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Human Monkeypox Virus Infection Part 2: What You Need to Know — Clinical Characteristics

  • Authors: Susan L. Smith, MN, PhD
  • CME / ABIM MOC / CE Released: 8/25/2022
  • Valid for credit through: 8/25/2023, 11:59 PM EST
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Target Audience and Goal Statement

This activity is intended for clinicians who work in primary care and public health settings.

The goal of this activity is that learners will be better able to identify the clinical presentation of human-to-human monkeypox virus infection.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Clinical presentation of monkeypox virus infection in the 2022 outbreak
    • Implications for the healthcare team
  • Have greater competence related to
    • Testing for monkeypox virus infection


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  • Susan L. Smith, MN, PhD


    Owns stock (publicly traded) in: Hepion

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    Director, Accreditation and Compliance, Medscape, LLC


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Human Monkeypox Virus Infection Part 2: What You Need to Know — Clinical Characteristics

Authors: Susan L. Smith, MN, PhDFaculty and Disclosures

CME / ABIM MOC / CE Released: 8/25/2022

Valid for credit through: 8/25/2023, 11:59 PM EST


Note: The information on the monkeypox virus outbreak is continually evolving. The content within this activity serves as a historical reference to the information that was available at the time of this publication. We continue to add to the collection of activities on this subject as new information becomes available. It is the policy of Medscape Education to avoid the mention of brand names or specific manufacturers in accredited educational activities. However, manufacturer names related to monkeypox vaccines may be provided in this activity to promote clarity. The use of manufacturer names should not be viewed as an endorsement by Medscape of any specific product or manufacturer.


Before April 2022, monkeypox virus (MPXV) infection in humans was seldom reported outside of the African regions where it was considered endemic.[1] Thus, few practicing health care professionals in the US, aside from those who specialized in tropical medicine or global infectious diseases, had heard of MPXV until recently, when the Centers for Disease Control and Prevention (CDC) reported an outbreak (meaning that the number of cases is greater than expected in a geographical area) of MPXV infection in the US.[2] The first case in this outbreak was confirmed on May 17, 2022. As of August 22, 2022, there were 14,115 confirmed cases in the US, with all states except Wyoming affected,[3] and the US government had declared MPXV infection a public health emergency.[4] As of August 22, 2022, outside the US, more than 40,971 cases have been reported in 87 locations that have not historically reported MPXV, and the World Health Organization (WHO) has declared MPXV a public health emergency of international concern.[5]

Information on the outbreak is evolving, and the CDC is continually evaluating new evidence and adapting response strategies as new information and data on changing case demographics, clinical characteristics, transmission, and vaccine effectiveness become available.[6] Thus, health care professionals are encouraged to refer regularly to the CDC websites Information for Healthcare Professionals and Technical Report: Multi-National Monkeypox Outbreak, United States, 2022 for up-to-date US and global case counts and epidemiologic parameters associated with the outbreak.

This article is the second in a 3-part series intended to help health care professionals understand what MPXV is and its public health importance. Part 1 provides an overview of the ecology and epidemiology of MPXV. The objective of part 2 is to describe the clinical syndrome of MPXV infection, how it is diagnosed, and the associated burden of disease, including stigmatization. Part 3 summarizes current and emerging options for and guidance on prevention and treatment of MPXV infection.

The Clinical Syndrome of MPXV Infection

MPXV infection is a smallpox-like disease. The illness associated with the current outbreak of human-to-human MPXV (hMPXV) infection has 3 stages: the incubation period, prodromal period, and development of a rash (Table 1) that typically lasts 2 to 4 weeks.[7]

Table 1. Stages of hMPXV Infection

Stages Signs and Symptoms
Stage 1: Incubation period Asymptomatic, lasts approximately 1 to 2 weeks
Stage 2: Prodrome Fever and lymphadenopathy do not always precede the rash
Stage 3: Rash (Figure 1) Deep-seated vesicular or pustular rash that often begins centrally and spreads to the limbs


Figure 1. Lesions are firm or rubbery, well-circumscribed, deep-seated, and often develop umbilication (resembles a dot on the top of the lesion). The evolution of lesions progresses through 4 stages--macular, papular, vesicular, and pustular--before scabbing over and desquamating. [Source: CDC.]

Recent surveillance and case-series reports illustrate epidemiologic and clinical characteristics of the current outbreak of hMPXV infection (Table 2). Notably, viremia and shedding of MPXV DNA from the upper respiratory tract have been reported for at least 3 weeks after crusting of cutaneous lesions.[7,8]

Table 2. Epidemiologic and Clinical Characteristics of hMPXV Infections, 2022

Report Demographics Signs and Symptoms

O'Shea et al[9]

Data source: Available summary surveillance data on cases of hMPXV infection in the European Union, England, and the United States

Not reported


  • Prodome* did not always occur
  • Genital and perianal lesions were associated with severe and painful proctitis, urethritis, phimosis, and balanitis
  • Oropharyngeal symptoms: pain or difficulty swallowing, some associated with tonsillitis and epiglottitis


  • Mucosal involvement (genital, perianal, and oropharyngeal) in ~40% of cases

Philpott et al [6]

Data source: 2891 cases of hMPXV infection in the United States, May 17 to July 22, 2022 (analyses restricted to cases with available relevant data available)

  • 99% in men (94% with recent male-to-male sexual or close intimate contact during the 3 weeks before onset of symptoms)
  • 41% in White people, 28% in Hispanic people, 26% in Black people
  • 41% had HIV infection


