Smallpox
Smallpox | |
---|---|
Other names | variola, Infectious disease |
Symptoms | |
Supportive care[10] | |
Medication | Brincidofovir |
Prognosis | 30% risk of death[5] |
Frequency | Eradicated (last wild case in 1977) |
Smallpox was an
The initial symptoms of the disease included
The earliest evidence of the disease dates to around 1500 BC in Egyptian
Classification
Type of disease | Case fatality rate (%) | Frequency (%) | ||
---|---|---|---|---|
Unvac. | Vac. | Unvac. | Vac. | |
Ordinary discrete | 9.3 | 0.7 | 42.1 | 58.4 |
Ordinary confluent | 62 | 26.3 | 22.8 | 4.6 |
Ordinary semiconfluent | 37 | 8.4 | 23.9 | 7 |
Modified | 0 | 0 | 2.1 | 25.3 |
Malignant aka Flat | 96.5 | 66.7 | 6.7 | 1.3 |
Early hemorrhagic | 100 | 100 | 0.7 | 1.4 |
Late hemorrhagic | 96.8 | 89.8 | 1.7 | 2.0 |
There are two forms of the smallpox. Variola major is the severe and most common form, with a more extensive rash and higher fever.
Signs and symptoms
External videos | |
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Smallpox (US Army, 1967) on YouTube |
The initial symptoms were similar to other viral diseases that are still extant, such as
Variola virus tended to attack skin cells, causing the characteristic pimples, or
Ordinary
At least 90% of smallpox cases among unvaccinated persons were of the ordinary type.
By the sixth or seventh day, all the skin lesions had become pustules. Between seven and ten days the pustules had matured and reached their maximum size. The pustules were sharply raised, typically round, tense, and firm to the touch. The pustules were deeply embedded in the dermis, giving them the feel of a small bead in the skin. Fluid slowly leaked from the pustules, and by the end of the second week, the pustules had deflated and began to dry up, forming crusts or scabs. By day 16–20 scabs had formed over all of the lesions, which had started to flake off, leaving depigmented scars.[38]
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.[33]
Confluent
Sometimes, the blisters merged into sheets, forming a confluent rash, which began to detach the outer layers of skin from the underlying flesh. Patients with confluent smallpox often remained ill even after scabs had formed over all the lesions. In one case series, the case-fatality rate in confluent smallpox was 62%.[33]
Modified
Referring to the character of the eruption and the rapidity of its development, modified smallpox occurred mostly in previously vaccinated people. It was rare in unvaccinated people, with one case study showing 1–2% of modified cases compared to around 25% in vaccinated people. In this form, the prodromal illness still occurred but may have been less severe than in the ordinary type. There was usually no fever during the evolution of the rash. The skin lesions tended to be fewer and evolved more quickly, were more superficial, and may not have shown the uniform characteristic of more typical smallpox.[38] Modified smallpox was rarely, if ever, fatal. This form of variola major was more easily confused with chickenpox.[33]
Malignant
In malignant-type smallpox (also called flat smallpox) the lesions remained almost flush with the skin at the time when raised vesicles would have formed in the ordinary type. It is unknown why some people developed this type. Historically, it accounted for 5–10% of cases, and most (72%) were children.[3] Malignant smallpox was accompanied by a severe prodromal phase that lasted 3–4 days, prolonged high fever, and severe symptoms of viremia. The prodromal symptoms continued even after the onset of the rash.[3] The rash on the mucous membranes (enanthem) was extensive. Skin lesions matured slowly, were typically confluent or semi-confluent, and by the seventh or eighth day, they were flat and appeared to be buried in the skin. Unlike ordinary-type smallpox, the vesicles contained little fluid, were soft and velvety to the touch, and may have contained hemorrhages. Malignant smallpox was nearly always fatal and death usually occurred between the 8th and 12th day of illness. Often, a day or two before death, the lesions turned ashen gray, which, along with abdominal distension, was a bad prognostic sign.[3] This form is thought to be caused by deficient cell-mediated immunity to smallpox. If the person recovered, the lesions gradually faded and did not form scars or scabs.[39]
Hemorrhagic
Early
The early or
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.[3] 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.[33] 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.[34] This form of smallpox occurs anywhere from 3% to 25% of fatal cases, depending on the virulence of the smallpox strain.[36] 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.[3] The case fatality rate for late hemorrhagic smallpox is around 90–95%.[35] Pregnant women are slightly more likely to experience this form of the disease, though not as much as early hemorrhagic smallpox.[3]
Cause
Variola virus | |
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This virions . The "dumbbell-shaped" structure inside the virion is the viral core, which contains the viral DNA; Mag. = ~370,000×
| |
Virus classification | |
(unranked): | Virus |
Realm: | Varidnaviria |
Kingdom: | Bamfordvirae |
Phylum: | Nucleocytoviricota |
Class: | Pokkesviricetes |
Order: | Chitovirales |
Family: | Poxviridae |
Genus: | Orthopoxvirus |
Species: | †Variola virus |
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.[44] 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.[45]
A second estimate has placed the separation of variola virus from
Examination of a strain that dates from c. 1650 found that this strain was basal to the other presently sequenced strains.[47] 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
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.[33]
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
Both
Variola major
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The more common, infectious form of the disease was caused by the variola major virus strain.
