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.

There is currently an ongoing outbreak across several countries. A high index of suspicion is recommended when evaluating people with a characteristic rash, particularly if the patient meets one of the epidemiological criteria. As the clinical presentation may be atypical in this outbreak, include monkeypox in the differential diagnosis when a patient presents with a sexually transmitted infection (STI)-associated or STI-like rash, even if the rash is localised and not (yet) diffuse.[111]

Monkeypox 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.[22]

  • 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 1 metre 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 monkeypox 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 standardised 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.[22]

  • Standard, contact, and droplet precautions are recommended.

  • Airborne precautions are recommended when caring for suspected cases of monkeypox if chickenpox is suspected and until it is excluded. Respirators are recommended when caring for patients with confirmed monkeypox. 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.[112] 

  • Post-exposure 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.[113]

History

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

  • Epidemiological criteria include:[70][114][115]

    • 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 monkeypox 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.

  • However, epidemiological 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 MSM will identify as being at risk, or will disclose this information.[116]

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 a characteristic rash.

Common symptoms include:[22][66][117]

  • Rash

  • Fever

  • Chills

  • Lymphadenopathy

  • Headache

  • Backache

  • Myalgia

  • Pharyngitis

  • Cough

  • Asthenia

  • Malaise

  • Nausea/vomiting.

Less common symptoms include:[22][66]

  • Diarrhoea

  • Delirium/confusion

  • Seizures.

The prodromal period usually lasts 1 to 5 days, and the person may be contagious during this period. There is currently no evidence that people are infectious before the onset of the prodromal illness. The highest risk for onwards transmission of infection is from the onset of the prodrome until the lesions have scabbed over and fallen off.[113]

Multi-country outbreak (2022)

  • The clinical presentation has been variable, but many cases are not presenting with the classical clinical picture. Atypically, constitutional symptoms may occur after the appearance of the rash, and some patients may have no prodromal symptoms at all.[17][117][118] Many patients have no symptoms at all.[119]

  • Data from the largest study of confirmed cases to date indicate common symptoms preceding the rash included:[44]

    • Fever (62%)

    • Lymphadenopathy (56%)

    • Lethargy (41%)

    • Myalgia (31%)

    • Headache (27%)

    • Pharyngitis (21%)

    • Proctitis or anorectal pain (14%).

  • Some patients may present with severe/intense anorectal pain (including severe pain on defecation), tenesmus, rectal bleeding, or purulent or bloody stools, associated with perianal/rectal lesions and proctitis (initial skin lesions may be absent).[17][117][118][120][121]

    • Patients presenting with proctitis may have no signs of a rash.[122]

    • Men who engaged in anal-receptive sex presented with proctitis more frequently than men who did not engage in anal-receptive sex.[54]

  • Lesions on the external genitalia may cause severe swelling and pain.[7]

  • Specific case definitions for this outbreak are available, and these case definitions may change as investigations continue into the outbreak. Case definitions vary between regions. Consult your local public health authority for more information. For case definitions, see Criteria.

Special patient populations

  • Children and adolescents: clinical presentation is similar to adults.[74] Severe complications have been reported in infants and young children.[75]

  • Pregnant women: clinical presentation is similar to non-pregnant people.[76]

  • Immunocompromised people (including people with advanced or uncontrolled HIV infection): may present with atypical manifestations (e.g., disseminated rash, confluent or partially confluent rash, skin necrosis) or a more severe illness (e.g., sepsis).[81][82][123]

  • HIV infection: clinical presentation is similar to those without HIV infection.[124]

Physical examination

Physical examination usually reveals a rash and possibly lymphadenopathy. Perform a thorough skin and mucosal examination (e.g., anal, vaginal, oral, nasal, ophthalmic) for the characteristic vesiculo-pustular rash.[120] Examination may reveal lesions that the patient may not be aware of.

Rash/lesions (typical)

  • Shortly after the prodromal period, a characteristic rash develops. The rash usually presents 1 to 3 days after the onset of the acute febrile illness, and typically spreads to all parts of the body within 24 hours. The rash often affects the palms and soles. The lesions simultaneously progress through four stages (macular, papular, vesicular, and pustular) before scabbing over and resolving, typically over a period of 2 to 4 weeks.[22][66][117][125]

    • Lesions are typically described as painful until the healing phase when they become itchy. They may occur in the oral cavity, which can cause difficulties with eating and drinking, which may lead to dehydration and malnutrition.

