AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

Section 2 of 11  

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Background

In 1970, when smallpox was nearly eradicated, a previously unrecognized orthopoxvirus named monkeypox was identified in humans. The first known human case occurred in the Equateur province of Zaire (now known as the Democratic Republic of Congo [DRC]) when a 9-year-old boy developed a smallpoxlike illness, which was eventually confirmed as human monkeypox by the World Health Organization (Ladnyi, 1972). Retrospectively, similar cases occurring in 1970-1971 from the Ivory Coast, Liberia, Nigeria, and Sierra Leone were attributed to monkeypox infection.

Monkeypox was limited to the rain forests of central and western Africa until 2003, when the first cases in the Western Hemisphere were reported. In late spring 2003, multiple persons were identified in the midwestern United States who had developed fever, rash, respiratory symptoms, and lymphadenopathy following exposure to ill pet prairie dogs (Cynomys species) infected with the monkeypox virus.

Most confirmed cases reported direct contact or exposure to ill prairie dogs showing signs of profuse nasal discharge, ocular discharge, dyspnea, lymphadenopathy, and mucocutaneous lesions. Traceback investigators concluded that all confirmed cases of monkeypox were associated from a common animal distributor where prairie dogs were housed or transported with African rodents from Ghana. Among these rodents were Gambian rats, which are known reservoirs of monkeypox in their native habitat of Africa.

In this outbreak, imported asymptomatic animals transmitted a nonindigenous pathogen to an indigenous susceptible animal. After an average incubation period of 12 days, the animal became ill and was capable of transmitting the pathogen to humans when in close proximity. The potential for human-to-human transmission and human-to-animal transmission remains unknown.

Pathophysiology

The monkeypox virus is a member of the genus orthopox (family Poxviridae); other members include cowpox, vaccinia, and variola (smallpox) viruses. It is a zoonotic virus with primary transmission believed to occur through direct contact with infected animals or possibly by ingestion of their inadequately cooked flesh. Inoculation may be from cutaneous or mucosal lesions on the animal, especially when the skin barrier is compromised secondary to bites, scratches, or other trauma. The infection was first seen in laboratory monkeys in 1958, thus, the name monkeypox, although rodents are believed to be the major reservoir in Africa (Khodakevich, 1986; Hutin, 2001).

Secondary, or human-to-human, disease transmission was found to be another possible route in an outbreak in the DRC in 1996-1997 (Hutin, 2001). Studies of this outbreak suggested that within households, monkeypox was secondarily transmitted to 8-15% of human contacts. Prior to this, monkeypox was not identified as an important worldwide health problem because human infection rates were not known to play a significant role in the pathogenesis. Analysis of the 2003 US outbreak implicates animal-to-animal and animal-to-human transmission as the significant route of transmission. In only one case in the 2003 outbreak, human-to-human transmission could not be ruled out.

Frequency

United States

No cases have occurred in the United States until the late spring 2003 outbreak in the midwestern states. Between May 16 and June 20, 2003 71 suspected cases of monkeypox were investigated and 35 were confirmed by polymerase chain reaction (PCR). A later serum analysis detected immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies against orthopoxvirus antigen, confirming 37 cases (Karem, 2005).

International

This condition is rare and only known to be indigenous to the rain forests of western and central Africa. It was first recognized in humans in 1970 after the eradication of smallpox, possibly because of the subsequent unmasking of the infection. Surveillance reports from 1981-1986 documented 338 cases in the DRC (out of a 1982 estimated population of 5 million). In the 1996-1997 outbreak in the DRC, the attack rate was 22 cases per 1,000 population.

Mortality/Morbidity

The disease in the United States was generally self-limited, with resolution in 2-4 weeks, depending on the severity of the illness. However, a small subset of patients, most commonly pediatric patients, had a more severe course, with several patients requiring ICU care (Huhn, 2005).

Complications reported from African outbreaks include pitted scars, deforming scars, secondary bacterial infection, bronchopneumonia, respiratory distress, keratitis, corneal ulceration, blindness, septicemia, and encephalitis.

Data from the African outbreaks suggest that prior smallpox vaccination confers 85% protection from monkeypox; infection may be milder even several years after vaccination, and the incidence of complications may be reduced (Jezek, 1988; Fine, 1988). With the recent US outbreak, the Centers for Disease Control and Prevention (CDC) recommended smallpox vaccination up to 2 weeks, ideally within 4 days, after a significant, unprotected exposure to a diseased animal or a confirmed human case.

