Monkeypox

Are You Confident of the Diagnosis?

What you should be alert for in the history

Monkeypox was initially identified as an infectious agent in captive primates in Denmark in 1959. The first cases of human monkeypox were reported in Zaire (currently Democratic Republic of Congo) in 1970. Human monkeypox infection continues to occur in the same region of Africa, typically affecting children younger than 10 years old and individuals in direct contact with infected animals.

Human monkeypox was first detected in the Western hemisphere in May 2003, when a total of 71 cases of suspected or confirmed monkeypox were reported in the Midwestern United States in patients ages 1-51 years old, with a history of exposure to infected native prairie dogs (Cynomys species) from a distributor of exotic animals. The prairie dogs were housed with several rodents from Africa, including an ill Gambian giant-pouched rat, which were later found to have monkeypox.

Affected patients in the US outbreak included individuals who distributed, purchased and provided veterinary care for the infected prairie dogs. Patients were exposed through a bite or scratch from an affected animal, or became infected through exposure at a site of previous trauma. Households that purchased infected prairie dogs often had several members that developed monkeypox infection.

In 2003, the Centers for Disease Control and Prevention and the Food and Drug Administration released an order to prohibit the import of all African rodents and the sale, transport, or release into the wild of prairie dogs and several other small mammals.

Characteristic findings on physical examination

Human monkeypox was originally described in Africa, where it is typically characterized by initial fever, chills, headache, marked lymphadenopathy and back pain, followed by a monomorphic eruption consisting of macules and papules in a centrifugal distribution with subsequent vesicles, pustules and crusting.

In a review of 34 patients with confirmed US monkeypox infection, most patients experienced rash, fever, chills and lymphadenopathy. Skin lesions were typically monomorphic and involved the extremities, head and neck, chest, back, and palms. The majority of patients (80%) had 5-100 lesions, and almost half of the patients had lesions in a centrifugal distribution. The most common lesions included papules, vesicles, pustules, umbilicated lesions and macules.

In the original case series of 11 patients with suspected or confirmed monkeypox infection from Wisconsin, patients typically presented with fevers, headache and skin lesions. Five of the eleven patients had evidence of primary lesions, which developed as nodular lesions at the borders of bites or scratches (Figure 1 and Figure 2). Disseminated cutaneous lesions appeared over several days and evolved from papules to vesiculopustules (Figure 3). Some lesions had surrounding erythematous flares. Hemorrhagic and serous crusting developed as lesions resolved and central scarring occurred in larger lesions. Patients that were affected with multiple lesions showed simultaneous lesions in different stages of evolution.

Primary innoculation lesion for monkeypox infection at the site of a previous cat scratch. The patient was the monther of the index patient for the US monkeypox outbreak.

Disseminated monkeypox lesions in the index case for the US monkeypox outbreak.

The clinical findings of monkeypox infection are summarized below (Table I).

Table I.

Clinical Finding	% of Patients(Reed, n=11)	% of Patients(Huhn, n=34)	% of Patients(Reynolds, n=30)
Skin lesions	100	97	100
Headache	100	65
Fever	82		93.3
Sweats	82
Chills	82	71
Cough	73		56.7
Lymphadenopathy	55	71	66.7
Sore throat	55
Pharyngitis	27
Myalgias	<18	56
Mouth sores			26.7

Less common findings included tonsillar hypertrophy, tonsillar erosions, malaise, mild chest tightness, diarrhea, myalgias, back pain, nasal congestion, blepharitis, and nausea.

There are significant differences in mode of transmission, symptoms and lesional morphology between monkeypox infection in Africa and the US. Overall, patients with monkeypox infection during the US outbreak had less severe clinical presentations compared to patients with infections in Central Africa. See the table below for details regarding the variations in clinical features of monkeypox based on geographical location (Table II).

Table II.