    • The skin rash (exanthem) is preceded by a rash affecting the oropharynx and tongue (enanthem) in the 24 hours prior that often passes unnoticed.

  • Lesions are all of a similar stage of maturation on any part of the body, and tend to be more concentrated on the face and extremities (centrifugal) rather than on the trunk. Lesions range in size from 0.5 to 1 cm in diameter (but can be larger), and there may be few or several thousand. Lesions may be inflamed causing mild erythema and/or skin hyperpigmentation, and may be discrete or confluent.[22][66][112][117][125] 

    • Lesions may affect oral mucous membranes (in 70% of cases), genitalia (30%), and conjunctivae (20%), as well as the cornea (eyeball). In severe cases, lesions can coalesce until large sections of skin slough off.

    • The rash in the 2003 US outbreak was monomorphic in 68% of cases, pleomorphic in 29%, and absent in 3%. Localised lesions were seen in 26% of cases; when generalised, the peripheries were usually more obviously affected in 48% but an even distribution occurred in 23% and the trunk was more affected in 3%. Only 5 to 25 lesions were present in 47% of cases, with 26 to 100 lesions in 33% and >100 lesions in 20%.[33]

    • Differences in the appearance of the rash have been noted in vaccinated versus unvaccinated people. Vaccinated people tend to have fewer lesions, smaller lesions, and better representation of the centrifugal distribution.[125]

  • As the rash develops, macules progress to papules within 1 to 2 days. Papules then progress to vesicles within another 1 to 2 days.[22][66][117][125] 

    • The vesicles are well-circumscribed and located deep in the dermis, so individual vesicles do not readily rupture (unlike varicella and herpes simplex vesicles).

  • As the rash progresses, vesicles progress to pustules in another 1 to 2 days.[22][66][117][125] 

    • Pustules subsequently umbilicate before scabbing over and gradually separating after approximately 2 weeks.

    • Once the scab drops off, the person is no longer considered contagious. A depressed scar or areas of pigmentation may remain, most notably on the face.

  • The occurrence of a second febrile period when the lesions become pustular has been associated with deterioration of the patient’s general condition.[125]

Rash/lesions (2022 outbreak)

  • Nearly all patients present with a rash. However, rash lesions in this outbreak may be atypical.

    • Lesions tend to be localised to the genital, perineal/perianal, or perioral areas and often do not spread further. This suggests transmission occurs as a result of contact during sexual intercourse, with lesions possibly starting at the site of inoculation.[10][117][126][127][128][129][130] 

    • 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.[54]

    • Although most patients are men, localised genital lesions have also been reported in women.[131]

  • Other atypical presentations include:[10][117][132]

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

    • Absence of skin lesions with 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.

  • Approximately one third of patients presented with cutaneous manifestations at different stages of evolution at a single time point in one study.[118] Atypical single lesions can mimic abscesses and other deep-tissue phenomena.[116]

  • An erythematous maculopapular rash of varying distribution and rapid onset, separate to areas of blistering or pustules, has also been reported in some patients.[118]

  • Data from the largest study of confirmed cases to date indicate that 95% of patients presented with a rash.[44]

    • 64% had <10 lesions

    • 73% had anogenital lesions

    • 41% had mucosal lesions (e.g., anogenital, oropharyngeal, urethral, nasal, eye)

    • 10% had only a single genital lesion.

  • As a consequence of the concentration of lesions in the genital, perineal/perianal, or perioral areas, patients may present with the following complications:[7][54][118][119][133]

    • Severe penile oedema, paraphimosis/phimosis, balanitis

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

    • Perianal/groin abscess, rectal perforation

    • Urinary retention, urethritis.

  • The presentation may easily be confused with some STIs (e.g., syphilis, herpes, lymphogranuloma venereum) or other aetiologies of proctitis.[120]

    • Evaluate any patient with perianal or genital ulcers, diffuse rash, or proctitis for STIs according to your local guidelines.

