Approach

A definitive diagnosis can only be considered if the appropriate clinical case definition has been met, and the diagnosis has been confirmed by laboratory testing.

A high index of suspicion is recommended when evaluating people with a characteristic rash, particularly if the patient meets one of the epidemiologic criteria. As the clinical presentation may be atypical, include mpox in the differential diagnosis when a patient presents with a sexually transmitted infection (STI)-associated or STI-like rash, even if the rash is localized and not (yet) diffuse.[138]

Mpox is a notifiable condition and one case is considered an outbreak. Immediately report suspected cases to national or local public health authorities, regardless of whether you are also exploring other potential diagnoses.

Screening and triage

Perform screening and triage at the first point of contact with the health system for all people who present with a rash and fever or lymphadenopathy in order to identify people that have suspected or confirmed infection.[1]

  • A simplified questionnaire and screening protocol based on the World Health Organization (WHO) case definition (and adapted to local epidemiology) can be implemented at the point of entry to health care.

  • Conduct screening activities while maintaining a distance of at least 3 feet (1 meter) from the patient and using a "no touch" approach. Screening may be performed using telemedicine in certain situations, according to local pathways.

  • Enter patients with symptoms that meet the case definition for suspected infection into the mpox clinical care pathway immediately. Provide the patient with a well-fitting medical mask and isolate them in a well-ventilated single room.

  • Triage patients with suspected infection using a standardized triage tool.

Infection prevention and control

Immediately contact your regional infectious disease unit if there is a clinical suspicion of infection.

  • This will trigger procedures to be activated for the safe transfer of the patient to a negative-pressure isolation facility and the notification of the public health team.

  • It is important to keep records of everyone who has been in close contact with the symptomatic patient (e.g., household contacts, paramedical and medical staff) and whether there are any potential animal carriers present.

  • All suspected cases should be managed by experts, including public health officials, to prevent a potential emergency situation.

Follow your local infection prevention and control protocols.[1]

  • Standard, contact, and droplet precautions are recommended.

  • Airborne precautions are recommended when caring for suspected cases of mpox if chickenpox is suspected and until it is excluded. Respirators are recommended when caring for patients with confirmed mpox. Airborne precautions are recommended if aerosol-generating procedures are performed.

  • Treat all contaminated materials (e.g., linens, hospital gowns) and body fluids/solid waste of patients as potentially infectious.

Ideally all personnel likely to be in contact with the patient, bodily fluids, or fomites should have been vaccinated with the smallpox vaccine.[68]

  • Postexposure vaccination may be recommended for unvaccinated contacts (see Prevention).

  • Healthcare workers who are pregnant or severely immunocompromised should not assess or care for patients with suspected or confirmed infection, where possible.[139]

History

Consider the diagnosis in patients who present with an unexplained acute rash, particularly if the patient meets one of the epidemiologic criteria in the 21 days before symptom onset.

  • Epidemiologic criteria include:[81][140][141]

    • Recent travel to an endemic country (or country with a current outbreak)

    • Contact with a suspected, probable, possible, or confirmed case (or contaminated materials)

    • Intimate physical contact (including sexual contact) with people in a social network currently experiencing mpox activity (e.g., men who have sex with men [MSM]), or multiple and/or casual sexual partners

    • Contact with African-endemic species of wild animals or exotic pets (dead or alive) or products derived from these animals.

  • Epidemiologic criteria and case definitions vary between regions. Consult your local public health authority for more information. For case definitions, see Criteria.

