Monkeypox (Mpox)

Practice Essentials

In 1970, when smallpox was nearly eradicated, a previously unrecognized orthopoxvirus named monkeypox (mpox) 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.^[1] 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.^[2]

In the most recent outbreak in 2022, the United Kingdom reported 9 cases of monkeypox in early May 2022, with the first identified case having recently traveled to Nigeria. From this adult index case, there were 2 confirmed transmissions within the patient's family, to another adult and a toddler.^[3]  On May 18, 2022, the Massachusetts Department of Public Health announced a confirmed case of monkeypox in an adult male who had recently visited Canada.^[4]

From 2022 to July 31, 2024, more than 100,000 confirmed cases of mpox, caused by MPXV clade I and II, were reported globally across over 120 countries, resulting in over 200 deaths, according to the WHO's report on the 2022-24 Mpox (Monkeypox) Outbreak: Global Trends.

Cases of monkeypox in the US peaked in early August 2022 with a 7-day moving average of 439. Owing to vaccination and avoidance in at-risk populations, the 7-day average of 48 cases have decreased as of October 19, 2022. 

An overwhelming, though not exclusive, number of cases in the current outbreak are among men who have sex with men.^[8] While sexual transmission has not been definitively confirmed, this mode of transmission seems likely, especially given that initial lesions are often reported at sites of sexual contact.^{[9, 10]}  

In the 2003 US 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 exact potential for human-to-human transmission and human-to-animal transmission remains unknown.

Note the image below.

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Vesicular rash on the dorsal aspect of the hand. Vesicopustules are seen; some have a central umbilication.

In July 2021, a case of monkeypox was reported in Dallas, Texas in a traveler from Nigeria.^{[11, 12]} Later, in November of that year, a second US case was confirmed in Maryland in another traveler returning from Nigeria.^{[11, 13]}  These 2 cases represent the only reported incidents of monkeypox in the US during 2021. 

Etiology

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. Consumption of such so-called "bush meat" is particularly hazardous because the flesh is often undercooked. Because of the diversity of animals eaten by local inhabitants, conclusions about the relative risk of meat sources are not known with certainty.

Also see Etiology.

Prognosis

Mortality rates ranging from 1-10% have been reported in Africa, but no fatalities occurred in the United States 2003 outbreak.

Also see Prognosis.

History and physical examination

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

Transmission can occur from contact with ill animals or animal reservoirs from Western Africa (eg, prairie dogs, rabbits, rats, mice, squirrels, dormice, monkeys, porcupines, gazelles). Additionally, preparing or ingesting infected animals can transmit monkeypox infection. Finally, direct cutaneous (skin-to-skin) or respiratory contact with an animal or person who is infected can transmit the infection.

The incubation period averages 12 days, ranging from 4-20 days.

In the prodromal or preeruptive stage (lasts 1-4 days prior to the onset of rash),^[14]  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.

In the 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. However, in the current outbreak, painless anogenital lesions — often without a prodrome — are being observed in persons who have had close contact with an infected person or persons, including men who have sex with men.^[15]

Encephalitis with immunoglobulin M (IgM) found in the cerebrospinal fluid has been reported.^[16]

The most reliable clinical sign differentiating monkeypox from smallpox and chickenpox is enlarged lymph nodes, especially the submental, submandibular, cervical, and inguinal nodes.^[17]

Also see Physical Examination.

Complications

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

Diagnostics

On November 15, 2002, the United States Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for the cobas MPXV to detect monkeypox virus DNA in swabs from human monkeypox lesions in patients with suspected monkeypox cases.^[18]

Refer to the information established by the US Centers for Disease Control and Prevention (CDC) at Monkeypox: Clinical Recognition.

Also see Workup.

Treatment

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 2003 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.

In September 2019, the US Food and Drug Administration (FDA) approved an attenuated, live, nonreplicating smallpox and mpox (monkeypox) vaccine (Jynneos) for immunization of adults at high risk for smallpox or mpox infection.^{[19, 20]}  It also has an emergency use authorization (EUA) for use in children. 

