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Oct.18.2022

Monkeypox

Synopsis

Key Points

  • Monkeypox is a zoonotic viral disease spread via direct contact, respiratory secretions, and contaminated materials and surfaces r1r2r3r4
  • Monkeypox classically presents with rash, fever, lymphadenopathy, and a clinical course similar to that of smallpox but milder r3r5r6
  • Monkeypox is caused by monkeypox virus, which belongs to the Orthopoxvirus genus of the Poxviridae family; other members of Orthopoxvirus include variola virus (which causes smallpox), vaccinia virus (used in smallpox vaccines), cowpox virus, and various other animal poxviruses r1
  • WHO has proposed renaming the monkeypox disease and virus, in accordance with current best practices for naming infectious diseases; although no consensus has emerged yet, some alternative names currently in limited use include Mpox, MPV, MPX, MPXV, and hMPXV r7r8
  • Monkeypox is endemic in several African countries, and until 2022, nearly all reported cases arose in Africa, with rare sporadic cases elsewhere; in 2022, a multi-country outbreak arose in nonendemic countries, including the United States, with atypical clinical presentations and most cases identified in men who have sex with men r3r9
    • US has declared the ongoing 2022 multi-country outbreak a public health emergency; CDC provides frequent updates online regarding the domestic outbreak situation r10
    • WHO has declared the 2022 multi-country outbreak a public health emergency of international concern, and provides frequent updates online regarding the international outbreak situation r9
    • Although the 2022 multi-country outbreak is ongoing, case counts in the United States and worldwide have steadily declined in recent months (as of October 2022) r9r11
  • Monkeypox should be considered in a patient with appropriate clinical features, especially rash, and epidemiologic risk factors for recent monkeypox exposure; close person to person contact, especially intimate and sexual contact, has been identified as the primary mode of exposure in 2022 outbreak cases r12r13
  • Classically, there are prodromal symptoms of fever, chills, headache, myalgias, arthralgias, fatigue, and lymphadenopathy, with characteristic rash first appearing within several days of fever; in 2022 outbreak cases these symptoms may be very mild, be absent altogether, be concurrent with rash, or even develop after rash first appears r14r15r16r17
  • Rash is invariably present in monkeypox, with skin lesions that are typically deep-seated, well-demarcated, and umbilicated; initial lesions in mucosal regions (oral, genital, perianal) have been common in 2022 outbreak cases r15r18
  • Monkeypox is diagnosed via laboratory detection of monkeypox virus in the setting of appropriate epidemiologic risk factors and clinical findings
  • Diagnostic testing for monkeypox should be undertaken in consultation with public health authorities and may consist of either generic orthopox or monkeypox-specific real-time polymerase chain reaction testing of lesion material from swabs; laboratories may forward specimens from positive cases to CDC for further viral characterization and sequencing r14r19
  • Differential diagnosis for monkeypox includes other, more common causes of localized genital lesions and rash; the overall clinical features of monkeypox are similar to those of smallpox, which has been eradicated worldwide
  • Most patients with monkeypox have mild, self-limited disease that can be managed with supportive care; antiviral medications can be considered for patients with severe disease, high risk of severe disease, and infection involving high-risk anatomic areas r20
  • Currently there are no treatments approved specifically for monkeypox virus infection, but several antiviral agents originally developed for treatment of smallpox and other viral infections may be considered r20
  • Complicated disease may affect nearly any organ system and result in substantial morbidity and even death; disease course is more severe in persons with immunocompromise, most notably HIV
  • Monkeypox case fatality rates of 3% to 6% have previously been reported in African countries where the disease is endemic; the estimated case fatality rate associated with the 2022 multi-country outbreak has been substantially lower, at approximately 0.03% r3r9
  • Infection control measures, in both health care and home settings, are vital to minimize exposure and infection risk; they include appropriate isolation, hygiene measures, and use of personal protective equipment r21r22
  • Exposed persons should be monitored for symptoms and have an exposure risk assessment performed; postexposure prophylaxis with smallpox vaccination is recommended for high-risk exposures and can be considered for intermediate-risk exposures r23r24
  • One vaccine (Jynneos) is licensed in the United States for prevention of monkeypox and smallpox, and another (ACAM2000) is licensed for prevention of smallpox but considered effective for prevention of monkeypox as well; vaccination is recommended as preexposure prophylaxis for certain persons at ongoing significant risk for monkeypox exposure and can be used as postexposure prophylaxis for persons who have had recent confirmed or likely high-risk or intermediate-risk exposures r23r24
  • CDC Emergency Operations Center (telephone, 1-770-488-7100) is available for consultation regarding appropriate utilization of medical countermeasures for monkeypox and can facilitate obtaining antiviral medications and vaccines from the National Strategic Stockpile

Urgent Action

  • Clinicians should be vigilant for rash that may be consistent with monkeypox, particularly in patients with established high-risk epidemiologic features (ie, contact with someone with similar rash or confirmed monkeypox diagnosis, close contact with people in a social network with monkeypox activity, history of recent international travel to country with confirmed cases) r12r18
  • Suspected monkeypox cases should be reported to relevant hospital and local and state public health authorities (to facilitate necessary reporting and further diagnostic and management steps)

Pitfalls

  • Monkeypox cases in the ongoing 2022 outbreak event have had atypical clinical features, including absence of classic prodromal symptoms (including fever and lymphadenopathy) and predilection for initial lesions to appear in the genital and perianal regions r15
  • Monkeypox lesions in the genital and perianal regions can be easily confused with sexually transmitted infections by patients and clinicians alike, and therefore patients may initially present to outpatient settings such as sexual health clinics for care; coinfections with monkeypox and sexually transmitted diseases have been reported, and presence of a sexually transmitted infection does not preclude monkeypox r15r25

Terminology

Clinical Clarification

  • Monkeypox is a zoonotic viral disease spread via direct contact, respiratory secretions, and contaminated materials and surfaces r1r2r3r4
  • Monkeypox classically presents with rash, fever, lymphadenopathy, and a clinical course similar to that of smallpox but milder r3r5r6r26
  • Monkeypox is caused by monkeypox virus, which belongs to the Orthopoxvirus genus of the Poxviridae family; other members of Orthopoxvirus include variola virus (which causes smallpox), vaccinia virus (used in smallpox vaccines), cowpox virus, and various other animal poxviruses r1r2r4
  • Monkeypox is so named as it was first detected in monkeys; the natural host reservoir remains unknown, but rodents and other small mammals are most frequently implicated r1r2r4
  • WHO has proposed renaming the monkeypox disease and virus, in accordance with current best practices for naming infectious diseases and pathogens; although no consensus has emerged yet, some alternative names currently in limited use include Mpox, MPV, MPX, MPXV, and hMPXV r7r8
  • Monkeypox is endemic in several African countries, and until 2022, nearly all reported cases arose in Africa, with rare sporadic cases elsewhere; in 2022, a multi-country outbreak arose in nonendemic countries, including the United States, with atypical clinical features and most cases identified in men who have sex with men r9
    • First known significant outbreak of human monkeypox in the United States was in 2003 and involved 47 confirmed and probable cases that were traced to infected pet prairie dogs; no more outbreaks occurred in the United States until the 2022 outbreak r5r6
    • US has declared the ongoing 2022 multi-country outbreak a public health emergency; CDC provides frequent updates online regarding the domestic outbreak situation r10
    • WHO has declared the 2022 multi-country outbreak a public health emergency of international concern; it provides frequent updates online regarding the international outbreak situation r9
    • Although the 2022 multi-country outbreak is ongoing, case counts in the United States and worldwide have steadily declined in recent months (as of October 2022) r9r11
  • Monkeypox case fatality rates of 3% to 6% have previously been reported in African countries where the disease is endemic; the estimated case fatality rate associated with the 2022 multi-country outbreak has been substantially lower, at approximately 0.03% r3r9

Classification

  • CDC case definitions r12
    • Suspect case
      • New rash characteristic of monkeypox or
      • Meets 1 epidemiologic criterion within 21 days of symptom onset and high clinical suspicion for monkeypox
    • Probable case
      • Criteria met for suspect case and
      • No other known recent orthopoxvirus exposure (eg, via smallpox vaccination) and
      • Orthopoxvirus infection confirmed by one of the following:
        • Detection of orthopoxvirus DNA by polymerase chain reaction testing of a clinical specimen or
        • Presence of orthopoxvirus demonstrated by immunohistochemistry or electron microscopy or
        • Detection of anti-orthopoxvirus IgM antibody between 4 and 56 days after rash onset
      • CDC has stated that for the ongoing 2022 outbreak, all confirmed orthopoxvirus infection cases in the United States are presumed to be monkeypox unless proven otherwise r15
    • Confirmed case
      • Criteria met for suspect case and
      • Monkeypox infection confirmed by one of the following:
        • Detection of monkeypox virus DNA by polymerase chain reaction testing or next-generation sequencing of a clinical specimen or
        • Isolation of monkeypox virus in culture from a clinical specimen
  • WHO case definitions for the ongoing 2022 multi-country outbreak event are slightly different, as follows: r27
    • Suspected case
      • Known contact with probable or confirmed monkeypox case within 21 days of developing any of the following symptoms:
        • Acute onset of fever
        • Headache
        • Myalgia
        • Back pain
        • Lymphadenopathy
        • Profound weakness
      • Or presentation with unexplained acute rash, mucosal lesions, or lymphadenopathy that cannot be explained by other common causes of rash
    • Probable case
      • Unexplained acute rash, mucosal lesions, or lymphadenopathy and
      • One or more of the following:
        • Confirmed epidemiologic connection to a probable or confirmed monkeypox case within 21 days of symptom onset
        • Patient identifies as gay, bisexual, or other man who has sex with men
        • Multiple or casual sexual partners within 21 days of symptom onset
        • Detection of anti-orthopoxvirus IgM antibody between 4 and 56 days after rash onset, or a four-fold rise in IgG antibody titers based on acute samples (up to days 5-7) and convalescent samples (after day 21), in the absence of other known orthopoxvirus exposure (eg, via smallpox vaccination)
        • Confirmed orthopoxvirus infection (eg, via polymerase chain reaction or sequencing)
    • Confirmed case
      • Criteria met for suspected or probable case
      • Laboratory confirmation of monkeypox infection via real-time polymerase chain reaction or sequencing of monkeypox viral DNA

