Smallpox

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

Smallpox is a contagious disease unique to humans.^[1] 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.^[2][1] 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.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Smallpox is estimated to be at least 16,000 years old, and up until 1977, when it became the only human infectious disease to have been completely eradicated, smallpox played a major role in human history. The first clinical evidence of the disease was found in an Egyptian mummy, Ramses V. Smallpox has also been used as a weapon throughout history. The most recent example was the weaponization of smallpox during World War II. After successful vaccination campaigns in the 19th and 20th centuries, the WHO certified the eradication of smallpox in 1980.^[1]

Famous victims of this disease include Date Masamune of Japan (who lost an eye to the disease), Ramses V,^[2] the Shunzhi Emperor and Tongzhi Emperor of China (official history), Mary II of England, Maximilian III Joseph, Elector of Bavaria and Peter II of Russia. Guru Har Krishan 8th Guru of the Sikhs in 1664, Peter III of Russia in 1744 and Abraham Lincoln in 1863.^[3] Joseph Stalin, who was badly scarred by the disease early in life, often had photographs retouched to make his pockmarks less apparent.

Families prominent in history often had several people fall victim to the disease. For example, several relatives of Henry VIII survived the disease but were scarred by it. These include his sister Margaret, Queen of Scotland, his fourth wife, Anne of Cleves, and his daughter, Elizabeth I of England in 1562. His son and heir Edward VI died very shortly after apparently recovering from the disease. Some scholars assert that his death may have been due to complications from smallpox. A more distant relative Mary Queen of Scots contracted the disease as a child but had no visible scarring. Deaths from smallpox often impacted dynastic succession. Louis XV of France succeeded his great-grandfather through a series of deaths of smallpox or measles among those earlier in the succession line and himself died of the disease in 1774.

Between 1775 and 1782, a smallpox epidemic raged across much of North America, killing more than 130,000 people. Among other places it affected:

• The town of Boston during the British occupation and the American siege of 1775
• The American invasion of Quebec, 1775
• Smallpox ravaged the populations of escaped slaves who fled to the British lines in the South during the american revolutionary war
• New Orleans, 1778
• Tens of thousands of people died throughout Mexico beginning in 1779
• It swept through the Pueblos of New Mexico beginning in 1780
• It probably travelled among the people of the Great Plains
• It showed up in the interior trading posts of the Hudson’s Bay Company in 1782

The 1972 outbreak of smallpox in Yugoslavia was the last major outbreak of smallpox in Europe. It was centred in Kosovo and Belgrade, Serbia (both then part of SFR Yugoslavia. A Muslim pilgrim had contracted the smallpox virus in the Middle East. Upon returning to his home in Kosovo, he started the epidemic in which 175 people were infected, 35 of whom died. The epidemic was efficiently and ruthlessly contained by enforced quarantine and mass vaccination.

By 1972, vaccination for smallpox had long been widely available and the disease was considered to be eradicated in Europe. The population of Yugoslavia had been regularly vaccinated against smallpox for 50 years, and the last case was reported in 1930. This was the major cause for the initial slow reaction by doctors, who did not promptly recognize the symptoms of the disease.

In early 1972, a 38-year-old Muslim clergyman from Damnjan near Đakovica, Kosovo, undertook the pilgrimage to Mecca. He also visited holy sites in Iraq, where there were known cases of smallpox. He returned home on February 15. The following morning he felt achy and tired, but attributed this to the long bus journey. He soon realised that he had some kind of infection, but, after feeling feverish for a couple of days and developing a rash, he recovered – probably because he had been vaccinated two months earlier.

On March 3, Latif Musa, a thirty-year-old schoolteacher, who had just arrived in Djakovica to enroll at the local higher institute of education, fell ill. He had no known direct contacts with the clergyman, so he might have been infected by one of the clergyman’s friends or relatives who visited him during his illness, or by passing the clergyman in the street.

When Musa visited the local medical center two days later, the doctors tried to treat his fever with penicillin (smallpox is a virus, so this was ineffective). His condition didn’t improve, and after a couple of days his brother took him to the hospital in Čačak, 150 km to the north in Serbia. The doctors there could not help him, so he was transferred by ambulance to the central hospital in Belgrade.

On March 9, Musa was shown to medical students and staff as a case of an atypical reaction to penicillin, which was a plausible explanation for his condition. On the following day, Musa suffered massive internal bleeding and, despite efforts to save his life, died in the evening.