Another poxvirus vaccine (ACAM2000) gained FDA approval for mpox in 2024.

Also see Clinical management and infection prevention and control for monkeypox: Interim rapid response guidance, 10 June 2022 from the World Health Organization (WHO).

Also see Treatment and Medication.

• References

Pathophysiology

The monkeypox (mpox) virus is a member of the genus orthopox (family Poxviridae); other members include cowpox, vaccinia, and variola (smallpox) viruses.^[21] 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.^{[22, 23]} A 2010 study reaffirmed that several species of forest-dwelling rodents are at risk for orthopoxvirus (including monkeypox) infection. People living in or near the forested areas may have indirect or low-level exposure, possibly leading to subclinical infection.^[24]

Secondary, or human-to-human, disease transmission was found to be another possible route in an outbreak in the DRC in 1996-1997.^[23] 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. However, in the 2003 US outbreak, clear exposure to an infected animal could not be identified in 1 case, and, therefore, human-to-human transmission could not be excluded.

Human-to-human transmission has been confirmed as a major factor in the 2022 outbreak in multiple areas across the world. While many of the patients are men who have sex with men, sexual transmission of monkeypox has not been conclusively confirmed but appears likely.^{[8, 9, 10]}

• References

Etiology

In the DRC in 1997, animals caught from the wild were tested for the monkeypox (mpox) 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).^[23]

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.

• References

Epidemiology

Frequency

United States

In the most recent oubreak, a single confirmed case was identified May 18, 2022 in Massachusetts.^{[4, 11, 13]}  As of June 29, 2022, there were 351 confirmed cases in nearly 30 states.^[6]  By March 7, 2023, there had been 30,235 reported cases in the US and 38 mpox-associated deaths.^[7]

During the 2003 outbreak, no cases occurred in the United States until the late spring in the Midwestern states. Between May 16 and June 20, 2003, 71 suspected cases of monkeypox (mpox) were investigated.^[25] A total of 47 individuals were identified with confirmed (n = 37) or probable (n = 10) monkeypox virus infection. Monkeypox cases were confirmed on the basis of virus isolation or detection of the virus by polymerase chain reaction (PCR) from a clinical specimen (eg, skin biopsy or throat culture). Individuals who presented with fever and rash within 21 days of exposure to monkeypox and had serum positive for orthopox immunoglobulin M (IgM), but did not have culture- or PCR-positive clinical specimens, were classified as having a probable case of infection.^{[26, 27]}  

International

This condition is rare and only known to be indigenous to the rain forests of western and central Africa.^[28] 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 1000 population. 

The 2022 outbreak involved 51 locations as of June 29, 2022, and included 5,115 confirmed cases.^[5]   

Human infection with monkeypox has not been reported in West Africa since 1978. Monkeypox is considered endemic in northern and central DRC. Sporadic occurrences of disease are reported in neighboring countries.^[29] In 2003, 11 cases and 1 death were reported from the DRC and 10 cases with no deaths were reported from Sudan in 2005.^[30]

In 2009, interethnic violence in northwestern DRC lead to an influx of refugees into the Republic of the Congo (ROC). The United Nations International Children's Emergency Fund (UNICEF) sponsored a program of intensive community education in the refugee settlements that included modules on monkeypox recognition and prevention, which resulted in the indentification of 10 suspected cases of monkeypox. Seven of these 10 cases were tested and 2 were found to be positive by polymerase chain reaction assays.^[31]

The results of this outreach campaign suggest that intensive community education can lead to increased capacity for detection of monkeypox in high transmission–risk settings. They also highlight the need to educate physicians in the recognition and treatment of monkeypox.^[32]