Diagnosis

Clinical Presentation

History

  • Monkeypox should be considered in a patient with appropriate clinical features, especially rash, and epidemiologic risk factors for recent monkeypox exposure; close person to person contact, especially intimate and sexual contact, has been identified as the primary mode of exposure in 2022 outbreak cases r12
  • Epidemiologic history
    • Presence of one of the following high-risk epidemiologic features within 21 days of illness, in conjunction with clinical suspicion, can establish a suspect case of monkeypox per CDC case definitions: r12
      • Contact with another case or cases with a similar rash or diagnosis of confirmed or probable monkeypox or
      • Close or intimate in-person contact with persons in a social network experiencing monkeypox activity, such as men who have sex with men or
      • Travel outside the United States to a country with confirmed monkeypox or where monkeypox virus is endemic or
      • Contact with a wild animal or exotic pet that is an African endemic species, or use of a product from such an animal
  • Clinical history r16r17
    • Incubation period ranges from 3 to 17 days; patients are not contagious and may be asymptomatic during this time r25
    • Initial prodromal symptoms are nonspecific and may include fever, chills, malaise, headache, myalgia, respiratory symptoms, weakness, and lymphadenopathy; patients may be contagious during this period
    • Although prodromal symptoms preceding rash are typical of classic endemic monkeypox, atypical clinical presentations are common in 2022 outbreak cases; these symptoms may be very mild, be absent altogether, be concurrent with rash, or even develop after rash first appears r14r15r16r17
      • Of 2022 outbreak cases reported to CDC, aside from rash, the symptoms reported most frequently during the course of illness are fever (66%), malaise (65%), chills (62%), pruritus (60%), headache (58%), lymphadenopathy (57%) and myalgia (56%) r11r28
    • Rash is invariably present in monkeypox infection; absence of rash within 5 days of illness onset rules out monkeypox r12
      • Rash typically develops within several days of fever, but it can also be the initial symptom, without fever or other prodromal symptoms, or even be the only apparent symptom of infection r15r16r17
      • Although initial rash on the face or in the oral cavity is commonly described in classic endemic monkeypox; initial rash in mucosal regions (oral, anal, genital) is more typical of 2022 outbreak cases r29r30
      • Classic endemic monkeypox lesions tend to develop and evolve together on any given part of body (such as face or genitals); asynchronous evolution has been noted in 2022 outbreak cases r30r31
      • Lesions evolve through macular, papular, vesicular, and pustular morphologies before scabbing over and resolving
      • Lesions can be extremely painful until they heal
      • Patients are contagious until all lesions have scabbed over and healed with a fresh layer of intact skin
    • Rectal symptoms can result from perianal lesions; these can be severe and can be the presenting complaints, particularly if lesions elsewhere are not readily visible r29r30
      • Of 2022 outbreak cases reported to CDC, the most frequently reported rectal symptoms include rectal pain (40%), rectal bleeding (23%), tenesmus (20%), and proctitis (15%) r28
    • Clinical course is similar to that of smallpox, but familiarity with smallpox has waned in era of vaccination and subsequent smallpox eradication r25
    • Overall course of illness is typically 2 to 4 weeks

Physical examination

  • Fever
    • Temperature is often between 38.5 °C and 40.5 °C r32
    • Very common in classic endemic monkeypox; present in 66% of 2022 outbreak cases reported to CDC r14
  • Lymphadenopathy r17
    • Very common (90% of cases) in classic endemic monkeypox; present in 57% of 2022 outbreak cases reported to CDC r2r14
    • May be localized or generalized
    • May be unilateral or bilateral
    • Submandibular, cervical, axillary, and inguinal lymph nodes may be involved
    • Enlarged lymph nodes are firm and tender, and they may be painful r32
  • Rash r17
    • Invariably present; absence of rash within 5 days of illness onset effectively rules out monkeypox infection r12
    • Although rash typically follows fever and other prodromal symptoms in classic endemic monkeypox, rash may be the first or only symptom in 2022 outbreak cases r14r15r16r17
    • Initial rash on face is frequently described in endemic monkeypox cases; initial lesions in mucosal regions (oral, genital, perianal) have been more common in 2022 outbreak cases, and proctitis is possible as well r15r18r29
    • CDC has issued a health advisory urging clinicians to be vigilant for rash that may be consistent with monkeypox, especially in patients with epidemiologic risk factors; lesions can be confused with sexually transmitted infections, and therefore patients may present initially to outpatient settings such as sexual health clinics r18
    • Clinicians should undertake a thorough skin and mucosal (oral, genital, perianal) examination for characteristic lesions in patients presenting with potential monkeypox; this examination allows detection of lesions that the patient may not have been aware of r29
    • May be macular, papular, vesicular, or pustular; lesions evolve through this sequence before scabbing over and falling off
    • May be generalized or localized
    • May be discrete or confluent
    • Lesions are typically deep, firm, and well-demarcated; umbilication is often present
    • Lesions are typically around the same size, and with same morphology, on any part of body
    • Rash with nonclassic traits—few small lesions, more limited distribution, and asynchronous evolution on a given part of body—has been noted in 2022 outbreak cases r30r31
      • A large international case series for the 2022 outbreak found that most cases had 10 or fewer lesions, and more than 10% of cases presented with only a single genital ulcer r33
      • Anogenital lesions are especially common in 2022 outbreak cases and have been reported in over 70% of cases in several recent large case series and meta-analyses r33r34r35
    • If disseminated, rash has centrifugal distribution (concentrated on face and extremities)
    • Lesions may be present on palms and soles
    • Scarring and discoloration may remain after scabs have fallen off and healed

Causes and Risk Factors

Causes

  • Monkeypox virus r1r3r4
    • Member of the Orthopoxvirus genus in the Poxviridae family
    • Other members of the Orthopoxvirus genus that can cause diseases in humans include variola virus (smallpox virus), vaccinia virus, and cowpox virus; various other poxviruses cause diseases in animals
    • Monkeypox virus is the foremost orthopoxvirus affecting humans since the global eradication of smallpox r32r36
    • Natural reservoir of monkeypox virus is unknown; despite the name, rodents and other small mammals are implicated much more frequently than monkeys or other primates
    • 2 distinct monkeypox virus genetic groups (clades) have been characterized: clade I (formerly known as Central African or Congo Basin clade) associated with endemic outbreaks, and clade II (formerly known as West African clade), from which the 2022 outbreak appears to originate r2r9r17r37
  • Transmission is via contact with an infected person or animal, or other materials contaminated with the virus r13
    • Virus is believed to enter body via broken skin, mucous membranes, or respiratory tract r2
    • Human to human transmission is primarily through direct or indirect contact with monkeypox lesions, lesion material, respiratory secretions, other bodily fluids, and contaminated surfaces or materials (eg, dishes, utensils, clothing, bedding, linens) r2
    • Direct skin to skin contact, including intimate and sexual contact, has been identified as the primary mode of exposure and transmission in 2022 outbreak cases r33r38
    • Vertical transmission from mother to fetus via the placenta during pregnancy is possible r13
    • Unknown at this time whether semen, vaginal fluids, urine, and feces can propagate infection r13
    • Can also be transmitted from animals via bites or scratches, meat preparation, direct contact with infected animal matter, and indirect contact (eg, bedding)

