Eye on ID

Monkeypox, a close relative of smallpox, is still with us

Although smallpox has been eradicated, monkeypox has not. Monkeypox, which can easily be confused clinically with smallpox, should it ever reappear, is a disease found in central and western Africa. Although the reservoir is thought to be primarily in rodents, outbreaks can occur in other mammals including monkeys and humans. The virus has been isolated from wild animals in nature only twice, once from a rope squirrel in the Democratic Republic of the Congo, or DRC, and once from a sooty mangabey in the Ivory Coast. Monkeypox is probably a very old disease, although it has been recognized only in the past 50 years.

Thomas M. Yuill, PhD
Thomas M. Yuill
Donald Kaye, MD, MACP
Donald Kaye

The etiological agent of monkeypox is an Orthopoxvirus, the genus of the Poxviridae family that also includes the smallpox virus, vaccinia virus (used for smallpox immunization) and the viruses of cowpox, camelpox and taterapox of wild gerbils in Benin, according to the International Committee on Virus Taxonomy. It was first identified in laboratory monkeys in 1959; hence, the name “monkeypox,” even though monkeys are not the host in nature. It was first discovered in a human in the Equateur province of the DRC (then Zaire) in 1970. The clinical disease closely resembles varicella or a mild case of smallpox with one major exception — there is generalized lymphadenopathy, which did not occur in smallpox and is usually restricted to the cervical nodes in varicella. Varicella is, of course, caused by an unrelated Herpesvirus.

Epidemiology and pathogenesis

There are two clades of monkeypox virus: the Central African clade and the West African clade. Human disease with the Central African clade is more severe (the case fatality rate is up to 11%) than with the West African clade, which is associated with a lower mortality rate. Although person-to-person transmission is unusual, it is more likely to occur with the Central African clade than the West African clade. There have been many human cases in Africa since 1970, but there have been only two outbreaks recognized outside of Africa — one in 2003 in the United States and another in 2018 in the United Kingdom. Both of these outbreaks were caused by the less virulent West African strain.

This image from 1971 depicts the right hand and leg of a 4-year-old girl in Liberia with monkeypox.
This image from 1971 depicts the right hand and leg of a 4-year-old girl in Liberia with monkeypox.
Source: CDC.

The first human cases were described in the DRC in 1970. Numerous cases have been recognized in multiple other countries in Africa, but by far the greatest number of cases have occurred in the DRC, with more than 1,000 suspected cases every year since 2005. With one exception, no other country has seen more than 105 confirmed and suspected cases over the years. The exception is Nigeria, where there has been an ongoing outbreak that started in 2017 and resulted in 262 suspected and 115 confirmed cases from September 2017 to September 2018. Since 2016, five countries have reported small outbreaks, all in Africa. There were 88 cases in the Republic of the Congo, 22 cases in the Central African Republic and one to two cases each in Cameroon, Liberia and Sierra Leone. The 2003 outbreak in the U.S. involved 72 people (37 confirmed) in six mid-western states. The cases were related to exposure to infected pet prairie dogs. The prairie dogs had been distributed from a store that had a shipment of rodents from Ghana. The rodents included two African giant pouched rats, nine dormice and three rope squirrels that were subsequently shown to be infected with monkeypox virus of the West African (less virulent) clade. The prairie dogs had apparently acquired the virus from these infected rodents. There were no fatalities among the infected humans.

In September 2018, there were three cases reported in the U.K. The first was in a Nigerian who had been exposed in Nigeria and then traveled to the U.K. The second occurred in a traveler returning from Nigeria, and the third was in a health care worker who had been exposed to the second patient. All survived. In October 2018, a case was confirmed in Israel in a traveler from Nigeria.

The usual manner in which humans become exposed is by direct contact with an infected animal via body fluids, skin lesions, a bite, a scratch or when preparing an animal as bush meat for consumption. When human-to-human transmission does occur, it is by contact with body fluids or skin lesions or by the respiratory route via large droplets.

Clinical syndrome and diagnosis

After an incubation period as short as 5 days and as long as 21 days (usually about 10 days), there is onset of a prodrome of fever, headache and myalgia, followed by development of a macular rash in 1 to 3 days. The rash often starts on the face and moves downward. As with varicella and smallpox, the lesions evolve over a period of 2 to 4 weeks through stages as macules, papules, vesicles, pustules and finally scabs. Similar to smallpox, lesions may appear on the palms and soles. In the U.S. experience, lesions progressed at different stages simultaneously, which occurs with varicella (eg, papules vesicles and scabs present) as opposed to smallpox, in which all lesions progress together at the same stage. Generalized lymphadenopathy occurs as part of the prodrome. Cough is common in the illness.

The history (eg, travel or potential exposure) and the clinical syndrome should suggest the diagnosis, which can be confirmed by the isolation of the virus.

Treatment and prevention

It is assumed from past African data that smallpox vaccination protects against monkeypox, and in the 2003 outbreak, the CDC recommended vaccination to prevent monkeypox in those who had had a significant exposure, such as those caring for people or animals infected with the monkeypox virus. The vaccine is available only in the U.S. through the CDC or U.S. Army.

The CDC states that although no data are available, “smallpox vaccine, cidofovir, ST-246 [tecovirimat], and vaccinia immune globulin can be used to control a monkeypox outbreak.”

Possible use as a bioterrorism agent

Some have raised concerns that because of its resemblance to smallpox, monkeypox could potentially be used as an agent of bioterrorism against those who have never been vaccinated against smallpox. To us, monkeypox seems to be an unlikely agent to be developed for bioterrorism, considering the expense of developing it for this purpose and the relatively mild disease it typically causes.

