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Smallpox was an infectious disease caused by Variola virus, which belongs to the genus Orthopoxvirus. The last naturally occurring case was diagnosed in October 1977, and the World Health Organization (WHO) certified the global eradication of the disease in 1980, making smallpox the only human disease to have been eradicated.

Classification
There are two forms of the smallpox. Variola major is the severe and more common form, with a more extensive rash and higher fever. Variola minor is a less common presentation, causing less severe disease, typically discrete smallpox, with historical death rates of 1% or less. Subclinical (asymptomatic) infections with variola virus were noted but were not common. In addition, a form called variola sine eruptione (smallpox without rash) was seen generally in vaccinated persons. This form was marked by a fever that occurred after the usual incubation period and could be confirmed only by antibody studies or, rarely, by viral culture. In addition, there were two very rare and fulminating types of smallpox, the malignant (flat) and hemorrhagic forms, which were usually fatal. == Signs and symptoms ==
Signs and symptoms
The initial symptoms were similar to other viral diseases that are still extant, such as influenza and the common cold: fever of at least , muscle pain, malaise, headache and fatigue. As the digestive tract was commonly involved, nausea, vomiting, and backache often occurred. The early prodromal stage usually lasted 2–4 days. By days 12–15, the first visible lesions – small reddish spots called enanthem – appeared on mucous membranes of the mouth, tongue, palate, and throat, and the temperature fell to near-normal. These lesions rapidly enlarged and ruptured, releasing large amounts of virus into the saliva. ordinary, modified, malignant (or flat), and hemorrhagic smallpox. Historically, ordinary smallpox had an overall fatality rate of about 30%, and the malignant and hemorrhagic forms were usually fatal. The modified form was almost never fatal. In early hemorrhagic cases, hemorrhages occurred before any skin lesions developed. The incubation period between contraction and the first obvious symptoms of the disease was 7–14 days. Ordinary At least 90% of smallpox cases among unvaccinated persons were of the ordinary type. Ordinary smallpox generally produced a discrete rash, in which the pustules stood out on the skin separately. The distribution of the rash was most dense on the face, denser on the extremities than on the trunk, and denser on the distal parts of the extremities than on the proximal. The palms of the hands and soles of the feet were involved in most cases. The skin becomes dusky and erythematous, and this is rapidly followed by the development of petechiae and bleeding in the skin, conjunctiva and mucous membranes. Death often occurs suddenly between the fifth and seventh days of illness, when only a few insignificant skin lesions are present. Some people survive a few days longer, during which time the skin detaches and fluid accumulates under it, rupturing at the slightest injury. People are usually conscious until death or shortly before. This form is more likely to occur in pregnant women than in the general population (approximately 16% of cases in unvaccinated pregnant women were early hemorrhagic smallpox, versus roughly 1% in nonpregnant women and adult males). The case fatality rate of early hemorrhagic smallpox approaches 100%. Late There is also a later form of hemorrhagic smallpox (referred to late hemorrhagic smallpox, or variolosa pustula hemorrhagica). The prodrome is severe and similar to that observed in early hemorrhagic smallpox, and the fever persists throughout the course of the disease. Bleeding appears in the early eruptive period (but later than that seen in purpura variolosa), and the rash is often flat and does not progress beyond the vesicular stage. Hemorrhages in the mucous membranes appear to occur less often than in the early hemorrhagic form. Sometimes the rash forms pustules which bleed at the base and then undergo the same process as in ordinary smallpox. This form of the disease is characterized by a decrease in all of the elements of the coagulation cascade and an increase in circulating antithrombin. This form of smallpox occurs anywhere from 3% to 25% of fatal cases, depending on the virulence of the smallpox strain. Most people with the late-stage form die within eight to 10 days of illness. Among the few who recover, the hemorrhagic lesions gradually disappear after a long period of convalescence. The case fatality rate for late hemorrhagic smallpox is around 90–95%. Pregnant women are slightly more likely to experience this form of the disease, though not as much as early hemorrhagic smallpox. == Cause ==
Cause
