smallpox

| ICD9 | DiseasesDB 12219 | MedlinePlus 001356 | eMedicineSubj emerg | eMedicineTopic 885 | MeshName Smallpox | MeshNumber D012899 }} Smallpox is an infectious disease unique to humans, caused by either of two virus (biology) variants, Variola majorand Variola minorlt;/ref> The disease is also known by the Latin names Variolaor 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 .lt;/ref> Smallpox localizes in small blood vessel of the skin and in the mouth and throat. In the skin, this results in a characteristic maculopapular rash, and later, raised fluid-filled blister . V. majorproduces a more serious disease and has an overall mortality rate of 30–35%. V. minorcauses a milder form of disease (also known as alastrim cottonpox, milkpox, whitepox, and Cuban itch) which kills about 1% of its victims.lt;/ref> Long-term complications of V. majorinfection include characteristic scars, commonly on the face, which occur in 65–85% of survivors.lt;/ref> Blindness resulting from corneal ulcer tion 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 population about 10,000 BC. The earliest physical evidence of smallpox is likely the pustular rash on the mummified body of Pharaoh Ramses V of Egypt, who died in 1157 BC.lt;/ref> During the 18th century the disease killed an estimated 400,000 Europeans per year (including five reigning monarch ),"[http://books.google.com/books?id=GyE8Qt-kS1kC&pg=PA151&dq=&lr=&hl=en&cd=23#v=onepage&q=false Epidemics and pandemics: their impacts on human history]. J. N. Hays (2005). p.151. ISBN 1851096582 and was responsible for a third of all blindness."http://www.ncbi.nlm.nih.gov/books/bv.fcgi?ridvacc.chapter.3 Smallpox and Vaccinia]". National Center for Biotechnology Information.lt;/ref> Of all those infected, 20–60%—and over 80% of infected children—died from the disease.lt;/ref> Smallpox was responsible for an estimated 300–500 million deaths during the 20th century alone.lt;/ref>lt;/ref>http://www.sciencedaily.com/releases/2008/01/080131122956.htm How Poxviruses Such As Smallpox Evade The Immune System], ScienceDaily, February 1, 2008 In the early 1950s an estimated 50 million cases of smallpox occurred in the world each year. As recently as 1967, the World Health Organization (WHO) estimated that 15 million people contracted the disease and that two million died in that year.lt;/ref> After successful vaccination campaigns throughout the 19th and 20th centuries, the WHO certified the eradication of smallpox in December 1979. To this day, smallpox is the only human infectious disease to have been eradicated.lt;/ref>lt;/ref>

Classification

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. alastrim is a less common presentation of smallpox, and a much less severe disease, with historical death rates of 1% or less.lt;/ref> Subclinical (asymptomatic infections with variola virus have also been noted, but are not believed to be common. 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. Image:Smallpox child.jpg

Signs and symptoms

The incubation period between contraction and the first obvious symptoms of the disease is around 12 days. Once inhaled, variola major virus invades the oropharyngeal (mouth and throat) or the respiratory mucosa, migrates to regional lymph nodes and begins to multiply. In the initial growth phase the virus seems to move from cell to cell, but around the 12th day, lysis of many infected cells occurs and the virus is found in the blood tream 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 , myalgia malaise, headache, prostration and as the Gastrointestinal 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 enanthemappear on mucous membranes of the mouth, tongue, palate and throat, and temperature falls to near normal. These lesions rapidly enlarge and rupture, releasing large amounts of virus into the saliva Smallpox virus preferentially attacks skin cells, causing the characteristic pimples (called macule ) associated with the disease. A rash develops on the skin 24 to 48 hours after lesions on the mucous membranes appear. Typically the macules first appear on the forehead, then rapidly spread to the whole face, proximal portions of extremities, the trunk, and lastly to distal portions of extremities. The process takes no more than 24 to 36 hours, after which no new lesions appear. At this point Variola major infection can take several very different courses, resulting in four types of smallpox disease based on the Rao classification:Rao, A. R. (1972). Smallpox. Bombay: Kothari Book Depot. lt;/ref> ordinary, modified, malignant (or flat), and hemorrhagic. Historically, smallpox has an overall fatality rate of about 30%; however, the malignant and hemorrhagic forms are usually fatal.lt;/ref>