Risk factors and/or associations

Age
  • 2022 outbreak cases tend to occur at younger ages
    • Median patient age in the United States is 34 years r11
    • Median patient age worldwide is 35 years; male patients aged 18 to 44 years account for 79.5% of cases r9
Sex
  • For 2022 outbreak cases with available sex data, around 97% of cases in the United States, as well as worldwide, have been in males r26r30
Ethnicity/race
  • For 2022 outbreak cases in the United States with ethnicity/race data reported to CDC, approximately 34.7% of patients are Black, 29.8% are White, 29.7% are Hispanic, 3.3% are Asian American, and less than 3% reported as other ethnicity/race; data are missing for many cases r11
Other risk factors/associations
  • Sexual activity, especially male to male sexual contact r15r18r39r40
    • Most cases in the ongoing 2022 outbreak worldwide, including those in the United States, have been in men who identify as gay or bisexual or in other men who have sex with men
      • Early in the course of the US outbreak, per CDC data, a history of recent male to male sexual contact was self-reported in over 98% of male patients for whom such data was available; more recently, this proportion has declined to approximately 75% r11r14
      • Per WHO data, among cases worldwide with reported sexual orientation, 95.2% of patients identified as gay or bisexual or other men who have sex with men; a sexual encounter was implicated in 91% of all transmission events r41
      • A large international case series for the 2022 outbreak, reporting on 528 cases in 16 countries, similarly found that 98% of cases were in gay or bisexual men, with sexual activity implicated in transmission in 95% of persons with infection r33
    • Monkeypox is not considered a sexually transmitted infection in the traditional sense, but it can be spread via close skin to skin contact during sexual activity, including kissing, touching, oral sex, and penetrative sex, and by shared bedding, linens, and clothing r38
    • History of multiple casual sexual encounters or multiple sexual partners further increases risk of exposure and infection r31
  • Sexually transmitted infections
    • Concomitant sexually transmitted infections were reported in 29% of patients diagnosed with monkeypox in a recent large, international case series r33
    • A large case series reporting on 1969 patients with monkeypox in the United States found that 41% had been diagnosed with one or more reportable sexually transmitted infections in the preceding year r42
  • HIV
    • Among 2022 outbreak cases with reported HIV status, 45% of cases worldwide have been positive for HIV; rates in individual countries have ranged from 28% to 51% r26r43
    • A large case series reporting on 1969 patients with monkeypox in the United States found that HIV prevalence was 38% in this population r42
    • Unknown at this time whether HIV per se increases risk of monkeypox infection r43
  • Health care personnel r22
    • Health care personnel are at risk of monkeypox virus entry via their own unprotected skin or mucous membranes, through actions such as:
      • Touching a patient's skin, skin lesions, or bodily fluids
      • Touching contaminated materials such as linens or clothing
      • Allowing their own unprotected clothing to touch patient skin, skin lesions, bodily fluids, or contaminated materials such as linens or clothing
      • Being inside a patient's room or near a patient during aerosol-generating procedures
      • Close, prolonged presence near a patient
    • Degree of real-world risk to health care personnel of acquiring monkeypox after patient exposure appears to be very low; a recent report on 313 US health care personnel exposed to patients with monkeypox during the 2022 outbreak found that despite low adherence with recommended PPE use and postexposure prophylaxis vaccination, none of the monitored health care personnel acquired monkeypox r44
  • General public r21
    • Personal and household contacts are also at risk of monkeypox infection via direct and indirect contact with monkeypox lesions, lesion material, respiratory secretions, other bodily fluids, and contaminated surfaces or materials (eg, dishes, utensils, clothing, bedding, linens)

Diagnostic Procedures

Primary diagnostic tools

  • Monkeypox is diagnosed via laboratory detection of monkeypox virus in the setting of appropriate epidemiologic risk factors and clinical findings
  • CDC has defined a confirmed monkeypox case as: r12
    • Criteria met for suspect case and
    • Monkeypox infection confirmed by one of the following:
      • Detection of monkeypox virus DNA by polymerase chain reaction testing or gene sequencing or
      • Isolation of monkeypox virus in culture from a clinical specimen
    • Suspect case
      • New rash characteristic of monkeypox or
      • Meets one epidemiologic criterion within 21 days of symptom onset and high clinical suspicion for monkeypox exists
    • Epidemiologic criteria
      • Contact with another case or cases with a similar rash or diagnosis of confirmed or probable monkeypox or
      • Close or intimate in-person contact with persons in a social network experiencing monkeypox activity, such as men who have sex with men or
      • Travel outside the United States to a country with confirmed monkeypox or where monkeypox virus is endemic or
      • Contact with a wild animal or exotic pet that is an African endemic species, or use of a product from such an animal
    • Exclusion criteria
      • Alternative diagnosis fully explains illness or
      • A rash does not develop within 5 days of illness onset or
      • High-quality clinical specimens fail to demonstrate presence of orthopoxvirus or monkeypox virus or antibodies
  • For the ongoing 2022 monkeypox outbreak, CDC states that all confirmed orthopox cases (ie, a suspect case with orthopoxvirus infection confirmed by a state or authorized commercial laboratory) are presumed to be monkeypox unless proven otherwise r15
  • WHO has also published interim guidance for monkeypox surveillance, reporting, case investigation, and contact tracing, for international application r27

Laboratory

  • Specific diagnostic tests
    • Possible cases of monkeypox should be reported to applicable local and state public health authorities to help guide diagnosis; CDC is also available for consultation through the Emergency Operations Center (telephone, 1-770-488-7100) r15r45
    • 2 tests are currently in use to establish presence of monkeypox infection; either or both may be used: r14r46
      • State laboratories that are part of the Laboratory Response Network and certain authorized commercial laboratories can perform generic orthopox real-time polymerase chain reaction testing on lesion material; testing detects the presence of undifferentiated orthopoxvirus DNA, and a positive result establishes a confirmed orthopox case
        • At this time, all confirmed orthopox cases in the United States are presumed to be monkeypox unless proven otherwise, as there are no other clinically significant orthopoxviruses in circulation r14
        • Once an orthopox case is confirmed, laboratories may forward specimens to CDC for further monkeypox-specific viral characterization and sequencing
      • Certain authorized commercial laboratories and CDC can perform monkeypox-specific real-time polymerase chain reaction testing on lesion material; testing detects the presence of monkeypox DNA, and a positive result establishes a confirmed monkeypox case
        • Authorized commercial laboratories can perform this as initial testing, whereas CDC performs it as confirmatory testing on samples from established orthopox cases; commercial laboratories may forward specimens to CDC for further viral characterization and sequencing
    • Previously, other diagnostic tests for monkeypox and orthopox included viral culture and isolation, electron microscopy, immunohistochemistry, and testing for orthopox antibodies or antigens; although CDC case definitions still include these results, these modalities are no longer recommended in current practice r12r15r32
    • CDC recommends that swabs be collected for testing if: r30
      • Classic monkeypox rash is present or
      • Potential monkeypox rash is present and patient has epidemiologic risk factors as defined in CDC case definition (ie, contact with someone with similar rash or confirmed monkeypox diagnosis, close contact with people in a social network with monkeypox activity, history of recent international travel to country with confirmed cases)
    • Specimens should be collected with use of appropriate personal protective equipment, including gown, gloves, eye protection, and N95-comparable or higher-level respirator r19
    • Specimen type r14r19
      • Initial testing performed at Laboratory Response Network laboratories and authorized commercial laboratories is performed on lesion material; viral characterization at CDC can be performed on dry swabs of lesion material, swabs of lesion material in viral transport medium, or crusts r14r19
      • 2 to 3 lesion specimens per patient are suggested
      • Swab of lesion from any part of body is acceptable
      • CDC is evaluating feasibility of testing on other specimen types, such as blood or saliva
    • Consultation with CDC is required before submission of specimens to CDC; state and commercial laboratories may already have established processes in place to forward positive specimens to CDC r19r47
    • Complete information for specimen submission to CDC is available on the CDC website; highlights are as follows: r19r47
      • Dry swabs of lesion material, swabs of lesion material in viral transport medium, or viral crusts are acceptable
      • Synthetic swabs (eg, nylon, polyethylene terephthalate [eg, Dacron], other polyester) with plastic, wood, or thin aluminum shafts should be used; cotton swabs may interfere with polymerase chain reaction testing and should not be used
      • 2 swabs from each lesion should be sampled; lesions from different parts of the body or with different morphologic appearances in particular should be sampled
      • Specimens should be refrigerated (2 to 8 °C) or frozen (−20 °C or lower) within an hour of collection; frozen samples can be stored for up to 30 to 60 days, depending on the specimen type
      • If transport media is used, only viral transport medium is accepted at this time
      • Turnaround time for CDC testing is 5 days
    • WHO has also published interim guidance for laboratory testing for monkeypox virus, for international application r48
  • Additional laboratory testing
    • HIV status of all sexually active adults and adolescents with suspected or confirmed monkeypox should be ascertained r49
    • Specific testing for sexually transmitted infections is warranted for patients presenting with genital or perianal ulcers, in order to narrow differential diagnosis and assess for concurrent infections r25
    • Additional routine laboratory testing may be warranted to assess clinical status and determine eligibility for specific therapies; some systemic antiviral treatments, such as tecovirimat and cidofovir, are contraindicated in severe renal impairment