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 smallpox'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.[51] Variola minor was also called white pox, kaffir pox, Cuban itch, West Indian pox, milk pox, and pseudovariola.
Genome composition
The genome of variola major virus is about 186,000 base pairs in length.[52] It is made from linear double stranded DNA and contains the coding sequence for about 200 genes.[53] The genes are usually not overlapping and typically occur in blocks that point towards the closer terminal region of the genome.[54] The coding sequence of the central region of the genome is highly consistent across orthopoxviruses, and the arrangement of genes is consistent across chordopoxviruses[53][54]
The center of the variola virus genome contains the majority of the essential viral genes, including the genes for structural proteins, DNA replication, transcription, and mRNA synthesis.[53] The ends of the genome vary more across strains and species of orthopoxviruses.[53] These regions contain proteins that modulate the hosts' immune systems, and are primarily responsible for the variability in virulence across the orthopoxvirus family.[53] These terminal regions in poxviruses are inverted terminal repetitions (ITR) sequences.[54] These sequences are identical but oppositely oriented on either end of the genome, leading to the genome being a continuous loop of DNA[54] Components of the ITR sequences include an incompletely base paired A/T rich hairpin loop, a region of roughly 100 base pairs necessary for resolving concatomeric DNA (a stretch of DNA containing multiple copies of the same sequence), a few open reading frames, and short tandemly repeating sequences of varying number and length.[54] The ITRs of poxviridae vary in length across strains and species.[54] The coding sequence for most of the viral proteins in variola major virus have at least 90% similarity with the genome of vaccinia, a related virus used for vaccination against smallpox.[54]
Gene expression
Gene expression of variola virus occurs entirely within the cytoplasm of the host cell, and follows a distinct progression during infection.[54] After entry of an infectious virion into a host cell, synthesis of viral mRNA can be detected within 20 minutes.[54] About half of the viral genome is transcribed prior to the replication of viral DNA.[54] The first set of expressed genes are transcribed by pre-existing viral machinery packaged within the infecting virion.[54] These genes encode the factors necessary for viral DNA synthesis and for transcription of the next set of expressed genes.[54] Unlike most DNA viruses, DNA replication in variola virus and other poxviruses takes place within the cytoplasm of the infected cell.[54] The exact timing of DNA replication after infection of a host cell varies across the poxviridae.[54] Recombination of the genome occurs within actively infected cells.[54] Following the onset of viral DNA replication, an intermediate set of genes codes for transcription factors of late gene expression.[54] The products of the later genes include transcription factors necessary for transcribing the early genes for new virions, as well as viral RNA polymerase and other essential enzymes for new viral particles.[54] These proteins are then packaged into new infectious virions capable of infecting other cells.[54]
Research
Two live samples of variola major virus remain, one in the United States at the CDC in Atlanta, and one at the Vector Institute in Koltsovo, Russia.[55] 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).[55] Most research on poxviruses is performed using the closely related Vaccinia virus as a model organism.[54] Vaccinia virus, which is used to vaccinate for smallpox, is also under research as a viral vector for vaccines for unrelated diseases.[56]
The genome of variola major virus was first sequenced in its entirety in the 1990s.[53] The complete coding sequence is publicly available online. The current reference sequence for variola major virus was sequenced from a strain that circulated in India in 1967. In addition, there are sequences for samples of other strains that were collected during the WHO eradication campaign.[53] A genome browser for a complete database of annotated sequences of variola virus and other poxviruses is publicly available through the Viral Bioinformatics Resource Center.[57]
Genetic engineering
The WHO currently bans genetic engineering of the variola virus.[58] 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.[58] This gene, called GFP, or green fluorescent protein, would cause live samples of the virus to glow green under fluorescent light.[59] The insertion of this gene, which would not influence the virulence of the virus, would be the only allowed modification of the genome.[59] The committee stated the proposed modification would aid in research of treatments by making it easier to assess whether a potential treatment was effective in killing viral samples.[59] The recommendation could only take effect if approved by the WHA.[59] When the WHA discussed the proposal in 2005, it refrained from taking a formal vote on the proposal, stating that it would review individual research proposals one at a time.[60] Addition of the GFP gene to the Vaccinia genome is routinely performed during research on the closely related Vaccinia virus.[61]