Ordinary

Ninety percent or more of smallpox cases among unvaccinated persons are of the ordinary type. In this form of the disease, by the second day of the rash, the macules become raised papules By the third or fourth day the papules fill with an opalescent fluid to become [[Vesicle (dermatology)|vesicles]] This fluid becomes Opacity (optics) and turbid within 24–48 hours, giving them the appearance of pustule ; however, the so-called pustules are filled with tissue debris, not pus. By the sixth or seventh day, all the skin lesions have become pustules. Between 7 and 10 days the pustules mature and reach their maximum size. The pustules are sharply raised, typically round, tense, and firm to the touch. The pustules are deeply embedded in the dermis, giving them the feel of a small bead in the skin. Fluid slowly leaks from the pustules, and by the end of the second week the pustules deflate, and start to dry up, forming crusts (or scabs). By day 16-20 scabs have formed over all the lesions, which have started to flake off, leaving de-pigment d scars.lt;/ref> Ordinary smallpox generally produces a discreterash, 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 confluentrash, which begin to detach the outer layers of skin from the underlying flesh. Patients with confluent smallpox often remain ill even after scabs have formed over all the lesions. In one case series, the case-fatality rate in confluent smallpox was 62%.

Modified

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

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.lt;/ref> Malignant smallpox is accompanied by a severe prodromal phase that lasts 3–4 days, prolonged high fever, and severe symptoms of toxemia The rash on the tongue and palate is usually extensive. The skin lesions mature very slowly and by the seventh or eighth day the lesions are flat and appear to be buried in the skin. Unlike ordinary-type smallpox, the vesicles contain very little fluid, are soft and velvety to the touch, and may contain hemorrhages. Malignant smallpox is nearly always fatal.

Hemorrhagic

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

Cause

File:Smallpox virus virions TEM PHIL 1849.JPG depicts a number of smallpox virions. The “dumbbell-shaped” structure inside the virion is the viral core, which contains the viral DNA; Mag. ~370,000x.]] Smallpox is caused by infection with variola virus, which belongs to the genus Orthopoxvirus the family Poxviridae and subfamily chordopoxvirinae. Variola is a large brick-shaped virus measuring approximately 302 to 350 nanometer by 244 to 270 nm,lt;/ref> with a single linear dsDNA genome 186 kilobase pair (kbp) in size and containing a hairpin loop at each end.lt;/ref>lt;/ref> The two classic varieties of smallpox are variola major and variola minor. Four orthopoxviruses cause infection in humans: variola, vaccinia cowpox and monkeypox Variola virus infects only humans in nature, although primates and other animals have been infected in a laboratory setting. Vaccinia, cowpox, and monkeypox viruses can infect both humans and other animals in nature.lt;/ref> 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 Cell 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 viral envelope and unenveloped virions are infectious. The viral envelope is made of modified Golgi membranes containing viral-specific polypeptides, including hemagglutinin Infection with either variola major or variola minor confers immunity against the other.lt;/ref>

Transmission

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

Diagnosis

Image:Smallpox CAM.png Image:Smallpox (variola orthopox virus ) Early Rash vs chickenpox.gif 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. Microscope poxviruses produce characteristic cytoplasmic inclusions, the most important of which are known as Guarnieri bodies and are the sites of viral replication Guarnieri bodies are readily identified in skin biopsies stained with hematoxylin and eosin, and appear as pink blobs. They are found in virtually all poxvirus infections but the absence of Guarnieri bodies cannot be used to rule out smallpox.lt;/ref> The diagnosis of an orthopoxvirus infection can also be made rapidly by electron microscopy examination of pustular fluid or scabs. However, all orthopoxviruses exhibit identical brick-shaped virions by electron microscopy. Definitive laboratory identification of variola virus involves growing the virus on chorioallantoic membrane (part of a chicken embryo and examining the resulting pock lesions under defined temperature conditions.lt;/ref> Strains may be characterized by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. Serologic tests and enzyme linked immunosorbent assay (ELISA), which measure variola virus-specific immunoglobulin and antigen have also been developed to assist in the diagnosis of infection.lt;/ref> 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.