It is important to note that not all at-risk MSM will identify as being at risk, or will disclose this information.[142]

Determine the HIV status of all sexually active adults and adolescents, as patients with HIV-associated immunocompromise are at a higher risk for severe manifestations.[101]

Clinical presentation

During the incubation period (range 5 to 21 days), the patient usually does not have any symptoms and may report feeling fine. Patients typically develop a prodrome before the appearance of the rash/lesion(s), which may last 1 to 5 days. However, constitutional symptoms may occur after the appearance of the rash, and some patients may have no symptoms at all.[143][144][145][146]

Common symptoms include:[1][67][143]

  • Rash/lesion(s)

  • Anorectal symptoms

  • Fever

  • Chills

  • Lymphadenopathy

  • Fatigue/asthenia/malaise

  • Myalgia

  • Headache

  • Sore throat

  • Backache

  • Cough

  • Nausea/vomiting.

Less common symptoms include:[1][67]

  • Diarrhea

  • Delirium/confusion

  • Seizures.

Skin rash/lesion(s) (95%), fever (58%), and lymphadenopathy (53%) have been the most common symptoms reported in the 2022 global outbreak. Anorectal pain/proctitis has been reported in 18.5% of patients.[12] 

Severe and intense anorectal pain (including severe pain on defecation), tenesmus, rectal bleeding, or purulent or bloody stools associated with perianal/rectal lesions and proctitis has been an atypical presentation in the 2022 global outbreak. Patients presenting with proctitis may have no signs of a rash.[143][144][145][147][148][149] Men who engaged in anal-receptive sex presented with proctitis more frequently than men who did not engage in anal-receptive sex.[150] 

Special patient populations

  • Children and adolescents: clinical presentation is similar to adults.[94] Severe complications have been reported in infants and young children.[95]

  • Pregnant women: clinical presentation is similar to nonpregnant people.[96]

  • Immunocompromised people (including people with advanced or uncontrolled HIV infection): may present with atypical manifestations or a more severe illness (e.g., sepsis, disseminated rash, hemorrhagic disease, numerous confluent lesions, necrotic lesions, severe lymphadenopathy that may be obstructing, ocular or periorbital infections, pulmonary involvement, encephalitis, myocarditis, or other complications requiring hospitalization).[19][20][151]​ Patients with HIV may be more likely to have diarrhea, perianal rash/lesions, and a higher rash burden.[152]

Case definitions vary between regions. Consult your local public health authority for more information. For case definitions, see Criteria.

Physical exam

A rash or skin lesion(s) are usually the first sign of infection. Physical exam may reveal a rash or lesion(s), and possibly lymphadenopathy. Perform a thorough skin and mucosal (e.g., anal, vaginal, oral, nasal, ophthalmic) exam.[147] Exam may reveal lesions that the patient may not be aware of, or may reveal no lesions at all.​

Traditionally, patients develop a characteristic rash approximately 1 to 3 days after the onset of an acute febrile illness. The rash generally starts on the face and body and spreads centrifugally to the palms and soles (it may be preceded by a rash affecting the oropharynx and tongue in the 24 hours prior that often passes unnoticed). Lesions simultaneously progress through four stages - macular, papular, vesicular, and pustular - with each stage lasting 1 to 2 days, before scabbing over and resolving. Lesions are typically 5 to 10 mm in diameter, may be discrete or confluent, and may be few in number or several thousand. Vesicles are well-circumscribed and located deep in the dermis. The rash usually resolves over a period of 2 to 4 weeks.[1][67][68]​​​​​​[129][143]

In the 2022 global outbreak, the presentation has been atypical, with the rash presenting primarily in the anogenital region.[38]​ Lesions tend to be localized to the genital, perineal/perianal, or perioral areas and often do not spread further, suggesting that transmission occurs as a result of contact during sexual intercourse, with lesions possibly starting at the site of inoculation.[48][143][153][154][155][156][157]​​ A larger number of lesions in the mouth and throat has been linked to oral sex, and a larger number of lesions in the perianal area has been linked to anal-receptive sex.[150]

Other atypical features include:[48][143][145]​​​​[158]

  • Presentation of only a few lesions (or even just a single lesion) and may not be disseminated

  • Absence of skin lesions and anal pain and bleeding

  • Lesions appearing at different stages of development (asynchronous)

  • Rash does not always appear on palms and soles

  • Appearance of lesions before the prodrome.

