Differentials
Chickenpox
SIGNS / SYMPTOMS
Most common in children <10 years of age.
Lacks history of chickenpox or varicella vaccination.
Vesicles appear in crops (mpox lesions are traditionally all of a similar stage of evolution), are shallow (easily break, unlike typical deep-seated mpox lesions), and located mainly on the trunk (centripetal, the reverse of the typical centrifugal mpox rash).
Rash is usually polymorphic and generally evolves more quickly (<24 hours), and lesions on palms or soles are rare.[168]
Prodromal fever is uncommon (mild, if present).[168]
Lymphadenopathy is usually not present.[168]
No differentiating signs or symptoms if severe disease.
Coinfection is possible.[239] Patients with coinfections were more likely to report symptoms than varicella zoster-alone cases, and less likely than mpox-alone cases. Significantly higher lesion counts have been observed with coinfection cases compared with varicella zoster-alone cases, but less than mpox-alone cases.[240] More severe disease has been reported in patients with varicella zoster coinfection.[25]
INVESTIGATIONS
Polymerase chain reaction of vesicle fluid: positive for varicella-zoster virus DNA.
Usually performed automatically by reference laboratory as part of poxvirus screening.
Disseminated herpes zoster
SIGNS / SYMPTOMS
May occur in severely immunocompromised patients.
Vesicular rash involves several dermatomes, and visceral involvement may occur.
Coinfection is possible. Patients with coinfections were more likely to report symptoms than varicella zoster-alone cases, and less likely than mpox-alone cases. Significantly higher lesion counts have been observed with coinfection cases compared with varicella zoster-alone cases, but less than mpox-alone cases.[240]
INVESTIGATIONS
Polymerase chain reaction of vesicle fluid: positive for varicella-zoster virus DNA.
Herpes simplex
SIGNS / SYMPTOMS
May occur in severely immunocompromised patients.
Rash is not generalized and is not deep-seated.
INVESTIGATIONS
Polymerase chain reaction of vesicle fluid: positive for herpes simplex virus DNA.
Usually performed automatically by reference laboratory as part of poxvirus screening.
Syphilis
SIGNS / SYMPTOMS
Generalized rash of secondary syphilis does not vesiculate; it may extend to the palms and soles.
INVESTIGATIONS
Syphilis serology (e.g., rapid plasma reagin, Treponema pallidum particle agglutination [TPPA] test): positive.
Rapid plasma reagin: nonspecific but reflects disease activity.
TPPA test: specific, but remains positive after effective treatment.
Chancroid
SIGNS / SYMPTOMS
Painful genital papules in early stages, which then pustulate and ulcerate. Ulcers are soft and painful without induration. Buboes form in later stages.
Other symptoms may include urethritis, vaginal discharge, dysuria, dyspareunia, and extra-genital ulcers.
INVESTIGATIONS
Culture or polymerase chain reaction of ulcer swabs or bubo aspirates: positive for Haemophilus ducreyi. Gram stain may be useful and shows gram-negative coccobacilli or slender bacilli in railroad or chaining pattern.
Disseminated gonococcal infection
SIGNS / SYMPTOMS
Lesions may be papules, hemorrhagic pustules, bullae, petechiae, or necrotic, and are usually on the extremities.
Severe joint pain or polyarthritis.
Urogenital symptoms of gonorrhea may be absent in disseminated gonococcal infection.
INVESTIGATIONS
Polymerase chain reaction or culture: positive for gonorrhea.
Lymphogranuloma venereum (LGV)
SIGNS / SYMPTOMS
Painful unilateral inguinal or femoral lymphadenopathy ("groove sign of Greenblatt" may be seen) during secondary stage.
May be present in tertiary stages: genital elephantiasis; saxophone penis; esthiomene; or anogenital sinus tracts, strictures, or fistulae.
Erythema nodosum is occasionally present.
INVESTIGATIONS
Polymerase chain reaction of fluid or swab: positive for LGV-specific Chlamydia trachomatis genovars.
Hand-foot-and-mouth disease
SIGNS / SYMPTOMS
Most common in children <10 years of age.
Vesicles generally confined to the oral mucosa with small lesions on the hands and feet. Illness generally only lasts a few days if no complications.
INVESTIGATIONS
Typically a clinical diagnosis.
Virus isolation (from feces, throat swab, urine, or cerebrospinal fluid) is very labor-intensive.
Serologic tests are prone to cross reactivity and generally only allow retrospective diagnosis.
Viral RNA can be detected by reverse transcription-polymerase chain reaction but this is not routinely available.
Drug reaction
SIGNS / SYMPTOMS
Cutaneous drug reactions may be vesiculobullous, but the lesions are rarely uniform.
Rash is usually generalized.
History of exposure to a new drug.
INVESTIGATIONS
Clinical diagnosis.
Eczema vaccinatum
SIGNS / SYMPTOMS
Inoculation with the live smallpox vaccine can cause a generalized vesicular rash in the presence of eczema.
[Figure caption and citation for the preceding image starts]: Eczema vaccinatum skin lesions on the torso of a smallpox vaccine recipientCDC/Moses Grossman, MD/California Emergency Preparedness Office (Calif/EPO) [Citation ends].
History of vaccination or recent exposure to someone who has been vaccinated on a background of known eczema.
INVESTIGATIONS
Polymerase chain reaction of vesicle fluid: positive for vaccinia virus DNA but negative for monkeypox virus DNA.
Usually performed automatically by reference laboratory as part of poxvirus screening.
