This article deals with a disease. For the 1982 Serbian film see Variola Vera.
Classification & external resources
A child infected with smallpox
Variola virus (Smallpox)
Group: Group I (dsDNA)
Species: Variola vera
Smallpox (also known by the Latin names Variola or Variola vera) is a contagious disease unique to humans. Smallpox is caused by either of two virus variants named Variola major and Variola minor. The deadlier form, V. major, has a mortality rate of 30–35%, while V. minor causes a milder form of disease called alastrim and kills ~1% of its victims. Long-term side-effects for survivors include the characteristic skin scars. Occasional side effects include blindness due to corneal ulcerations and infertility in male survivors.
Smallpox killed an estimated 60 million Europeans, including five reigning European monarchs, in the 18th century alone. Up to 30% of those infected, including 80% of the children under 5 years of age, died from the disease, and one third of the survivors became blind.
Smallpox was responsible for an estimated 300–500 million deaths in the 20th century. As recently as 1967, the World Health Organization (WHO) estimated that 15 million people contracted the disease and that two million died in that year. After successful vaccination campaigns throughout the 19th and 20th centuries, the WHO certified the eradication of smallpox in 1979. To this day, smallpox is the only human infectious disease to have been completely eradicated from nature.
Child showing rash due to smallpox variola major virusSmallpox is highly contagious, although less so than other infectious diseases. Smallpox is not notably infectious in the prodromal period—viral shedding is usually delayed until the appearance of the rash. Smallpox is transmitted primarily through prolonged social contact or direct contact with infected body fluids or contaminated objects (fomites) such as bedding or clothes. Infection in the natural disease will be via the lungs. The fact that there has been no recurrence of wild smallpox since its elimination thirty years ago makes the assumptions made at the start of the elimination campaign - that human smallpox carriers do not exist, and that the virus does not exist outside humans - some of the most certain facts in medical science.
Smallpox is a member of the family poxviridae, subfamily chordopoxvirinae. Its closest viral relative is molluscum contatiosum virus molluscum contagiosum, which like smallpox, infects only humans. However, unlike smallpox, molluscum infection is benign. The lifecycle of poxviruses is complicated by having multiple infectious forms, with differing mechanisms of cell entry. It is a large virus, with a double stranded DNA genome of about 200 kilobases, making it more complicated than many bacteria.
The incubation period between contraction and the first obvious symptoms of the disease is around 12 days. In the initial growth phase the virus seems to move from cell to cell, but around the 12th day, lysis of many infected cells occurs and the virus is found in the bloodstream in large numbers. The initial or prodromal symptoms are similar to other viral diseases such as influenza and the common cold: fevers, muscle pain, stomach aches, etc. The digestive tract is commonly involved, leading to vomiting. Most people become prostrated at this stage.
Smallpox virus preferentially attacks skin cells, and by days 12–15, smallpox infection becomes obvious. The attack on skin cells causes the characteristic pimples associated with the disease. The pimples tend to erupt first in the mouth, then on the arms and the hands, and later on the rest of the body. At this point the pimples, called macules, are usually still fairly small. This is the stage at which the victim is most contagious.
By days 15–16 the condition worsens, and at this point the disease can take two very different courses, depending on whether it is malignant or hemorrhagic smallpox. The most common type is classic ordinary smallpox, in which the pimples grow into vesicles and then fill up with pus, turning them into pustules. Ordinary smallpox generally takes one of two basic courses. In discrete ordinary smallpox, the pustules stand out on the skin separately. There is a greater chance of surviving this form. In confluent ordinary smallpox, the blisters merge together into sheets which begin to detach the outer layers of skin from the underlying flesh. This form is usually fatal. If the patient survives the course of the disease, the pustules deflate in time (the duration is variable), and start to dry up, usually beginning on day 28. Eventually the pustules completely dry and start to flake off. Once all of the pustules flake off, the patient is considered cured, and is no longer contagious.
Chickenpox and smallpox can be distinguished in the field via several methods. An examination of the patient’s palms and soles is necessary: 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.
 Hemorrhagic smallpox
Electron microscope of smallpox.In the other form of Variola major smallpox, known as hemorrhagic smallpox, a mortality of 96 percent has been reported. An entirely different set of symptoms starts to develop. The skin does not blister, but remains smooth. Instead, bleeding occurs under the skin, making the skin look charred and black (this is known as black pox). The eyes also hemorrhage, making the whites of the eyes turn deep red (and, if the victim lives long enough, black). At the same time, bleeding begins in the organs. Death may occur from bleeding (fatal loss of blood or by other causes such as brain hemorrhage), or from loss of fluid. The entry of other infectious organisms, since the skin and intestine are no longer a barrier, can also lead to multi-organ failure. This form of smallpox occurs in anywhere from 3–25% of fatal cases (depending on the virulence of the smallpox strain).