Disclosures: Kaye and Yuill report no relevant financial disclosures.

Although smallpox has been eradicated, monkeypox has not. Monkeypox, which can easily be confused clinically with smallpox, should it ever reappear, is a disease found in central and western Africa. Although the reservoir is thought to be primarily in rodents, outbreaks can occur in other mammals including monkeys and humans. The virus has been isolated from wild animals in nature only twice, once from a rope squirrel in the Democratic Republic of the Congo, or DRC, and once from a sooty mangabey in the Ivory Coast. Monkeypox is probably a very old disease, although it has been recognized only in the past 50 years.

Thomas M. Yuill, PhD
Thomas M. Yuill
Donald Kaye, MD, MACP
Donald Kaye

The etiological agent of monkeypox is an Orthopoxvirus, the genus of the Poxviridae family that also includes the smallpox virus, vaccinia virus (used for smallpox immunization) and the viruses of cowpox, camelpox and taterapox of wild gerbils in Benin, according to the International Committee on Virus Taxonomy. It was first identified in laboratory monkeys in 1959; hence, the name “monkeypox,” even though monkeys are not the host in nature. It was first discovered in a human in the Equateur province of the DRC (then Zaire) in 1970. The clinical disease closely resembles varicella or a mild case of smallpox with one major exception — there is generalized lymphadenopathy, which did not occur in smallpox and is usually restricted to the cervical nodes in varicella. Varicella is, of course, caused by an unrelated Herpesvirus.

Epidemiology and pathogenesis

There are two clades of monkeypox virus: the Central African clade and the West African clade. Human disease with the Central African clade is more severe (the case fatality rate is up to 11%) than with the West African clade, which is associated with a lower mortality rate. Although person-to-person transmission is unusual, it is more likely to occur with the Central African clade than the West African clade. There have been many human cases in Africa since 1970, but there have been only two outbreaks recognized outside of Africa — one in 2003 in the United States and another in 2018 in the United Kingdom. Both of these outbreaks were caused by the less virulent West African strain.

This image from 1971 depicts the right hand and leg of a 4-year-old girl in Liberia with monkeypox.
This image from 1971 depicts the right hand and leg of a 4-year-old girl in Liberia with monkeypox.
Source: CDC.

The first human cases were described in the DRC in 1970. Numerous cases have been recognized in multiple other countries in Africa, but by far the greatest number of cases have occurred in the DRC, with more than 1,000 suspected cases every year since 2005. With one exception, no other country has seen more than 105 confirmed and suspected cases over the years. The exception is Nigeria, where there has been an ongoing outbreak that started in 2017 and resulted in 262 suspected and 115 confirmed cases from September 2017 to September 2018. Since 2016, five countries have reported small outbreaks, all in Africa. There were 88 cases in the Republic of the Congo, 22 cases in the Central African Republic and one to two cases each in Cameroon, Liberia and Sierra Leone. The 2003 outbreak in the U.S. involved 72 people (37 confirmed) in six mid-western states. The cases were related to exposure to infected pet prairie dogs. The prairie dogs had been distributed from a store that had a shipment of rodents from Ghana. The rodents included two African giant pouched rats, nine dormice and three rope squirrels that were subsequently shown to be infected with monkeypox virus of the West African (less virulent) clade. The prairie dogs had apparently acquired the virus from these infected rodents. There were no fatalities among the infected humans.

In September 2018, there were three cases reported in the U.K. The first was in a Nigerian who had been exposed in Nigeria and then traveled to the U.K. The second occurred in a traveler returning from Nigeria, and the third was in a health care worker who had been exposed to the second patient. All survived. In October 2018, a case was confirmed in Israel in a traveler from Nigeria.

The usual manner in which humans become exposed is by direct contact with an infected animal via body fluids, skin lesions, a bite, a scratch or when preparing an animal as bush meat for consumption. When human-to-human transmission does occur, it is by contact with body fluids or skin lesions or by the respiratory route via large droplets.

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Clinical syndrome and diagnosis

After an incubation period as short as 5 days and as long as 21 days (usually about 10 days), there is onset of a prodrome of fever, headache and myalgia, followed by development of a macular rash in 1 to 3 days. The rash often starts on the face and moves downward. As with varicella and smallpox, the lesions evolve over a period of 2 to 4 weeks through stages as macules, papules, vesicles, pustules and finally scabs. Similar to smallpox, lesions may appear on the palms and soles. In the U.S. experience, lesions progressed at different stages simultaneously, which occurs with varicella (eg, papules vesicles and scabs present) as opposed to smallpox, in which all lesions progress together at the same stage. Generalized lymphadenopathy occurs as part of the prodrome. Cough is common in the illness.

The history (eg, travel or potential exposure) and the clinical syndrome should suggest the diagnosis, which can be confirmed by the isolation of the virus.

Treatment and prevention

It is assumed from past African data that smallpox vaccination protects against monkeypox, and in the 2003 outbreak, the CDC recommended vaccination to prevent monkeypox in those who had had a significant exposure, such as those caring for people or animals infected with the monkeypox virus. The vaccine is available only in the U.S. through the CDC or U.S. Army.

The CDC states that although no data are available, “smallpox vaccine, cidofovir, ST-246 [tecovirimat], and vaccinia immune globulin can be used to control a monkeypox outbreak.”

Possible use as a bioterrorism agent

Some have raised concerns that because of its resemblance to smallpox, monkeypox could potentially be used as an agent of bioterrorism against those who have never been vaccinated against smallpox. To us, monkeypox seems to be an unlikely agent to be developed for bioterrorism, considering the expense of developing it for this purpose and the relatively mild disease it typically causes.

Disclosures: Kaye and Yuill report no relevant financial disclosures.

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