African cases have mortality rates of 1-10%, with the highest rates occurring in children and individuals without vaccination. In general, the prognosis is related to the amount of exposure to the virus, host immune response, comorbidities, vaccination status, and severity of complications.

Sex

The incidence is equal in males and females.

Age

In the African epidemics, 90% of the patients were children younger than 15 years (Jezek, 1987). In the recent US outbreak, of the confirmed cases in 2003 (n = 35), 11 patients were younger than 18 years and 24 were older.

CLINICAL

Section 3 of 11  

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History

Monkeypox can cause a syndrome clinically similar to smallpox but overall is less infectious and less deadly.

• Transmission
• • Contact with ill animals or animal reservoirs from Western Africa (eg, prairie dogs, rabbits, rats, mice, squirrels, dormice, monkeys, porcupines, gazelles)
  • Preparing or ingesting infected animals
  • Direct cutaneous (skin-to-skin) or respiratory contact with an animal or person who is infected
• The incubation period averages 12 days, ranging from 4-20 days.
• Prodrome or preeruptive stage (lasts 1-10 d)
• • Fever is commonly the first symptom (usually 38.5-40.5°C).
  • The febrile illness is often accompanied by chills, drenching sweats, severe headache, backache, myalgia, malaise, anorexia, prostration, pharyngitis, shortness of breath, and cough (with or without sputum).
  • Lymphadenopathy appears within 2-3 days after the fever. In the 2003 outbreak, 47% of patients had nodes measuring several centimeters in diameter in the cervical and submental areas.
• Exanthem (eruptive) stage: Most persons develop a rash within 1-10 days after the onset of fever. The rash often starts on the face and then spreads to the rest of the body. It persists for 2-4 weeks until all lesions have shed the crusts.
• Encephalitis with IgM found in the cerebrospinal fluid has been reported (Sejvar, 2004).

Physical

• The most reliable clinical sign differentiating monkeypox from smallpox and chickenpox is enlarged lymph nodes, especially the submental, submandibular, cervical, and inguinal nodes.
• Enanthema: Nonspecific lesions and inflammation of the pharyngeal, conjunctival, and genital mucosae have been observed.
• Exanthema
• • Within a particular body region, lesions evolve synchronously over 14-21 days, similar to the development of lesions with smallpox. However, unlike smallpox, skin lesions may appear in crops. In contrast to smallpox, the lesions do not have a strong centrifugal distribution.
  • Lesions progress from macules to papules to vesicles and pustules; umbilication, crusting, and desquamation follow. Most lesions are 3-15 mm in diameter.
  • The face, the trunk, the extremities, and the scalp are involved. Lesions appear in covered and uncovered areas.
  • Lesions may be seen on the palms and the soles.
  • Necrosis, petechiae, and ulceration may be features.
  • Pain is unusual, and, if it occurs, it is often associated with secondary bacterial infection. Pruritus may occur.
  • In patients who have been previously vaccinated against smallpox, a milder form of disease occurs. In children, the lesions may appear as nonspecific, erythematous papules that are 1-5 mm in diameter and suggestive of arthropod bite reactions. Subtle umbilication may be seen.
  • In the African outbreaks, 20% of unvaccinated patients developed a confluent, erythematous eruption on the face and the upper part of the trunk, which some authors have termed the septicemic rash of monkeypox (Jezek, 1987).
  • Hemorrhagic and flat forms, which can be seen with smallpox, have not been reported in patients with monkeypox.
  • Deep pock scars can result as the lesions resolve.

Causes

Outbreaks in western and central Africa have been linked to exposure to rats, rabbits, squirrels, monkeys, porcupines, and gazelles. Inhabitants of remote tropical rain forests may become infected from direct contact while capturing, slaughtering, and/or preparing these animals for food; ingestion has also been linked to infection. Because of the diversity of animals eaten by local inhabitants, conclusions about the relative risk of meat sources are not known with certainty.

In the DRC in 1997, animals caught from the wild were tested for the monkeypox virus. The following animals were found to have neutralizing antibodies against the monkeypox virus, suggesting a role as natural reservoirs: domestic pig (Sus scrofa), Gambian rat (Cricetomys emini), elephant shrew (Petrodromus tetradactylus), Thomas's tree/rope squirrel (Funisciurus anerythrus), Kuhl's tree squirrel (Funisciurus congicus), and sun squirrel (Heliosciurus rufobrachium) (Hutin, 2001).