The historical modes of death are similar to those in burns, with catastrophic losses of fluid, protein and electrolytes beyond the capacity of the body to replace or assimilate, and fulminating sepsis, both due to the removal of the barrier between the internal milieu and outside world. Supportive treatments have improved since the last large smallpox epidemics, but it would be grossly optimistic to imagine that, even with a small number of patients, the most intensive modern treatment would ensure survival, even where the damage is predominantly only in the skin. A reduction in the severity of the disease by raising immunity is likely to make a large difference in numbers reaching the threshold of death, and supportive treatment a small one in elevating that threshold.
It is important to note that, while historical epidemics and pandemics are believed by some historians to have been early outbreaks of smallpox, contemporary records are not detailed enough to make a definite diagnosis at this distance.
The Plague of Athens devastated the city of Athens in 430 BCE, killing around a third of the population, according to Thucydides. Historians have long considered this an example of bubonic plague, but more recent examination of the reported symptoms led some scholars to believe the cause may have been measles, smallpox, typhus, or a viral hemorrhagic fever (like Ebola).
The Antonine Plague that swept through the Roman Empire and Italy in 165–180 is also thought to be either smallpox or measles.  A second major outbreak of disease in the Empire, known as the Plague of Cyprian (251–266), was also either smallpox or measles.
The next major epidemic believed to be smallpox occurred in
Smallpox did not definitively enter Western Europe until about 581 when Bishop Gregory of Tours provided an eyewitness account that describes the characteristic findings of smallpox. Most of the details about the epidemic that followed are lost, probably due to the scarcity of surviving written records of early medieval society.
 The Americas
Documented Smallpox Epidemics in the New World
Year Location Description
1520-1527 Mexico, Central America, South America Smallpox kills millions of native inhabitants of Mexico. Unintentionally introduced at Veracruz with the arrival of Panfilo de Narvaez on April 23, 1520 and was credited with the victory of Cortes over the Aztec empire at Tenochtitlan (present-day Mexico City) in 1521. Kills the Inca ruler, Huayna Capac, and 200,000 others and destroys the Incan Empire.
1617-1619 North America northern east coast Killed 90% of the Massachusetts Bay Indians
1674 Cherokee Tribe Death count unknown. Population in 1674 about 50,000. After 1729, 1738, and 1753 smallpox epidemics their population was only 25,000 when they were forced to Oklahoma on the Trail Of Tears
1692 Boston, MA
1702-1703 St. Lawrence Valley, NY
1721 Boston, MA
1738 South Carolina
1754-1767 North East U.S. and South East Canada "Smallpox was probably first used as a biological weapon during the French and Indian Wars of 1754-1767 when British forces in North America distributed blankets that had been used by smallpox patients among them to Native Americans collaborating with the French."
1770s West Coast of North America Kills out 30% of the West Coast Native Americans
1781-1783 Great Lakes
1830s Alaska Reduced Dena’ina Athabaskan population in Cook Inlet region of southcentral Alaska by half. Smallpox also devastated Yup’ik Eskimo populations in western Alaska.
1865-1873 Philadelphia, PA, New York, Boston, MA and New Orleans, LA Same period of time, in Washington DC, Baltimore, MD, Memphis, TN Cholera and a series of recurring epidemics of Typhus, Scarlet Fever and Yellow Fever
1877 Los Angeles, CA
After first contacts with Europeans and Africans, some believe that the death of 90–95% of the native population of the New World was caused by Old World diseases. It is suspected that smallpox was the chief culprit and responsible for killing nearly all of the native inhabitants of the Americas. For more than 200 years, this disease affected all new world populations, mostly without intentional European transmission (excluding the British settlements), from contact in the early 1500s to until possibly as early as the French and Indian Wars (1754-1767).
In 1519 Hernán Cortés landed on the shores of what is now Mexico and was then the Aztec empire. In 1520 another group of Spanish came from Cuba and landed in Mexico. Among them was an African slave who had smallpox. When Cortés heard about the other group, he went and defeated them. In this contact, one of Cortés’s men contracted the disease. When Cortés returned to Tenochtitlan, he brought the disease with him.