[Figure caption and citation for the preceding image starts]: Images of individual lesions (multi-country outbreak 2022)UKHSA [Citation ends].com.bmj.content.model.Caption@7a27bdaa

Lymphadenopathy

  • Lymphadenopathy may be generalised or localised 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.[125]

  • Lymphadenopathy is a common distinguishing feature, but is rare in smallpox and other diseases in the differential diagnosis.[22][33][66][125]

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.[86][117] 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.[66][112]

  • 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.[22]

  • 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 urea

    • Hypoalbuminaemia

    • 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 UK, severe disease is defined as:[134]

  • Adults with severe clinical illness (e.g., National Early Warning Score [NEWS] 2 score of ≥5), which may include significant lower respiratory symptoms, confusion/encephalitis, and other complications (e.g., secondary bacterial infection, sepsis)

  • Widely disseminated lesions and very many in number (≥100)

  • Suspected infection of the cornea

  • Severe, refractory pain from lesions requiring hospitalisation to achieve symptomatic control

  • Lesions associated with complications due to pain or swelling (e.g., constipation, urinary retention, inability to swallow)

  • Confirmed infection, regardless of severity, in immunocompromised people, pregnant women, or children aged ≤16 years.

In the US, severe disease is defined as patients with:[86]

  • A large number of lesions such that they are confluent

  • Sepsis

  • Encephalitis

  • Haemorrhagic disease

  • Ocular or periorbital infections

  • Any other condition that requires hospitalisation.

Evaluate the patient to determine whether there are any risk factors present. Patient groups at higher risk of severe disease or complications include:[22][86][134]

  • 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

  • People with one or more complication(s).

Use clinical judgement to assess the extent of immunosuppression. When assessing patients with HIV infection, consider viral suppression and CD4 count when determining the patient’s risk of severe outcomes.[81][82]

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.[22] Offer testing to any person who meets the case definition for a suspected, possible, or probable case.[135] The decision to test should be based on both clinical and epidemiological factors, linked to an assessment of the likelihood of infection.

  • Undertake diagnostic testing for other diseases in the differential diagnosis in parallel with monkeypox testing.[136]

  • 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.[135][136][137][138]

  • 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 epidemiological link, non-MSM populations, signs/symptoms inconsistent with monkeypox) due to the risk of a false-positive result.[139] A positive test for Orthopoxvirus or monkeypox virus DNA in a person without epidemiological criteria or known risk factors should be verified by repeat testing and/or confirmatory testing, and other possible causes of rash considered.[140] 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 non-infectious specimens.[139][141]

  • 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.[135][137] Skin lesion swabs are the most effective means of detecting monkeypox virus DNA using PCR.[142] Specimen type may vary depending on the phase of the rash.

  • 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.[136] 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.[54][143]

  • 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.[144][145]

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

Also order routine blood tests in patients, including:

  • Full blood count

  • Urea and electrolytes

  • Liver function tests.

Other investigations

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 serological testing.[135] Serology may be helpful in epidemiological investigations, retrospective diagnosis of past infections, and diagnosis of late clinical manifestations.[146]

  • Cell culture is restricted to accredited biosafety level 3 reference laboratories.[146]

Always rule out co-infection 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.

CRISPR-based assays are in development as a faster alternative to PCR, but are not yet available.[147]

Differential diagnosis

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

  • Keep in mind possible differential diagnoses as these are far more likely to be the cause (monkeypox is usually rare).

  • Co-infections with other infectious agents are also possible.

  • 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 monkeypox should be tested, particularly if the children meet epidemiological criteria.[74]

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 monkeypox needs to be differentiated from dermatoses of pregnancy.[76] Common causes of a vesiculopustular rash in pregnant women (e.g., varicella zoster, syphilis, herpes simplex) can be excluded with PCR testing.[77]

Multi-country outbreak (2022)

  • The clinical features may easily be confused with an STI. Therefore, it is important to comprehensively evaluate patients presenting with genital or perianal ulcers for STIs, and to consider monkeypox in the differential diagnosis. However, co-infections are possible, and the presence of an STI does not rule out monkeypox.[111]

  • Co-infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is possible, and SARS-CoV-2 positivity and influenza-like symptoms should not exclude testing for monkeypox in a high-risk individual.[148]

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

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