Controversies
The public availability of the variola virus complete sequence has raised concerns about the possibility of illicit synthesis of infectious virus.[62] Vaccinia, a cousin of the variola virus, was artificially synthesized in 2002 by NIH scientists.[63] They used a previously established method that involved using a recombinant viral genome to create a self-replicating bacterial plasmid that produced viral particles.[63]
In 2016, another group synthesized the
Transmission
Smallpox was highly contagious, but generally spread more slowly and less widely than some other viral diseases, perhaps because transmission required close contact and occurred after the onset of the rash. The overall rate of infection was also affected by the short duration of the infectious stage. In
Transmission occurred through inhalation of
Some infections of laundry workers with smallpox after handling contaminated bedding suggested that smallpox could be spread through direct contact with contaminated objects (
Mechanism
Once inhaled, the variola virus invaded the mucus membranes of the mouth, throat, and respiratory tract. From there, it migrated to regional
Diagnosis
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.
Definitive laboratory identification of variola virus involved growing the virus on
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]
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Smallpox virus lesions on the chorioallantoic membrane of a developing chick
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In contrast to the rash in smallpox, the rash in chickenpox occurs mostly on the torso, spreading less to the limbs.
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An Italian female smallpox patient whose skin displayed the characteristics of late-stage confluent maculopapular scarring, 1965
Prevention
The earliest procedure used to prevent smallpox was
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.[72] 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".[73] 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.[33]
The current formulation of the smallpox vaccine is a live virus preparation of the 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) several 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.[74]
The
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
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.
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
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]
Prognosis
The mortality rate from variola minor is approximately 1%, while the mortality rate from variola major is approximately 30%.[87]
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.[43] The case-fatality rate for variola minor is 1% or less.[38] There is no evidence of chronic or recurrent infection with variola virus.[38] In cases of flat smallpox in vaccinated people, the condition was extremely rare but less lethal, with one case series showing a 66.7% death rate.[3]
In fatal cases of ordinary smallpox, death usually occurs between days 10-16 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.[33] 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.[3] In flat smallpox modes of death are similar to those in burns, with loss of fluid, protein and electrolytes, and fulminating sepsis.[81]
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.[33]
Other complications include
Between 65 and 80% of survivors are marked with deep pitted scars (pockmarks), most prominent on the face.
History
Disease emergence
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),
A different viewpoint is that smallpox emerged 1588 CE and the earlier reported cases were incorrectly identified as smallpox.[94][95]
The timing of the arrival of smallpox in Europe and south-western Asia is less clear. Smallpox is not clearly described in either the
While the
There were no credible descriptions of smallpox-like disease in the
By the mid-18th century, smallpox was a major
Eradication
The first clear reference to smallpox inoculation was made by the Chinese author Wan Quan (1499–1582) in his Dòuzhěn xīnfǎ (痘疹心法, "Pox Rash Teachings") published in 1549,[104] with earliest hints of the practice in China during the 10th century.[105] 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.[106] Voltaire (1742) reports that the Chinese had practiced smallpox inoculation "these hundred years".[73] Variolation had also been witnessed in Turkey by Lady Mary Wortley Montagu, who later introduced it in the UK.[107]
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.[108][109] 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.[110] He was reputed not to have lost a single patient.[110] Arthur Edmondston, in writings on Notions' technique that were published in 1809, stated, "Had every practitioner been as uniformly successful in the disease as he was, the small-pox might have been banished from the face of the earth, without injuring the system, or leaving any doubt as to the fact."[111]
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 "Vaccinov" by Catherine the Great, and was educated at the expense of the nation.[112]
The introduction of the vaccine to the New World took place in