The cause of death was listed as “reaction to penicillin”. In fact he had contracted black pox, a highly contagious form of smallpox. Before his death, Musa directly infected 38 people (including nine doctors and nurses), eight of whom would consequently die.

By March 22, medical authorities realised that Musa had died of smallpox. The government’s reaction was swift. Martial law was declared. Measures included blockades of villages and neighbourhoods, roadblocks, prohibition of public meetings, closure of borders and prohibition of all non-essential travel. Hotels were requisitioned for quarantines in which 10,000 people who may have been in contact with the virus were held under guard by the army. The authorities undertook a massive revaccination of the population, helped by the World Health Organization. Donald Henderson, the world’s foremost authority on smallpox, was flown in to help the effort.

Within two weeks, almost the entire population had been revaccinated. By mid-May the spread of the disease was stopped and the country returned to normal life. During the epidemic, 175 people contracted smallpox and 35 of them died.

The Yugoslav government received international praise for the successful containment of the epidemic, which was also one of the finest hours for Donald Henderson and the WHO, as well as one of crucial steps in the eradication of smallpox.

Two months of martial law, the fear and the helplessness during of the epidemic left a lasting mark on an entire generation. Another, more tangible mark, was left in the shape of the small scars on millions of arms, left by the vaccination.

• February 15 1972 – A clergyman returns from pilgrimage to Mecca infected with the smallpox virus.
• February 16 – The clergyman feels unwell.
• February 21 – Ljatif Muzza, a thirty-year old school teacher, arrives in Djakovica to continue his studies.
• March 3 – Muzza falls ill with a highly contagious form of smallpox.
• Between March 3 and March 9 Muzza is misdiagnosed and moved to hospitals in Čačak and then Belgrade. During this time, he directly infects 38 people.
• March 9 – Muzza is shown to medical students in the Belgrade hospital as a case of reaction to penicillin.
• March 10 – Muzza develops massive internal bleeding and dies.
• March 22 – Doctors correctly diagnose the cause of Muzza’s death and government begins measures to contain the epidemic.
• Early April – Mass revaccination begins. Donald Henderson arrives.
• Late May – The epidemic is over. 175 people were infected, 35 died.

By 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.^[5] 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 of the Royal College of Physicians Pierce Dod) continued for some time.

In 1721, Onesimus was the slave of a Boston preacher when smallpox came to Boston via a ship arriving from Barbados.^[6] His owner, Cotton Mather asked his slave if he ever had smallpox. Onesimus said, “Yes and no,” and explained a technique from his homeland in Africa, thought to be in Sudan. He explained that pus from an infected person was deliberately rubbed into a scratch or cut of a non-infected person, and when successful, the person had immunity. This remedy from an African slave was the precursor to inoculations. Cotton Mather, the son of a former Harvard University dean, was waging a campaign of his own to promote the process, although religious resistance to inoculation was very strong. At one point, Cotton Mather was in danger from a crowd that wanted to hang him. After six patients died from the procedure, he was called a murderer. But, when the population of Boston returned after the end of a smallpox epidemic in 1722, he was an instant hero. Out of the population of Boston, 7% had died from smallpox. Out of the 300 people that chose to inoculate themselves, only 2% died. In 1750, the English magazine, Gentleman’s Magazine, reprinted a 1725 pamphlet that argued in support of smallpox inoculations. By 1774, it was considered odd not to choose inoculation. Onesimus was later freed by Mather, not for his knowledge and help in combating smallpox, but because Mather considered him to be disobedient.

Even though inoculation was a powerful method of controlling smallpox, it was far from perfect. Inoculation caused a mild case of smallpox which resulted in death in about 2% of the cases. It was also difficult to administer. Sick patients had to be locked away to prevent them from transmitting the disease to others. Thus George Washington initially hesitated to have his Revolutionary War troops inoculated during a smallpox outbreak in February 1777, writing, “should We inoculate generally, the Enemy, knowing it, will certainly take Advantage of our Situation;” but the virulence of the outbreak soon prompted him to order inoculation for all troops and recruits who had not had the disease.^[7]

In 1796, a young boy in England was inoculated by Edward Jenner. The boy suffered from the disease for an entire month and recovered completely.

In World War II, scientists from the United Kingdom and the United States were involved in research into producing a biological weapon from smallpox. 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.^[8]

The first smallpox weapons factory in the Soviet Union was established in 1947 in the city of Zagorsk, close to Moscow ^[9]. It was produced by injecting small amounts of the virus into chicken eggs. An especially virulent strain (codenamed India-1967 or India-1) was brought from India in 1967 by a special Soviet medical team that was sent to India to help to eradicate the virus. The pathogen was manufactured and stockpiled in large quantities throughout the 1970s and 1980s.

