp?ContentID=180

  and http://www.montaguemillennium.com/familyresearch/h_1762_mary.htm
  

• N Sjoerd on Tue 17 Aug 2004, 01:41pm. Flag this

  Sorry, that second son was a Sidney, not an Edward. So the two sons that were first inoculated against smallpox by Lady Mary were grandsons of the Sidney that stayed overnight at the pepys household for fear of smallpox.

  See http://www.geocities.com/mbrodgers/wga77.html#I18482

  for a family tree
  

• N Paul Timbrell on Fri 3 Sep 2004, 09:14am. Flag this

  It seems to me that these comments are barking up the wrong tree for 2nd September 1661. This is not a reference to smallpox but to venereal disease.The context is ” the vices of the Court “. Surely smallpox was not as common as eating and swearing. The Oxford Dictionary defines pox as syphilis.

• N Tim Owen on Fri 3 Sep 2004, 12:27pm. Flag this

  In context this almost certainly means venereal disease. If true, given the incubation period and symptoms of syphillis it is more likely to be a less critical GU infection. However I suspect this is a comment generally critical of Court morals with minimal basis in fact - then, as now, I don’t think prominent members of society would reveal such an infection.

• N vicente on Fri 3 Sep 2004, 10:00pm. Flag this

  pox: Pock- mark: pox on ye , cow- small- chicken-, any of the outbreak of pustles or eruptions; or animal poxes. Then the unmentionable not in polite company.
  

• N Jess A on Mon 22 Nov 2004, 08:15pm. Flag this

  Hey I was wondering why did milk maids way way way back then, didn’t get small pox?

• N guye ffalkes on Mon 22 Nov 2004, 08:58pm. Flag this

  No one put two and two to-gether to make a case of molehills out of the mountain. “didn

• N Grahamt on Mon 22 Nov 2004, 09:38pm. Flag this

  Why milkmaids didn’t get smallpox
  Follow the links above for the full story, but:
  Edward Jenner noticed that milkmaids who developed cowpox, a less serious disease, did not develop the deadly smallpox. In 1796, Jenner took the fluid from a cowpox pustule on a dairymaid’s hand and inoculated an 8-year-old boy. Six weeks later, he exposed the boy to smallpox, and the boy did not develop any symptoms. Jenner coined the term “vaccine” from the word “vaca” which means “cow” in Latin. (more at: http://dermatology.about.com/cs/smallpox/a/smallpoxhx.htm ) variolation described above used actual smallpox matter, not cowpox, and killed 2-3% of the patients.

• N Cumgranissalis on Sun 31 Jul 2005, 03:48am. Flag this

  For the enquiring mind on ‘pox or “The Speckled Monster ” . by Jennifer Lee Carrell PHD lit Harvard, dothe write a nice but not a best seller [maybe not enough on the famous cousen ‘pox and its means of transmission] on the Disease that killed more than the bubonic, only to be eradicated by 1980’s although some governments have been rumored to keep a few samples for future scientfic studies.
  Book going for 5$ orig 26 bucks At Barnes and Nobel. The notes and sources be worth that for those that be interested in 17C/18C doings.
  It be a nice insight to the life of the wealthy, as added plus for those wish to know the life of the betters .
  A quote from a letter of Lady Mary to Papa “… the Small Pox—-so fatal and so general amongst us —-is here rendered harmless, by the invention of engrafting {which is the term the give it}. There is a set of old women who make it their business t perform the operation. Every autumn in the month of September, when the great heat is abated,……They make parties for this purpose, and when they are met…..the old woman comes with a nutshell full of the matter of the best sort of smallpox and asks what veins you please to have opened. ….”Page 73. dated April 1 1717 Adrianople Lady Mary [Mortley]
  was this another BBC Panorama story it being the day it be.

• N Cumgranissalis on Sun 31 Jul 2005, 04:51am. Flag this

  The poxes, there be cow, small then there be the one that will be never mention in Polite Society -The Great Pox [syphalis]

• N Cumgranissalis on Sun 7 Aug 2005, 05:19am. Flag this

  Where are you going my prety maid?
  I’m going a-milking, Sir she said
  whats’s your fortune my pretty maid?
  My face is my fortune Sir, she said. Anon
  A good read be ” The Armies of Pestilence ” by R.S. Bray

  Virus transmission by air droplets not by touch. It came in three strengths : Haemorihagic, Purpuric, and Confluent. Kill Rate 25% to 100 %
  then their be another version, alastrum [fast spreading] death rate only 1%;
  It was known, that once had, it never to be had again.
  Strangely, it was reckoned to less contageous than Chicken pox as the droplets had to be inbedded deeper into the brachea.