Prevention

File:Variolation vial India.jpg material (India)]] The earliest procedure used to prevent smallpox was inoculation (also known as variolation). Inoculation was possibly practiced in India as early as 1000 BC,lt;/ref> and involved either nasal Wiktionary: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.Wujastyk, Dominik. (1995). "Medicine in India," in Oriental Medicine: An Illustrated Guide to the Asian Arts of Healing 19–38. Edited by Serindia Publications. London: Serindia Publications. ISBN 0906026369. p. 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 Temple, Robert. (1986). The Genius of China: 3,000 Years of Science, Discovery, and Invention With a forward by Joseph Needham. New York: Simon and Schuster, Inc. ISBN 0671620282. p. 135–7. If successful, inoculation produced lasting immunity (medical) 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. 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.http://www.fordham.edu/Halsall/mod/montagu-smallpox.html Modern History Sourcebook: Lady Mary Wortley Montagu (1689-1762): Smallpox Vaccination in Turkey] 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 (linguistics) 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 Genetics lly distinct from both. The origin of vaccinia virus and how it came to be in the vaccine are not known. The current formulation of smallpox vaccine is a live virus preparation of infectious vaccinia virus. The vaccine is given using a bifurcated (two-pronged) needle that is dipped into the vaccine solution. The needle is used to prick the skin (usually the upper arm) a number of times in a few seconds. If successful, a red and itchy bump develops at the vaccine site in three or four days. In the first week, the bump becomes a large blister (called a “Jennerian vesicle”) which fills with pus, and begins to drain. During the second week, the blister begins to dry up and a scab forms. The scab falls off in the third week, leaving a small scar. File:Smallpox vaccine.jpg kit including the diluent a vial of Dryvax vaccinia vaccine, and a bifurcated needle.]] The antibodies induced by vaccinia vaccine are cross-protective for other orthopoxviruses (such as monkeypox, cowpox, and variola (smallpox) viruses). Neutralizing antibodies are detectable 10 days after first-time vaccination, and seven days after revaccination. Historically, the vaccine has been effective in preventing smallpox infection in 95% of those vaccinated. Smallpox vaccination provides a high level of immunity for three to five years and decreasing immunity thereafter. If a person is vaccinated again later, immunity lasts even longer. Studies of smallpox cases in Europe in the 1950s and 1960s demonstrated that the fatality rate among persons vaccinated less than 10 years before exposure was 1.3%; it was 7% among those vaccinated 11 to 20 years prior, and 11% among those vaccinated 20 or more years prior to infection. By contrast, 52% of unvaccinated persons died.lt;/ref> There are side effects and risks associated with the smallpox vaccine. In the past, about 1,000 people for every 1 million people vaccinated for the first time experienced serious, but non-life-threatening, reactions including toxic or allergic reaction at the site of the vaccination (erythema multiforme , spread of the vaccinia virus to other parts of the body, and to other individuals. Potentially life-threatening reactions occurred in 14 to 500 people out of every 1 million people vaccinated for the first time. Based on past experience, it is estimated that 1 or 2 people in 1 million (0.000198%) who receive the vaccine may die as a result, most often the result of postvaccinial encephalitis or severe necrosis in the area of vaccination (called progressive vaccinia). Given these risks, as smallpox became effectively eradicated and the number of naturally occurring cases fell below the number of vaccine-induced illnesses and deaths, routine childhood vaccination was discontinued in the United States in 1972, and was abandoned in most European countries in the early 1970s.lt;/ref> Routine vaccination of healthcare workers was discontinued in the U.S. in 1976, and among military recruits in 1990. Military members deploying to the Middle East and Korea still receive the vaccination.http://www.smallpox.mil/resource/qaAll.asp?cID364 Questions and Answers] - DoD Smallpox Vaccination Program (SVP) By 1986, routine vaccination had ceased in all countries. It is now primarily recommended for laboratory workers at risk for occupational exposure.

