of the illness. the cause of death from smallpox is not clear, but the infection is now known to involve multiple organs. circulating immune complexes, overwhelming viremia, or an uncontrolled immune response may be contributing factors. in early hemorrhagic smallpox, death occurs suddenly about six days after the fever develops. the cause of death in early hemorrhagic cases is commonly due to heart failure and 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 electrolytes, 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 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 main article: history of smallpox disease emergence statue of sopona, 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, who died more than 3000 years ago (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. 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 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. the timing of the arrival of smallpox in europe and south-western asia is less clear. smallpox is not clearly described in either the old or new testaments of the bible or in the literature of the greeks or romans. while some have identified the plague of athens – which was said to have originated in "ethiopia" and egypt – or the plague that lifted carthage's 396 bce siege of syracuse – with smallpox, many scholars agree it is very unlikely such a serious disease as variola major would have escaped being described by hippocrates if it had existed in the mediterranean region during his lifetime. while the antonine plague that swept through the roman empire in 165–180 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, and saint gregory of tours recorded a similar outbreak in france and italy in 580, the first use of the term variola. other historians speculate that arab armies first carried smallpox from africa into southwestern europe during the 7th and 8th centuries. in the 9th century the persian physician, rhazes, provided one of the most definitive descriptions 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). 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, where it had a mortality rate as high as 30 percent. this endemic occurrence of smallpox in europe is of particular historical importance, as successive exploration and colonization by europeans tended to spread the disease to other nations. by the 16th century, smallpox had become a predominant cause of morbidity and mortality throughout much of the world. drawing accompanying text in book xii of the 16th-century florentine codex (compiled 1555–1576), showing nahuas of conquest-era central mexico with smallpox. there were no credible descriptions of smallpox-like disease in the americas before the westward exploration by europeans in the 15th century ce. smallpox was introduced into the caribbean island of hispaniola in 1507, and into the mainland in 1520, when spanish settlers from hispaniola arrived in mexico, inadvertently carrying smallpox with them. because the native amerindian population had no acquired immunity to this new disease, their peoples were decimated by epidemics. such disruption and population losses were an important factor in the spanish achieving conquest of the aztecs and the incas. similarly, english settlement of the east coast of north america in 1633 in plymouth, massachusetts was accompanied by devastating outbreaks of smallpox among native american populations, 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, though colonial surgeons, who by 1829 were attempting to distinguish between smallpox and chickenpox (which could be almost equally fatal to aborigines), were divided as to whether the 1829–1830 epidemic was chickenpox or smallpox. although smallpox was never endemic on the continent, it has been described as the principal cause of death in aboriginal populations between 1780 and 1870. global number of reported smallpox cases from 1920 to 2016. 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, and the death rate of infants in russia might have been even 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. by the mid-20th century, variola minor occurred along with variola major, in varying proportions, in many parts of africa. patients with variola minor experience only a mild systemic illness, are often ambulant throughout the course of the disease, and are therefore able to more easily spread disease. infection with variola minor virus induces immunity against the more deadly variola major form. thus, as variola minor spread all over the us, into canada, the south american countries, and great britain, it became the dominant form of smallpox, further reducing mortality rates. eradication