Race, sex, and age

Poxvirus infections have no racial predilection, and the incidence is equal in males and females, except in the 2022 epidemic, where patients are overwhelmingly male. A survey of 528 infections confirmed from April 27, 2022 to June 24, 2022, in 16 countries found that 98% of patients were men who have sex with men, 75% were White, and 41% were HIV positive. The median patient age was 38 years.^[33]

A morbidity and mortality report from the US Centers for Disease Control and Prevention revealed that, in the 2022/2023 outbreak, there were 38 mpox-related deaths (1.3 per 1000 cases). Men represented 94.7% of mortalities, with 86.8% of mortalities being Black persons. The overwhelming majority of those who succumbed were immunocompromised secondary to HIV infections. The median patient age at death was 34 years.^[7]  

In the African epidemics, 90% of the patients were children younger than 15 years.^[34] In the 2003 US outbreak, of the confirmed cases (n = 35), 11 patients were younger than 18 years and 24 were older. Although the highest age-specific incidences and the greatest number of cases occur among persons younger than 15 years, a trend toward increasing incidence among persons aged 15-30 years has been seen in recent years. It has been hypothesized that cessation of smallpox vaccination may be a factor in the increasing incidence in this age group, but this theory fails to account for why the disease has not reemerged in countries where the disease was seen previously, such as West Africa.^[30]

• References

Prognosis

Mortality rates ranging from 1-10% have been reported in Africa, but no fatalities occurred in the United States 2003 outbreak. 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.

There were 38 mpox-related death in the US during the 2022/2023 outbreak.^[7]

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.^[35]

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.^{[36, 37]} With the 2003 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.^[38]

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.

Genomic sequencing of US, western African, and central African monkeypox (mpox) isolates have confirmed the existence of 2 distinct monkeypox clades.^[39] The isolates from the United States were identical to the western African isolates. The disease course for individuals infected with the western African isolates is milder with less human-to-human transmission than for those infected with isolates from central Africa.^[40] In 2010, a dosage comparison using a prairie dog animal model reconfirmed that the clade I (formerly known as the Congo Basin or Central African clade) of monkeypox virus is more virulent than the clade II (formerly the West African clade) of monkeypox virus.^[41]

• References

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 Centers for Disease Control and Prevention (CDC) and the US Food and Drug Administration (FDA) 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 species), rope squirrels (Funisciurus species), dormice (Graphiurus species), Gambian giant pouched rats (Cricetomys species), brush-tailed porcupines (Atherurus species), and striped mice (Hybomys species).

Investigation of the exotic pet industry by state and federal authorities was triggered by the 2003 outbreak. The FDA lifted its restrictions on pet prairie dogs in 2008. The FDA consulted with the CDC and determined that the domestic restrictions placed on certain African rodents, prairie dogs, and certain other animals were no longer needed. However, the CDC restriction on the importation of all African rodents remains in effect to prevent any reintroduction of the monkeypox virus into the United States.^[42]

Patients, especially those who are immunocompromised, should be counselled to avoid risky behaviors such as condomless sex and educated on monkeypox (mpox) signs and symptoms.^[9]

• References

Physical Examination

The most reliable clinical sign differentiating monkeypox (mpox) from smallpox and chickenpox is enlarged lymph nodes, especially the submental, submandibular, cervical, and inguinal nodes.^[17] Note the image below.

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Lymphadenopathy in monkeypox. Large nodes in the mandibular, cervical, or inguinal region are commonly seen in monkeypox. The presence of significant ....

The 2022 outbreak has produced atypical symptoms when compared to previous monkeypox outbreaks.^[9] These symptoms may include:

• Scant or even single lesions or even the complete absence of skin lesions
• Lesions mostly confined to the genital and perianal areas, presenting with anal pain and bleeding
• Lack of prodromal symptoms, such as fever, myalgias, fatigue, and headache before the appearance of a rash

Some patients experience herald cutaneous lesions at the point of sexual contact prior to further symptoms.