Clinical Feature	Africa	United States
Epidemiology Age Gender	80% of cases occur in children <10 years oldMostly male	Median age of infected patients was 28, with range from 1-51 years old
Transmission	Direct contact with infected animal for food, sport or other (72%)Transmission through ingestion of infected meat also likelyHuman-to-human transmission (28%)	Direct contact with captive wild animal or prairie dogTransmission through skin contact with infected animalHuman-to-human transmssion not confirmed
Incubation period	7-17 days, mean 12 days	1-31 days, median 12 days
Signs and symptoms	Fever, headache, fatigueBack pain commonMarked lymphadenopathy	Fever, chills, headache, sweats, chills, cough, sore throat (See Table I: US monkeypox clinical presentation)Lymphadenopathy common but less prominent
Skin findings	Predictable morphologyLesions evolve from macules to papules to pustules; then umbilication and desquamationLesions last 14-21 daysScarring oftenInnoculation lesions uncommonNumerous lesions(49% with >100 lesions)Centrifugal distribution usually	Variable morphologyLesions evolve from papules to vesicles to pustules; significant erythematous flaresHealing occurs with hemorrhagic crustingLesions last 3-25 days, median 12 daysScarring uncommonInnoculation lesions in 5 of 11 patients in initial case seriesLess numerous lesions(20% with >100 lesions)Centrifugal distribution in 48%
Fatality rate	10-17%	None

Expected results of diagnostic studies

Laboratory testing is essential for definitive diagnosis of monkeypox infection, since the clinical features are similar to other disease entities, such as chickenpox and smallpox.

Histopathology

In human monkeypox infection, examination of skin biopsy specimens with hematoxylin and eosin (H&E) stain shows necrosis of the epidermis, ballooning degeneration of keratinocytes and spongiosis. The epidermis and superficial dermis have a moderate inflammatory infiltrate composed of neutrophils and lymphocytes. Large multinucleated cells and eosinophilic viral inclusion bodies may be seen in sections of the epidermis (Figure 4). The histologic findings of monkeypox infection are nonspecific and are similar to other viral processes such as herpes simplex, variola, cowpox, varicella zoster, and vaccinia.

Immunohistochemical

Immunohistochemical staining with antibodies against orthopoxviruses can distinguish a poxvirus from a herpes virus infection.

Viral Culture

In the original case series of 11 patients with suspected or confirmed cases of monkeypox, viral culture was completed for seven patients by inoculating tissue samples onto various cell lines. Cytopathic changes were typically identified within one to four days.

Ultrastructure evaluation

Electron microscopy is helpful in identifying the Orthopoxvirus family of viruses, but cannot distinguish monkeypox specifically. Poxvirus virions are typically brick-shaped with lateral bodies and a dumbbell-shaped core. Keratinocytes have intracellular mature virions in addition to immature virions assembling in the cytoplasm.

Genetic Tests

Polymerase chain reaction (PCR) evaluation of a specimen can differentiate monkeypox infection from a variety of samples, including tissue, swabs, “touch” preparations and cell-culture supernatants. PCR testing is only available through the CDC.

The monkeypox virus can also be identified with the use of a DNA oligonucleotide microarray with the TNF receptor gene crmB.

The CDC case definition for human monkeypox infection involves several epidemiologic criteria, clinical features and laboratory findings, which are summarized below (Table III). The complete guidelines for the case definition are available from the Centers for Disease Control (CDC).

Table III.

Epidemiologic Criteria	Clinical Features	Laboratory Findings
Exposure to exotic or wild mammalian pet with evidence of illness, obtained on or after April 15, 2003Exposure to exotic or wild mammalian pet with or without evidence of illness that was in contact with human or animal subject with monkeypoxExposure to suspect, probable or confirmed case of human monkeypox	RashFever, subjective or >37.4COther features including chills, sweats, headache, backache, lymphadenopathy, sore throat, cough, shortness of breath	Monkeypox virus isolation in cultureIdentification of monkeypox viral DNA by PCR testing of clinical specimenIdentification of orthopoxvirus by electron microscopy (in absence of exposure to another orthopoxvirus)Immunohistochemical testing for presence of orthopoxvirus in tissue (in absence of exposure to another orthopoxvirus)

PCR, polymerase chain reaction.

Human monkeypox cases are classified into suspected, probable, or confirmed infections, based on the criteria in the table below (Table IV). To meet the definition for a particular classification, the patient must have one component from the epidemiologic, clinical, and laboratory/other categories.