  • Prodrome* did not always occur
  • Rectal symptoms: purulent or bloody stools (21%), pain (22%), and bleeding (10%)


  • Most common on the genitals (46%), arms (40%), face (38%), and legs (37%)

Thornhill et al[1]

Data source: 528 cases of PCR-confirmed hMPXV infection in 16 countries (43 sites), April 27 to June 24, 2022

  • 98% in gay or bisexual men
  • 41% with HIV infection
  • 75% in White people
  • Median age 38 years


  • Prodrome* did not always occur


  • 64% had fewer than 10 lesions
  • Anogenital lesions (73%), mucosal lesions (41%)
PCR = polymerase chain reaction.
*Prodrome: headache, fever, chills, myalgia, and/or lymphadenopathy preceding rash.
†The rash associated with monkeypox can be confused with other diseases that are encountered in clinical practice, such as secondary syphilis, herpes, chancroid, and varicella zoster.

Diagnosis of MPXV Infection

MPXV infection is diagnosed by a polymerase chain reaction test, the non-variola Orthopoxvirus real-time PCR primer and probe set (nonvariola Orthopoxvirus [NVO]) assay.[10] The CDC recommends that 2 specimens collected by swabs, each from multiple lesions, preferably from different locations on the body, and from lesions with differing appearances be collected for each patient.[10] The swabs should be sent to a Laboratory Response Network laboratory validated to perform the NVO assay in viral transport media. Clinicians who suspect a case of MPXV infection can contact their local or state health department for guidance on handling and submitting specimens. Clinicians can also initiate treatment (described in part 3 of this series) before testing if MPXV infection is suspected on the basis of clinical signs and symptoms and can advise patients to isolate while awaiting test results and take measures to prevent further transmission, such as limiting close contact with others and avoiding the sharing of potential contaminated items.[10]

Who should be tested?

Although most cases in the current outbreak to date have occurred among gay, bisexual, and other men who have sex with men (MSM), any patient, regardless of sexual or gender identity, with a rash consistent with MPXV infection should be considered for testing. One reason is that the characteristic rash associated with MPXV can be confused with the rashes associated with more common sexually transmitted infections (STIs). Three recent analyses provide evidence of concurrent STIs in patients with PCR test-confirmed hMPXV infection. An observational analysis of demographic and clinical characteristics of 54 patients (all MSM) who attended a sexual health center in the UK from May 14 to May 25, 2022, showed that 25% had a concurrent STI.[11] All patients presented with skin lesions, of which 51 (94%) were anogenital. A multicenter, prospective, observational cohort study of 181 patients with PCR test-confirmed hMPXV infection (92% identified as gay, bisexual, or other MSM) who attended 3 sexual health clinics in Madrid and Barcelona, Spain, showed that 17% had a concurrent STI.[12] A retrospective observational analysis of clinical features among 197 people (196 identified as gay, bisexual, or other MSM) with PCR test-confirmed MPXV infection who were tested and managed in a High Consequence Infectious Diseases center in south London, United Kingdom, showed that 31.5% of those screened for STIs had a concurrent STI.[13] The CDC recommends that patients with a characteristic rash should be considered for testing, even if tests for other infectious diseases are positive.[14]

These analyses also shed some light on the clinical course of hMPXV infection. Although prodromal symptoms do not always occur, fever, lymphadenopathy, and myalgia were common findings.[11-13] In addition, although uncommon, hospitalization occurred for pain from rectal involvement and penile swelling,[13] bacterial cellulitis,[13] and bacterial abscess.[11,12]

Monkeypox and Stigma

Stigma is associated with STIs in general and hinders efforts to test for, disclose, treat, and prevent them, as well as negatively affects the health and quality of life of persons with STIs.[15] "Monkeypox" is actually a misnomer because the virus does not originate in monkeys. The name comes from the discovery of MPXV in monkeys imported from Singapore in a Danish laboratory in 1958.[16,17] On July 26, 2022, the New York City Department of Health and Mental Hygiene sent a letter to the director-general of WHO asking that monkeypox be renamed as soon as possible, expressing serious concern use the stigma the term may engender, and "the painful and racist history within which terminology like this is rooted for communities of color."[18] 

For tips on messaging to general and gay and bisexual men audiences, the CDC recommends that MPXV be described as a legitimate public health issue that is relevant to all people.[19] Communication strategies for decreasing stigma include:[15]

  • Using inclusive language (ie, us and we pronouns)
  • Using positive, diverse, and credible language and images vs nonsensationalistic language and images
  • Emphasizing prevention strategies, recognition of symptoms, and the treatable nature of monkeypox to minimize fear and promote action and a sense of personal agency

Clinical Implications

  • The clinical presentation of hMPXV infection is a syndrome that may or may not include a prodrome (fever, lymphadenopathy, and/or myalgia) that precedes the development of a rash on the face and distal extremities and painful lesions of the oral, perianal, and/or rectal mucosa. Cellulitis and abscess of perianal and rectal lesions can occur.
  • MPXV infection is diagnosed by a PCR test, the non-variola Orthopoxvirus real-time PCR primer and probe set (NVO) assay.
  • Although most cases in the current outbreak to date have occurred among gay, bisexual, and other MSM, any patient, regardless of sexual or gender identity, with a rash consistent with MPXV infection should be considered for testing. The CDC recommends that clinicians collect 2 specimens by swabs, each from multiple lesions, preferably from different locations on the body, and from lesions with differing appearances for each patient.


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