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.lt;/ref> 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 (circulatory) such as Fluid replacement Patients with semi-confluent and confluent types of smallpox may have therapeutic issues similar to patients with extensive skin burn . No drug is currently approved for the treatment of smallpox. However, antiviral drug 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.lt;/ref>

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. 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 complex s, overwhelming viremia or an uncontrolled immune response may be contributing factors. In early hemorrhagic smallpox, death occurs suddenly about six days after the fever develops. Cause of death in hemorrhagic cases involved heart failure sometimes accompanied by pulmonary edema In late hemorrhagic cases, high and sustained viremia, severe platelet loss and poor immune response were often cited as causes of death. In flat smallpox modes of death are similar to those in burns, with loss of fluid, protein and electrolyte beyond the capacity of the body to replace or acquire, and fulminating sepsis

Complications

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

History

Viral evolution

File:FlorentineCodex BK12 F54 smallpox.jpg (compiled 1540–1585), showing Nahua peoples of conquest-era central Mexico suffering from smallpox.]] Smallpox likely diverged from an ancestral African rodent-borne variola-like virus between 16,000 and 68,000 years ago.lt;/ref> The more severe form (variola major) is thought to have originated in Asia between 400 and 1600 years ago. Alastrim minor a second form 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.

Human history

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.)Originally published as Princes and Peasants: Smallpox in History(1983), ISBN 0-226-35177-7 The earliest credible clinical evidence of smallpox is found in the Ancient Egypt 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. In Japan, the epidemic of 735-737 is believed to have killed as much as one-third of the population. At least seven religious deities have been specifically dedicated to smallpox, such as the god Sopona in the Yoruba religion In India, the Hindu goddess of smallpox, Shitala Devi was worshiped in temples throughout the country.lt;/ref> The arrival of smallpox in Europe and south-western Asia is less clear. Smallpox is not described in either the Old Testament or New Testament 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. While the Antonine Plague that swept through the Roman Empire in 165–180 AD may have been caused by smallpox,http://news.bbc.co.uk/2/hi/health/4381924.stm Past pandemics that ravaged Europe], BBC News November 7, 2005 other historians speculate that Arab armies first carried smallpox out of Africa to Southwestern Europe during the 7th and 8th centuries AD. In the 9th century the Islamic medicine Muhammad ibn Zakariya ar-Razi 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.lt;/ref> 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. 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. Image:SmallpoxvictimIllinois1912.jpg There are no credible descriptions of smallpox-like disease in the Americas before the westward exploration in the 15th century AD. 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 Aztec and the Inca by the Spaniards. 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,"[http://books.google.com/books?id=o-BNU7QuJkYC&pg=PA164&dq&hl=en#v=onepage&q=&f=false Encyclopedia of North American Indians]. Frederick E. Hoxie (1996). p.164. ISBN 0395669219 and subsequently among the native-born colonists.lt;/ref> Some estimates indicate case fatality rates of 80-90 % in Native American populations during smallpox epidemics."[http://books.google.com/books?id=qubTdDk1H3IC&pg=PA205&dq&hl=en#v=onepage&q=&f=false The Cambridge encyclopedia of human paleopathology]. Arthur C. Aufderheide, Conrado Rodríguez-Martín, Odin Langsjoen (1998). Cambridge University Press p.205. ISBN 0521552036 Smallpox was introduced into Australia in 1789 and again in 1829 and caused devastation among the Indigenous Australians , but quickly died out on both occasions. By the mid-18th century smallpox was a major Endemic (epidemiology) 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.http://www.ncbi.nlm.nih.gov/books/bv.fcgi?ridvacc.chapter.3 Smallpox and Vaccinia] Through the century smallpox resulted in the deaths of perhaps 10% of all the infants of Sweden every year, and the death rate of infants in Russia may have been ever higher. The widespread use of variolation in a few countries, notably Great Britain, its North American colonies, and China, somewhat reduced the impact of smallpox among the wealthy classes during the latter part of the 18th century, but a real reduction in its incidence did not occur until vaccination became a common practice toward the end of the 19th century. Improved vaccines and the practice of re-vaccination led to a substantial reduction in cases in Europe and North America, but smallpox remained almost unchecked everywhere else in the world. In the United States and South Africa a much milder form of smallpox, variola minor was recognized just before the close of the 19th century. By the mid-20th century variola minoroccurred along with variola major in varying proportions, in many parts of Africa. Patients with variola minorexperience only a mild systemic illness, are often walk throughout the course of the disease, and are therefore able to more easily spread disease. Infection with v. minorinduces immunity against the more deadly variola majorform. Thus as v. minorspread all over the USA, into Canada, the South American countries and Great Britain it became the dominant form of smallpox, further reducing mortality rates.