Table IV.

Classification	Epidemiologic	Clinical	Laboratory/Other
Confirmed	N/A	N/A	One positive laboratory test
Probable	One epidemiologic criteria	Fever	Vesicular-pustular rash, onset <21 days after last exposure that meets epidemiologic criteraORRash and presence of orthopoxvirus IgM antibodies 7-56 days after rash onset
Suspected	One epidemiologic criteria	FeverORUnexplained rash	Two or more other signs or symptoms, onset <21 days after last expsosure that meets epidemiologic criteria

A suspected or probable case of human monkeypox can be excluded if another diagnosis fully explains the illness or the case was based on exposure to an animal that was later established not to have monkeypox. In addition, if a case without initial rash does not develop a rash within 10 days of the onset of other clinical symptoms, the case is considered negative. A case may also be excluded if the patient did not have detectable IgM levels within 7-56 days after rash onset, or if the PCR testing is negative for non-variola generic orthopoxvirus.

Diagnosis confirmation

Several conditions must be considered on the differential diagnosis for patients presenting with monkeypox infection, including other viral diseases that share some common clinical features. These conditions are discussed below, including distinguishing findings that differentiate the disease entities.

Varicella

The skin lesions and other clinical features of varicella may be similar to monkeypox infection. Primary varicella (chickenpox) is typically characterized by fever and macular skin rash that evolves into papules and vesicles, followed by crusting that resolves in 1-2 weeks. Skin lesions may involve mucosal surfaces. Constitutional symptoms such as headache, malaise and decreased appetite may also occur. Although varicella is most common in children 1-9 years of age, the infection may occur in adults, especially in tropical climates. More severe infections tend to occur in adults and immunocompromised patients. Central nervous system complications may occur in varicella infection, such as cerebellar ataxia, meningitis and vasculopathy.

Varicella infection is transmitted through direct contact with skin lesions or respiratory aerosols and is highly contagious.

The fever, malaise, and headache of varicella are usually less severe than monkeypox infection. Lesions in varicella are superficial, heterogeneous and have a centripital distribution, in contrast to the homogeneous, centrifugal rash of monkeypox. Involvement of the palms and soles is rare in varicella, but common in monkeypox. Lymphadenopathy is another important feature for differentiating monkeypox from varicella, since it is a prominent feature in monkeypox but is not present in varicella.

Smallpox

Smallpox is caused by the variola virus, which is a member of the genus Orthopoxvirus, family Poxviridae. The presenting signs and symptoms of smallpox infection are variable depending on the clinical type and may resemble monkeypox infection. The most common type of variola major is ordinary smallpox, which typically begins with fever, headache, back pain, chills, abdominal pain and vomiting. After 1 to 4 days of the viral prodrome, patients develop lesions on the mouth, tongue, and oropharynx. The skin eruption usually occurs 1 day after the enanthem and is initially characterized by macular lesions, which then develop into papules, vesicles, and pustules, eventually forming crusts.

The lesions of smallpox usually start on the face, then spread to other areas of the body with a centrifugal distribution. Palmar and plantar lesions occur in most patients. Lesions on one area of the body are all in the same stage of development, unlike chickenpox and monkeypox.

The fever and headache in smallpox infection tend to be more severe compared to monkeypox. Lymphadenopathy is a prominent, distinguishing feature that is common in monkeypox infection, but absent in smallpox .

Vaccinia

The vaccinia virus is a member of the Orthopoxvirus genus and is used for smallpox vaccination. Typically, patients develop an erythematous papule at the site of vaccination 3-5 days after receiving the vaccine. The papule progresses to a vesicular lesion, then forms a pustule and enlarges. As the pustule dries, a crust forms over the lesion, which then resolves 2 to 3 weeks after the vaccination, resulting in scar formation. This typical reaction pattern signifies that the individual has responded successfully to the vaccination. Patients may also experience symptoms such as fatigue, headache, fever, myalgias, regional lymphadenopathy, and satellite lesions.