Differential Diagnosis

Most common

  • Genital and perianal lesions
    • Genital herpes d1
      • Caused by HSV (herpes simplex virus), mostly HSV-2
      • Painful thin-walled vesicular lesions on erythematous base; often bilateral on labia, vulva, perineum, perianal areas, or shaft or glans of penis
      • Vesicles rupture to form small painful ulcers
      • Diagnosis confirmed by polymerase chain reaction, antigen assays, and microscopic examination
    • Syphilis d2
      • Caused by Treponema pallidum pallidum spirochete
      • Firm, generally single, painless genital lesion with clean base, indurated border, and associated regional painless adenopathy; frequently found in perineum, cervix, anogenital area, lips, oropharynx, and hands
      • Diagnosis confirmed with VDRL testing (Venereal Disease Research Laboratory) or RPR testing (rapid plasma reagin) followed by confirmatory treponemal antigen testing, demonstration of Treponema pallidum on darkfield microscopy, or detection with polymerase chain reaction
    • Chancroid d3
      • Caused by Haemophilus ducreyi
      • Nonindurated, painful, exudative genital ulcer with necrotic base that bleeds when scraped
      • Tender and suppurative inguinal adenopathy
      • Definitive diagnosis is determined by culture of exudate from lesion and exclusion of genital herpes and syphilis
    • Lymphogranuloma venereum d4
      • Caused by Chlamydia trachomatis
      • Unilateral small papules or pustules that are painless and may erode, resulting in formation of small ulcers
      • Tender inguinal lymphadenopathy, usually unilateral, is common
      • Diagnosis confirmed via culture or nucleic acid amplification testing, performed on swab of skin lesion or lymph node aspirate
    • Genital warts d5
      • Caused by HPV (human papillomavirus)
      • Flat, papular, or pedunculated growths in or around the anogenital area; warts are highly variable in size and appearance
      • Diagnosis is made by visual inspection of external genital lesions with ascertainment of typical genital wart morphology; biopsy can be diagnostic if lesions are atypical
    • Granuloma inguinale
      • Caused by Klebsiella granulomatis
      • Painless, beefy red, foul-smelling ulcer and absence of regional lymphadenopathy, although pseudobuboes may form
      • Diagnosis is usually clinical, but Giemsa- or Wright-stained smears may be confirmatory
  • Diffuse rash
    • Syphilis d2
      • Secondary syphilis can result in a maculopapular erythematous rash that involves the trunk and extremities, including palms and soles
      • Diagnosis confirmed with VDRL testing (Venereal Disease Research Laboratory) or RPR testing (rapid plasma reagin) followed by confirmatory treponemal antigen testing, demonstration of Treponema pallidum on darkfield microscopy, or detection with polymerase chain reaction
    • Varicella (chickenpox) d6
      • Caused by varicella-zoster virus
      • Lesions evolve from macules to papules to thin-walled vesicles, which become cloudy or pustular in appearance and may umbilicate before crusting; presence of lesions in various stages of healing is characteristic
      • Lesions are superficial and typically denser on trunk than on face and extremities r2
      • Diagnosis is usually clinical, but it may be confirmed by polymerase chain reaction assay, culture, direct antigen testing, or serology
    • Disseminated herpes zoster (shingles) infection d7
      • Caused by reactivation of varicella-zoster virus acquired from previous varicella infection or vaccination
      • Usually has limited dermatomal distribution, but disseminated disease may occur, especially in immunocompromised patients
      • Erythematous maculopapular lesions evolve over several days into clusters of vesicles, which may coalesce to form bullae
      • Diagnosis is usually clinical, but it may be confirmed by viral culture, polymerase chain reaction, Tzanck test, or direct fluorescent antibody test
    • Disseminated herpes simplex infection d1
      • Immunocompromised patients may develop severe disseminated infection
      • Superficial painful vesicles that can rupture to form small ulcers
      • Diagnosis is confirmed by polymerase chain reaction, antigen assays, and microscopic examination
    • Molluscum contagiosum
      • Caused by molluscum contagiosum virus
      • In children, trunk and proximal extremities are commonly affected, although lesions can occur on any part of body, including face and genitals, via autoinoculation. Sexually transmitted infection in adults primarily affects the perineum and thighs
      • Skin-colored, dome-shaped, smooth, pearly papules with central umbilication
      • Diagnosis is usually clinical, but histopathology can be diagnostic
    • Other poxvirus infections r1
      • Other orthopoxviruses that can cause disease in humans include the causative agents of smallpox, vaccinia, and cowpox
      • Overall clinical course and features of monkeypox are quite similar to those of smallpox, which has been eradicated globally and is no longer seen r17r32
      • Lymphadenopathy is frequently present in monkeypox but absent in smallpox r16r17
      • Vaccinia occurs in the context of smallpox vaccination or direct contact with the unhealed inoculation site of a person who has recently been vaccinated
      • Cowpox occurs after exposure to infected animals (cows and others)
      • CDC and certain authorized commercial laboratories can perform monkeypox-specific polymerase chain reaction testing to differentiate monkeypox from other orthopoxviruses; however, CDC states that there are no other clinically significant orthopoxviruses in circulation in the United States at this time r14

Treatment

Goals

  • Supportive care for all patients; supportive care alone suffices for many patients with monkeypox
  • Antiviral treatment to ameliorate severe disease and reduce risk for patients with high risk of severe disease or high-risk disease features
  • Management of specific disease manifestations and complications of disease

Disposition

Admission criteria

  • Patients with mild disease can be managed at home, with appropriate isolation and infection control precautions in place
  • Admission may be appropriate for the same patient groups who may be considered for antiviral therapy:
    • Patients with severe disease or severe disease-related complications (eg, hemorrhagic disease, confluent lesions, sepsis, encephalitis, ocular disease, bronchopneumonia, or other conditions requiring hospitalization)
    • Patients at high risk of severe disease, such as those with significant immunocompromise or certain preexisting skin conditions, children, pregnant or breastfeeding adults
    • Patients with infection involving high-risk anatomic areas (eg, eyes, mouth, genitals, anus) with potential for serious adverse outcomes
  • CDC states that the few monkeypox-related hospitalizations in the United States thus far have been primarily for pain management r30
  • Hospitalization rates around 10% have been reported internationally for the 2022 outbreak, with pain management and treatment of secondary bacterial infections the most commonly reported reasons r33r50

Recommendations for specialist referral

  • Monkeypox is a reportable disease; suspected cases should be reported to relevant hospital officials (for inpatients) and to local and state public health authorities, to facilitate necessary reporting and further diagnostic and management steps

Treatment Options

Most patients with monkeypox have mild, self-limited disease, which can be managed with supportive care alone r20

Consider systemic antiviral treatment for the following patients after consultation with state health authorities or CDC through the Emergency Operations Center (telephone, 1-770-488-7100): r20

  • Patients with severe disease or severe disease-related complications (eg, hemorrhagic disease, confluent lesions, sepsis, encephalitis, ocular disease, bronchopneumonia, or other conditions requiring hospitalization)
  • Patients at high risk of severe disease, such as those with significant immunocompromise or certain preexisting skin conditions, children, pregnant or breastfeeding adults
  • Patients with infection involving high-risk anatomic areas (eg, eyes, mouth, genitals, anus) with potential for serious adverse outcomes

Currently there are no treatments approved specifically for monkeypox virus infection, but several antiviral agents originally developed for treatment of smallpox and other viral infections may be considered and obtained from the Strategic National Stockpile upon request from state health authorities after consultation with CDC. Efficacy data for these agents are lacking, owing to infeasibility of human smallpox experimentation r20

  • Tecovirimat r51r52
    • Approved for treatment of human smallpox disease in adults and children weighing at least 3 kg
    • CDC has an EA-IND protocol (expanded access–investigational new drug) that allows use in treatment of monkeypox in an outbreak
    • Demonstrated efficacy against a diverse range of orthopoxviruses per in vitro and in vivo animal studies; efficacy data for treating monkeypox in humans is unavailable r53
    • Preferred therapy for most patients in whom systemic antiviral treatment is indicated, including patients with HIV, pregnant or breastfeeding patients, and pediatric patients
    • Instructions on obtaining and using tecovirimat, as well as required forms, are available at the CDC website r52r54
      • Tecovirimat is available through the Strategic National Stockpile upon request from state and territorial health departments; certain states and territories have pre-positioned supplies to facilitate faster access
      • CDC has streamlined the process for health care professionals to provide tecovirimat treatment for patients with monkeypox under its EA-IND protocol r54
        • Treatment can begin upon receipt of the medication, after informed consent is obtained
        • Required forms under the EA-IND can be returned to CDC after treatment begins
    • Available in capsule and injection form
    • Injection is contraindicated in severe renal impairment
    • A recent report on clinical use of tecovirimat for treatment of monkeypox infection under the CDC EA-IND protocol found that among 549 treated patients, 99.8% were prescribed oral tecovirimat, 93.1% were not hospitalized, and very few adverse events were reported overall r55
  • Cidofovir r56
    • Originally approved for treatment of cytomegalovirus in patients with AIDS; has been used for other viral infections
    • CDC has an EA-IND protocol that allows use in treatment of monkeypox in an outbreak
    • IV infusion; must be administered with probenecid
    • BLACK BOX WARNINGS for renal impairment and neutropenia
    • Contraindicated in patients with severe renal impairment, those receiving potentially nephrotoxic agents, and those with hypersensitivity to cidofovir or severe hypersensitivity to probenecid or other sulfa-containing medications
  • VIGIV (vaccinia immune globulin intravenous) r57
    • Approved for treatment of complications due to vaccinia vaccination
    • CDC has an EA-IND protocol that allows use in treatment of monkeypox in an outbreak
    • For IV use only
    • BLACK BOX WARNING for interactions with glucose monitoring systems
      • Measure blood glucose level with a glucose-specific method during VIGIV therapy; VIGIV contains maltose and may falsely elevate glucose readings with some types of glucose monitoring systems
    • Contraindicated in patients with history of anaphylaxis or other severe reaction to IV immune globulin, and in IgA-deficient patients with anti-IgA antibodies and history of IgA hypersensitivity
  • Brincidofovir r58
    • Approved for treatment of human smallpox disease in adults and children, including neonates
    • CDC is currently developing an EA-IND protocol to facilitate use in treatment of monkeypox; not currently available from the Strategic National Stockpile at this time
    • Available in tablet and oral suspension form
    • BLACK BOX WARNING for increased mortality risk when used for prolonged durations
    • No contraindications noted in prescribing information
  • Trifluridine r59
    • Approved for treatment of primary keratoconjunctivitis and recurrent epithelial keratitis due to herpes simplex virus, types 1 and 2
    • Has demonstrated in vitro activity against orthopoxviruses; has been the preferred treatment for ocular vaccinia infection resulting as complication of smallpox vaccination with ACAM2000 vaccine r30
    • May be considered for use in patients with ocular monkeypox involvement; prophylactic use can be considered for patients with eye-adjacent lesions r60
    • For topical ophthalmic use only
    • Contraindicated in patients who develop hypersensitivity reactions or chemical intolerance to trifluridine