Eradication

Image:Fighting smallpox in Niger, 1969.jpg 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 Empire in the Americas and the Philippines, and establish mass vaccination programs there.http://www.doh.gov.ph/sphh/balmis.htm Dr. Francisco de Balmis and his Mission of Mercy, Society of Philippine Heath History] The US Congress passed the Vaccine Act of 1813 to ensure that safe smallpox vaccine would be available to the American public. By about 1817, a very solid state vaccination program existed in the Dutch East Indies http://www.newasiabooks.org/index.php?qnode/7020 Against all odds: vanquishing smallpox in far-flung Japan] In British India a program was launched to propagate smallpox vaccination, through Indian vaccinators, under the supervision of European officials.http://www.smallpoxhistory.ucl.ac.uk/Other%20Asia/ongoingwork.htm Smallpox History - Other histories of smallpox in South Asia] By 1832, the federal government of the United States established a smallpox vaccination program for Native Americans.http://muse.jhu.edu/login?uri/journals/wicazo_sa_review/v018/18.2pearson01.html Lewis Cass and the Politics of Disease: The Indian Vaccination Act of 1832] In 1842, the United Kingdom banned inoculation, later progressing to Vaccination Act The British government introduced compulsory smallpox vaccination by an Act of Parliament in 1853.http://www.amazon.com/dp/0822334232 Bodily Matters: The Anti-Vaccination Movement in England, 1853–1907] In the United States, from 1843 to 1855 first Massachusetts, and then other states required smallpox vaccination. Although some disliked these measures, 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.C.V. Chapin. Variation in type of infectious disease as shown by the history of smallpox in the United States 1895–1912. Infect Dis 1913. 13: 171–196. 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.lt;/ref> The first Western Hemisphere wide effort to eradicate smallpox was made in 1950 by the Pan American Health Organization lt;/ref> The campaign was successful in eliminating smallpox from all American countries except Argentina, Brazil, Colombia, and Ecuador. In 1958 Professor Viktor Zhdanov, Deputy Minister of Health for the Soviet Union called on the World Health Assembly to undertake a global initiative to Eradication of infectious diseases smallpox. The proposal (Resolution WHA11.54) was accepted in 1959.lt;/ref> At this point, 2 million people were dying from smallpox every year. Overall, however, the 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 lt;/ref> File:Rahima Banu.jpg of Bangladesh was the last person infected with naturally occurring Variola major in 1975]] 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 asymptomatic carrier 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. The last major European outbreak of smallpox was in 1972 outbreak of smallpox 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.lt;/ref> 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.lt;/ref> 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 early and mid-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. The last naturally occurring case of the more deadly Variola majorhad been detected in October 1975 in a two-year-old Bangladesh girl, Rahima Banu lt;/ref> 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 1980lt;/ref> 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."lt;/ref>

Post-eradication

Image:Directors of Global Smallpox Eradication Program.jpg The last cases of smallpox in the world occurred in an outbreak of two cases (one of which was fatal) in Birmingham 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, after which the scientist responsible for smallpox research at the university, Professor Henry Bedson, committed suicide In light of this accident, all known stocks of smallpox were destroyed or transferred to one of two WHO reference laboratories which had Biosafety level#Biosafety level 4 facilities; the Centers for Disease Control and Prevention (CDC) in the United States and the State Research Center of Virology and Biotechnology VECTOR in Koltsovo, Novosibirsk Oblast Russia.lt;/ref> 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 1999.lt;/ref> In 2002 the policy of the WHO changed to be against its final destruction.lt;/ref> Destroying existing stocks would reduce the risk involved with ongoing smallpox research; the stocks are not needed to respond to a smallpox outbreak.lt;/ref> However, the stocks may be useful in developing new vaccines, antiviral drugs, and diagnostic tests.lt;/ref> In March 2004 smallpox Coagulation were found tucked inside an envelope in a book on American Civil War medicine in Santa Fe, New Mexico lt;/ref> 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.