Patients with generalized vaccinia typically exhibit an eruption with macules and papules or vesicles, often with an erythematous base, that usually develops 6-9 days after vaccination. Any site of the body may be affected and the eruption may be extensive or limited. The lesions of vaccinia may appear similar to smallpox, but they lack the centrifugal distribution usually seen in smallpox infection.

Other diseases that should be considered in the differential diagnosis of monkeypox include herpes zoster, herpes simples, molluscum contagiosum, erythema multiforme, acne, drug reactions, impetigo, allergic dermatitis, scabies, and syphilis.

Who is at Risk for Developing this Disease?

Providers should take a careful history regarding recent exposure to ill animals, especially rodents or other animals that may have originated from or been in contact with animals from Africa.

Patients may have a history of being scratched or bitten by the infected animal. Others may become infected through a previously acquired open wound. Individuals may also be exposed through contact with contaminated animal bedding .

Patients should be asked if they have been exposed to persons with monkeypox infection, since person-to-person transmission is known to occur. The incubation time ranges from 4-24 days with a mean time around 12-14.5 days after exposure. In an analysis of 29 patients with confirmed human monkeypox infection in the US, incubation time was 12 days, with interquartile range of 11-18 days.

What is the Cause of the Disease?

Etiology

Monkeypox is a zoonotic disease caused by a double-stranded DNA virus from the genus Orthopoxvirus, family Poxviridae, subfamily Chordopoxvirinae. The monkeypox strain that affected the US originated from the West African clade, which is less virulent compared to the Central African clade.

The reservoir for monkeypox virus is unknown, but is thought to be rodents or squirrels in central Africa. Besides African species, studies have shown that there are multiple potential hosts for monkeypox virus including primates, rabbits and rodents. Since monkeypox virus has an animal reservoir, complete eradication of the disease is not possible.

Pathophysiology

Exposure to an infected animal by a bite or through direct contact with skin lesions or body fluids appears to be the primary mechanism of infection in the US monkeypox outbreak. Transmission through contact with contaminated bedding or cages is possible, though not confirmed.

Monkeypox has confirmed person-to-person transmission in African cases, from direct contact and respiratory droplets. Although there is no evidence of human-to-human transmission in the US, there are cases where this cannot be excluded. Airborne transmission of the monkeypox virus is theoretically possible, especially in patients with cough. In Africa, infection may also occur through ingestion of an infected animal for food.

The period of communicability, similar for both humans and animals, ranges from 1 day prior to the onset of the rash until 3 weeks after rash onset or fever onset, or until all of the lesions have formed crusts.

Systemic Implications and Complications

In the original case series of 11 patients with suspected or confirmed monkeypox infection from Wisconsin, examination of the cardiac, gastrointestinal, neurologic, and musculoskeletal systems was normal in all patients examined. Four of the eleven patients were hospitalized for treatment of their infection. Clinical course was self-limited for all patients in the case series.

In a review of 34 confirmed cases of human monkeypox infection in the US, nine patients were hospitalized. Risk factors for hospitalization included fever, extensive skin lesions (>100), adenopathy, mouth sores, dysphagia, nausea, and vomiting. Common laboratory abnormalities for 21 patients included low blood urea nitrogen (61%), elevated transaminase levels (50%), hypoalbuminemia (50%), leukocytosis (45%) and thrombocytopenia (35%).

Monkeypox infection may have systemic effects beyond the readily apparent cutaneous involvement. Hypoalbuminemia and gastointestinal fluid losses seen in patients with monkeypox are indicative of the fluid shifts that often occur in systemic infections.

Pediatric patients were significantly more likely to be hospitalized compared to adults. A 6-year old pediatric patient was intubated for encephalitis and underwent care in the pediatric intensive care unit. Another pediatric patient was hospitalized with a large retropharyngeal abscess and lymphadenopathy that led to airway compromise.

There were no fatalities in the US monkeypox outbreak, though mortality rates in Africa range from 10-17%.

Treatment Options

Data regarding treatment modalities for human monkeypox infection is limited. There are no licensed treatments currently available to treat monkeypox infection. The various therapeutic approaches for monkeypox infection are described below (also see Table V).

Table V.