Other management considerations should be individualized depending on specific monkeypox disease manifestations or disease-related complications, and may include the following: r61r62

  • Fever
    • Antipyretic medications and external cooling measures
  • Pain
    • Topical steroids, topical anesthetic agents, OTC analgesics (eg, acetaminophen, NSAIDs), and prescription analgesics (eg, gabapentin, opioids)
  • Inflammation/lymphadenopathy
    • Antiinflammatory and analgesic medications
  • Pruritus/itching
    • Oral antihistamines; topical agents such as calamine lotion
  • Oropharyngeal lesions
    • Mucosal care, saltwater rinses, oral antiseptic mouthwash, local anesthetic agents, prescription analgesic mouthwash
  • Rectal lesions
    • Stool softeners, warm sitz baths, general pain control measures
  • Genital lesions
    • General pain control measures, topical steroids for localized swelling
  • Vomiting/diarrhea
    • Oral or IV hydration and antiemetic/antidiarrheal medications
  • Respiratory tract
    • Suctioning, incentive spirometry, chest physiotherapy, bronchodilators, antibiotics for secondary respiratory infections, nebulizer treatments, bronchoscopy, noninvasive ventilation, intubation/ventilation
  • Sepsis
    • Antibiotics, IV fluids, vasopressors, supplemental oxygen
  • Skin compromise
    • Cleaning, moist dressings, topical antibiotics, surgical debridement, skin grafts
  • Secondary skin infection
    • Antibiotics, incision and drainage, advanced wound management

CDC has developed more detailed clinical guidance for the following specific clinical scenarios:

  • Ocular involvement r60
    • Ocular involvement is an uncommon but potentially serious manifestation of monkeypox infection
    • Though high rates of ocular involvement have been reported with endemic monkeypox disease, less than 1% of individuals in the ongoing outbreak have had eye involvement
    • Ocular disease may result in a range of ocular complications, including corneal scarring and loss of vision; bacterial superinfection may also result in severe adverse outcomes
    • Ophthalmologic consultation should be obtained urgently if ocular monkeypox involvement is suspected, and a comprehensive ophthalmic examination should be performed, with appropriate isolation protocols and personal protective equipment in place
    • Systemic antiviral therapy should be considered for patients severe monkeypox disease or severe disease-related complications, which include eye involvement
    • Though efficacy data is lacking, tecovirimat is frequently given for systemic therapy; VIGIV may also be considered after consultation with CDC
    • Topical antiviral therapy with trifluridine may be considered in consultation with an ophthalmologist; prophylactic treatment with topical trifluridine can also be considered for patients with eye-adjacent lesions
    • Topical lubricants and antibiotics can be considered to prevent bacterial superinfection; topical steroids may exacerbate corneal damage and should be avoided

Drug therapy

  • There are no treatments approved specifically for monkeypox; dosing recommendations are based on approved uses in smallpox or other viral infections
  • Antivirals
    • Tecovirimat r51
      • Oral
        • Administer within 30 minutes after a full meal containing moderate or high fat (approximately 600 calories and 25 grams of fat)
        • Capsules may be opened and mixed with 30 mL of liquid or soft food for patients who cannot swallow capsules
        • Tecovirimat Oral capsule; Neonates, Infants, and Children weighing less than 13 kg: 200 mg PO every 12 hours for 14 days is the dose for children and adolescents weighing 13 to 24 kg. The CDC EA-IND protocol notes that capsules may be opened and contents mixed with semi-solid food for pediatric patients weighing less than 13 kg; however, specific dosing recommendations are not provided.
        • Tecovirimat Oral capsule; Children and Adolescents weighing 13 to 24 kg: 200 mg PO every 12 hours for 14 days.
        • Tecovirimat Oral capsule; Children and Adolescents weighing 25 to 39 kg: 400 mg PO every 12 hours for 14 days.
        • Tecovirimat Oral capsule; Children and Adolescents weighing 40 to 119 kg: 600 mg PO every 12 hours for 14 days.
        • Tecovirimat Oral capsule; Children and Adolescents weighing 120 kg or more: 600 mg PO every 8 hours for 14 days.
        • Tecovirimat Oral capsule; Adults weighing 40 to 119 kg: 600 mg PO every 12 hours for 14 days.
        • Tecovirimat Oral capsule; Adults weighing 120 kg or more: 600 mg PO every 8 hours for 14 days.
      • Intravenous
        • Transition patients to oral therapy to complete the 14-day treatment course as soon as oral therapy is tolerated
        • Tecovirimat Solution for injection; Neonates, Infants, Children, and Adolescents weighing 3 to 34 kg: 6 mg/kg/dose IV every 12 hours for 14 days.
        • Tecovirimat Solution for injection; Children and Adolescents weighing 35 to 119 kg: 200 mg IV every 12 hours for 14 days.
        • Tecovirimat Solution for injection; Children and Adolescents weighing 120 kg or more: 300 mg IV every 12 hours for 14 days.
        • Tecovirimat Solution for injection; Adults weighing 35 to 119 kg: 200 mg IV every 12 hours for 14 days.
        • Tecovirimat Solution for injection; Adults weighing 120 kg or more: 300 mg IV every 12 hours for 14 days.
    • Cidofovir r63
      • Administer oral probenecid with each cidofovir dose to minimize nephrotoxicity potential
      • Cidofovir Solution for injection; Adults: 5 mg/kg/dose IV once weekly for 2 weeks is the FDA-approved induction dose for patients with cytomegalovirus retinitis.
    • Brincidofovir r64
      • CDC does not have an EA-IND protocol for brincidofovir for monkeypox, but it is currently developing one, to facilitate use
      • Administer on an empty stomach
      • Brincidofovir Oral suspension; Neonates: 6 mg/kg/dose PO once weekly for 2 weeks (on days 1 and 8).
      • Brincidofovir Oral suspension; Infants, and Children weighing less than 10 kg: 6 mg/kg/dose PO once weekly for 2 weeks (on days 1 and 8).
      • Brincidofovir Oral suspension; Children and Adolescents weighing 10 to 47 kg: 4 mg/kg/dose PO once weekly for 2 weeks (on days 1 and 8).
      • Brincidofovir Oral suspension; Children and Adolescents weighing 48 kg or more: 200 mg PO once weekly for 2 weeks (on days 1 and 8).
      • Brincidofovir Oral suspension; Adults weighing less than 48 kg: 4 mg/kg/dose PO once weekly for 2 weeks (on days 1 and 8).
      • Brincidofovir Oral tablet; Adults weighing 48 kg or more: 200 mg PO once weekly for 2 weeks (on days 1 and 8).
    • Trifluridine
      • Trifluridine Ophthalmic drops, solution; Children and Adolescents: 1 drop in the affected eye(s) every 2 hours (Max: 9 drops/day) until reepithelialization, then 1 drop in the affected eye(s) every 4 hours (Min: 5 drops/day) for 7 days. Continue treatment until all periocular lesions have healed. Max duration: 21 days.
      • Trifluridine Ophthalmic drops, solution; Adults: 1 drop in the affected eye(s) every 2 hours (Max: 9 drops/day) until reepithelialization, then 1 drop in the affected eye(s) every 4 hours (Min: 5 drops/day) for 7 days. Continue treatment until all periocular lesions have healed. Max duration: 21 days.
  • Probenecid r63
    • Administer oral probenecid with each cidofovir dose to minimize nephrotoxicity potential
    • Probenecid Oral tablet; Adults: 2 g PO given 3 hours prior to each cidofovir infusion, followed by 1 g PO at 2 and 8 hours following completion of the infusion.
  • Vaccinia immune globulin r65
    • Human Vaccinia Virus Immune Globulin Solution for injection; Adults: 6,000 units/kg/dose IV as soon as symptoms appear; may consider repeat dosing depending on symptom severity and treatment response and 9,000 units/kg/dose in patients not responding to the initial dose.