Smallpox is caused by infection with Variola virus, which belongs to the family Poxviridae, subfamily Chordopoxvirinae, genus Orthopoxvirus. Evolution The date of the appearance of smallpox is not settled. It most probably evolved from a terrestrial African rodent virus between 68,000 and 16,000 years ago. 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 (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 virus from Taterapox (an Orthopoxvirus of some African rodents including gerbils) at 3,000 to 4,000 years ago. This is consistent with archaeological and historical evidence regarding the appearance of smallpox as a human disease which suggests a relatively recent origin. If the mutation rate is assumed to be similar to that of the herpesviruses, the divergence date of variola virus from Taterapox has been estimated to be 50,000 years ago. The mutation rate of this virus is well modeled by a molecular clock. Diversification of strains only occurred in the 18th and 19th centuries. Virology Variola virus is large and brick-shaped and is approximately 302 to 350 nanometers by 244 to 270 nm, with a single linear double stranded DNA genome 186 kilobase pairs (kbp) in size and containing a hairpin loop at each end. 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 an experimental setting. Vaccinia, cowpox, and monkeypox viruses can infect both humans and other animals in nature. The life cycle of poxviruses is complicated by having multiple infectious forms, with differing mechanisms of cell entry. Poxviruses are unique among human DNA viruses in that they replicate in the cytoplasm of the cell rather than in the nucleus. 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. Variola major The more common, infectious form of the disease was caused by the variola major virus strain, known for its significantly higher mortality rate compared to its counterpart, variola minor. Variola major had a fatality rate of around 30%, while variola minor's mortality rate was about 1%. Throughout the 18th century, variola major was responsible for around 400,000 deaths annually in Europe alone. Survivors of the disease often faced lifelong consequences, such as blindness and severe scarring, which were nearly universal among those who recovered. In the first half of the 20th century, variola major was the primary cause of smallpox outbreaks across Asia and most of Africa. Meanwhile, variola minor was more commonly found in regions of Europe, North America, South America, and certain parts of Africa. Variola minor Variola minor virus, also called alastrim, was a less common form of the virus, and much less deadly. Although variola minor had the same incubation period and pathogenetic stages as smallpox, it is believed to have had a mortality rate of less than 1%, as compared to variola major's 30%. Like variola major, variola minor was spread through inhalation of the virus in the air, which could occur through face-to-face contact or through fomites. Infection with variola minor virus conferred immunity against the more dangerous variola major virus. Because variola minor was a less debilitating disease than smallpox, people were more frequently ambulant and thus able to infect others more rapidly. As such, variola minor swept through the United States, Great Britain, and South Africa in the early 20th century, becoming the dominant form of the disease in those areas and thus rapidly decreasing mortality rates. Along with variola major, the minor form has now been totally eradicated from the globe. The last case of indigenous variola minor was reported in a Somali cook, Ali Maow Maalin, in October 1977, and smallpox was officially declared eradicated worldwide in May 1980. It is made from linear double stranded DNA and contains the coding sequence for about 200 genes. The genes are usually not overlapping and typically occur in blocks that point towards the closer terminal region of the genome. The coding sequence of the central region of the genome is highly consistent across orthopoxviruses, and the arrangement of genes is consistent across chordopoxviruses. Research with the remaining virus samples is tightly controlled, and each research proposal must be approved by the WHO and the World Health Assembly (WHA). The genome of variola major virus was first sequenced in its entirety in the 1990s. Genetic engineering The WHO currently bans genetic engineering of the variola virus. However, in 2004, a committee advisory to the WHO voted in favor of allowing editing of the genome of the two remaining samples of variola major virus to add a marker gene. The insertion of this gene, which would not influence the virulence of the virus, would be the only allowed modification of the genome. Addition of the GFP gene to the Vaccinia genome is routinely performed during research on the closely related vaccinia virus. Controversies The public availability of the variola virus complete sequence has raised concerns about the possibility of illicit synthesis of infectious virus. Vaccinia, a cousin of the variola virus, was artificially synthesized in 2002 by NIH scientists. They used a previously established method that involved using a recombinant viral genome to create a self-replicating bacterial plasmid that produced viral particles. The researchers argued that their work would be beneficial to creating a safer and more effective vaccine for smallpox, although an effective