Biological warfare

The British at least considered using smallpox as a biological warfare agent at the Pontiac's Rebellion#Siege of Fort Pitt during the French and Indian Wars (1754–63) against France and its Indigenous peoples of the Americas allies .Peckham, Indian Uprising 226; Anderson, Crucible of War 542, 809n.Anderson, Crucible of War 809n; Grenier, First Way of War 144; Nester, Haughty Conquerors" 114–15. Although it is not clear whether the actual use of smallpox had official sanction, on June 24, 1763, William Trent, a local trader, wrote, "Out of our regard for them sc. representatives of the besieging Delawares], we gave them two Blankets and an Handkerchief out of the Small Pox Hospital. I hope it will have the desired effect." http://www.history.org/Foundation/journal/Spring04/warfare.cfm Colonial Germ Warfare], Harold B. Gill Jr., CW Journal: Spring 04Anderson, Crucible of War 541–42; Jennings, Empire of Fortune 447n26. Historians do not agree on whether this effort to broadcast the disease was successful. It has also been alleged that smallpox was used as a weapon during the American Revolutionary War (1775–83).lt;/ref>Elizabeth A. Fenn. "Biological Warfare in Eighteenth-Century North America: Beyond Jeffrey Amherst, 1st Baron Amherst " The Journal of American History Vol. 86, No. 4 (Mar., 2000), pp. 1552–1580 During World War II scientists from the United Kingdom, United States and Japan were involved in research into producing a biological weapon from smallpox.lt;/ref> 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 lt;/ref> In 1947 the Soviet Union established a smallpox weapons factory in the city of Zagorsk 75 km to the northeast of Moscow.lt;/ref> An outbreak of weaponized smallpox possibly occurred during testing at the factory 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 Yuri Andropov who at that time was Chief of KGB, and informed him of the exclusive recipe of smallpox obtained on Vozrazhdenie Island.”– ^{http://scholar.google.co.uk/scholar?hlen&lr&qintitle%3AThe+Russian+biological+weapons+program%3A+vanished+or+disappeared%3F&as_publicationCrit.+Rev.+Microbiol.&as_ylo2004&as_yhi2004&btnGSearch Scholar search]}}}lt;/ref> Others contend that the first patient may have contracted the disease while visiting Uyaly or Komsomolsk two cities where the boat docked.lt;/ref> Responding to international pressures, in 1991 the Soviet government allowed a joint US-British inspection team to tour four of its main weapons facilities at Biopreparat The inspectors were met with evasion and denials from the Soviet scientists, and were eventually ordered out of the facility. In 1992 Soviet defector Ken Alibek confirmed that the Soviet bioweapons program at Zagorsk had produced a large stockpile—as much as twenty tons—of weaponized smallpox (possibly engineered to resist vaccines), along with refrigerated warhead to deliver it. It is not known whether these stockpiles still exist in Russia. In 1997, however, the Russian government announced that all of its remaining smallpox samples would be moved to the State Research Center of Virology and Biotechnology VECTOR in Koltsovo lt;/ref> With the breakup of the Soviet Union and unemployment of many of the weapons programs scientists, there is 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.http://www.bt.cdc.gov/agent/smallpox/training/overview/pdf/eradicationhistory.pdf History and Epidemiology of Global Smallpox Eradication] From the training course titled "Smallpox: Disease, Prevention, and Intervention". The CDC and the World Health Organization Slide 16-17. Concern has been expressed by the possibility to use artificial gene synthesis from existing digital genomes of the smallpox virus to recreate the virus for use in biological warfare. Insertion of the synthesized smallpox DNA into existing related pox virus s could theoretically be used to recreate the virus.http://www.biosafety-info.net/file_dir/413148854af122567.pdf The Genetic Engineering of Smallpox. WHO’s Retreat from the Eradication of Smallpox Virus and Why it Should be Stopped] A BRIEFING PAPER BY THE SUNSHINE PROJECT. 2002.