Human-to-human transmission supplanted the prominence of animal-to-human transmission in the 1996-1997 outbreak in the DRC. Crowded living quarters, poor hygiene, discontinuation of the smallpox vaccination, and decreased herd immunity were implicated. Respiratory droplets and direct contact with mucocutaneous lesions or fomites have been postulated as routes of human-to-human transmission.

DIFFERENTIALS

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Other Problems to be Considered

Pseudocowpox/paravaccinia
Varicella-zoster
Diseases transmitted by prairie dogs (eg, tularemia, plague, parapox virus)
Eczema herpeticum

WORKUP

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Lab Studies

• Information regarding procurement and disposition of specimens for the CDC may be obtained at Laboratory Testing of Human and Animal Specimens.
• A viral culture should be obtained from an oropharyngeal or nasopharyngeal swab. A skin biopsy specimen of the vesiculopustular rash or a sample of the roof of an intact vesiculopustule should be analyzed.
• Tissue for PCR of DNA sequence-specific for the monkeypox virus may be obtained.
• Paired sera for acute and convalescent titers may be analyzed. Serum collected more than 5 days for IgM detection or serum collected more than 8 days after rash onset for IgG detection was most efficient for the detection of the monkeypox virus infection (Karem, 2005).
• A Tzanck smear can help differentiate monkeypox from other nonviral disorders in the differential diagnosis. However, a Tzanck smear does not differentiate a monkeypox infection from smallpox or herpetic infections.

Histologic Findings

Histologically, papular lesions show acanthosis, individual keratinocyte necrosis, and basal vacuolization. This is accompanied by a superficial and deep perivascular, lymphohistiocytic infiltrate in the dermis. Lesions in the vesicular stage demonstrate spongiosis with reticular and ballooning degeneration. Multinucleated epithelial giant cells may be seen. Pustular lesions are characterized by epidermal necrosis with numerous eosinophils and neutrophils, many displaying karyorrhexis. Necrosis may extend through full-thickness epidermis with sharp lateral demarcation from adjacent intact epidermis. The associated perivascular infiltrate includes eosinophils and neutrophils in addition to lymphocytes and histiocytes. Petechial lesions demonstrate secondary vasculitis. Amphophilic intranuclear structures suggestive of viral inclusions may be seen in keratinocytes.

Immunohistochemistry staining for orthopox viral antigens can be performed in a reference laboratory. With electron microscopy, intracytoplasmic, round-to-oval inclusions with sausage-shaped structures centrally, measuring 200-300 µm, are observed. Inclusions are consistent with orthopox viruses, permitting differentiation from parapox and herpes viruses.

Diagnostic criteria

The diagnostic criteria are summarized below; refer to the current criteria established by the CDC at Updated Interim Case Definition for Human Monkeypox, January 2004.

• Confirmed case
• • Meets 1 or more of the following laboratory criteria:
  • • Isolation of the monkeypox virus in culture from a sample obtained from the patient
    • Demonstration of the monkeypox virus on PCR in a specimen obtained from the patient
    • Demonstration of the orthopox virus by electron microscopy in samples obtained from the patient in the absence of exposure to other orthopoxviruses
    • Demonstration of the monkeypox virus by immunohistochemical methods in samples obtained from the patient in the absence of exposure to another orthopoxvirus
• Probable case
• • Contact that meets current epidemiologic criteria per the CDC
  • Fever and vesicular-pustular rash with the onset of the first sign or symptom at most 21 days after the last exposure, meeting the epidemiologic exposure
• Suspected case
• • Contact that meets current epidemiologic criteria per the CDC
  • Fever or unexplained rash and 2 or more other signs or symptoms, with the onset of the first sign or symptom at most 21 days after exposure, meeting the epidemiologic criteria
  • • Chills and/or sweats
    • Lymphadenopathy
    • Sore throat
    • Cough
    • Shortness of breath
    • Headache
    • Backache

TREATMENT

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Medical Care

The disease is usually self-limited; resolution occurs in 2-4 weeks. In the African cases, the mortality rate was 1-10%, and death was related to the patients' health status, and other comorbidities. Most patients died of secondary infections. No fatalities were reported in the recent US outbreak.