  There was a cure, not fully understood or practiced way back in China [early christian era] and elsewhere , it be called practice of variopation, or putting the scabs of small pox into the nostrils of those wish to have their skin unmarked, dosage be uneven so success be uneven.
  The beginnings of story of the virus be lost by the lack of documentaion, but there be some that claim Athens and Cathage had their differences resolved by an out break of the disease.The Disease had a reputation for changeing the course of many dynasties.

• N Cumgranissalis on Sun 7 Aug 2005, 05:27am. Flag this

  The Great pox appeared in Europe after The Discovery of the West Indies. Small pox was known as killer long before the lower brain version.

• N Cumgranissalis on Sun 7 Aug 2005, 09:19pm. Flag this

  ref 2 sep 61: be the pox that be the one that does not kill in days of it showing only to disappear, then erode the little gray cells then the demise. This be a virus by contact, selecting ones victim by attraction, not by sleeping or convorting , needs more than a friendly kiss or rubbing noses. ‘Tis why it be called the Great pox.
  “…how the pox is so common there,…”
  

• N Horst Fassl on Fri 16 Mar 2007, 07:24am. Flag this

  Most probably it was not small-pox but syphilis, signs and symptoms are rather typical. Fassl

• N cumsalisgrano on Tue 1 May 2007, 07:27pm. Flag this

  From Ruben
  Measles [ http://www.pepysdiary.com/p/7119.php ] versus smallpox not an easy diagnosis in Pepys time.
  A famous Poster published by Thomas Thacher in the colonies explains some. See:
  http://www.countway.harvard.edu/rarebooks/exhibits/gilt/gilt3.html

  From terry F:
  “[T]he first scientific description of the [measles] and its distinction from smallpox is attributed to the Persian physician Ibn Razi (Rhazes) 860-932 who published a book entitled “Smallpox and Measles” (in Arabic: Kitab fi al-jadari wa-al-hasbah).” http://en.wikipedia.org/wiki/Measles
  

• N bitter o salt on Fri 17 Aug 2007, 03:22am. Flag this

  syphilis not a word in use as a medical problem in Egland until 1718?
  OED
  Also 8 siphylis, 9 siphilis, syphylis. [mod.L. syphilis (syphilid-), orig. the title (in full, Syphilis, sive Morbvs Gallicvs) of a poem, published 1530, by Girolamo Fracastoro or Hieronymus Fracastorius (1483-1553), a physician, astronomer, and poet of Verona, but used also as the name of the disease in the poem itself; the subject of the poem is the story of a shepherd Syphilus, the first sufferer from the disease, the name Syphilis being formed on the analogy of Æneis, Thebais, etc. (The poem was translated in 1686 by Nahum Tate with the title ‘Syphilis: or, a Poetical History of the French Disease’.) The term was employed systematically by Fracastoro in his treatise De Contagione II. xi. (1546). Cf. F. syphilis, It. sifilide, Sp. sifilis, Pg., G., etc. syphilis.
  The source of the name Syphilus is disputed; it has been suggested that it is a corrupt mediæval form of Sipylus, the name of a son of Niobe (so called after a mountain) in Ovid Metam. VI. 146 ff. (See F. Boll in Neue Jahrb. f.d. klass. Altertum, 1910, XXV. 72 ff., 168.)]

  A specific disease caused by Treponema pallidum (Spirochæte pallida) and communicated by sexual connexion or accidental contact (acquired form) or by infection of the child in utero (congenital form).
  Three stages of the disease are distinguished, primary, secondary, and tertiary syphilis; the first characterized by chancre in the part infected, the second by affections of the skin and mucous membranes, the third involving the bones, muscles, and brain.
  1718 J. F. NICHOLSON (title) The Modern Siphylis: or, the true method of curing every stage and symptom of the venereal disease, etc.
  

References in the diary

1660

Dec: 20

1661

Aug: 12, 13
Sep: 2

1663

Dec: 31

1664

Mar: 15
Apr: 29
Aug: 15
Oct: 31

1665

Jan: 15
Mar: 17
Aug: 16