[Figure caption and citation for the preceding image starts]: Images of individual lesions (2022 global outbreak)UKHSA [Citation ends].com.bmj.content.model.Caption@7b4da84

Most patients (64%) have <10 lesions, with approximately 10% of patients having only a single genital lesion.[73] Atypical single lesions can mimic abscesses and other deep-tissue phenomena.[142] Approximately one third of patients presented with lesions at different stages of evolution at a single time point in one study.[145]

The most common type of lesions in the outbreak have been anogenital lesions (66%). Oropharyngeal/oral lesions have been present in 21% of patients.[12] Oral lesions may be observed in different parts of the oral mucosa including the lips, tongue, and, most commonly, the tonsils. Lesions have also been reported in the esophagus.[159][160]​​ Rarely, auricular lesions may occur.[161]

Although most patients in the outbreak have been men, localized genital lesions (vulvar and intravaginal) and cervical lesions have been reported in women.[162][163][164][165]​​​​ Vulvovaginal lesions have been predominant in cisgender women and anorectal features have been predominant in transgender women, anatomically reflecting sexual practices.[21]

Lesions may be classified as papules, vesicles, blisters, pustules, erosions, ulcers, or crusts.[166] They may be painful initially, and become itchy during the healing phase. 

Lesions on the external genitalia may cause severe swelling and pain. Oral lesions may cause difficulties with eating and drinking, which may lead to dehydration and malnutrition. Patients may present with the following complications depending on the location of the rash/lesion(s) (see Complications):[145][146][167]​​​​​

  • Severe penile or scrotal edema, paraphimosis/phimosis, balanitis

  • Tonsillitis, peritonsillar cellulitis, tonsillar/peritonsillar abscess, epiglottitis

  • Perianal/groin abscess, rectal perforation

  • Urinary retention, urethritis.

Erythematous maculopapular, generalized purpuric, and morbilliform rashes have been reported in some patients in the 2022 global outbreak.[145][166][168]​​​

Lymphadenopathy

  • Lymphadenopathy may be generalized or localized to several areas. It typically occurs with onset of fever and preceding the rash or, rarely, with the onset of the rash. May be submandibular, cervical, axillary, or inguinal, and may occur on both sides of the body or just one side.

  • Enlarged lymph nodes are approximately 1 to 4 cm in diameter, firm, tender, and sometimes painful.[129]

  • Lymphadenopathy is a common distinguishing feature, but is rare in smallpox and other diseases in the differential diagnosis.[1][31][67][129]

Disease severity and risk factors for severe disease

Most cases are mild, but the spectrum of disease ranges from mild to severe, and can be fatal.

  • Disease severity depends on the initial health of the patient, their immune response, previous vaccination status, presence of comorbidities, the route of exposure, and the virus strain.[105][143] The Clade II virus is associated with milder disease compared with the Clade I virus.[5]

  • Asymptomatic infection has been described, but the extent to which asymptomatic infection may occur is unknown.[67][68][69]

  • Immunity from past vaccination substantially reduces the frequency and intensity of clinical signs and symptoms.[5]

Evaluate the patient to determine whether they have signs and symptoms of severe or complicated disease.[1]

  • Clinical signs and symptoms of complications:

    • Nausea and vomiting

    • Painful cervical lymphadenopathy causing dysphagia

    • Poor oral intake or dehydration

    • Eye pain or vision abnormalities

    • Hepatomegaly

    • Sepsis

    • Respiratory distress/pneumonia

    • Confusion.

  • Laboratory abnormalities:

    • Elevated hepatic transaminases

    • Low blood urea nitrogen

    • Hypoalbuminemia

    • Leukocytosis

    • Thrombocytopenia.

  • Skin lesion severity score:

    • Mild (<25 lesions)

    • Moderate (25-99 skin lesions)

    • Severe (100-250 skin lesions)

    • Very severe (>250 skin lesions).

