Smallpox
Smallpox was an infectious disease caused by variola virus (often called smallpox virus), which belongs to the genus Orthopoxvirus.[7][11] 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,[10] making smallpox the only human disease to have been eradicated to date.[12]
"Variola" redirects here. For other uses, see Variola (disambiguation).Smallpox
Scarring of the skin, blindness[6]
1 to 3 weeks following exposure[5]
About 4 weeks[5]
variola major virus, variola minor virus (spread between people)[6][7]
30% risk of death[5]
Eradicated (last wild case in 1977)
The initial symptoms of the disease included fever and vomiting.[5] This was followed by formation of ulcers in the mouth and a skin rash.[5] Over a number of days, the skin rash turned into the characteristic fluid-filled blisters with a dent in the center.[5] The bumps then scabbed over and fell off, leaving scars.[5] The disease was transmitted from one person to another primarily through prolonged face-to-face contact with an infected person or (rarely) via contaminated objects.[6][13][14] Prevention was achieved mainly through the smallpox vaccine.[9] Once the disease had developed, certain antiviral medications could potentially have helped, but such medications did not become available until after the disease was eradicated.[9] The risk of death was about 30%, with higher rates among babies.[6][15] Often, those who survived had extensive scarring of their skin, and some were left blind.[6]
The earliest evidence of the disease dates to around 1500 BC in Egyptian mummies.[16][17] The disease historically occurred in outbreaks.[10] In 18th-century Europe, it is estimated that 400,000 people died from the disease per year, and that one-third of all cases of blindness were due to smallpox.[10][18] Smallpox is estimated to have killed up to 300 million people in the 20th century[19][20] and around 500 million people in the last 100 years of its existence.[21] Earlier deaths included six European monarchs, including Louis XV of France in 1774.[10][18] As recently as 1967, 15 million cases occurred a year.[10]
Inoculation for smallpox appears to have started in China around the 1500s.[22][23] Europe adopted this practice from Asia in the first half of the 18th century.[24] In 1796, Edward Jenner introduced the modern smallpox vaccine.[25][26] In 1967, the WHO intensified efforts to eliminate the disease.[10] Smallpox is one of two infectious diseases to have been eradicated, the other being rinderpest (a disease of even-toed ungulates) in 2011.[27][28] The term "smallpox" was first used in England in the 16th century to distinguish the disease from syphilis, which was then known as the "great pox".[29][30] Other historical names for the disease include pox, speckled monster, and red plague.[3][4][30]
Mechanism
Once inhaled, the variola virus invaded the mucus 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.
In contrast to the rash in smallpox, the rash in chickenpox occurs mostly on the torso, spreading less to the limbs.
An Italian female smallpox patient whose skin displayed the characteristics of late-stage confluent maculopapular scarring, 1965
The clinical definition of ordinary smallpox is an illness with acute onset of fever equal to or greater than 38.3 °C (101 °F) followed by a rash characterized by firm, deep-seated vesicles or pustules in the same stage of development without other apparent cause.[33] When a clinical case was observed, smallpox was 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.[66] 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.[34] If particles with the characteristic morphology of herpesviruses are seen this will eliminate smallpox and other orthopoxvirus infections.
Definitive laboratory identification of variola virus involved growing the virus on chorioallantoic membrane (part of a chicken embryo) and examining the resulting pock lesions under defined temperature conditions.[67] 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.[68]
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.[33]
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.[75] 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.[81]
In July 2018, the Food and Drug Administration approved tecovirimat, the first drug approved for treatment of smallpox.[82] Antiviral treatments have improved since the last large smallpox epidemics, and studies suggest that the antiviral drug cidofovir might be useful as a therapeutic agent. The drug must be administered intravenously, and may cause serious kidney toxicity.[83]
ACAM2000 is a smallpox vaccine developed by Acambis. It was 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.[79] The vaccine is not routinely available to the US public; it is, however, used in the military and maintained in the Strategic National Stockpile.[84]
In June 2021, brincidofovir was approved for medical use in the United States for the treatment of human smallpox disease caused by variola virus.[85][86]
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.[155][156][157] A group of Native American warriors laid siege to British-held Fort Pitt on June 22.[158] 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 [sic] the Indians by means of Blankets that may fall in their hands".[159] 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."[160][155] 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).[161][162]
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.[163] This theory was also considered earlier in Bulletin of the History of Medicine[164] and by David Day.[165] 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 chickenpox—a more infectious disease which, at the time, was often confused, even by surgeons, with smallpox, and may have been comparably deadly to Aborigines and other peoples without natural immunity to it.[166] 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.[102] In 2007, Christopher Warren offered evidence that the British smallpox may have been still viable.[167] However, the only non-Aborigine reported to have died in this outbreak was a seaman called Joseph Jeffries, who was recorded as being of "American Indian" origin.[168]
W. S. Carus, an expert in biological weapons, has written that there is circumstantial evidence that smallpox was deliberately introduced to the Aboriginal population.[169] However Carmody and the Australian National University's Boyd Hunter continue to support the chickenpox hypothesis.[170] In a 2013 lecture at the Australian National University,[171] Carmody pointed out that chickenpox, unlike smallpox, was known to be present in the Sydney Cove colony. He also suggested that all c. 18th century (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."[172]