Previous outbreaks

With regard to enanthema, nonspecific lesions and inflammation of the pharyngeal, conjunctival, and genital mucosae have been observed.

In the exanthema stage, 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.

Note the image below.

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Umbilicated papule on the lower part of the leg. This smaller lesion still shows the typical umbilicated morphology.

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.^[34]

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. 

Ocular monkeypox

Ocular monkeypox is a potentially sight-threatening infection and requires urgent assessment and treatment. Signs and symptoms include vision changes, eye pain, itching, redness, swelling, and foreign body sensation. Clinicians should consider prompt initiation of treatment with systemic antiviral therapy, in addition to trifluridine ophthalmic drops in patients with ocular manifestations. 

• References

Diagnostic Criteria

The diagnostic criteria are summarized below; refer to the current criteria established by the CDC at Monkeypox: Clinical Recognition.

Confirmed case

Meets 1 or more of the following laboratory criteria:

• Isolation of the monkeypox (mpox) 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

This is contact that meets current epidemiologic criteria per the CDC. It is the occurrence of 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

This is contact that meets current epidemiologic criteria per the CDC. It the occurrence of 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. Symptoms are as follows:

• Chills and/or sweats
• Lymphadenopathy
• Sore throat
• Cough
• Shortness of breath
• Headache
• Backache

• References

Laboratory Studies

On November 15, 2002, the US FDA issued an EUA for the cobas MPXV to detect monkeypox (mpox) virus DNA in swabs from human monkeypox lesions in patients with suspected monkeypox cases.^[18]

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.^[43]

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.^[26]

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.

A pilot of the Tetracore Orthopox BioThreat Alert provided promising results using lesion specimens from acute Orthopoxvirus infections. This assay correctly identified 5 of 6 clinical specimens tested. Although not specific for monkeypox virus, this assay could be used in monkeypox-endemic areas for Orthopoxvirus confirmation by proxy.^[44]

• References

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.^[45] Inclusions are consistent with orthopox viruses, permitting differentiation from parapox and herpes viruses.

• References

Medical Care

Also see Guidelines.

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 2003 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 Infection Prevention and Control of Monkeypox in Healthcare Settings.

Isolation must be continued until the last crust is shed. 

Also see, CDC Monkeypox resources for healthcare professionals

Antiviral Agents

Tecovirimat 

Tecovirimat (TPOXX) is approved by the FDA and is indicated for treatment of human smallpox disease caused by variola virus. Also, the CDC holds an expanded access investigational new drug (EA-IND), also called compassionate use, that allows for the use of stockpiled tecorvirimat to treat monkeypox (mpox) during an outbreak. Tecovirimat is stockpiled by the US federal Strategic National Stockpile, but administration of the drug is under an IND exemption application.^{[46, 47]}  Preliminary data from two randomized clinical trials (PALM007 [NCT05559099] and STOMP [NCT05534984]) aimed at evaluating the effectiveness and safety of tecovirimat for treating mpox indicated that although tecovirimat is safe, it did not shorten the duration for mpox lesions to heal. Tecovirimat remains available to certain high risk patient populations

Cidofovir 

Data on the effectiveness of cidofovir in human cases of monkeypox are not available. It is indicated for cytomegalovirus in the United States. Although cidofovir has proven activity against poxviruses in in vitro  and animal studies, it is not known whether or not a patient with severe monkeypox infection will benefit from treatment. The CDC holds an EA-IND that allows for the use of stockpiled cidofovir for the treatment of orthopoxviruses (including monkeypox) in an outbreak.^[46]  

Brincidofovir

Brincidofovir (Tembexa) is indicated for treatment of smallpox caused by virola virus in adults and children, including neonates. Brincidofovir is a prodrug of cidofovir diphosphate. Cidofovir diphosphate selectively inhibits orthopoxvirus DNA polymerase-mediated viral DNA synthesis. Brincidofovir may have an improved safety profile over cidofovir as severe renal toxicity or other adverse events have not been observed during treatment of cytomegalovirus infections with brincidofovir in comparison to treatment using cidofovir. The CDC is currently developing an EA-IND for to help facilitate use of brincidofovir as a treatment for monkeypox.^{[46, 47]}  

Vaccinia immune globulin (VIG)

Data are not available on the effectiveness of VIG in treatment of monkeypox complications. Use of VIG is administered under an EA-IND for treatment of orthopoxviruses (including monkeypox) in an outbreak. It is not known whether a patient with severe monkeypox infection will benefit from VIG treatment.