In the US, the Centers for Disease Control and Prevention defines severe disease as patients with:[105]

  • A large number of lesions such that they are confluent

  • Hemorrhagic disease

  • Necrotic lesions

  • Severe lymphadenopathy that can be necrotizing or obstructing (e.g., in airways)

  • Involvement of multiple organ systems and associated comorbidities (e.g., sepsis, encephalitis, myocarditis, ocular or periorbital infections, pulmonary involvement with nodular lesions)

  • Any other condition that requires hospitalization.

Evaluate the patient to determine whether there are any risk factors present. Patient groups at higher risk of severe disease or complications include:[1][105][169]

  • Children (particularly <8 years of age)

  • Pregnant or breastfeeding women

  • Immunocompromised people (e.g., advanced or poorly controlled HIV infection, malignancy, transplant recipients, autoimmune disease with immunodeficiency)

  • People with acute or chronic skin conditions.

When assessing patients with HIV infection, consider viral suppression and CD4 count when determining the patient’s risk of severe outcomes.[19][20]

Initial investigations

Definitive diagnosis requires laboratory confirmation. Testing is available at regional public health laboratories.

  • Testing should be conducted in patients with suspected infection as soon as possible.[1] Offer testing to any person who meets the case definition for a suspected, possible, or probable case.[170] The decision to test should be based on both clinical and epidemiologic factors, linked to an assessment of the likelihood of infection.

  • Undertake diagnostic testing for other diseases in the differential diagnosis in parallel with mpox testing.[171]

  • Patients should remain in isolation while their test result is pending.

Nucleic acid amplification testing (NAAT), using real-time polymerase chain reaction (RT-PCR) or conventional PCR, is the preferred laboratory test given its accuracy and sensitivity.[170][171][172][173][174]

  • NAAT can be generic to Orthopoxvirus or specific to monkeypox virus (preferable).

  • Caution is required when interpreting a single test result in patients with a low pretest probability of infection (e.g., lack of epidemiologic link, non-MSM populations, signs/symptoms inconsistent with mpox) due to the risk of a false-positive result.[175] A positive test for Orthopoxvirus or monkeypox virus DNA in a person without epidemiologic criteria or known risk factors should be verified by repeat testing and/or confirmatory testing, and other possible causes of rash considered.[176] Repeat testing (re-extraction and retesting of the specimen) is recommended in patients with high RT-PCR cycle threshold values (i.e., ≥34), as this indicates a low level of viral DNA and poorly- or noninfectious specimens.[175][177]

  • Sequencing is useful to determine virus clade and to understand epidemiology.

The recommended specimen type is skin lesion material, including swabs of lesion exudate, roofs from more than one lesion, or lesion crusts.[170][171][172]​ Skin lesion swabs are the most effective means of detecting monkeypox virus DNA using PCR.[178][179]​ Specimen type may vary depending on the phase of the rash.

  • Aspiration or unroofing of lesions before swabbing is not necessary (or recommended) due to the risk for sharps injury.

  • Collect other diagnostic material as dictated by the reference laboratory protocol, such as oropharyngeal swabs, ethylenediamine tetra-acetic acid (EDTA) blood, or urine.

  • Oropharyngeal swabs are recommended for high-risk contacts of a confirmed or highly probable case who have developed systemic symptoms but do not have a rash or lesion for sampling. A throat swab should also be taken if there are pharyngeal lesions.[171] However, viral load is higher in lesion swabs than in pharyngeal specimens, and oropharyngeal swabs are known to be unreliable standalone specimen types for primary diagnosis.[150][180]

  • There are limited clinical data to support the use of sample types other than swab samples taken directly from a lesion (e.g., blood, saliva). Testing samples not taken from a lesion may lead to false positive results.[181][182][183]

Collect, label, package, and send specimens according to local or national protocols. Notify the laboratory of the possibility of mpox prior to sending specimens. There are local protocols in place for the safe handling of these specimens in the laboratory and onward transport of virologic materials to the reference laboratory. Package samples for testing for other infections separately.