• Patients often feel poorly during the febrile stage of the illness; therefore, bedrest along with supportive care may be necessary.
• Hospitalization may be necessary in more severe cases; a negative pressure room is preferable.
• To avoid infection of health care workers and close contacts, airborne and contact precautions should be applied. See the current CDC recommendations at Guideline for Isolation Precautions in Hospitals and Updated Interim Infection Control and Exposure Management Guidance in the Health-Care and Community Setting for Patients with Possible Monkeypox Virus Infection.
• Isolation must be continued until the last crust is shed.

MEDICATION

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The CDC recommends a smallpox vaccination within 2 weeks of exposure, ideally within 4 days, for exposed health care workers and household contacts of confirmed cases. Cidofovir has been suggested as a possible treatment option in severe, life-threatening cases only. Vaccinia immune globulin (VIG) has not demonstrated efficacy in either treatment or prophylaxis.

Drug Category: Vaccine, Inactivated Virus

Drug Category: Antiviral Agent

FOLLOW-UP

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Further Outpatient Care

• Outpatient management is appropriate and cost-effective in most cases of human infection, but care must be taken to follow recommended quarantine procedures at home.
• • Contact and respiratory isolation precautions should be exercised to prevent the spread of disease.
  • Direct contact with skin lesions or fomites is considered infectious until the crust detaches from the last skin lesion.
  • Patients and unexposed contacts should wear masks until respiratory symptoms resolve.
  • Health care workers and others who are asymptomatic and in contact with patients who are infected must closely monitor their symptoms and their temperature for 21 days after the last known contact. See the current CDC recommendations at Updated Interim Infection Control and Exposure Management Guidance in the Health-Care and Community Setting for Patients with Possible Monkeypox Virus Infection.

Deterrence/Prevention

• Importation of exotic animals as domestic pets poses a threat to the health of both people and animals by introducing nonindigenous pathogens. Animals, especially those implicated above (see Causes) or those in contact with them, demonstrating signs of respiratory distress, mucocutaneous lesions, rhinorrhea, ocular discharge, and/or lymphadenopathy should be quarantined immediately. Avoidance of contact, especially bites, scratches, and exposure to fluids/secretions, is essential. Guidance can be obtained from veterinarians, state/local authorities, and the CDC. See the current CDC recommendations at Monkeypox Infections In Animals: Updated Interim Guidance for Veterinarians
  .

Complications

• Complications include pitted scars, deforming scars, secondary bacterial infection, bronchopneumonia, respiratory distress, keratitis, corneal ulceration, blindness, septicemia, and encephalitis.

Prognosis

• Mortality rates ranging from 1-10% have been reported in Africa, but, to date, no fatalities have occurred in the United States. Death rates are disproportionately high in African children. Health status, comorbidities, vaccination status, and severity of complications influence the prognosis in the United States and Africa.
• Uncomplicated cases resolve in 2-4 weeks, with only pock scars remaining.

Patient Education

• After the 2003 outbreak, the CDC implemented an immediate embargo on the importation of all rodents (order Rodentia) from Africa.
• In addition, the CDC and the Food and Drug Administration prohibited

  the transportation or offering for transportation in interstate commerce, or the sale, offering for sale, or offering for any other type of commercial or public distribution, including release into the environment of prairie dogs and the following rodents from Africa: tree squirrels (Heliosciurus sp.), rope squirrels (Funisciurus sp.), dormice (Graphiurus sp.), Gambian giant pouched rats (Cricetomys sp.), brush-tailed porcupines (Atherurus sp.), and striped mice (Hybomys sp.).

• Investigation of the exotic pet industry by state and federal authorities was triggered by the 2003 outbreak; conclusions and actions are pending. For more information, see Public Health Lawyers.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Failure to identify the infection may lead to a missed opportunity to vaccinate, which might limit the infection.