vaccine is already available. Some infections of laundry workers with smallpox after handling contaminated bedding suggested that smallpox could be spread through direct contact with contaminated objects (fomites), but this was found to be rare. Concern about possible use of smallpox for biological warfare led in 2002 to Donald K. Milton's detailed review of existing research on its transmission and of then-current recommendations for controlling its spread. He agreed, citing Rao, Fenner and others, that "careful epidemiologic investigation rarely implicated fomites as a source of infection"; noted that "Current recommendations for control of secondary smallpox infections emphasize transmission 'by expelled droplets to close contacts (those within 6–7 feet)'"; but warned that the "emphasis on spread via large droplets may reduce the vigilance with which more difficult airborne precautions [i.e. against finer droplets capable of traveling longer distances and penetrating deeply into the lower respiratory tract] are maintained". == Mechanism ==
Mechanism
Once inhaled, the variola virus invaded the mucous membranes of the mouth, throat, and respiratory tract. From there, it migrated to regional lymph nodes and began to multiply. In the initial growth phase, the virus seemed to move from cell to cell, but by around the 12th day, widespread lysis of infected cells occurred and the virus could be found in the bloodstream in large numbers, a condition known as viremia. This resulted in the second wave of multiplication in the spleen, bone marrow, and lymph nodes. == Diagnosis ==
Diagnosis
The clinical definition of ordinary smallpox is an illness with acute onset of fever equal to or greater than followed by a rash characterized by firm, deep-seated vesicles or pustules in the same stage of development without other apparent cause.. With greater testing availability, clinically diagnosed cases of smallpox were confirmed using laboratory tests. Microscopically, poxviruses produce characteristic cytoplasmic inclusion bodies, 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 could not be used to rule out smallpox. The diagnosis of an orthopoxvirus infection can also be made rapidly by electron microscopic examination of pustular fluid or scabs. All orthopoxviruses exhibit identical brick-shaped virions by electron microscopy. Strains were characterized by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. Serologic tests and enzyme linked immunosorbent assays (ELISA), which measured variola virus-specific immunoglobulin and antigen were also developed to assist in the diagnosis of infection. Chickenpox was commonly confused with smallpox in the immediate post-eradication era. Chickenpox and smallpox could 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 were available for detecting chickenpox in the evaluation of suspected smallpox cases. File:Smallpox CAM.png|Smallpox virus lesions on the chorioallantoic membrane of a developing chick File:Smallpox versus chickenpox english plain.svg|In contrast to the rash in smallpox, the rash in chickenpox occurs mostly on the torso, spreading less to the limbs. File:Female smallpox patient -- late-stage confluent maculopapular scarring.jpg|An Italian female smallpox patient whose skin displayed the characteristics of late-stage confluent maculopapular scarring, 1965 == Prevention ==
Prevention
kit including the diluent, a vial of Dryvax vaccinia vaccine, and a bifurcated needle The earliest procedure used to prevent smallpox was inoculation with variola minor virus (a method later known as variolation after the introduction of smallpox vaccine to avoid possible confusion), which likely occurred in India, Africa, and China well before the practice arrived in Europe. Accounts of inoculation against smallpox in China can be found as early as the late 10th century, and the procedure was widely practiced by the 16th century, during the Ming dynasty. If successful, inoculation produced lasting immunity to smallpox. 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 percent mortality rate, considerably less than the 20–30 percent mortality rate of smallpox. 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. According to Voltaire (1742), the Turks derived their use of inoculation from neighbouring Circassia. Voltaire does not speculate on where the Circassians derived their technique from, though he reports that the Chinese have practiced it "these hundred years". In 1721, Cotton Mather and colleagues provoked controversy in Boston by inoculating hundreds. After publishing The present method of inoculating for the small-pox in 1767, Dr Thomas Dimsdale was invited to Russia to variolate the Empress Catherine the Great of Russia and her son, Grand Duke Paul, which he successfully did in 1768. 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 the vaccinia virus. Vaccinia is in the same family as cowpox and variola virus but is genetically distinct from both. The origin of the vaccinia virus and how it came to be in the vaccine are not known.. If successful vaccination via the bifurcated needle occurs, 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. The antibodies induced by the 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 percent of those vaccinated. 