Comorbidities

  • HIV r43r66r67
    • Patients with advanced or uncontrolled HIV are at higher risk of severe or complicated monkeypox infection and prolonged monkeypox symptoms; effective antiretroviral therapy appears to attenuate risk
    • Unclear at this time whether monkeypox differentially infects people with and without HIV
    • Signs and symptoms of monkeypox are generally similar in patients with and without HIV; significant immunocompromise such as in advanced or uncontrolled HIV may predispose to disseminated or atypical rash (ie, genital lesions or confluent rash)
    • Monkeypox vaccination considerations, antiviral treatments, and monitoring for patients with HIV should account for viral suppression and CD4 count in weighing risk of severe outcomes from monkeypox
    • Antiretroviral therapy and prophylaxis for opportunistic infections should be continued in all patients with HIV who develop monkeypox
    • Assessment for drug interactions between available antiviral treatments for monkeypox and antiretroviral therapy for HIV is advised
    • Vaccination with Jynneos vaccine is considered safe in patients with HIV; ACAM2000 vaccine should not be used in this population, regardless of immune status, owing to risk of progressive vaccinia and other severe adverse effects

Special populations

  • Pregnant or breastfeeding patients r68
    • Limited data exist regarding monkeypox in pregnancy; unclear if pregnancy increases risk of infection or more severe outcomes, although pregnant and breastfeeding patients are still considered a priority group for antiviral treatment
    • Adverse pregnancy outcomes, including fetal loss, have been reported in patients with monkeypox infection during pregnancy
    • Signs and symptoms of monkeypox are similar in pregnant and nonpregnant patients
    • If antiviral treatment is judged to be indicated, after consultation with CDC, then tecovirimat should be first line therapy for patients who are pregnant, recently pregnant, or breastfeeding; in animal studies, tecovirimat did not demonstrate any specific fetal effects, whereas cidofovir and brincidofovir showed evidence of teratogenicity
    • Jynneos vaccine data in humans are insufficient to assess vaccine-associated risks in pregnancy and breastfeeding, but Jynneos vaccination can be considered in patients who are otherwise eligible; ACAM2000 vaccine is contraindicated in pregnancy and breastfeeding, owing to risk of vaccinia virus infection and other severe adverse effects
    • Patients in isolation for monkeypox should not breastfeed and should not have direct skin to skin contact with infants until criteria for discontinuation of isolation for monkeypox have been met
  • Children and adolescents r69
    • Limited data exist regarding whether children have higher risk of monkeypox infection or different clinical outcomes compared with adults
    • Data from endemic monkeypox cases suggest higher risk of severe disease in children younger than 8 years and in those with preexisting immunocompromise or certain skin conditions
    • Signs and symptoms of monkeypox are similar in pediatric and adult patients
    • Antiviral treatment considerations for pediatric patients are similar to those for adults
    • If antiviral treatment is judged to be indicated, after consultation with local health authorities, priority groups for treatment include children (particularly those younger than 8 years) with: r69
      • Severe disease or severe disease-related complications (eg, hemorrhagic disease, confluent lesions, sepsis, encephalitis, ocular disease, bronchopneumonia, or other conditions requiring hospitalization)
      • Severe immunocompromise or conditions affecting skin integrity
      • Infection involving high-risk anatomic areas (eg, eyes, face, genitals, anus) with potential for serious adverse outcomes
    • Tecovirimat is first line antiviral treatment for children and adolescents; other treatments, including cidofovir, brincidofovir, and VIGIV, can be considered, but they should be used with caution (owing to potential toxicity) r69
    • No vaccines are currently licensed specifically for monkeypox prevention in children or adolescents; Jynneos vaccine can be offered for pediatric cases under an FDA emergency use authorization, after consultation with jurisdictional health authorities and CDC r69r70
      • No significant adverse events have been reported to date in infants and children who have received Jynneos vaccine
      • Pediatric data are lacking for ACAM2000 vaccine; many serious adverse effects, including progressive vaccinia and encephalitis, were reported in young children when the vaccine precursor to ACAM2000, which also contained replicating vaccinia virus, was used for smallpox prevention up through the early 1970s
    • VIGIV and tecovirimat can also be considered for use as monkeypox postexposure prophylaxis through EA-IND authorization if vaccines are otherwise contraindicated; effectiveness of these medications as postexposure prophylaxis is unknown r69

Complications and Prognosis

Complications

  • Pitted scarring (pockmarks) is the most common long-term sequela for survivors r32
  • Oral lesions and regional lymphadenopathy can lead to difficulties with swallowing and thus with eating and drinking r32
  • Vomiting and diarrhea, resulting in severe dehydration r32
  • Perianal lesions can lead to severe pain, tenesmus, and bleeding r30
  • Secondary bacterial infections of skin r32
  • Secondary infections of lungs, resulting in bronchopneumonia and respiratory distress, potentially requiring intubation r32
  • Neurologic complications including encephalitis and transverse myelitis r32r49
  • Cardiac complications including myocarditis and pericardial disease r49
  • Urologic complications including urethritis and penile necrosis r49
  • Septicemia r32
  • Hemodynamic instability requiring vasopressor support r49
  • Ocular infections, which can result in corneal scarring and permanent vision loss r32

Prognosis

  • Monkeypox has a mild, self-limited course for most patients r5r6r30
  • Monkeypox case fatality rates of 3% to 6% have previously been reported in African countries where the disease is endemic; the estimated case fatality rate associated with the 2022 multi-country outbreak has been substantially lower, at approximately 0.03% r5r6r9
  • Mortality is higher in children and young adults; disease is more severe in persons with immunocompromise, most notably HIV r2r49