An outbreak of weaponized smallpox occurred during its testing in the 1970s. General Prof. Peter Burgasov, former Chief Sanitary Physician of the Soviet Army, and a senior researcher within the Soviet program of biological weapons described this incident:

“On Vozrozhdeniya Island in the Aral Sea, the strongest recipes of smallpox were tested. Suddenly I was informed that there were mysterious cases of mortalities in Aralsk. A research ship of the Aral fleet came 15 km away from the island (it was forbidden to come any closer than 40 km). The lab technician of this ship took samples of plankton twice a day from the top deck. The smallpox formulation— 400 gr. of which was exploded on the island—”got her” and she became infected. After returning home to Aralsk, she infected several people including children. All of them died. I suspected the reason for this and called the Chief of General Staff of Ministry of Defense and requested to forbid the stop of the Alma-Ata—Moscow train in Aralsk. As a result, the epidemic around the country was prevented. I called Andropov, who at that time was Chief of KGB, and informed him of the exclusive recipe of smallpox obtained on Vozrazhdenie Island.” ^[10][11]

A production line to manufacture smallpox on an industrial scale was launched in the Vector Institute in 1990.^[9] The development of genetically altered strains of smallpox was presumably conducted in the Institute under leadership of Dr. Sergei Netyosov in the middle of the 1990s, according to Kenneth Alibek, although this has never been proven due to the classified nature of the program^[9]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

Smallpox virus may be transmitted from contaminated surfaces or aerosolized particles. It is capable of inducing harm by evading the host’s immune system and replicating inside host’s cells. The virus may cause 3 forms of the disease: 1) ordinary; 2) flat-type; or 3) hemorrhagic smallpox. It infects different cells of the body, being known by it’s propensity to cause characteristic pock like lesions on the skin.

Smallpox virus is transmitted by:^[1]

• Physical contact
• Contact with infected body fluids
• Contact with infected objects
• Air through aerosolized particles

Smallpox pathogenicity is due to its ability to evade the host’s immune system. Most proteins responsible for the pathogenesis of the virus are located at the terminal DNA regions of the virus.

Genetic comparisons of the smallpox virus with the vaccinia virus allowed to observe certain genetic changes that may be responsible for the virulence of the smallpox virus. However, without studying the gene transcripts, it is not possible to draw objective conclusions.^[2]

The smallpox virus commonly enters the body through the upper respiratory tract, invading the oropharyngeal and respiratory mucosa.^[3] Other possible ports of entry include: skin, conjunctiva as well as through the placenta.^[4] Although the viral scabs may contain life viruses, they are commonly contained within thickened material, which limits transmission.

Once in the respiratory mucosa, the infection commonly progresses as:^[5][4][6]

• Asymptomatic respiratory mucosa infection
• Viral replication within respiratory epithelium
• Transient primary asymptomatic viraemia
• Virus enters macrophages and spreads to lymph nodes and reticuloendothelial system, where it replicates during 4 – 14 days
• Exuberant secondary viraemia, leading to symptom onset

During secondary viraemia the virus infects mucous cells of the pharynx and mouth, and endothelium of the capillaries of the dermis, causing skin lesions. Other organs with high viral loads include:^[6]

• Spleen

• Liver

• Bone marrow

• Kidneys

Before development of the rash, the first lesions appear on the oropharyngeal mucosa, at which time the virus is released through the mucosal secretions, making that patient infectious.

Skin lesions develop due to migration of macrophages to the infected areas of the dermis, leading to edema and necrosis. With the influx of more polymorphonuclear cells, skin pustules will develop.^[5]

The immune system responds to the viremia with activation of lymphocytes T and B and concomitant production of:^[6]

• Neutralizing antibodies, during first week of disease, remaining for many years

• Hemagglutination-inhibition antibodies, by the 16th day of infection, beginning to decrease after 1 year

• Complement-fixation antibodies, by the 18th day of infection, beginning to decrease after 1 year

• Memory T cells, remaining for 50 years

Death by smallpox was commonly due to toxemia, following:^[5]

• Hypotension

• Coagulopathy

• Multiorgan failure

• Bacterial infections

Depending on the status of the patient’s immune system, there are 3 forms of smallpox:^[7]

Ordinary smallpox is characterized by the following progression of lesions:^[8]

• Initial hypopigmented macules, which appear first in the mouth
• Macules progress into papules and subsequently to vesicles
• Vesicles become pustules
• At the 14th day, pustules loose liquid content and become crusted
• At the 3rd week, most crusts will separate (palms and soles last)

This form of smallpox is typical of an immunocompetent patient, in whom the immune system is able to inhibit viral replication.