On August 26, 1807, Bavaria became the first country in the world to introduce compulsory vaccinations. Baden followed in 1809, Prussia in 1815, Württemberg in 1818, Sweden in 1816 and the German Empire in 1874 through the Reichs Vaccination Act.[116][117] In Lutheran Sweden, the Protestant clergy played a pioneering role in voluntary smallpox vaccination as early as 1800.[118] The first vaccination was carried out in Liechtenstein in 1801, and from 1812 it was mandatory to vaccinate.[119]
In
In the United States, from 1843 to 1855, first Massachusetts and then other states required smallpox vaccination. Although some disliked these measures,[90] coordinated efforts against smallpox went on, and the disease continued to diminish in the wealthy countries. 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 as protection against reintroduction until the mid to late 1970s. 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.[124]
The first hemisphere-wide effort to eradicate smallpox was made in 1950 by the Pan American Health Organization.[125] The campaign was successful in eliminating smallpox from all countries of the Americas except Argentina, Brazil, Colombia, and Ecuador.[124] In 1958 Professor Viktor Zhdanov, Deputy Minister of Health for the USSR, called on the World Health Assembly to undertake a global initiative to eradicate smallpox.[126] The proposal (Resolution WHA11.54) was accepted in 1959.[126] At this point, 2 million people were dying from smallpox every year. Overall, the progress towards eradication was disappointing, especially in Africa and in the Indian subcontinent. In 1966 an international team, the Smallpox Eradication Unit, was formed under the leadership of an American, Donald Henderson.[127] 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.[128]
In the early 1950s, an estimated 50 million cases of smallpox occurred in the world each year.[10] To eradicate smallpox, each outbreak had to be stopped from spreading, by isolation of cases and vaccination of everyone who lived close by.[129] 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 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 vaccine was produced in developing countries.[124] The Soviet Union provided one and a half billion doses between 1958 and 1979, as well as the medical staff.[130]
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.[131] 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.[132]
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.[133] 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.[33] The last naturally occurring case of the more deadly Variola major had been detected in October 1975 in a three-year-old Bangladeshi girl, Rahima Banu.[40]
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.[10][134] 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.[135]
Costs and benefits
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.[136]
Post-eradication
The last case of smallpox in the world occurred in
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.[141] 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.[142] Destroying existing stocks would reduce the risk involved with ongoing smallpox research; the stocks are not needed to respond to a smallpox outbreak.[143] Some scientists have argued that the stocks may be useful in developing new vaccines, antiviral drugs, and diagnostic tests;[144] 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.[145] The latter view is frequently supported in the scientific community, particularly among veterans of the WHO Smallpox Eradication Program.[146]
On March 31, 2003, smallpox scabs were found inside an envelope in an 1888 book on Civil War medicine in Santa Fe, New Mexico.[147] 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.[148][149] After studies were conducted, the CDC destroyed the virus under WHO observation on February 24, 2015.[150]
In 2017, scientists at the
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.[154]
Society and culture
Biological warfare
In 1763,
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]
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.[173] 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.[161]
In 1947, the
On
Others contend that the first patient may have contracted the disease while visiting Uyaly or Komsomolsk-on-Ustyurt, two cities where the boat docked.[177][178]
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.[179] In 1992, Soviet defector Ken Alibek alleged 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, Alibek further alleged), along with refrigerated warheads to deliver it. Alibek's stories about the former Soviet program's smallpox activities have never been independently verified.
In 1997, the Russian government announced that all of its remaining smallpox samples would be moved to the Vector Institute in Koltsovo.[179] 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.[180] Specific allegations made against Iraq in this respect proved to be false.[181]
Notable cases
Famous historical figures who contracted smallpox include Lakota Chief
Prominent families throughout the world often had several people infected by and/or perish from the disease. For example, several relatives of
In Europe, deaths from smallpox often changed dynastic succession.