Screening and Prevention

Prevention

  • General infection control measures r71r72
    • Avoid close, skin to skin contact, including intimate or sexual contact, with anyone that has a monkeypox-like rash r40
    • Avoid contact with potentially infected animals or animal products
    • Avoid contact with items or materials that have been in contact with sick animals or people
    • Isolate infected patients
    • Appropriate hand hygiene
    • Use appropriate personal protective equipment when caring for patients or collecting specimens for diagnosis
  • Infection control in home settings r21
    • Isolation and personal protective equipment
      • Patients who do not require hospital admission may isolate at home
      • Patients should not leave the home except for emergencies or necessary medical care
      • Visitors should refrain from visiting during the isolation period
      • Patients should isolate separately from and avoid close contact with other household members and pets; patients and household members should both wear medical masks when close contact is necessary or cannot be avoided
      • A separate bathroom should be used if possible
      • Patients should manage their own wound care, linens, and laundry if possible, using disposable gloves and appropriate hand hygiene; if assistance from household members is required, disposable medical gloves and a medical mask should be used
      • Skin lesions should be covered as much as much as possible, with long sleeves, long pants, and gloves
      • Patients should avoid use of contact lenses and shaving rash-covered areas to prevent further spread of lesions
    • Hand hygiene and household disinfection r73
      • Potentially contaminated personal items (eg, clothing, linens, towels, dishes, utensils) should be washed properly and not shared
      • Frequently touched surfaces, such as counters and light switches, should be regularly cleaned and disinfected
      • Hand hygiene, with an alcohol-based hand rub or soap and water, should be performed after any contact with rash material or potentially contaminated materials and surfaces
      • If use of a separate bathroom is not possible, potentially contaminated surfaces should be cleaned and disinfected after each use of the shared space
      • CDC has published detailed guidance for household cleaning and disinfection of monkeypox r73
    • Sexual activity
      • Patients should refrain from all sexual activity during the isolation period r25
      • Barrier practices (eg, condoms) are recommended after recovery; data to guide duration are sparse, but some countries recommend at least 8 weeks r25
    • Isolating with animals in the home r21r74
      • Patients with monkeypox should avoid contact with mammals, including pets
      • Potentially contaminated materials, including bandages, linens, and laundry, should be kept away from domestic animals
    • Infection control precautions should be maintained until all lesions have scabbed off, separated, and healed with a fresh layer of intact skin, or until cleared by public health authorities r38
  • Infection control in health care settings r22
    • Regarding prevention of monkeypox transmission in health care settings, CDC references 2007 guidelines for preventing transmission of infectious agents in these settings r75
    • Patients with suspected or confirmed monkeypox infection should be placed in single-person rooms with standard precautions; special air handling is not necessary unless high-risk procedures are performed
    • Visitation should be limited to that which is necessary for patient care and wellbeing
    • Intubation, extubation, and any high-risk procedures likely to spread oral secretions should be performed in airborne isolation rooms
    • Personal protective equipment for health care staff entering the patient's room should include gown, gloves, eye protection, and N95-comparable or higher-level respirator
    • Waste management should be performed in accordance with hazardous materials regulations
    • Soiled laundry should be managed in accordance with recommended standard practices for environmental infection control r76
    • Cleaning and disinfection should be performed using hospital-grade disinfectant with an emerging viral pathogen claim
    • Wet cleaning methods are preferred; dry dusting, sweeping, and vacuuming should be avoided
    • Infection control precautions should be maintained until monkeypox infection is ruled out in patients in whom it is suspected, or until all lesions have scabbed off, separated, and healed with a fresh layer of intact skin for those with confirmed monkeypox infection; consultation with local or state health department might be necessary, depending on locale r38
  • Safer sex practices
    • Male to male sexual contact between gay, bisexual, and other men who have sex with men appears to be the primary mode of transmission in the ongoing 2022 outbreak; various harm reduction efforts have focused on safer sex practices in these populations r9
    • CDC has issued recommendations for safer sexual practices to help reduce the risk of monkeypox exposure and transmission, including: r39
      • Taking a break from potential high-risk sexual behaviors, until completion of vaccination for monkeypox
      • Limiting number of sexual partners
      • Avoiding venues such as sex clubs and sex parties, where anonymous sexual contact with multiple partners occurs
      • Use of barrier protection such as condoms
      • Avoidance of kissing or exchanging saliva
      • Reducing as much skin to skin contact as possible during sexual activity
      • Virtual or touchless sexual activities
      • Washing hands, sex toys, and potentially contaminated fabrics (eg, bedding, towels, clothes) after sex
    • WHO previously issued public health advice for gay, bisexual, and other men who have sex with men, with recommendations to: r40
      • Isolate at home and seek medical attention if symptoms develop
      • Avoid close contact, including sexual contact, with anyone with symptoms
      • Clean hands, objects, and surfaces that have been touched regularly
      • Wear a mask if in close contact with anyone with symptoms
    • Modeling of sexual transmission between gay, bisexual, and other men who have sex with men has indicated that reductions in one-time sexual encounters can significantly reduce transmission r39r77
    • In August 2022, in an online survey of gay, bisexual, and other men who have sex with men, respondents reported adopting the following strategies to prevent potential monkeypox transmission in light of the ongoing outbreak: r78
      • 48% reported reducing number of sexual partners
      • 50% reported reducing one-time sexual encounters
      • 50% reported reducing sex with partners from dating apps or sex venues
  • Exposure management
    • Exposures in the community r23
      • Confer with appropriate public health authorities when monitoring of exposed contacts is undertaken r15
      • Exposure risk assessment should be performed to determine possible need for postexposure prophylaxis
      • Contacts with confirmed monkeypox exposure should monitor for the following signs and symptoms of infection for 21 days after the last exposure:
        • New rash, including oral, genital, and anal lesions
        • Fever
        • Chills
        • Lymphadenopathy
        • Fatigue
        • Myalgias and backache
        • Headache
        • Respiratory symptoms
      • Asymptomatic contacts can continue routine daily activities during the monitoring period but should not donate blood, bodily fluids, cells, tissues, or organs during that period
      • If rash develops during the monitoring period, contacts should self-isolate until rash can be evaluated by a health care professional and monkeypox is ruled out
      • If other symptoms develop during the monitoring period, contacts should isolate at home for 5 days and monitor for emergence of new symptoms; if no new symptoms develop and no skin or oral lesions appear during the 5-day period, isolation can stop
    • Exposures in health care settings r22
      • Notify hospital infection control when monitoring of exposed patients is undertaken
      • Asymptomatic exposed patients do not need to be isolated, but should be monitored
      • Exposure risk assessment should be performed to determine possible need for postexposure prophylaxis
      • Monitoring should include at least daily assessment of potential signs and symptoms of monkeypox for 21 days after the last exposure, inclusive of a thorough skin and oral examination
      • If rash develops during the monitoring period, the patient should be placed on empiric isolation precautions for monkeypox until rash is evaluated and monkeypox has been ruled out
      • If other symptoms develop during the monitoring period, the patient should be placed on empiric isolation precautions for monkeypox and monitored for 5 days for the emergence of new symptoms; if no new symptoms develop and no skin or oral lesions appear during the 5-day period, isolation precautions can be discontinued
    • Exposed health care professionals r22
      • Confer with applicable public health and occupational health authorities to guide decisions on monitoring exposed health care professionals
      • Exposure risk assessment should be performed to determine possible need for postexposure prophylaxis
      • Asymptomatic health care professionals may continue to work but should monitor for signs and symptoms of monkeypox for 21 days after the last exposure
      • If rash develops during the monitoring period, the person should not go to work until rash is evaluated and monkeypox has been ruled out
      • If other symptoms develop during the monitoring period, the person should not go to work for 5 days and should monitor for emergence of new symptoms; if no new symptoms develop and no skin or oral lesions appear during the 5-day period, the person may return to work if cleared by occupational health physician
    • Exposure risk assessment and postexposure prophylaxis r22r23
      • Exposure risk assessment for all persons with potential monkeypox exposure should be performed to determine need for postexposure prophylaxis
      • Management recommendations depend on degree of exposure:
        • High-risk: symptom monitoring is necessary; postexposure prophylaxis with ACAM2000 or Jynneos vaccination is recommended
          • High-risk exposures include:
            • Community settings:
              • Contact between an exposed person's broken skin or mucous membranes and the skin lesions, bodily fluids, or potentially contaminated materials (eg, linens, clothing, sex toys) from a person with monkeypox or
              • Any sexual or intimate contact involving the mucous membranes of a person with monkeypox
            • Health care settings:
              • Unprotected contact between an exposed person's broken skin or mucous membranes and the skin lesions, bodily fluids, or potentially contaminated materials (eg, linens, clothing) from a patient with monkeypox or
              • Being inside the patient's room or within 6 feet of a patient with monkeypox during aerosol-generating procedures without wearing an N95-comparable or higher-level respirator and eye protection
        • Intermediate-risk: symptom monitoring is necessary; need for postexposure prophylaxis can be determined on an individual basis
          • Intermediate-risk exposures include:
            • Community settings:
              • Contact between an exposed person's intact skin and the skin lesions, bodily fluids, or potentially contaminated materials (eg, linens, clothing, sex toys) from a person with monkeypox or
              • Contact between an exposed person's sleeves or other clothing and the skin lesions, bodily fluids, or contaminated materials from a person with monkeypox
            • Health care settings:
              • Being within 6 feet for 3 hours or more (cumulative) of an unmasked patient with monkeypox without wearing at least a surgical mask or
              • Unprotected contact between an exposed person's intact skin and the skin lesions, bodily fluids, or potentially contaminated materials (eg, linens, clothing) from a patient with monkeypox or
              • Contact between an exposed person's sleeves or other clothing and the skin lesions, bodily fluids, or contaminated materials from a patient with monkeypox while not wearing a gown
        • Low-risk: symptom monitoring is recommended; postexposure prophylaxis is not indicated
          • Low-risk exposures include:
            • Community settings:
              • Entry into the living space of a person with monkeypox, in the absence of other exposures
            • Health care settings:
              • Entering the room or patient care area of a patient with monkeypox without all recommended personal protective equipment, in the absence of other exposures
        • No risk: neither symptom monitoring nor postexposure prophylaxis is indicated
          • No contact with the person with monkeypox or potentially contaminated materials, and no entry into their room or living space
  • Preexposure prophylaxis
    • One vaccine, Jynneos, is licensed in the United States for the prevention of monkeypox and smallpox; another, ACAM2000, is licensed for the prevention of smallpox but is considered effective for the prevention of monkeypox as well; although there are not yet robust vaccine efficacy data for the current outbreak, efficacy is estimated to be over 85%, based on prior data from Africa, as well as immunologic and animal studies r24r79
    • Before the 2022 multi-country outbreak, the Advisory Committee on Immunization Practices (of CDC) recommended limited use of Jynneos or ACAM2000 for preexposure vaccination of certain laboratory and health care personnel at ongoing risk for occupational exposure to orthopoxviruses, including: r80
      • Research laboratory personnel
      • Clinical laboratory personnel performing diagnostic testing for orthopoxviruses
      • Designated response team members