Flat-type smallpox is characterized by the following progression of lesions:^[9]

• Delayed appearance of macules
• Slow progression of the lesions, usually with flat and soft appearance
• Possible slough of skin sections

Most cases are fatal with presence of severe toxemia. This form of smallpox is typical of patients with weak cellular immune response to the virus.

Hemorrhagic-type smallpox is characterized by the following progression of lesions:^[10]

• Skin petechiae
• Mucous membrane and conjunctival bleeding
• Subcutaneous hemorrhage gives skin and conjunctivae deep red appearance
• Organ bleeding
• Early death by multi organ failure, usually before appearance of maculae.

This rare form of smallpox is typical of patients with severely compromised immune response, in which there is intense viral replication in the bone marrow and spleen. It is also associated with intense toxemia.

The typical skin vesicles observed in smallpox occur following:^[11]

• Viral infection of the epidermal cell
• Cells in malpighian layer entering balloon degeneration, from formation of vacuoles
• Cytoplasmic enlargement leading to loss of nuclear material
• Destruction of upper and middle layers of stratum spinosum
• Formation of vesicles, with high viral index

On the other hand, in the infected mucous surfaces, the viral proliferation and absence of the stratum corneum, lead to the formation of ulcers. These ultimately lead to the release of greater loads of virus into the oropharynx.^[12]

Poxviruses are characterized by cytoplasmic inclusions, however, these do not identify specifically the smallpox virus on a biopsy. There are 2 types of inclusion bodies:^[13]

Typical of some viruses of the:

• Genus Orthopoxvirus:

• Cowpox virus
• Ectromelia virus

• Genus Avipoxvirus

• In areas of active viral replication
• Present in infections by all poxviruses
• Appear as basophilic bodies near the nucleus on hematoxylin and eosin-stained samples
• Evident at epithelial cells underlying vesicles and pustules

• 
  Hematoxylin and eosin (H&E)-stained tissue sample, reveals some of the histopathologic changes found in a human skin tissue sample from the site of a smallpox lesion. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.^[14]
• 
  hematoxylin and eosin (H&E)-stained tissue sample, reveals some of the histopathologic changes found in a human skin tissue sample from the site of a smallpox lesion. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.^[14]
• 
  This is a chickenpox scab (left), and smallpox scab (right) viewed in profile as a demonstration in comparative morphology. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.^[14]
• 
  This image depicts three mounted chickenpox scabs seen from the side revealing the superficiality of these scabs when morphologically compared to a smallpox scab.Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.^[14]
• 
  Viewed from above, this image depicts a smallpox scab (left), and chickenpox scab (right) as a demonstration in comparative morphology. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.^[14]
• 
  Cytoarchitectural pathologic changes found in a sample of skin tissue from a eczema vaccinatum lesion, which had manifested itself after this patient had received a smallpox vaccination.Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.^[14]
• 
  Cytoarchitectural pathologic changes found in a sample of skin tissue from a eczema vaccinatum lesion, which had manifested itself after this patient had received a smallpox vaccination.Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.^[14]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

Smallpox is caused by the variola virus, a dsDNA virus of the Poxviridae family. There are two forms of this virus with different virulences, as evidenced by their respective death rates. The virus survives in the cold and aerosoled environments, which explains its oral transmission among humans. Humans are the viruses only host which likely facilitated its eradication. Unlike other DNA viruses, smallpox replicates within the cytoplasm, to which it shows tropism.

Viruses; dsDNA; Poxviridae; Chordopoxvirinae; Orthopoxvirus; Variola vera

Variola virus, also known as smallpox virus, is an orthopoxvirus, from the family Poxviridae, the largest viruses to infect humans. It is a 200-400 nm dsDNA virus, lacking icosahedral symmetry. The other viruses of the family Poxviridae include:^[1]

• Vaccinia virus
• Molluscum contagiosum virus
• Cowpox virus
• Monkeypox virus

The viral structure includes:^[2][3][4]

• 1 Outer membrane
• 2 lateral bodies
• 1 dsDNA molecule in its core, containing 186,999 base pairs

Variola virus genes are similar to the ones of vaccinia virus. Since there is cross-protection between poxviruses, it was possible to use the second as a vaccine for smallpox virus.^[5]

There are 2 forms of variola virus:

• Variola major
• Variola minor

Both strains of the virus share a large amount of genome, yet they differ clinically. This leads to the assumption that the difference in virulence resides in alternate gene expression.^[1][6]

Poxviruses survive in cold and dry environments being able to survive in the aerosoled form, and are killed by hospital disinfectants and UV light.^[1][6][7][8]

Unlike other DNA viruses, poxviruses replicate within the cytoplasm of the host cell. In order 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.