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 spread 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 percent) 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). 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). By 1986, routine vaccination had ceased in all countries. The smallpox vaccine is also effective in, and therefore administered for, the prevention of mpox. ACAM2000 is a smallpox vaccine developed by Acambis, approved for use in the United States by the U.S. FDA on August 31, 2007. It contains live vaccinia virus, cloned from the same strain used in an earlier vaccine, Dryvax. While the Dryvax virus was cultured in the skin of calves and freeze-dried, ACAM2000s virus is cultured in kidney epithelial cells (Vero cells) from an African green monkey. Efficacy and adverse reaction incidence are similar to Dryvax. == Treatment ==
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 the disease. Other than vaccination, treatment of smallpox is primarily supportive, such as wound care and infection control, fluid therapy, and possible ventilator assistance. Flat and hemorrhagic types of smallpox are treated with the same therapies used to treat shock, such as fluid resuscitation. People with semi-confluent and confluent types of smallpox may have therapeutic issues similar to patients with extensive skin burns. In July 2018, the Food and Drug Administration approved tecovirimat, the first drug approved for treatment of smallpox. However, during treatment viral mutations causing resistance have been known to occur, especially since its use in the 2022–2023 mpox outbreak which jeopardize its effectiveness for smallpox biothreat preparedness. In June 2021, Brincidofovir was approved for medical use in the United States for the treatment of human smallpox disease caused by variola virus. == Prognosis ==
Prognosis
in his left eye, 1972 The mortality rate from variola minor is approximately 1%, while the mortality rate from variola major is approximately 30%. 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 or late hemorrhagic type smallpox is 90% or greater and nearly 100% is observed in cases of early hemorrhagic smallpox. Complications Complications of smallpox arise most commonly in the respiratory system and range from simple bronchitis to fatal pneumonia. Respiratory complications tend to develop on about the eighth day of the illness and can be either viral or bacterial in origin. Secondary bacterial infection of the skin is a relatively uncommon complication of smallpox. When this occurs, the fever usually remains elevated. Other complications include encephalitis (1 in 500 patients), which is more common in adults and may cause temporary disability; permanent pitted scars, most notably on the face; and complications involving the eyes (2% of all cases). Pustules can form on the eyelid, conjunctiva, and cornea, leading to complications such as conjunctivitis, keratitis, corneal ulcer, iritis, iridocyclitis, and atrophy of the optic nerve. Blindness results in approximately 35–40% of eyes affected with keratitis and corneal ulcer. Hemorrhagic smallpox can cause subconjunctival and retinal hemorrhages. In 2–5% of young children with smallpox, virions reach the joints and bone, causing osteomyelitis variolosa. Bony lesions are symmetrical, most common in the elbows, legs, and characteristically cause separation of the epiphysis and marked periosteal reactions. Swollen joints limit movement, and arthritis may lead to limb deformities, ankylosis, malformed bones, flail joints, and stubby fingers. Between 65 and 80% of survivors are marked with deep pitted scars (pockmarks), most prominent on the face. == History ==
History
Disease emergence , the Yoruba god thought to cause the disease The earliest credible clinical evidence of smallpox is found in the descriptions of smallpox-like disease in medical writings from ancient India (as early as 1500 BCE), and China (1122 BCE), as well as a study of the Egyptian mummy of Ramses V (died 1145 BCE). It has been speculated that Egyptian traders brought smallpox to India during the 1st millennium BCE, where it remained as an endemic human disease for at least 2000 years. Smallpox was probably introduced into China during the 1st century CE from the southwest, and in the 6th century was carried from China to Japan. At least seven religious deities have been specifically dedicated to smallpox, such as the god Sopona in the Yoruba religion in West Africa. In India, the Hindu goddess of smallpox, Shitala, was worshipped in temples throughout the country. A different viewpoint is that smallpox emerged 1588 CE and the earlier reported cases were incorrectly identified as smallpox. While the Antonine Plague that swept through the Roman Empire in 165180 CE may have been caused by smallpox, Saint Nicasius of Rheims became the patron saint of smallpox victims for having supposedly survived a bout in 450, During the Middle Ages several smallpox outbreaks occurred