Also order routine blood tests in patients, including:

  • Complete blood count

  • Urea and electrolytes

  • Liver function tests.

Test all sexually active adults and adolescents for HIV infection and other STIs.[101]

Other investigations

Consider a computed tomography (CT) scan of the abdomen/pelvis in patients with severe anorectal proctitis. Contrast-enhanced CT may reveal circumferential anorectal mural thickening with broad discrete nonenhancing hypoattenuated zones due to intramural ulcers. Additional findings may include perirectal fat infiltration, presacral edema, ascites, and an increased number of small inguinal lymph nodes.[184]

Order a blood culture while the patient is in isolation and prior to antibiotic therapy, if there is suspicion of bacterial superinfection of cutaneous lesions or bacterial infection in a very sick patient.

Serology, cell culture, and antigen detection methods are not currently recommended for diagnosis.

  • Serology (paired serum samples collected at least 21 days apart, with the first collected during the first week of illness) can aid diagnosis if tested samples yield inconclusive results. Recent vaccination may interfere with serologic testing.[170] Serology may be helpful in epidemiologic investigations, retrospective diagnosis of past infections, and diagnosis of late clinical manifestations.[185] Orthopoxviruses are serologically cross-reactive; therefore, serologic testing is not specific to mpox.[186]

  • Cell culture is restricted to accredited biosafety level 3 reference laboratories. The major disadvantage of culture-based diagnosis is the prolonged assay time, which is not suitable for mass testing scenarios.[174][185]

Always rule out coinfection with malaria in any febrile patient who has been to a malaria-endemic area, especially in the 3 weeks prior to onset of fever. An antigen detection test poses less of an infection hazard to laboratory staff than preparation of thick and thin films.

Several diagnostic methods are emerging. CRISPR-based assays are in development as a faster alternative to PCR, but are not yet available.[187] Loop-mediated isothermal amplification (LAMP) assays for the specific detection of monkeypox virus are also in development.[174][188] Image analysis-based tools are in development.[174]

Differential diagnosis

The rash may be confused with other diseases that are more commonly encountered in clinical practice.[189]

  • Keep in mind possible differential diagnoses as these are far more likely to be the cause (mpox is usually rare but may be more common in certain populations in the event of an outbreak).

  • Clinical features may easily be confused with some STIs or other etiologies of proctitis. Therefore, it is important to comprehensively evaluate patients presenting with genital/perianal ulcers or proctitis for STIs, and to consider mpox in the differential diagnosis. However, STI coinfections are possible, and the presence of an STI does not rule out mpox.[138][147]

  • Coinfections with other infectious agents are also possible. Coinfection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been reported, and SARS-CoV-2 positivity and influenza-like symptoms should not exclude testing for mpox in a high-risk individual.[190]

  • See Differentials.

Children and adolescents

  • The rash may be confused with other rash illnesses that are common in children (e.g., chickenpox, hand-foot-and-mouth disease, measles, scabies, molluscum contagiosum, allergic skin rashes, drug reactions). Children and adolescents presenting with signs and symptoms suspicious for mpox should be tested, particularly if they meet epidemiologic criteria.[94]

Pregnancy

  • The cause of fever may be difficult to differentiate from other infections (e.g., chorioamnionitis) until the rash appears. A rash in a pregnant woman with risk factors for mpox needs to be differentiated from dermatoses of pregnancy.[96] Common causes of a vesiculopustular rash in pregnant women (e.g., varicella zoster, syphilis, herpes simplex) can be excluded with PCR testing.[97]

The Centers for Disease Control and Prevention has published a useful technical presentation for clinicians that contains images of the rash associated with mpox and the rash associated with common differential diagnoses.

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