The date of the origin of the smallpox virus is not settled. It most likely evolved from a rodent virus between 68,000 and 16,000 years ago.^[9][10] This broad range of dates is due to the different records used to calibrate the molecular clock. It appears that the smallpox virus derived from a remote zoonosis from another animal host, that is today extinct.^[11]

Little is known about the mechanism responsible for host species tropism of smallpox virus. The virus is known to bind mammalian cells unspecifically. There appears to be no particular extracellular receptors involved in viral internalization and initial transcription. However, intracellular availability of trans-acting factors and viral capacity to block host cells antiviral response, such as the interferon pathway, are though to be important intracellular factors, determining viral tropism. The overall immune response by the host towards the virus, will be the key determinant of the infection’s outcome and potential transmission to other hosts.^[11]

Humans are the only known natural reservoir of the smallpox virus.^[12]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

Prior to its eradication, smallpox would need to be differentiated from other diseases that cause a vesicular rash and a fever including chickenpox (which was often mistaken for smallpox), herpes zoster and erythema multiforme.^[1]

Different rash-like conditions may be misdiagnosed with smallpox, particularly during the initial maculopapular phase, including:^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

Smallpox was declared eradicated in 1980 by the WHO. The true incidence of smallpox before its eradication is difficult to estimate due to poor reporting from endemic regions, which may have reported only 1-2% of the cases. Children and young adults were the most often affected, especially in regions with low levels of immunity. There is no evidence of gender or race differences in the incidence of the disease. Developing countries had a higher incidence of the disease.^[1]

The number of new cases, reported to the international health authorities, was often inaccurate. The data obtained from non-endemic countries, with good health services, was probably the most accurate. Yet, according to the Intensified Smallpox Eradication Programme, the reported incidence amounted only to 1-2% of the actual number of cases, which made it impossible to obtain an accurate estimate of the incidence.^[1]

In endemic regions there were periods called epidemic years in which the incidence was much higher. In order to try to justify this discrepancy, several possibilities were evoked, such as:^[1]

• Viability of the virus
• Changes in susceptibility of the host
• Social factors, such as dispersion of the population
• Seasonal variation in incidence in relation to eradication

The age adjusted incidence of the disease may vary depending upon the level of acquired immunity in the population. When populations were exposed to the disease for the first time, all ages would be affected. In endemic regions, where there was some previous level of immunity, children and young adults were the most severely affected.^[2][1][3]

Smallpox affected males and females equally.^[1][3]

The incidence of smallpox did not differ according to the race.^[1][3]

Developed countries, due to a better and established health system, had lower incidence of smallpox and better reports of new cases to international organizations.^[1]

In developing countries where healthcare facilities are sometimes not trusted by the population, cases were sometimes not reported to public health authorities. Also, vaccination was not sanctioned by some religious beliefs. Taken together, these factors might explain at least in part the higher incidence of smallpox in developing countries.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

People who work in laboratories with the virus are at risk of contracting smallpox. Before its eradication, risk factors for developing smallpox included: physical contact with a patient with the disease, contact with contaminated body fluids, and exposure to contaminated aerosolized particles.^[1]

• Physical contact with someone with smallpox

• Direct contact with infected bodily fluids

• Direct contact with contaminated surfaces

• Exposure to aerosolized particles from someone with smallpox

• Laboratory work with the virus

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

The natural history and outcome of smallpox depend on the form of disease. The common progress will start with flu-like symptoms followed by a skin rash that generally progresses in a typical fashion, leading to the formation of scabs that will fall off, leaving a scar. The complications may include respiratory conditions, from bronchitis to pneumonia, but may also involve the joints, bones and/or eyes. The overall fatality rate for the variola major form was about 30%.