in Europe. However, smallpox had not become established there until the population growth and mobility marked by the Crusades allowed it to do so. By the 16th century, smallpox had become entrenched across most of Europe, and subsequently among the native-born colonists. Case fatality rates during outbreaks in Native American populations were as high as 90%. Smallpox was introduced into Australia in 1789 and again in 1829, Although smallpox was never endemic on the continent, By the mid-18th century, smallpox was a major endemic disease everywhere in the world except in Australia and small islands untouched by outside exploration. In 18th century Europe, smallpox was a leading cause of death, killing an estimated 400,000 Europeans each year. Up to 10 percent of Swedish infants died of smallpox each year, with earliest hints of the practice in China during the 10th century. In China, powdered smallpox scabs were blown up the noses of the healthy. People would then develop a mild case of the disease and from then on were immune to it. The technique did have a 0.5–2.0% mortality rate, but that was considerably less than the 20–30% mortality rate of the disease itself. Two reports on the Chinese practice of inoculation were received by the Royal Society in London in 1700: one by Dr. Martin Lister who received a report by an employee of the East India Company stationed in China and another by Clopton Havers. Voltaire (1742) reports that the Chinese had practiced smallpox inoculation "these hundred years". by country An early mention of the possibility of smallpox's eradication was made in reference to the work of Johnnie Notions, a self-taught inoculator from Shetland, Scotland. Notions found success in treating people from at least the late 1780s through a method devised by himself despite having no formal medical background. His method involved exposing smallpox pus to peat smoke, burying it in the ground with camphor for up to 8 years, and then inserting the matter into a person's skin using a knife, and covering the incision with a cabbage leaf. He was reputed not to have lost a single patient. , 1969 The English physician Edward Jenner demonstrated the effectiveness of cowpox to protect humans from smallpox in 1796, after which various attempts were made to eliminate smallpox on a regional scale. In Russia in 1796, the first child to receive this treatment was bestowed the name "Vaktsinov" by Catherine the Great, and was educated at the expense of the nation. The introduction of the vaccine to the New World took place in Trinity, Newfoundland in 1800 by Dr. John Clinch, boyhood friend and medical colleague of Jenner. As early as 1803, the Spanish Crown organized the Balmis expedition to transport the vaccine to the Spanish colonies in the Americas and the Philippines, and establish mass vaccination programs there. The U.S. Congress passed the Vaccine Act of 1813 to ensure that safe smallpox vaccine would be available to the American public. By about 1817, a robust state vaccination program existed in the Dutch East Indies. On March 26, 1806, the Swiss canton Thurgau became the first state in the world to introduce compulsory smallpox vaccinations, by order of the cantonal councillor Jakob Christoph Scherb. Half a year later, Elisa Bonaparte issued a corresponding order for her Principality of Lucca and Piombino. Baden followed in 1809, Prussia in 1815, Württemberg in 1818, Sweden in 1816 and the German Empire in 1874 through the Reichs Vaccination Act. In Lutheran Sweden, the Protestant clergy played a pioneering role in voluntary smallpox vaccination as early as 1800. The first vaccination was carried out in Liechtenstein in 1801, and from 1812 it was mandatory to vaccinate. In British India a program was launched to propagate smallpox vaccination, through Indian vaccinators, under the supervision of European officials. Nevertheless, British vaccination efforts in India, and in Burma in particular, were hampered by indigenous preference for inoculation and distrust of vaccination, despite tough legislation, improvements in the local efficacy of the vaccine and vaccine preservative, and education efforts. By 1832, the federal government of the United States established a smallpox vaccination program for Native Americans. In 1842, the United Kingdom banned inoculation (variolation), later progressing to mandatory vaccination. The British government introduced compulsory smallpox vaccination by an Act of Parliament in 1853. An epidemic in Sheffield in 1887/88 demonstrated that, in addition to the vaccine, several other factors such as extensive isolation measures contributed to the control of the disease. In the United States, from 1843 to 1855, first Massachusetts and then other states required smallpox vaccination. Although some disliked these measures, The first hemisphere-wide effort to eradicate smallpox was made in 1950 by the Pan American Health Organization. The campaign was successful in eliminating smallpox from all countries of the Americas except Argentina, Brazil, Colombia, and Ecuador.. At this point, 2 million people were dying from smallpox every