VIG can be considered for prophylactic use in a monkeypox-exposed person with severe immunodeficiency in T-cell function for which smallpox vaccination following monkeypox exposure is contraindicated.^[46]

Treatment of ocular monkeypox

Patients with monkeypox can experience serious ocular complications. Cases of monkeypox are mostly self-limited; however, lesions that involve anatomically vulnerable sites can cause complications. Ocular monkeypox may occur when the virus is introduced into the eye, most typically from autoinoculation. Ocular infection can potentially cause conjunctivitis, blepharitis, keratitis, and vision loss. 

Clinicians should consider prompt initiation of systemic antiviral therapy in addition to topical trifluridine in patients with ocular manifestations. Patients with ocular monkeypox, including those with HIV-associated immunocompromise, have experienced delays in treatment initiation, prolonged illness, hospitalization, and vision impairment The CDC emphasizes the importance of reducing the risk of ocular complications by practicing good hand hygiene and to instruct patients with ocular monkeypox to avoid touching their eyes and refrain from using contact lenses.^[48]  

• References

Prevention

Immunization

In September 2019, the FDA approved an attenuated, live, nonreplicating smallpox and monkeypox (mpox) vaccine (Jynneos) for immunization of adults at high risk for smallpox or monkeypox infection. Approval was determined in a clinical study comparing the immune responses in study participants who received either Jynneos or ACAM2000, an FDA-approved vaccine for the prevention of smallpox. The study included approximately 400 healthy adults, aged 18-42 years who had never been vaccinated for smallpox. Half of the study participants received 2 doses of Jynneos administered 28 days apart, and half received 1 dose of ACAM2000. The group vaccinated with Jynneos had an immune response that was not inferior to immune responses to ACAM2000.^{[19, 20, 47]}  

The FDA granted emergency use authorization (EUA) August 9, 2022 for Jynneos to expand vaccine supply by administering a 0.1-mL intradermal dose to adults. The EUA also expands use to include children aged 18 years and younger to receive the subcutaneous 0.5-mL dose. 

Another poxvirus vaccine (ACAM2000) gained FDA approval for mpox in 2024.    

Individuals who should receive vaccine

The Advisory Committee on Immunization Practices (ACIP) recommends that people whose jobs may expose them to orthopoxviruses, such as monkeypox, get vaccinated with either ACAM2000 or monkeypox vaccine to protect them if they are exposed to an orthopoxvirus.^[49]  

In October 2024, the Advisory Committee on Immunization Practices (ACIP) approved the Recommended Immunization Schedule for Adults Ages 19 Years or Older, United States, 2025. The language regarding the vaccination of health care personnel was updated to clarify that vaccination to mitigate occupational risks in health care settings is not routinely recommended.

Widespread vaccination during the 2022 outbreak is not recommended; however, the CDC recommends vaccination for individuals who have been exposed to monkeypox and those who may be more likely to become infected.