Smallpox, considered eradicated since 1980 by the WHO, affected mainly children, young adults and family members of infected patients. Symptoms depended on the form of the disease. For the most common form, the ordinary smallpox, symptoms usually developed according to the following sequence:^[1]

• Duration approximately 12 – 14 days
• Noncontagious
• Asymptomatic

• Duration approximately 2 – 4 days
• Sometimes contagious
• Fever
• Malaise
• Muscle pain and headache
• Vomiting

• Duration approximately 4 days
• Most contagious stage
• Rash as small red spots in the mouth
• Rash turns into sores releasing the virus
• Rash appears on the skin, starting on the face, moving towards arms and hands, eventually spreading to the rest of the body within 24 hours
• At this time, fever usually falls and the person feels better
• At the 3rd day of rash, it turns into raised bumps
• At the 4th day of rash, bumps are filled with fluid, with a central depression
• Fever will then raise again, until scabs are formed

• Duration approximately 5 days
• Contagious
• Bumps turn into pustules

• Duration approximately 5 days
• Contagious
• Pustules first form a crust and than a scab

• Duration approximately 6 days
• Scabs start to fall leaving scars not the skin
• Contagious, until all scabs have fallen
• Most scabs will have fallen 3 weeks after start of rash

• All scabs have fallen off
• Person is no longer contagious

Common complications of smallpox include:

• Respiratory complications (viral or bacterial):

• Bronchitis
• Fatal pneumonia

• Secondary bacterial skin infection
• Encephalitis – 1 in 500 patients, commonly in adults
• Permanent pitted scars
• Eye problems – 2% of all cases; pustules can form on the eyelid, conjunctiva, and cornea, leading to:

• Conjunctivitis
• Keratitis
• Corneal ulcer
• Iritis
• Iridocylcitis
• Optic atrophy
• Blindness – occurs in 35% to 40% of eyes affected with keratitis and corneal ulcer
• Subconjunctival and retinal hemorrhages.

• Osteomyelitis – lesions are symmetrical, most common in the elbows, tibia, and fibula
• Arthritis may lead to limb deformities
• Ankylosis

The prognosis of smallpox depends on the form of the disease:

• Fatality rate about 10% for patients with discrete lesions and 60% for those with confluent lesions^[2]
• In fatal cases, death usually occurs between the 10th and 16th days of illness
• Unclear cause of death
• Infection often affected multiple organs
• Possible contributors include:

• Circulating immune complexes
• Severe viremia
• Uncontrolled immune response

• Fatality rate about 90%
• Cause of death commonly included: loss of fluids, electrolytes and protein, as well as severe sepsis

• Fatality rate near 100%, usually between 6th and 7th day after the beginning of fever
• Cause of death was often heart failure, or in late cases intense viremia, with severe platelet loss and weak immune response

• Fatality rate about ≤1%

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Reprinted below is the entire series of reports published during May-July 1963 about a smallpox outbreak in Sweden. Selected tables and figures from these reports also have been recreated to resemble the originals as closely as possible.

Sweden — Stockholm was declared a smallpox infected area on May 16. A seaman who returned from Indonesia in late March is the apparent source of an outbreak which has now spread through two generations of transmission and has resulted in one fatality. Preliminary information on cases to date, received from the Ministry of Health, Sweden, and forwarded by Dr. Reimert T. Ravenholt, Epidemiologic Consultant, Division of Foreign Quarantine, U.S. Public Health Service, Paris, is given below:

The outbreak was recognized on May 13 when the diagnosis of smallpox was first suspected in Case #7. The disease was sufficiently mild in Cases 1, 4, 5 and 12 that medical assistance was not sought. The only fatality to date occurred in Case #2 who apparently suffered an acute hemorrhagic form of the disease, diagnosed as smallpox in retrospect.

This outbreak is of unique interest in that it represents one of the few epidemics in Western nations in recent years not evidencing a predominant spread among hospital contacts. Recent immunization programs among hospital personnel presumably have altered the pattern of hospital spread observed in other recent outbreaks. The mildness of the disease in several of the earlier cases, resulting in the failure of these patients to seek medical care and hospitalization, has contributed to the pattern of community transmission.

The outbreak emphasizes the sinister role of mild or vaccine-modified cases of smallpox in initiating and propagating outbreaks of severe disease. Since the outbreak was discovered during the second generation of indigenous cases, it is possible that Americans recently in Stockholm have been unknowingly exposed to the disease, and cases of suspicious febrile illness in such individuals should receive the utmost scrutiny by clinicians and public health authorities.

Four additional cases of smallpox have been identified in Stockholm with onsets of illness since May 18. All four presumably acquired their disease as a result of hospital contact.