year. Progress towards eradication during this time was disappointing, especially in Africa and in the Indian subcontinent. The Soviet Union continued to advocate for greater support of the smallpox eradication effort. In 1966 an international team, the Smallpox Eradication Unit, was formed under the leadership of an American physician, Donald Henderson. In 1967, the World Health Organization intensified the global smallpox eradication by contributing $2.4 million annually to the effort, and adopted the new disease surveillance method promoted by Czech epidemiologist Karel Raška. of Bangladesh (pictured) was the last person infected with naturally occurring variola major, in 1975. In the early 1950s, an estimated 50 million cases of smallpox occurred in the world each year. This process is known as "ring vaccination". The key to this strategy was the 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 (the virus only infected humans and not other animals) 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 percent of all vaccines were produced in developing countries. 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 widespread re-vaccination of the population, enlisting the help of the WHO. In two months, the outbreak was over. 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. 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, containment, and vaccination program was undertaken in these countries in early and mid-1977, under the direction of Australian microbiologist Frank Fenner. As the campaign neared its goal, Fenner and his team played an important role in verifying eradication. 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. The global eradication of smallpox was certified, based on intense verification activities, by a commission of eminent scientists on 9 December 1979 and subsequently endorsed by the World Health Assembly on 8 May 1980. The first two sentences of the resolution read: The World Health Organization records of the smallpox eradication programme, from 1948 to 1987, were added to the UNESCO Memory of the World register in 2017. Costs and benefits The WHO smallpox eradication program ultimately involved hundreds of thousands of people, from senior WHO leadership to local village health workers. The cost of the eradication effort, from 1967 to 1979, was roughly US$300 million. Roughly a third came from the developed world, which had largely eradicated smallpox decades earlier. The United States, the largest contributor to the program, has reportedly recouped that investment every 26 days since in money not spent on vaccinations and the costs of incidence. The eradication of smallpox has been called "one of the noblest and best things that we have ever done, as a species". In the last 100 years of its existence, smallpox was thought to have killed at least 500 million people; by comparison, all wars on the planet during that time killed an estimated 150 million. Since eradication The last case of smallpox in the world occurred in an outbreak in the United Kingdom in 1978. A medical photographer, Janet Parker, contracted the disease at the University of Birmingham Medical School and died on 11 September 1978. Although it has remained unclear how Parker became infected, the source of the infection was established to be the variola virus grown for research purposes at the Medical School laboratory. All known stocks of smallpox worldwide were subsequently destroyed or transferred to two WHO-designated reference laboratories with BSL-4 facilities – the United States' Centers for Disease Control and Prevention (CDC) and the Soviet Union's (now Russia's) State Research Center of Virology and Biotechnology VECTOR. WHO first recommended destruction of the virus in 1986 and later set the date of destruction to be 30 December 1993. This was postponed to 30 June 1999. Due to resistance from the U.S. and Russia, in 2002 the World Health Assembly agreed to permit the temporary retention of the virus stocks for specific research purposes. Destroying existing stocks would reduce the risk involved with ongoing smallpox research; the stocks are not needed to respond to a smallpox outbreak. Some scientists have argued that the stocks may be useful in developing new vaccines, antiviral drugs, and diagnostic tests; a 2010 review by a team of public health experts appointed by WHO concluded that no essential public health purpose is served by the U.S. and Russia continuing to retain virus stocks. The latter view is frequently supported in the scientific community, particularly among veterans of the WHO Smallpox Eradication Program. On March 31, 2003, smallpox scabs were found inside an envelope in an 1888 book on Civil War medicine in Santa Fe, New Mexico. The envelope was labeled as containing scabs from a vaccination and gave scientists at the CDC an opportunity to study the history of smallpox vaccination in the United States. On July 1, 2014, six sealed glass vials of smallpox dated 1954, along with sample vials of other pathogens, were discovered in a cold storage room in an FDA laboratory at the National Institutes of Health location in