Treatment Modality	Therapeutic Options
Medical Topical Systemic	NoneSmallpox vaccinationVaccinia immune globulinCidofovir* Only consider for severe infections or as prophylaxis for certain immunocompromised patients *Only consider for severe infections
Surgical	None
Physical	None

Smallpox Vaccination

Studies of monkeypox in Africa have shown that vaccination of individuals with the smallpox vaccine 3-19 years prior to exposure to the monkeypox virus is protective against disease (85%), but the effects of smallpox vaccination in the US outbreak were less clear. A case-control study of the US monkeypox outbreak compared 30 patients with confirmed or probable monkeypox infection to 28 controls with no evidence of disease but history of exposure to an infected prairie dog. All of the patients with a prior history of smallpox vaccination received the more than 25 years prior to the monkeypox outbreak, when vaccination was required in the US. Patients with a history of remote smallpox vaccination showed a decrease risk of monkeypox infection, but the effects of age and exposure history were not considered in this data, and may have independent contributions to the risk of monkeypox infection.

Although there is no data available to establish the efficacy of postexposure vaccination, the CDC recommended smallpox vaccination for certain individuals during the US outbreak. According to guidelines published in June 2003, household, intimate and close contacts of individuals with confirmed human monkeypox infection should receive the smallpox vaccine if they are within 4 days of the initial direct exposure, and considered for vaccination if they are within 2 weeks of the most recent exposure.

Individuals are considered to have close contact if they have been in face-to-face contact within 6 feet of the affected human for at least 3 hours. Close contact with an animal occurs when an individual has been within six feet of an animal that is suspected to have monkeypox with symptoms of the disease, in an environment where the animal has been handled. Intimate contact involves exposure to body fluids or lesions of people or animals that are ill.

Consultation with state and local health departments should be obtained to provide advice on vaccination of contacts, especially in cases where individuals do not meet criteria for close or intimate contact.

Although routine vaccination of health care workers is not recommended, individuals should be vaccinated if they have been exposed to a patient with confirmed monkeypox infection or plan to care for patients with monkeypox in the future. Likewise, veterinarians and veterinary staff should not receive routine vaccination, except in situations where they have been exposed to a case of monkeypox. Laboratory workers who are involved in processing specimens from probable or confirmed cases of monkeypox should also have the smallpox vaccine. Individuals who are involved in the investigation of suspected monkeypox cases should receive the smallpox vaccine, ideally before contact with the cases.

Patients should be evaluated for adequate response to the smallpox vaccine 6 to 8 days after the vaccine administration. The presence of a major reaction site indicates successful vaccination. If patients do not develop an adequate response, they should undergo revaccination within 2 weeks of exposure to monkeypox.

Many contraindications for smallpox vaccination are considered precautions in the setting of exposure to monkeypox, since the benefits of vaccination are thought to outweigh the risks. Although considered contraindications to smallpox vaccination in pre-event settings, pregnancy, age and history of eczema are considered precautions and not contraindications in the setting of monkeypox exposure.

There are some contraindications to smallpox vaccination for persons exposed to monkeypox, including HIV infection with CD4 count less than 200, transplant recipients or other patients on high doses of immunosuppressive therapy, lymphosarcoma, hematological malignancies, primary T-cell congenital immunodeficiencies, life-threatening allergy to latex or any component of the smallpox vaccine.

Vaccinia immune globulin (VIG)

There is no data available for the effectiveness of VIG for treatment of monkeypox. Treatment with VIG may be considered in certain circumstances, such as patients with severe infection or as prophylaxis for exposed individuals with severe T-cell deficiency that cannot receive the smallpox vaccine.

Cidofovir

There are no FDA-approved antiviral medications for the treatment of human monkeypox infection. Cidofovir is a broad-spectrum intravenous antiviral medication that has been demonstrated to be effective in preventing monkeypox infection in primate models. However, no data is available for the effectiveness of cidofovir in treatment of human monkeypox infection. Use of cidofovir should only be considered in patients with severe monkeypox infection, as it has significant risks, such as renal toxicity.