Soon, the Aztecs rose up in rebellion against Cortés and his men. Outnumbered, the Spanish were forced to flee. In the fighting, the Spanish soldier carrying smallpox died. After the battle, the Aztecs contracted the virus from the invaders’ bodies. Cortes would not return to the capital until August 1521. In the meantime smallpox devastated the Aztec population. It killed most of the Aztec army, the emperor, and 25% of the overall population.  A Spanish priest left this description: "As the Indians did not know the remedy of the disease…they died in heaps, like bedbugs. In many places it happened that everyone in a house died and, as it was impossible to bury the great number of dead, they pulled down the houses over them so that their homes become their tombs." On Cortés’s return, he found the Aztec army’s chain of command in ruins. The soldiers who lived were still weak from the disease. Cortés then easily defeated the Aztecs and entered Tenochtitlán, where he found that smallpox had killed more Aztecs than had the cannons. The Spaniards said that they could not walk through the streets without stepping on the bodies of smallpox victims.
The effects of smallpox on Tahuantinsuyu (or the Inca empire) were even more devastating. Beginning in Colombia, smallpox spread rapidly before the Spanish invaders first arrived in the empire. The spread was probably aided by the efficient Inca road system. Within months, the disease had killed the Sapa Inca Huayna Capac, his successor, and most of the other leaders. Two of his surviving sons warred for power and, after a bloody and costly war, Atahualpa become the new Sapa Inca. As Atahualpa was returning to the capital Cuzco, Francisco Pizarro arrived and through a series of deceits captured the young leader and his best general. Within a few years smallpox claimed between 60% and 90% of the Inca population, with other waves of European disease weakening them further. However, some historians[attribution needed] think a serious native disease called Bartonellosis may have been responsible for some outbreaks of illness. The effects of smallpox were depicted in the ceramics of the Moche people of ancient Peru.
Even after the two mighty empires of the Americas were defeated by the virus and disease, smallpox continued its march of death. In 1633 in Plymouth, Massachusetts, the Native Americans were struck by the virus. As it had done elsewhere, the virus wiped out entire population groups of Native Americans. It reached Lake Ontario in 1636, and the lands of the Iroquois by 1679, killing millions.
The worst sequence of smallpox attacks took place in Boston, Massachusetts. From 1636 to 1698, Boston endured six epidemics. In 1721, the most severe epidemic occurred. The entire population fled the city, bringing the virus to the rest of the Thirteen Colonies. In the late 1770s, during the American Revolutionary War, smallpox returned once more and killed an estimated 125,000 people. Peter Kalm in his “Travels in North America”, described how in that period, the dying Indian villages became overrun with wolves feasting on the corpses and weakened survivors.
Smallpox inoculation sign, 1801By that time, a preventive treatment for smallpox had finally arrived. It was a process called inoculation, also known as insufflation or variolation. Inoculation was not a sudden innovation, as it is known to have been practiced in India as early as 1000 BC. The Indians rubbed pus into the skin lesions. The Chinese blew powdered smallpox scabs up the noses of the healthy after discovery, by a Buddhist nun, that this inoculated non-immune people. The patients would then develop a mild case of the disease and from then on were immune to it. This technique is known as variolation and although variolation had a 0.5-2% mortality rate, this was considerably less than the 20-30% mortality rate of the disease itself. The process spread to Turkey where Lady Mary Wortley Montagu, wife of the British ambassador, learned of it from Emmanuel Timoni (ca. 1670–1718), a doctor affiliated with the British Embassy in Istanbul. She had the procedure performed on her son and daughter, aged 5 and 4 respectively. They both recovered quickly and the procedure was hailed as a success and reported to the Royal Society in England. Timoni, from the University of Padova, Italy and a member of the Royal Society of London since 1703, published “an account, or history, of the procuring the smallpox by incision” in December 1713 in the Philosophical Transactions. His work was published again in 1714 in Leipzig and was followed by those of Pylarino (1715), Leduc (1722), and Maitland (1722).
In 1721, an epidemic of smallpox hit London and left the British Royal Family in fear. Reading of Lady Wortley Montagu’s efforts, they wanted to use inoculation on themselves. Doctors told them that it was a dangerous procedure, so they decided to try it on other people first. The test subjects they used were condemned prisoners. The doctors inoculated the prisoners and all of them recovered in a couple of weeks. So assured, the British royal family inoculated themselves and reassured the English people that it was safe.
But inoculation still had its critics. Prominent among them were religious preachers who claimed that smallpox was God’s way of punishing people and that inoculation was a tool of Satan. This resistance only encouraged Montagu and the others to work even harder. By 1723 inoculations were extremely common in England, but even scientific opposition (such as the Fellow "