The outbreak now totals 16 cases, with three generations of transmission following the importation of smallpox by a seaman who presumably acquired his disease in transit through Southeast Asia. Information on cases to date received from Dr. Bo Zetterberg, Chief, Epidemiology Division, State Bacteriology Laboratory, Stockholm, is summarized in the table below:

The first case to be identified occurred in an unvaccinated 19-year-old bricklayer (Case 7) who had onset of fever, vomiting, and backache on May 5. He was hospitalized three days later and subsequently developed an extensive maculo-papular rash which became pustular by May 12. Smallpox was suspected and confirmed the following day by the laboratory.

Immediate epidemiologic investigation revealed that an aunt of the bricklayer (Case 2) had developed on April 18 an acute febrile illness, manifest by hemorrhagic skin lesions, and had died shortly after admission to the hospital on April 23. Ten other cases of smallpox were identified May 14-16.

The original source of the outbreak was a 24-year-old seaman who after two weeks residence in Australia left Darwin on March 22 on BOAC Flight #709. In-transit stops of not more than 50 minutes each were made in Djakarta, Singapore, Rangoon, Calcutta, Karachi, Teheran, and Damascus en route to Zurich. At Zurich, the seaman deplaned and the following day boarded Swissair Flight #250, reaching Stockholm March 24. He apparently acquired his disease as a result of in-transit exposure either at a terminal or on the plane. On April 6, 15 days after the flight, he developed a moderate fever and mild rash and remained in the home of his grandmother (Case 3) throughout his illness. Cases 2, 3, 4, and 5 all had contact with him in the grandmother’s home during the course of his illness. On April 21, the grandmother fell ill, subsequently exposing three women (Cases 8-10) who visited the home to provide nursing care to the elderly woman prior to her hospitalization on May 27. She was originally diagnosed as having chickenpox and recovered uneventfully. Another resident of the building (Case 11) who lived two stories above the grandmother, developed smallpox but denied acquaintance or contact with the grandmother.

Case 2, the first fatality, apparently acquired the illness from the seaman during a visit to the grandmother’s apartment and subsequently transmitted it to her husband (Case 6) and her nephew (Case 7) the first identified case. Case 12 who had only fever and serologic evidence of infection, acquired his disease presumably from his fiancee, Case 4.

The appearance of cases among hospital contacts is more consistent with the previously observed patterns of imported smallpox in Western countries. Case 13 is a gardener at the Infectious Disease Hospital where Cases 3 and 6 were admitted as presumptive chickenpox on April 27 and May 7, respectively. He is thought to have handled laundry from these patients prior to the first suspicion of smallpox on May 12. He was initially employed by the hospital only two months previous and had not yet been vaccinated in the hospital’s annual revaccination program.

Case 14 was a patient admitted to the Infectious Disease Hospital with pertussis on April 30. She was located in the same hospital vicinity as Case 6, although there was no connection between the rooms housing these patients. Cases 15 and 16 were patients on the same hospital ward to which Case 9 was admitted on May 9. Case 9 was originally thought to have a toxic drug eruption prior to her diagnosis of smallpox on May 15.

With the exception of Case 12 who had an exceptionally mild illness, it is apparent that spread of the disease to date has been primarily among individuals vaccinated at times far distant in the past. Of the three fatalities to date, one occurred in a person never vaccinated and the other two in persons vaccinated more than 50 years prior to exposure. The absence of additional spread to hospital personnel is probably related to efforts in Sweden to emphasize revaccination of hospital personnel at frequent intervals. Notably, the last four cases have occurred in persons already identified and isolated by virtue of being known contacts.

Some 8,000 persons living in neighborhoods of the earlier cases have been vaccinated. In addition, vaccination has been provided for other residents of Stockholm on request and to date some 300,000 persons have availed themselves of this protection.

Three additional cases, two hospital acquired, were identified last week bringing to 19 the total number of smallpox cases comprising the current outbreak, according to information made available by Dr. Bo Zetterberg, Chief, Epidemiology Division, State Bacteriology Laboratory, Stockholm.

Two of the three cases are actually part of the second generation of transmission, having now been identified retrospectively by serologic means. Neither patient developed a rash. Both were nurses in the Stockholm Infectious Disease Hospital in close contact with the smallpox cases admitted there. The first, a 44-year-old female, cared for Case No. 3 from April 27 to May 7 daily, including bathing and local treatment of the lesions. On May 9, the nurse developed fever and headache, as well as nausea and low back pain. Except for May 13 and 14, she continued to work throughout her illness until isolated on May 18. She was found to have a very high hemagglutination inhibition antibody titer suggesting recent infection. Her last vaccination prior to onset of illness was in 1962. She was also in daily contact with Cases 6 and 14, and directly or indirectly may have transmitted the disease to Case 14.