People more likely to get monkeypox include:

• People identified by public health officials as a contact of someone with monkeypox 
• People who are aware that one of their sexual partners in the past 2 weeks was diagnosed with monkeypox 
• People who had multiple sexual partners in the past 2 weeks in an area with known monkeypox 

People whose jobs may expose them to orthopoxviruses, such as: 

• Laboratory workers who perform testing for orthopoxviruses 
• Laboratory workers who handle cultures or animals with orthopoxviruses 
• Some designated healthcare or public health workers 

Immunization following exposure 

CDC recommends that the monkeypox vaccine be given within 4 days from the date of exposure in order to prevent onset of the disease. If given between 4-14 days after the date of exposure, vaccination may reduce the symptoms of disease, but may not prevent the disease.^[49]  

A 2010 report describes experimental low-dose intranasal infection in a STAT1-deficient C57BL/6 mouse model that caused 100% mortality. However, vaccination with modified vaccinia virus Ankara, followed by a booster vaccination, was protective against intranasal infection and produced a more vigorous immune response compared with a single vaccination.^[50]  Other mouse models are being used to investigate monkeypox pathogenesis, disease progression, viral shedding, and virulence, with the possible aim of testing antivirals and next-generation vaccines.^[51]  

Animal importation

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. 

• References

Long-Term Monitoring

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 Infection Prevention and Control of Monkeypox in Healthcare Settings.

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Guidelines Summary

Clinical guidance on monkeypox (mpox) and smallpox vaccination was updated in June 2022 by the US Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP).^[49]

ACIP recommends that individuals with occupations that may expose them to orthopoxvirus diseases receive pre-exposure prophylaxis with either Jynneos or ACAM2000. Examples of such occupations include healthcare workers as designated by public health authorities, clinical laboratory personnel directly involved with orthopoxvirus testing, and research laboratory personnel handling orthopoxvirus cultures.

If a person is exposed to monkeypox virus and has not received smallpox vaccination within the last 3 years, the CDC recommends administration of Jynneos within 4 days of exposure. Vaccination may mitigate symptoms without preventing the disease if received within 4-14 days of exposure.

Persons with HIV Infection 

CDC has developed clinical considerations for prevention and treatment of monkeypox in persons with HIV infection, including pre-exposure and postexposure prophylaxis with Jynneos vaccine, treatment with tecovirimat, and infection control. The 2022 outbreak disproportionately affected gay, bisexual, and other men who have sex with men.^[8]   

Antiretroviral treatment and opportunistic infection prophylaxis should be continued in all persons with HIV infection who acquire monkeypox. The safety and immunogenicity of Jynneos have been specifically evaluated in persons with HIV infection. Clinical trials demonstrate that Jynneos is well-tolerated with similar immunogenicity and rates of adverse events in persons with HIV infection with CD4 cell counts of 200-750/μL and persons without HIV infection.^[52]  

Because ACAM2000 contains a replication-competent, attenuated strain of vaccinia virus, severe localized or systemic complications of ACAM2000 (e.g., progressive vaccinia) can occur in persons with weakened immune systems, including from HIV infection.^[53]  

Tecovirimat is the first-line medication recommended for treatment of monkeypox, including among persons with HIV infection.^[8]  

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Medication Summary

The CDC recommends a smallpox or smallpox/monkeypox (mpox) vaccination within 2 weeks of exposure, ideally within 4 days, for exposed health care workers and household contacts of confirmed cases. Antiviral agents (ie, tecovirimat, brincidofovir, cidofovir) are possible treatment options in severe, life-threatening cases.^{[54, 55]} These agents may be used under an expanded access investigational new drug (EA-IND) available from the CDC.^{[46, 47]}  Additionally, vaccinia immune globulin (VIG) may be considered, but has not demonstrated efficacy as either treatment or prophylaxis.^{[46, 47]} Smallpox preparedness research has led to the development of new antiviral agents for the treatment of orthopoxvirus infections. 

In September 2019, the FDA approved an attenuated, live, nonreplicating smallpox and mpox vaccine (Jynneos) for immunization of adults at high risk for smallpox or mpox infection.^{[19, 20, 47]}  

The FDA granted emergency use authorization (EUA) August 9, 2022 for Jynneos to expand vaccine supply by administering a 0.1-mL intradermal dose to adults. The EUA also expands use to include children aged 18 years and younger to receive the subcutaneous 0.5-mL dose. 