      • Health care personnel who administer ACAM2000 or care for patients infected with orthopoxviruses
    • During the 2022 U.S. monkeypox outbreak, in jurisdictions with sufficient vaccine supply, CDC recommends that monkeypox preexposure prophylaxis be offered to those with the highest potential for monkeypox exposure, such as: r79
      • Gay, bisexual, or other men who have sex with men, transgender, or nonbinary people who within the past 6 months have received a diagnosis of one or more reportable sexually transmitted diseases or have had more than one sex partner
      • People who within the past 6 months have had sex at a commercial sex venue or in association with a large public event in an area with known monkeypox transmission
      • Sex partners of people with above risks
      • People who anticipate experiencing above risks
    • Vaccination for all front-line healthcare workers, or for the general public at large, is not recommended at this time r25
    • Vaccines for preexposure prophylactic vaccination can be obtained from CDC Drug Service after consultation with CDC Emergency Operations Center (telephone, 1-770-488-7100) r15
    • It is unclear how much protection against monkeypox is conferred by previous smallpox vaccination; CDC recommends following the same vaccination schedules as for those not previously vaccinated r79
  • Postexposure prophylaxis
    • Vaccines are effective in preventing disease before monkeypox exposure, and it is believed that they may prevent or ameliorate disease after exposure as well r24
    • Recommended for postexposure prophylaxis in persons with high-risk exposures and can be considered on an individual basis for persons with intermediate-risk exposures r23
    • Vaccination within 4 days of exposure is recommended to prevent disease r24
    • Vaccination between 4 and 14 days after exposure may reduce disease severity but may not prevent disease r24
    • Vaccines for postexposure prophylaxis can be obtained from the Strategic National Stockpile via CDC; requests should be initiated through state or territorial health authorities, but CDC Emergency Operations Center (telephone, 1-770-488-7100) is available for consultations to assist with appropriate vaccine use r15
    • For the 2022 outbreak event, some public health jurisdictions are employing an expanded postexposure prophylaxis strategy (notated as PEP++), with vaccination offered to persons at increased risk of recent monkeypox exposure (even without confirmed exposure), including the following: r24r79
      • Known monkeypox contacts identified through case investigation, contact tracing, and risk exposure assessments
      • A sexual partner in the past 14 days diagnosed with monkeypox
      • Certain gay, bisexual, or other men who have sex with men, or transgender people who have sex with men, with any of the following in the past 14 days:
        • Sex with multiple partners
        • Sex at a commercial sex venue
        • Sex in association with an event, venue, or defined area with known monkeypox transmission
    • Current vaccination efforts in the 2022 outbreak response in the United States are primarily deploying Jynneos vaccine; any consideration of ACAM2000 should be made in consultation with CDC r79
    • Persons diagnosed with monkeypox during the current outbreak are believed to have immune protection, and at present CDC does not recommend vaccination in such persons r25
    • Other agents for postexposure prophylaxis r14r69
      • Although clinical efficacy is unknown, VIGIV and tecovirimat may be considered for use as monkeypox postexposure prophylaxis in certain limited circumstances if vaccines are contraindicated (eg, severe allergy to vaccine components)
      • Any such use must be in clinical consultation with CDC
  • Vaccines
    • Jynneos r79r81r82
      • Approved for prevention of smallpox and monkeypox disease in patients aged 18 years or older who are determined to be at high risk for infection; FDA has issued an emergency use authorization for use in the prevention of monkeypox disease in patients younger than 18 years r70
      • Nonreplicating live virus (vaccinia) preparation
      • Completion of standard regimen requires 2 subcutaneous injections 4 weeks apart; vaccination is considered complete 2 weeks after the second dose r24
      • As a means of increasing available vaccine supply, an alternative regimen via intradermal administration may be used for patients aged 18 years or older under an FDA emergency use authorization; intradermal and subcutaneous routes of administration elicited similar immune responses in clinical studies r70r83
        • CDC states that when necessary, a person aged 18 years or older who received 1 Jynneos vaccine dose with the standard subcutaneous regimen may receive a second dose with the alternative intradermal regimen at the recommended interval to complete the series
        • Similarly, a person who has received 1 dose intradermally (alternative regimen) may receive the second dose subcutaneously (standard regimen) r25
      • Although some domestic and international jurisdictions are delaying the second dose, or employing a "1 dose only" strategy because of supply limitations, CDC states that 2 doses are required for most patients, as this is the only FDA-approved regimen r79
        • Recommended interval between the 2 doses of vaccine is at least 4 weeks; doses may be up to 5 weeks apart r82
          • If the second dose is not administered within the recommended interval, it should be administered as soon as possible; there is no need to restart the regimen or add doses if the dosing interval is extended r82
      • CDC is collecting data on Jynneos vaccine efficacy in the 2022 outbreak. Because of currently limited knowledge about the effectiveness of vaccines in this outbreak, people who are vaccinated should continue to take steps to protect themselves from infection by avoiding close, skin to skin contact with individuals who have monkeypox r79
        • Early data suggests that even 1 dose of Jynneos vaccine is protective against monkeypox infection; a recent study reporting on 5402 monkeypox cases occurring among males aged 14 to 49 years in the United States found that the average monkeypox incidence among unvaccinated persons was 14.3 times that among persons who had received 1 dose of Jynneos vaccine 14 or more days earlier r84
      • Preferred vaccine for most patients in whom vaccination is indicated, including patients with HIV, pregnant or breastfeeding patients, and pediatric patients r43r68r69
        • Elicited higher peak neutralizing antibody titers against smallpox compared with ACAM2000 in clinical trials, with better safety profile r85
        • Less potential for adverse events compared with ACAM2000 vaccine r24
        • Can be used in certain immunocompromised patients in whom ACAM2000 vaccine is contraindicated r85
      • Generally well-tolerated, with few adverse reactions noted in clinical studies r80
      • Warnings listed for severe allergic reactions (including anaphylaxis) and diminished response in immunocompromised patients
      • Preexposure prophylaxis r81
        • Subcutaneous
          • Modified Vaccinia Ankara Suspension for injection; Infants, Children, and Adolescents: 0.5 mL subcutaneously for 2 doses administered 4 weeks apart.
          • Modified Vaccinia Ankara Suspension for injection; Adults: 0.5 mL subcutaneously for 2 doses administered 4 weeks apart.
        • Intradermal
          • Modified Vaccinia Ankara Suspension for injection; Adults: 0.1 mL intradermally for 2 doses administered 4 weeks apart.
      • Postexposure prophylaxis r24r81
        • Subcutaneous
          • Modified Vaccinia Ankara Suspension for injection; Infants, Children, and Adolescents: 0.5 mL subcutaneously for 2 doses administered 4 weeks apart. Administer within 4 days from exposure date to prevent onset of disease. If administered between 4 and 14 days after exposure, vaccination may reduce symptoms of disease, but not prevent disease.
          • Modified Vaccinia Ankara Suspension for injection; Adults: 0.5 mL subcutaneously for 2 doses administered 4 weeks apart. Administer within 4 days from exposure date to prevent onset of disease. If administered between 4 and 14 days after exposure, vaccination may reduce symptoms of disease, but not prevent disease. If it has been more than 3 years since vaccination, consider revaccinating.
        • Intradermal
          • Modified Vaccinia Ankara Suspension for injection; Adults: 0.1 mL intradermally for 2 doses administered 4 weeks apart. Administer within 4 days from exposure date to prevent onset of disease. If administered between 4 and 14 days after exposure, vaccination may reduce symptoms of disease, but not prevent disease. If it has been more than 3 years since vaccination, consider revaccinating.
    • ACAM2000 r86
      • Approved for active immunization against smallpox disease in persons aged 16 years or older determined to be at high risk for infection
      • CDC-held EA-IND protocol allows use for non-smallpox orthopoxvirus infection (eg, monkeypox) during an outbreak r30
      • Live preparation of vaccinia inoculated directly into skin via percutaneous scarification
      • Results in a localized viral inoculation lesion; vaccinia can progress and spread in the vaccine recipient, and it can even be transmitted to close contacts and result in clinically significant infection
      • Greater potential for serious adverse events compared with Jynneos vaccine
      • Contraindicated in severe immunodeficiency, owing to possible severe localized or systemic vaccinia infection
      • Contraindicated in patients with HIV (regardless of immune status) and pregnant or breastfeeding patients; Jynneos vaccine is preferred in pediatric populations when vaccination is indicated r43r68r69
      • BLACK BOX WARNING for numerous rare complications potentially resulting in severe disability, permanent impairment, and death, including myocarditis and pericarditis, encephalitis, encephalopathy, progressive or generalized vaccinia, severe skin infections or reactions, ocular complications, blindness, and fetal death
      • Preexposure prophylaxis r86
        • Vaccinia Virus Strain New York City Board of Health Live Antigen Solution for percutaneous scarification; Adolescents 16 to 17 years: 0.0025 mL (a droplet of vaccine) administered percutaneously onto the arm by rapidly making 15 needle punctures. If a major reaction is not obtained 6 to 8 days after vaccination, check vaccination procedures, and repeat vaccination with vaccine from another vial or vaccine lot, if available. If a repeat vaccination using vaccine from another vial or vaccine lot fails to produce a major reaction, consult CDC or state or local health department before giving another vaccination. Patients who are at continued high risk of monkeypox exposure may be revaccinated every 3 years. For booster vaccination, make 15 needle punctures. There may be a reduced cutaneous response to revaccination; do not revaccinate.
        • Vaccinia Virus Strain New York City Board of Health Live Antigen Solution for percutaneous scarification; Adults: 0.0025 mL (a droplet of vaccine) administered percutaneously onto the arm by rapidly making 15 needle punctures. If a major reaction is not obtained 6 to 8 days after vaccination, check vaccination procedures, and repeat vaccination with vaccine from another vial or vaccine lot, if available. If a repeat vaccination using vaccine from another vial or vaccine lot fails to produce a major reaction, consult CDC or state or local health department before giving another vaccination. Patients who are at continued high risk of monkeypox exposure may be revaccinated every 3 years. For booster vaccination, make 15 needle punctures. There may be a reduced cutaneous response to revaccination; do not revaccinate.
      • Postexposure prophylaxis r24r86
        • Vaccinia Virus Strain New York City Board of Health Live Antigen Solution for percutaneous scarification; Adolescents 16 to 17 years: 0.0025 mL (a droplet of vaccine) administered percutaneously onto the arm by rapidly making 15 needle punctures. Administer within 4 days from exposure date to prevent onset of disease. If administered between 4 and 14 days after exposure, vaccination may reduce symptoms of disease, but not prevent disease. If it has been more than 3 years since vaccination, consider revaccinating. If a major reaction is not obtained 6 to 8 days after vaccination, check vaccination procedures, and repeat vaccination with vaccine from another vial or vaccine lot, if available. If a repeat vaccination using vaccine from another vial or vaccine lot fails to produce a major reaction, consult CDC or state or local health department before giving another vaccination. There may be a reduced cutaneous response to revaccination; do not revaccinate.
        • Vaccinia Virus Strain New York City Board of Health Live Antigen Solution for percutaneous scarification; Adults: 0.0025 mL (a droplet of vaccine) administered percutaneously onto the arm by rapidly making 15 needle punctures. Administer within 4 days from exposure date to prevent onset of disease. If administered between 4 and 14 days after exposure, vaccination may reduce symptoms of disease, but not prevent disease. If it has been more than 3 years since vaccination, consider revaccinating. If a major reaction is not obtained 6 to 8 days after vaccination, check vaccination procedures, and repeat vaccination with vaccine from another vial or vaccine lot, if available. If a repeat vaccination using vaccine from another vial or vaccine lot fails to produce a major reaction, consult CDC or state or local health department before giving another vaccination. There may be a reduced cutaneous response to revaccination; do not revaccinate.
    • WHO has also published interim guidance on vaccines and immunization for monkeypox, for international application; WHO and CDC recommendations are largely congruent r87
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