Bethesda, Maryland. The smallpox vials were subsequently transferred to the custody of the CDC in Atlanta, where virus taken from at least two vials proved viable in culture. After studies were conducted, the CDC destroyed the virus under WHO observation on February 24, 2015. In 2017, scientists at the University of Alberta recreated an extinct horse pox virus to demonstrate that the variola virus can be recreated in a small lab at a cost of about $100,000, by a team of scientists without specialist knowledge. Although the scientists performed the research to help development of new vaccines as well as trace smallpox's history, the possibility of the techniques being used for nefarious purposes was immediately recognized, raising questions on dual use research and regulations. In September 2019, the Russian lab housing smallpox samples experienced a gas explosion that injured one worker. It did not occur near the virus storage area, and no samples were compromised, but the incident prompted a review of risks to containment. == Society and culture ==
Society and culture
Biological warfare In 1763, Pontiac's War broke out as a Native American confederacy led by Pontiac attempted to counter British control over the Great Lakes region. A group of Native American warriors laid siege to British-held Fort Pitt on June 22. In response, Henry Bouquet, the commander of the fort, ordered his subordinate Simeon Ecuyer to give smallpox-infested blankets from the infirmary to a Delaware delegation outside the fort. Bouquet had discussed this with his superior, Sir Jeffrey Amherst, who wrote to Bouquet stating: "Could it not be contrived to send the small pox among the disaffected tribes of Indians? We must on this occasion use every stratagem in our power to reduce them." Bouquet agreed with the proposal, writing back that "I will try to inocculate the Indians by means of Blankets that may fall in their hands". On 24 June 1763, William Trent, a local trader and commander of the Fort Pitt militia, wrote, "Out of our regard for them, we gave them two Blankets and an Handkerchief out of the Small Pox Hospital. I hope it will have the desired effect." The effectiveness of this effort to broadcast the disease is unknown. There are also accounts that smallpox was used as a weapon during the American Revolutionary War (1775–1783). According to a theory put forward in Journal of Australian Studies (JAS) by independent researcher Christopher Warren, Royal Marines used smallpox in 1789 against indigenous tribes in New South Wales. This theory was also considered earlier in Bulletin of the History of Medicine and by David Day. However it is disputed by some medical academics, including Professor Jack Carmody, who in 2010 claimed that the rapid spread of the outbreak in question was more likely indicative of chickenpoxa more infectious disease which, at the time, was often confused, even by surgeons, with smallpox, and may have been comparably deadly to Aboriginals and other peoples without natural immunity to it. Carmody noted that in the 8-month voyage of the First Fleet and the following 14 months there were no reports of smallpox amongst the colonists and that, since smallpox has an incubation period of 10–12 days, it is unlikely it was present in the First Fleet; however, Warren argued in the JAS article that the likely source was bottles of variola virus possessed by First Fleet surgeons. Ian and Jennifer Glynn, in The life and death of smallpox, confirm that bottles of "variolous matter" were carried to Australia for use as a vaccine, but think it unlikely the virus could have survived till 1789. However, the only non-Aboriginal reported to have died in this outbreak was a seaman called Joseph Jeffries, who was recorded as being of "American Indian" origin. W. S. Carus, an expert in biological weapons, has written that there is circumstantial evidence that smallpox was deliberately introduced to the Aboriginal population. However Carmody and the Australian National University's Boyd Hunter continue to support the chickenpox hypothesis. In a 2013 lecture at the Australian National University, Carmody pointed out that chickenpox, unlike smallpox, was known to be present in the Sydney Cove colony. He also suggested that all (and earlier) identifications of smallpox outbreaks were dubious because: "surgeons ... would have been unaware of the distinction between smallpox and chickenpox – the latter having traditionally been considered a milder form of smallpox." During World War II, scientists from the United Kingdom, United States, and Japan (Unit 731 of the Imperial Japanese Army) were involved in research into producing a biological weapon from smallpox. 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. 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: Others contend that the first patient may have contracted the disease while visiting Uyaly or Komsomolsk-on-Ustyurt, two cities where the boat docked. Responding to international pressures, in 1991 the Soviet government allowed a joint U.S.–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. With the breakup of the Soviet Union and unemployment of many of the weapons program's scientists, U.S. 