Another poxvirus vaccine (ACAM2000) gained FDA approval for mpox in 2024.   

Also see further vaccine information under Medical Care.

• References

Tecovirimat (TPOXX)

• Dosing, Interactions, etc.

Clinical Context:  Antiviral agent indicated for treatment of human smallpox disease caused by variola virus in adults and children who weigh at least 13 kg. It is available under an expanded access (ie, compassionate use) investigational new drug protocol for adults and children (weighing at least 6 kg) for treatment of mpox. 

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Cidofovir

• Dosing, Interactions, etc.

Clinical Context:  Cidofovir is a nucleotide analog that selectively inhibits viral DNA production in CMV and other herpes viruses.

• References

Brincidofovir (Tembexa)

• Dosing, Interactions, etc.

Clinical Context:  Indicated for treatment of human smallpox disease caused by variola virus in adult and pediatric patients, including neonates.

• References

Class Summary

Tecovirimat may be used under an expanded access investigational new drug (EA-IND) available from the CDC. Cidofovir and brincidofovir have proven activity against poxviruses in in vitro and animal studies, but only cidofovir is currently available either commercially or from the Strategic National Stockpile. 

• References

Smallpox and mpox vaccine, live, nonreplicating (Jynneos)

• Dosing, Interactions, etc.

Clinical Context:  August 9, 2022: Emergency use authorization (EUA) granted by FDA to expand vaccine supply by administering a 0.1-mL intradermal dose to adults. The EUA also expands use to include children aged 18 years and younger to receive the subcutaneous 0.5-mL dose.    

This vaccine is derived from a vaccinia virus, a virus that is closely related to, but less harmful than, variola and mpox viruses and can protect against both of these diseases. It is indicated for prevention of smallpox and mpox disease in adults who are at high risk for smallpox or mpox infection. It is administered as a 2-dose series administered 4 weeks apart.

• References

Smallpox and mpox (vaccinia) vaccine, live (ACAM2000)

• Dosing, Interactions, etc.

Clinical Context:  Indicated for active immunization for prevention of smallpox and mpox disease in individuals determined to be at high risk for infection.

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Class Summary

Vaccinia vaccine promotes active immunity against the smallpox virus by inducing specific antibodies. Currently available stocks of vaccinia vaccine were derived from the vaccinia strain maintained at the New York Board of Health. Wyeth Laboratories manufactured the last batches of the vaccine (Dryvax) in the early 1980s. These batches were made by using the calf lymph method, and they were lyophilized but are no longer available.

Several attenuated vaccinia vaccine candidates are undergoing investigation, with ACAM2000 receiving FDA approval as a replacement for Dryvax. It was approved for mpox in 2024. Another vaccine (smallpox [vaccinia] and mpox vaccine, live, nonreplicating [Jynneos]) has also been approved by the FDA for immunization of adults at high risk for smallpox or mpox infection.

New, cell-derived lots of vaccinia appear to have adverse effect profiles similar to the older, calf lymph–derived lots.

Primary immunization as soon as possible after exposure or at the first sign of infection is indicated for the prevention and management of smallpox. Currently, US military personnel, US Department of Defense civilian employees, and health care professionals are recommended candidates to receive the vaccination because they will likely be at highest risk in case of a biologic attack (eg, bioterrorism).

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Trifluridine ophthalmic (Viroptic)

• Dosing, Interactions, etc.

Clinical Context:  Fluorinated pyrimidine nucleoside with in vitro and in vivo activity against herpes simplex virus, types 1 and 2 and vacciniavirus. It is approved by the FDA for treatment of primary keratoconjunctivitis and recurrent epithelial keratitis due to herpes simplex virus, types 1 and 2. The CDC recommend off-label use for mpox ocular infections. 

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Class Summary

Clinician should consider prompt initiation of systemic antiviral therapy in addition to topical trifluridine in patients with ocular manifestations.

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