Optimal Therapeutic Approach for this Disease

Currently, vaccination against the smallpox virus is the recommended therapy for monkeypox infection. Ideally, the vaccine is administered to individuals at risk for infection prior to exposure, according to the guidelines for vaccination from the CDC, as outlined above. Vaccination is also used in post-exposure settings within 4 days of the initial contact and may be considered up to 2 weeks after the last contact with an infected individual or animal. Many of the contraindications for vaccination are considered precautions in the setting of monkeypox exposure, since the benefits of vaccination likely outweigh the risks.

Since vaccinia immune globulin (VIG) and cidofovir have not been studied for the treatment of monkeypox infection, these medications should only be used in the setting of severe disease. VIG may also be used as prophylaxis in certain immunocompromised patients.

Appropriate hand hygiene, isolation procedures and managment of contaminated waste is important for controlling the further spread of monkeypox infection, as specified below.

Patient Management

During the outbreak of monkeypox in the US, most affected individuals were managed as outpatients, though some required hospitalization and a few patients required intensive care. Risk factors for hospitalization include fever, extensive skin lesions (>100), adenopathy, mouth sores, dysphagia, nausea, and vomiting.

Proper isolation precautions are essential for patients with monkeypox infection to avoid further transmission of disease. If a negative pressure room is not available, a private examination room should be used for patients with vesiculopustular rash and fever presenting for evaluation. The patient should wear a mask over the nose and mouth, and cover all skin lesions. If a patient with monkeypox is admitted to the hospital, placement in a negative pressure room with contact, droplet, and airborne precautions is advised. A private room should be used if a negative pressure room is not available.

CDC recommendations for infection control in the setting of human monkeypox infection include proper hand hygiene and correct use of personal protective equipment such as gowns, gloves, eye protection, and respirator masks. Proper handling of contaminated waste and linens must be maintained to avoid transmission of infection. In addition, careful handling of patient care equipment to avoid contamination of skin and clothing, and proper cleaning of the patient care environment is essential. Please see the CDC guidelines for infection control at http://www.cdc.gov/ncidod/monkeypox for complete recommendations.

Unusual Clinical Scenarios to Consider in Patient Management

Treatment of monkeypox infection in immunocompromised patients is challenging, as smallpox vaccination is contraindicated in patients with severe T-cell deficiency. Patients with HIV infection with CD4 lymphocyte count less than 200 (or equivalent in children) should not receive the smallpox vaccine. In addition, vaccination is contraindicated in patients with solid organ or bone marrow transplants and for patients taking high doses immunosuppresive medications.

Patients with lymphosarcoma, hematological malignancies, and primary T-cell congenital immunodeficiencies should not receive the smallpox vaccine. In patients with diseases involving severe T-cell deficiency, vaccinia immune globulin may be considered for prophylaxis if patients are exposed to monkeypox. State and local health departments should be consulted to provide recommendations regarding management of these patients.

What is the Evidence?

Sale, TA, Melski, JW, Stratman, EJ. “Monkeypox: an epidemiologic and clinical comparison of African and US disease”. J Am Acad Dermatol. vol. 55. 2006 Sep. pp. 478-81. (The authors compare and contrast the clinical and epidemiologic features of monkeypox infection in the US and Africa. They identified several differences between the two areas, including the age of affected individuals, skin lesion morphology and fatality rates.)

Ligon, BL. “Monkeypox: a review of the history and emergence in the Western hemisphere”. Semin Pediatr Infect Dis. vol. 15. 2004 Oct. pp. 280-7. (The author summarizes the course of the US monkeypox outbreak in 2003. The history of monkeypox in Africa is reviewed, and the characteristics of the monkeypox outbreak in 1996-1997 were contrasted with previous outbreaks in the region. Clinical features and treatment recommendations are summarized.)

Reed, KD, Melski, JW, Graham, MB, Regnery, RL, Sotir, MJ, Wegner, MV. “The detection of mokeypox in humans in the Western Hemisphere”. N Engl J Med. vol. 350. 2004 Jan 22. pp. 342-50. (The authors present the original case series of patients in the US monkeypox outbreak in 2003. They include epidemiologic findings and describe the association of the outbreak with ill pet prarie dogs. They review the clinical and laboratory findings for the involved patients.)