Famous sufferers

Famous historical figures who contracted smallpox include Lakota Chief Sitting Bull Ramses V of Egypt lt;/ref> 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, George Washington Peter II of Russia in 1730 (died),lt;/ref> and Maximilian III Joseph, Elector of Bavaria in 1777. Ranjit Singh the Lion of the Punjab lost sight in his left eye due to an attack of smallpox during his childhood.lt;/ref>lt;!-- this source may be a best seller but it seems to be highly questionable as a reliable source - some of it may be common knowledge & some may not be viable - it is a popular book, not a scholarly work - done by of all things by a TV consultant... ~~~~ --> 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 Tudor his fourth wife, Anne of Cleves and his two daughters: Mary I of England in 1527 and Elizabeth I of England in 1562 (as an adult she would often try to disguise the pockmarks with heavy makeup). His great-niece, Mary, Queen of Scots contracted the disease as a child but had no visible scarring. In Europe, deaths from smallpox often changed dynastic succession. The only surviving son of Henry VIII of England Edward VI of England died from complications shortly after apparently recovering from the disease, thereby rendering his sires infamous efforts to provide England with a male heir moot. (His immediate successors were all females.) Louis XV of France succeeded his great-grandfather Louis XIV through a series of deaths of smallpox or measles among those earlier in the succession line. He himself died of the disease in 1774. William III of England lost his mother to the disease when he was only ten years old in 1660, and named his uncle Charles as legal guardian: her death from smallpox would indirectly spark a chain of events that would eventually lead to the permanent ousting of the Stuart line from the British throne. William IIIs wife, Mary II of England died from smallpox as well. In China, the Qing Dynasty had extensive protocols to protect Manchu from the Peking s endemic smallpox. Most notably, the Kangxi Emperor was promoted to the throne because he had survived the disease, ahead of older brothers who had not yet had it. Mozart and smallpox and Beethoven contracted and survived the disease as children; both had visible pockmark scars on their faces. 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.lt;/ref> Jackson developed the illness after being taken prisoner by the British during the American Revolution, and though he recovered, his brother Robert did not. Lincoln contracted the disease during his Presidency, possibly from his son Tad, and was quarantined shortly after giving the Gettysburg address in 1863. Famous theologian Jonathan Edwards died of smallpox in 1758 following an inoculation. U.S.S.R. leader 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.Montefiore, Young Stalin, p. 61 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.Szinnyei József: http://mek.niif.hu/03600/03630/html/k/k12495.htm Magyar írók élete és munkái], Arcanum, Budapest, 2000, ISBN 9638602996

References

External links

*http://www.cidrap.umn.edu/cidrap/content/bt/smallpox/biofacts/smllpx-summary.html Detailed CIDRAP Smallpox overview] *http://www.upmc-biosecurity.org/website/focus/agents_diseases/fact_sheets/smallpox.html Agent Fact Sheet: Smallpox], Center for Biosecurity * http://webeye.ophth.uiowa.edu/eyeforum/atlassearch1.htm?appSession108815523085552 Photographs of eye damage due to smallpox] * http://www.logicalimages.com/resourcesBTAgentsSmallpox.htm Smallpox Images and Diagnosis Synopsis] * http://www.poxvirus.org/query.asp?web_taxonomyvariola%20virus Variola Virus Genomes] database search results from the http://www.poxvirus.org Poxvirus Bioinformatics Resource Center] Category:Infectious diseases Category:Smallpox Category:Eradicated diseases Category:Virus-related cutaneous conditions ar:جدري an:Picueta gn:Mbiru'a ay:Chuqu usu bn:গুটিবসন্ত zh-min-nan:Thian-hoa bs:Boginje bg:Едра шарка ca:Verola cs:Neštovice cy:Brech wen da:Kopper de:Pocken dv:ކަށި ވިދުރި nv:Łóódtsoh el:Ευλογιά es:Viruela eo:Variolo eu:Baztanga fa:آبله fr:Variole ga:Bolgach gl:Varíola ko:천연두 hi:चेचक hr:Boginje id:Variola os:Хæбуз is:Bólusótt it:Variola vera he:אבעבועות שחורות la:Variola lv:Bakas lt:Raupai hu:Himlő ml:വസൂരി mr:कांजिण्या ms:Cacar nah:Mātlālzahuatl nl:Pokken ja:天然痘 no:Kopper (sykdom) nn:Koppar oc:Veròla pnb:چیچک pms:Vairòle pl:Ospa prawdziwa pt:Varíola ro:Variolă qu:Muru unquy ru:Натуральная оспа simple:Smallpox sk:Kiahne sl:Črne koze sr:Богиње sh:Boginje fi:Isorokko sv:Smittkoppor tl:Bulutong ta:பெரியம்மை te:మశూచి th:ฝีดาษ tr:Çiçek hastalığı uk:Натуральна віспа vi:Đậu mùa fiu-vro:Hernetõbi war:Pandok bat-smg:Raupā zh:天花

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