In China, the
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.[185] Jackson developed the illness after being taken prisoner by the British during the American Revolution, and though he recovered, his brother Robert did not.[185] Lincoln contracted the disease during his presidency, possibly from his son Tad, and was quarantined shortly after giving the Gettysburg address in 1863.[185]
The famous theologian Jonathan Edwards died of smallpox in 1758 following an inoculation.[186]
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.[187]
Hungarian poet Ferenc Kölcsey, who wrote the Hungarian national anthem, lost his right eye to smallpox.[188]
Tradition and religion
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: 痘疹娘娘).[189] 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 天花, literally "heaven flower").[190] 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.[190] If a case of smallpox did occur, shrines would be set up in the homes of the victims, to be worshipped and offered to as the disease ran its course. If the victim recovered, the shrines were removed and carried away in a special paper chair or boat for burning. If the patient did not recover, the shrine was destroyed and cursed, to expel the goddess from the house.[189]
In the Yoruba language smallpox is known as ṣọpọná, but it was also written as shakpanna, shopona, ṣhapana, and ṣọpọnọ. The word is a combination of 3 words, the verb ṣán, meaning to cover or plaster (referring to the pustules characteristic of smallpox), kpa or pa, meaning to kill, and enia, meaning human. Roughly translated, it means One who kills a person by covering them with pustules.[191] 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.[192] Worship of Shopona was highly controlled by his priests, and it was believed that priests could also spread smallpox when angered.[192] However, Shopona was also seen as a healer who could cure the diseases he inflicted, and he was often called upon by his victims to heal them.[193] The British government banned the worship of the god because it was believed his priests were purposely spreading smallpox to their opponents.[193][192]
India's first records of smallpox can be found in a medical book that dates back to 400 CE. This book describes a disease that sounds exceptionally like smallpox.[190] India, like China and the Yorùbá, created a goddess in response to its exposure to smallpox. The Hindu goddess Shitala was both worshipped and feared during her reign. It was believed that this goddess was both evil and kind and had the ability to inflict victims when angered, as well as calm the fevers of the already affected.[194][195] Portraits of the goddess show her holding a broom in her right hand to continue to move the disease and a pot of cool water in the other hand in an attempt to soothe patients.[190] Shrines were created where many Indian natives, both healthy and not, went to worship and attempt to protect themselves from this disease. Some Indian women, in an attempt to ward off Shitala, placed plates of cooling foods and pots of water on the roofs of their homes.[196]
In cultures that did not recognize a smallpox deity, there was often nonetheless a belief in
See also
- List of epidemics
- List of epidemics and pandemics § Chronology
- Population history of indigenous peoples of the Americas § Depopulation by Old World diseases
- 1971 Aral smallpox incident
- Jacobson v. Massachusetts
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Further reading
- Fenn, Elizabeth A. Pox Americana: the great smallpox epidemic of 1775-82 (Macmillan, 2001) online.
- Fenner F (1988). Smallpox and Its Eradication (History of International Public Health, No. 6) (PDF). Geneva: World Health Organization. ISBN 978-92-4-156110-5. Archived(PDF) from the original on 19 February 2015. Retrieved 7 September 2007.
- Henderson, Donald Ainslie. Smallpox: the death of a disease: the inside story of eradicating a worldwide killer. (Prometheus Books, 2009).
- Hopkins, Donald R. The greatest killer: smallpox in history (U of Chicago press, 2002) online, a major scholarly history
- Koplow, David A. Smallpox: The Fight to Eradicate a Global Scourge (U of California Press, 2003)
- Kotar, S.L. and J.E. Gessler. Smallpox: A History (McFarland, 2013) online anecdotal accounts from letters and editorials in local newspapers.
- Pallen M (2018). The Last Days of Smallpox: Tragedy in Birmingham. UK: Amazon KDP. ISBN 978-1-9804-5522-6.
- Reinhardt BH (2015). The End of a Global Pox: America and the Eradication of Smallpox in the Cold War Era. University of North Carolina Press. pp. xviii, 268.
- Tucker JB (2001). Scourge: The Once and Future Threat of Smallpox. New York: Grove Press. ISBN 978-0-8021-3939-9.
- Wharncliffe L, Thomas WM, eds. (1861). The Letters and Works of Lady Mary Wortley Montagu. Vol. 1. London: Henry G. Bohn.
External links
- Smallpox Biosafety: A Website About Destruction of Smallpox Virus Stocks
- Detailed CIDRAP Smallpox overview Archived 6 May 2013 at the Wayback Machine
- Agent Fact Sheet: Smallpox, Center for Biosecurity
- Smallpox Images and Diagnosis Synopsis Archived 29 July 2008 at the Wayback Machine
- Virus Pathogen Database and Analysis Resource (ViPR): Poxviridae[permanent dead link]
- Episode 1 (of 4): Vaccines of the BBC Four and PBS show: Extra Life: A Short History of Living Longer (2021)