The second nurse, a 22-year-old female, also employed in the Stockholm Infectious Disease Hospital, had daily contact with Case No. 2 during the period April 27-May 7. On May 11, she experienced onset of headache, fever, and sore throat and was absent from work May 11 through May 13. No rash developed. A high HAI titer verified the diagnosis of smallpox. She had previously been vaccinated in 1950 but at the time of exposure had not yet been revaccinated under the hospital’s annual revaccination program.

The final additional case is that of a 47-year-old man who had onset of illness May 21 while already isolated as a contact. He is the father of Case 7, the first identified case. He had never been vaccinated until 7 days before onset of illness.

The total number of hospital-acquired cases now stands at 6, one-third of the secondary indigenous cases. The evidence supports close contact as the primary requisite for spread both in the hospital and in the community. The disease has spread among persons vaccinated more than 7 years prior to the time of their exposure with 2 notable exceptions, both patients with mild disease without rash. The table below presents data on the vaccination status of the 18 indigenous cases {See table below}:

Two additional cases of smallpox were identified in Stockholm last week bringing to 21 the total number of cases in the current outbreak. Unique circumstances involving these two persons, neither of whom were under surveillance as contacts at the time of their detection, indicates that the outbreak may perhaps be expected to continue.

Information made available by Dr. Bo Zetterberg, Chief, Epidemiology Division, State Bacteriology Laboratory, Stockholm, indicates that on June 6 an 85-year-old woman, who lives with her daughter, went to a hospital out-patient department for routine follow-up of a chronic medical problem. The daughter called in advance informing clinic personnel that the elderly woman had developed a rash. On arrival at the out-patient clinic, the mother spent some time in the general waiting room and was then referred to the dermatology clinic, and again spent some time in the dermatology waiting room. When seen by physicians, a clinical diagnosis of smallpox was made. In all, she had spent some four hours at the hospital and presumably exposed some 450 persons in the two crowded waiting rooms. It was noted that on May 28 she had developed a low-grade fever with dizziness, followed by the appearance of rash on June 2.

She and her 54-year-old daughter share an apartment in a boarding house for women housing some 100 occupants. The daughter works as a mortician and on April 26 had prepared the body of smallpox Case 2 of the outbreak for cremation. She had been placed under surveillance as a contact and 16 days after her exposure to the dead woman, having had no symptoms or signs of illness, she was released from quarantine. She denied any evidence of illness since being released from surveillance. The total elapsed time from her contact with the body of Case 2 and the onset of disease in her mother was 32 days, consistent with two incubation periods of smallpox. Except for the daughter’s exposure, no epidemiologic evidence could be found linking the mother with a source of smallpox. Neither the mother nor daughter had been vaccinated since childhood. The daughter demonstrated a high HAI titer on June 6, suggesting a recent infection, and in the absence of an alternative explanation, it may be presumed that the daughter developed a sub-clinical infection and transmitted virus to her mother. Two very unusual aspects of smallpox transmission seem apparent. The daughter, unvaccinated since childhood and exposed to hemorrhagic smallpox, developed an infection so mild as to produce no symptoms, yet developed serologic evidence of infection. Despite the presumed absence of any rash or systemic manifestations of disease, she was apparently able to transmit the illness to her mother.

The inadvertent exposure of the mother during her eruptive stage to some 450 persons at the hospital, as well as possible contacts in the boarding house, establishes an additional large group of contacts in which cases may yet occur.

An epidemic curve for the outbreak to date is presented showing the chronologic relationship of the generations of transmission {See Figure below}:

Using the median date in the span of onset dates for each generation, it is apparent that the median incubation periods for all generations are strikingly similar. No new cases have been reported during the past week. The total number of confirmed cases remains at 23, including four deaths. The fourth death reported involved an unvaccinated 47-year-old male who died on June 15, 25 days after onset of illness. He was the father of case 7, also a fatality.

Two additional cases of smallpox were reported from Stockholm on July 11 and July 12, respectively. One of these, an 89-year-old female patient in a mental hospital, had onset of rash and fever on July 7, 15 days after onset of illness in Case 23, a 73-year-old woman also hospitalized at this institution.

The total number of confirmed cases that has occurred during the outbreak is 25, including four deaths.

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• Smallpox Fact Sheet from the CDC
• CDC.gov—‘Bioterrorism Agents > Smallpox Info for Specific Groups: What Everyone Should Know,’ CDC

• Vaccine Research Center (VRC) – Information concerning vaccine research studies

• WHO.int—‘Smallpox: Historical significance,’ World Health Organization (WHO)