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. Specific allegations made against Iraq in this respect proved to be false. Notable cases survived a smallpox outbreak in Austria that killed Holy Roman Empress Maria Josepha, who became the second consecutive wife of Holy Roman Emperor Joseph II to die of the disease, as well as Archduchess Maria Josepha. (See Mozart and smallpox.) Famous historical figures who contracted smallpox include Lakota Chief Sitting Bull, Ramses V, the Kangxi Emperor (survived), Shunzhi Emperor and Tongzhi Emperor of China, Emperor Komei of Japan (died of smallpox in 1867), and 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 (causing a civil war of succession in the Inca empire and the eventual conquest by the Spaniards). More recent public figures include Guru Har Krishan, 8th Guru of the Sikhs, in 1664, Louis I of Spain in 1724 (died), Peter II of Russia in 1730 (died), George Washington (survived), Louis XV of France in 1774 (died), and Maximilian III Joseph of Bavaria in 1777 (died). Prominent families throughout the world often had several people infected by and/or perish from the disease. For example, several relatives of Henry VIII of England survived the disease but were scarred by it. These include his sister Margaret, his wife Anne of Cleves, and his two daughters: Mary I in 1527 and Elizabeth I in 1562. Elizabeth tried to disguise the pockmarks with heavy makeup. 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 higher in the succession line. He himself died of the disease in 1774. Peter II of Russia died of the disease at 14 years of age. Also, before becoming emperor, Peter III of Russia caught the virus and suffered greatly from it. He was left scarred and disfigured. His wife, Catherine the Great, was spared but fear of the virus clearly had its effects on her. She feared for the safety of her son, Paul, so much that she made sure that large crowds were kept at bay and sought to isolate him. Eventually, she decided to have herself inoculated by a British doctor, Thomas Dimsdale. While this was considered a controversial method at the time, she succeeded. Paul was later inoculated as well. Catherine then sought to have inoculations throughout her empire stating: "My objective was, through my example, to save from death the multitude of my subjects who, not knowing the value of this technique, and frightened of it, were left in danger." By 1800, approximately two million inoculations had been administered in the Russian Empire. In China, the Qing dynasty had extensive protocols to protect Manchus from 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. Jackson developed the illness after being taken prisoner by the British during the American Revolution, and though he recovered, his brother Robert did not. 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. Hungarian poet Ferenc Kölcsey, who wrote the Hungarian national anthem, lost his right eye to smallpox. Tradition and religion was worshipped to prevent or cure smallpox. In the face of the devastation of smallpox, various smallpox gods and goddesses have been worshipped throughout parts of the Old World, for example in China and India. In China, the smallpox goddess was referred to as T'ou-Shen Niang-Niang (). Chinese believers actively worked to appease the goddess and pray for her mercy, by such measures as referring to smallpox pustules as "beautiful flowers" as a euphemism intended to avert offending the goddess, for example (the Chinese word for smallpox is , literally "heaven flower"). In a related New Year's Eve custom it was prescribed that the children of the house wear ugly masks while sleeping, so as to conceal any beauty and thereby avoid attracting the goddess, who would be passing through sometime that night. Among the Yorùbá people of West Africa, and also in Dahomean religion, Trinidad, and in Brazil, The deity Sopona, also known as Obaluaye, is the deity of smallpox and other deadly diseases (like leprosy, HIV/AIDS, and fevers). One of the most feared deities of the orisha pantheon, smallpox was seen as a form of punishment from Shopona. Worship of Shopona was highly controlled by his priests, and it was believed that priests could also spread smallpox when angered. The British government banned the worship of the god because it was believed his priests were purposely spreading smallpox to their opponents. In cultures that did not recognise a smallpox deity, there was often nonetheless a belief in smallpox demons, who were accordingly 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 colour red. This led to the invention of the so-called red treatment, where patients and their rooms would be decorated in red. The practise spread to Europe in the 12th century and was practised by (among others) Charles V of France and Elizabeth I of England. Afforded scientific credibility through the studies by Niels Ryberg Finsen showing that red light reduced scarring, this belief persisted even until the 1930s. == See also ==
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