Smallpox

128 languages
 Article
 Talk
 Read
 View source
 View history
Tools

















From Wikipedia, the free encyclopedia

"Variola" redirects here. For other uses, see Variola (disambiguation).

Smallpox
Other names variola,[1] variola vera,
[2] pox,[3] red plague[4]

A child with smallpox in Bangladesh in 1973. The

 bumps filled with thick fluid and a depression or
dimple in the center are characteristic.
Specialty Infectious disease
Symptoms Early: Fever, vomiting, mouth sores[5]
Later: Fluid
filled blisters which scab over[5]
Complications Scarring of the skin,
blindness[6]
Usual onset 1 to 3 weeks following
exposure[5]
Duration About 4 weeks[5]
Causes variola major virus, variola
minor virus (spread between
people)[6][7]
Diagnostic method Based on symptoms and
confirmed by PCR[8]
Differential Chickenpox, impetigo, mollus
diagnosis cum contagiosum, monkeypox[8]
Prevention Smallpox vaccine[9]
Treatment Supportive care[10]
Medication Brincidofovir
Prognosis 30% risk of death[5]
Frequency Eradicated (last wild case in
1977)

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]

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]

Classification
Case fatality rate and frequency of smallpox by type and vaccination status
according to Rao case study[31]
Case fatality rate
Frequency (%)
Type of disease (%)
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. Variola minor is a
less common presentation, causing less severe disease, typically discrete
smallpox, with historical death rates of 1% or less.[32] Subclinical
(asymptomatic) infections with variola virus were noted but were not common.
[33] In addition, a form called variola sine eruptione (smallpox without rash)
was seen generally in vaccinated persons. This form was marked by a fever
that occurred after the usual incubation period and could be confirmed only
by antibody studies or, rarely, by viral culture.[33] In addition, there were two
very rare and fulminating types of smallpox, the malignant (flat) and
hemorrhagic forms, which were usually fatal.

Signs and symptoms

External videos
Smallpox (US Army, 1967) on YouTube

The initial symptoms were similar to other viral diseases that are still extant,
such as influenza and the common cold: fever of at least 38.3 °C
(101 °F), muscle pain, malaise, headache and fatigue. As the digestive
tract was commonly involved, nausea, vomiting, and backache often
occurred. The early prodromal stage usually lasted 2–4 days. By days 12–15,
the first visible lesions – small reddish spots called enanthem – appeared on
mucous membranes of the mouth, tongue, palate, and throat, and the
temperature fell to near-normal. These lesions rapidly enlarged and ruptured,
releasing large amounts of virus into the saliva.[34]
Variola virus tended to attack skin cells, causing the characteristic pimples,
or macules, associated with the disease. A rash developed on the skin 24 to
48 hours after lesions on the mucous membranes appeared. Typically the
macules first appeared 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 took no more than 24 to 36 hours, after which no
new lesions appeared.[34] At this point, variola major disease could take
several very different courses, which resulted in four types of smallpox
disease based on the Rao classification:[35] ordinary, modified, malignant (or
flat), and hemorrhagic smallpox. Historically, ordinary smallpox had an
overall fatality rate of about 30%, and the malignant and hemorrhagic forms
were usually fatal. The modified form was almost never fatal. In early
hemorrhagic cases, hemorrhages occurred before any skin lesions
developed.[36] The incubation period between contraction and the first obvious
symptoms of the disease was 7–14 days.[37]

Ordinary

A child showing rash due to ordinary-type smallpox

(variola major)

At least 90% of smallpox cases among unvaccinated persons were of the

ordinary type.[33] In this form of the disease, by the second day of the rash the
macules had become raised papules. By the third or fourth day, the papules
had filled with an opalescent fluid to become vesicles. This fluid
became opaque and turbid within 24–48 hours, resulting in pustules.

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

Modified smallpox in a vaccinated 4 year old

in Cardiff, Wales, 1962

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
 Malignant hemorrhagic smallpox in a baker
during an 1896 epidemic in Gloucester, England. Died 8 days after admission.

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

Hemorrhagic smallpox is a severe form accompanied by extensive bleeding

into the skin, mucous membranes, gastrointestinal tract, and viscera. This
form develops in approximately 2% of infections and occurs mostly in adults.
[33] Pustules do not typically form in hemorrhagic smallpox. Instead, bleeding
occurs under the skin, making it look charred and black,[33] hence this form of
the disease is also referred to as variola nigra or "black pox".[40] Hemorrhagic
smallpox has very rarely been caused by variola minor virus.[41] While
bleeding may occur in mild cases and not affect outcomes,[42] hemorrhagic
smallpox is typically fatal.[43] Vaccination does not appear to provide any
immunity to either form of hemorrhagic smallpox and some cases even
occurred among people that were revaccinated shortly before. It has two
forms.[3]

Early
 An unvaccinated person with probable
hemorrhagic smallpox in a 1925 Milwaukee, Wisconsin epidemic. He later
died of the disease.

The early or fulminant form of hemorrhagic smallpox (referred to as purpura

variolosa) begins with a prodromal phase characterized by a high fever,
severe headache, and abdominal pain.[39] The skin becomes dusky and
erythematous, and this is rapidly followed by the development
of petechiae and bleeding in the skin, conjunctiva and mucous membranes.
Death often occurs suddenly between the fifth and seventh days of illness,
when only a few insignificant skin lesions are present. Some people survive a
few days longer, during which time the skin detaches and fluid accumulates
under it, rupturing at the slightest injury. People are usually conscious until
death or shortly before.[43] Autopsy reveals petechiae and bleeding in the
spleen, kidney, serous membranes, skeletal muscles, pericardium, liver,
gonads and bladder.[41] Historically, this condition was frequently
misdiagnosed, with the correct diagnosis made only at autopsy.[41] This form
is more likely to occur in pregnant women than in the general population
(approximately 16% of cases in unvaccinated pregnant women were early
hemorrhagic smallpox, versus roughly 1% in nonpregnant women and adult
males).[43] The case fatality rate of early hemorrhagic smallpox approaches
100%.[43]

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

This transmission electron

micrograph depicts a number of
smallpox 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: Nucleocytoviricot
a
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 Taterapox (an Orthopoxvirus of some African rodents including gerbils)
at 3,000 to 4,000 years ago.[46] This is consistent with archaeological and
historical evidence regarding the appearance of smallpox as a human disease
which suggests a relatively recent origin. If the mutation rate is assumed to be
similar to that of the herpesviruses, the divergence date of variola virus from
Taterapox has been estimated to be 50,000 years ago.[46] While this is
consistent with the other published estimates, it suggests that the
archaeological and historical evidence is very incomplete. Better estimates of
mutation rates in these viruses are needed.

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 nanometers by 244 to 270 nm,[48] with a single linear double stranded
DNA genome 186 kilobase pairs (kbp) in size and containing a hairpin loop at
each end.[49][50]

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 cytoplasm of the cell rather than in
the nucleus. 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 enveloped and unenveloped virions are infectious. The viral envelope is
made of modified Golgi membranes containing viral-specific polypeptides,
including hemagglutinin.[49] Infection with either variola major virus or variola
minor virus confers immunity against the other.[34]

Variola major
This section needs expansion.
You can help by adding to
it. (June 2023)

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]