Disseminated (generalized) vaccinia
SIGNS / SYMPTOMS
Self-limiting viremic illness from exposure to vaccinia (either deliberate or through contact with a vaccine).
Additional lesions subsequent to and distant from the original inoculation site.
INVESTIGATIONS
Clinical diagnosis that may be confirmed by the demonstration of vaccinia virus DNA in distant lesions.
Erythema multiforme
SIGNS / SYMPTOMS
Vesicular, pleomorphic, often with large vesicles. Often associated with conjunctivitis, stomatitis, and urethritis (Stevens-Johnson syndrome).
INVESTIGATIONS
Clinical diagnosis.
Usually there are no specific diagnostic tests for erythema multiforme, but sometimes the underlying precipitant may be identified (e.g., mycoplasma infection).
Meningococcal septicemia
SIGNS / SYMPTOMS
Purpuric lesions.
INVESTIGATIONS
Polymerase chain reaction of ethylenediamine tetra-acetic acid (EDTA) blood: detection of meningococcal DNA.
Isolation of gram-negative diplococci from blood culture subsequently proven to be Neisseria meningitidis.
Measles
SIGNS / SYMPTOMS
Widespread blotchy rash that does not vesiculate.
Occurs in the context of coryza and conjunctivitis.
INVESTIGATIONS
Raised antimeasles IgM in serum.
Isolation of measles virus from throat swab or urine.
Tanapox
SIGNS / SYMPTOMS
Single or a few localized and slowly evolving lesions that do not pustulate.
Zoonosis found mainly in Kenya and Zaire.
May be preceded by a mild febrile prodrome.
INVESTIGATIONS
Polymerase chain reaction of DNA from lesional material: positive for tanapox virus DNA.
Usually performed automatically by reference laboratory as part of poxvirus screening.
Orf
SIGNS / SYMPTOMS
Usually solitary lesions, not associated with systemic illness.[241]
Patient systemically well.
History of exposure to sheep and/or farms.
INVESTIGATIONS
Polymerase chain reaction of DNA from lesional material: positive for orf (parapox) virus DNA.
Insect bites
SIGNS / SYMPTOMS
Usually bites do not vesiculate or appear as monomorphic lesions (an exception might be sudden exposure to bed bugs).
Absence of prodromal illness or systemic symptoms.
INVESTIGATIONS
Clinical diagnosis.
Acne
SIGNS / SYMPTOMS
Lesions can form pustules typically involving the face, occasionally the trunk, and rarely the limbs.
Prolonged history of acne in the absence of any prodromal illness.
INVESTIGATIONS
Clinical diagnosis.
Oral aphthous ulcers
SIGNS / SYMPTOMS
Risk factors may be present (e.g., local trauma).
Absence of lesions on other parts of the body (particularly perineal/perianal and genital areas).
Absence of systemic symptoms (e.g., fever, myalgia, headache, lymphadenopathy).
INVESTIGATIONS
Clinical diagnosis.
Polymerase chain reaction: negative for monkeypox virus DNA.
Behcet syndrome
SIGNS / SYMPTOMS
Family history may be present.
Common in young people 20-40 years of age.
Diagnosis is based on defined clinical criteria.
Clinical manifestations may involve various organs (e.g., eye, gastrointestinal, vascular, pulmonary, central nervous system).
INVESTIGATIONS
Laboratory testing and imaging are not useful but may play a role in ruling out alternative diagnoses.
Polymerase chain reaction: negative for monkeypox virus DNA.
Molluscum contagiosum
SIGNS / SYMPTOMS
Most common in children, young adults, and immunocompromised people.
Localized papular lesions that may show central umbilication but not vesiculation caused by the poxvirus molluscum contagiosum.
Commonly affects face and genitals, but can occur anywhere.
May be widespread in the immunosuppressed.
Does not cause systemic illness.
INVESTIGATIONS
Clinical diagnosis that may be confirmed by standard histology.
Electron microscopy (not usually performed): reveals typical poxvirions.
Scabies
SIGNS / SYMPTOMS
Symmetrical erythematous papules, vesicles, and excoriations of the web spaces, axillae, areola, periumbilical areas, and male genitalia; typically spares the face in adults.
Presence of burrows is pathognomonic.
Thick crusted lesions with dystrophic nails may be seen in Norwegian scabies.
Does not cause systemic illness.
Positive ink burrows test.
INVESTIGATIONS
Ectoparasite prep shows presence of mites, eggs, or fecal material of mites.
Eczema herpeticum
SIGNS / SYMPTOMS
Severe skin infection caused by herpes simplex virus in patient with eczema.
Characteristic lesions are grouped vesicles or pustules, and may later progress to "punched out" ulcerations.
May affect multiple organs.
INVESTIGATIONS
Clinical diagnosis.
Vesicular fluid polymerase chain reaction testing: positive for herpes simplex virus DNA.
Rickettsialpox
SIGNS / SYMPTOMS
Rash is usually macular or papular in rickettsial diseases but is vesicular in some infections (e.g., rickettsialpox due to Rickettsia akari).
Eschar may be present.
INVESTIGATIONS
Serology is positive for antibodies to Rickettsia species.
Polymerase chain reaction is positive for R akari DNA.
Smallpox
SIGNS / SYMPTOMS
Smallpox has been eradicated so it is very unlikely, unless the patient has a history of contact with a known smallpox repository or is a laboratory worker who accidentally encounters the variola virus while disposing of archival material, or there has been a deliberate release.
Lymphadenopathy is usually absent.
More severe illness and more numerous lesions.
INVESTIGATIONS
Polymerase chain reaction of lesion material or exudate: positive for variola virus DNA.
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