“Update: Multistate Outbreak of Monkeypox–Illinois, Indiana, Kansas, Missouri, Ohio and Wisconsin”. MMWR Weekly. vol. 52. July 11, 2003. pp. 642-646. (The report addresses epidemiologic data, the use of smallpox vaccination and animal traceback investigations for the 2003 monkeypox outbreak in the United States.)

Huhn, GD, Bauer, AM, Yorita, K, Graham, MB, Sejvar, J, Likos, A. “Clinical characteristics of human monkeypox, and risk factors for severe disease”. Clin Infect Dis 2005 Dec. vol. 41. 15. pp. 1742-51. (The authors review demographic, clinical, and laboratory findings from the 34 patients with confirmed monkeypox infection in the US outbreak in 2003. They identified risk factors for hospitalization and intensive care, and found that remote history of smallpox vaccination did not affect disease severity or hospitalization.)

Updated interim case definition for human monkeypox. (The guidelines present the case definition for human monkeypox for the US outbreak. They identify clinical, epidemiologic, and laboratory criteria that are used to classify cases into suspected, probable, or confirmed infections.)

Reynolds, MG, Davidson, WB, Curns, AT, Conover, CS, Huhn, G, Davis, JP. “Spectrum of infection and risk factors for human monkeypox, United States, 2003”. Emerg Infect Dis. vol. 13. 2007 Sep. pp. 1332-9. (In this case-control study, the authors identified risk factors for human monkeypox infection, including handling of an ill animal. A history of remote smallpox vaccination was found to be protective against infection, though the effects of age and exposure history were not considered when assessing this effect. They reviewed the epidemiologic and clinical characteristics of case patients and the controls.)

Nalca, A, Rimoin, AW, Bavari, S, Whitehouse, CA. “Reemergence of monkeypox: prevalence, diagnostics, and countermeasures”. Clin Infect Dis 2005 Dec. vol. 41. 15. pp. 1765-71. (The authors present a review of the history of monkeypox in Africa and describe the typical clinical findings for the disease. They provide a table that compares and contrasts the clinical features of monkeypox, smallpox and chickenpox. The various diagnostic tests for monkeypox are reviewed.)

Mueller, NH, Gilden, DH, Cohrs, RJ, Mahalingam, R, Nagel, MA. “Varicella zoster virus infection: clinical features, molecular pathogenesis of disease, and latency”. Neurol Clin. vol. 26. 2008 Aug. pp. 675-97. (The authors review the typical clinical features of primary varicella infection and reactivation, including complications of the disease.)

Moore, ZS, Seward, JF, Lane, JM. “Smallpox”. Lancet. vol. 367. 2006 Feb4. pp. 425-35. (The authors review the clinical features, complications and differential diagnosis of smallpox infection. They compare and contrast smallpox with varicella and monkeypox, citing important distinguishing features for each disease.)

Cono, J, Casey, CG, Bell, DM. “Centers for Disease Control and Prevention. Smallpox vaccination and adverse reactions. Guidance for clinicians”. MMWR Recomm Rep. vol. 52. 2003 Feb21. pp. 1-28. (The authors summarize the clinical findings associated with smallpox vaccination, including signs of successful vaccination. They describe potential complications of vaccination.)

“Updated interim infection control and exposure management guidance in the health-care and community setting for patients with possible monkeypox virus infection”. July 18, 2003. (The guidelines address infection control procedures for patients with possible monkeypox infection, including isolation precautions, hand hygiene, personal protective equipment, and environmental cleaning.)

“Updated interim CDC guidance for use of smallpox vaccine, cidofovir, and vaccinia immune globulin (VIG) for prevention and treatment in the setting of an outbreak of monkeypox infections”. June 25, 2003. (The guidelines address recommendations for the use of smallpox vaccination, cidofovir and VIG in the treatment of human monkeypox infection. They provide recommendations for smallpox vaccination of health care workers, contacts of human monkeypox cases and veterinary workers. They present contraindications to smallpox vaccination and describe the treatment options for immunocompromised patients.)

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