Differentials
Mpox (monkeypox)
SIGNS / SYMPTOMS
Travel history to endemic country or nonendemic country where there is currently a mpox outbreak.
Contact with exotic or unwell animals in endemic areas.
Lymphadenopathy is present in the majority of cases, but is rare in smallpox.
Usually a milder illness and lesions are generally less numerous.
Lesions may be atypical (e.g., localized to the genital, perineal/perianal, or perioral areas).
INVESTIGATIONS
Polymerase chain reaction of lesion material or exudate: positive for monkeypox virus DNA.
Chickenpox
SIGNS / SYMPTOMS
Most common in children <10 years of age.
Lacks history of chickenpox or varicella vaccination.
Vesicles appear in crops (smallpox lesions are all of a similar stage of evolution), are shallow (easily break, unlike deep-seated smallpox lesions), and are located mainly on the trunk (centripetal, the reverse of the centrifugal smallpox rash).
Rash generally evolves more quickly (<24 hours), and lesions on palms or soles are rare.[28]
Prodromal fever is uncommon (mild, if present).[28]
Lymphadenopathy is usually not present.[28]
INVESTIGATIONS
Polymerase chain reaction of vesicle fluid: positive for varicella-zoster virus DNA.
Usually performed automatically by reference laboratory as part of smallpox screening.
Disseminated herpes zoster
SIGNS / SYMPTOMS
May occur in severely immunocompromised patients.
Vesicular rash involves several dermatomes, and visceral involvement may occur.
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 DNA.
Usually performed automatically by reference laboratory as part of smallpox screening.
Syphilis
SIGNS / SYMPTOMS
Generalized rash of secondary syphilis is usually maculopapular and 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.
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 smallpox vaccine vaccinia 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 DNA but negative for smallpox DNA.
Usually performed automatically by reference laboratory as part of smallpox 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 vaccinial 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 DNA.
Usually performed automatically by reference laboratory as part of smallpox screening.
Orf
SIGNS / SYMPTOMS
Usually solitary lesions, not associated with systemic illness.
Patient systemically well.
History of exposure to sheep and/or farms.
INVESTIGATIONS
Polymerase chain reaction of DNA from lesional material: positive for orf (parapox) 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.
Molluscum contagiosum
SIGNS / SYMPTOMS
Localized papular lesions that may show central umbilication but not vesiculation caused by the poxvirus molluscum contagiosum.
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 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.
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