MULTIMEDIA

Section 10 of 11  

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• Multimedia
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Media file 1:  Vesicular rash on the dorsal aspect of the hand. Vesicopustules are seen; some have a central umbilication.
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Media type:  Photo

Media file 2:  Umbilicated papule on the lower part of the leg. This smaller lesion still shows the typical umbilicated morphology.
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Media type:  Photo

Media file 3:  Lymphadenopathy in monkeypox. Large nodes in the mandibular, cervical, or inguinal region are commonly seen in monkeypox. The presence of significant lymphadenopathy helps differentiate monkeypox from smallpox and chickenpox.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 11 of 11

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• Bayer-Garner IB. Monkeypox virus: histologic, immunohistochemical and electron-microscopic findings. J Cutan Pathol. Jan 2005;32(1):28-34. [Medline].
• Breman JG. Monkeypox: an emerging infection for humans? In: Scheld WM, Craig WA, Hughes JM, eds. Emerging Infections 4. Washington, DC: ASM Press;2000:45-76.
• CDC. Centers for Disease Control and Prevention. Monkeypox [CDC Web site]. Available at: http://www.cdc.gov/ncidod/monkeypox/index.htm. Accessed June 14, 2003. [Full Text].
• CDC. Centers for Disease Control and Prevention. Multistate Outbreak of Monkeypox-Illinois, Indiana, Kansas, Missouri, Ohio, and Wisconsin, 2003. Morb Mortal Wkly Rep [serial online]. 2003; 52(27): 642-645. Available at: http://www.cdc.gov/mmwr/preview/mmwr. [Full Text].
• CDC. Centers for Disease Control and Prevention. Smallpox [CDC Web site]. March 31, 2003. Available at: http://www.bt.cdc.gov/agent/smallpox/index.asp. Accessed June 15, 2003. [Full Text].
• Cono J, Casey CG, Bell DM; CDC. Smallpox vaccination and adverse reactions. Guidance for clinicians. MMWR Recomm Rep. Feb 21 2003;52(RR-4):1-28. [Medline].
• De Clercq E. Cidofovir in the therapy and short-term prophylaxis of poxvirus infections. Trends Pharmacol Sci. Oct 2002;23(10):456-8. [Medline].
• Diven D. Poxviruses. In: Tyring SK, ed. Mucocutaneous Manifestations of Viral Diseases. New York: Marcel Dekker;2002.
• Fine PE, Jezek Z, Grab B, Dixon H. The transmission potential of monkeypox virus in human populations. Int J Epidemiol. Sep 1988;17(3):643-50. [Medline].
• Huhn GD, Bauer AM, Yorita K, et al. Clinical characteristics of human monkeypox, and risk factors for severe disease. Clinical Infectious Diseases. 2005;41(12):1742-51. [Medline].
• Hutin YJF, Williams JR, Malfait P, et al. Outbreak of Human Monkeypox, Democratic Republic of Congo, 1996 to 1997. Emerg Infect Dis [serial online]. 2001 May-Jun; 7:434-438. Available at: http://www.cdc.gov/ncidod/eid/vol7no3/hutin.htm. [Full Text].
• Jezek Z, Fenner F. Human monkeypox. In: Melnick JL, ed. Monographs in Virology. Vol 17. Basel: Karger;1988.
• Jezek Z, Szczeniowski M, Paluku KM, Mutombo M. Human monkeypox: clinical features of 282 patients. J Infect Dis. Aug 1987;156(2):293-8. [Medline].
• Karem KL. Characterization of acute-phase humoral immunity to monkeypox: use of immunoglobulin M enzyme-linked immunosorbent assay for detection of monkeypox infection during the 2003 North American outbreak. Clinical and Diagnostic Laboratory Immunology. 2005;12(7):867-72. [Medline].
• Khodakevich L, Jezek Z, Kinzanzka K. Isolation of monkeypox virus from wild squirrel infected in nature. Lancet. Jan 11 1986;1(8472):98-9. [Medline].
• Ladnyj ID, Ziegler P, Kima E. A human infection caused by monkeypox virus in Basankusu Territory, Democratic Republic of the Congo. Bull World Health Organ. 1972;46(5):593-7. [Medline].
• Reed KD, Melski JW, Graham MB, et al. The detection of monkeypox in humans in the Western Hemisphere. N Engl J Med. Jan 22 2004;350(4):342-50. [Medline].
• Sejvar JJ. Human monkeypox infection: a family cluster in the midwestern United States. Journal of Infectious Diseases. 2004;190(10):1833-40. [Medline].
• Sherman DS, Fish DN. Cidofovir. AIDS Read. May-Jun 1999;9(3):215-20. [Medline].

Article Last Updated: Apr 11, 2006