a 45-year - old man with a lifelong history of atopic dermatitis had a year - long unremitting exacerbation for which he had started systemic therapy . after treatment with cyclosporine for several weeks , laboratory abnormalities and nonspecific neurologic signs prompted a switch to methotrexate . within 4 weeks , he was hospitalized ( in an overseas us military hospital ) for generalized umbilicated papulopustules accompanied by profound hypothermia , hypotension , and mental status changes . he had large pustules on his trunk , inner thighs , and upper extremities ( figure 1 , panel a ) . he was transferred to our intensive care unit with widespread umbilicated pustules and normal mental status . the pustules were deep seated , monomorphic , dome shaped , and firm and were distributed densely on the patient s forearms and abdomen ( figure 1 , panels b and c ) . clinical photographs of the patient . a ) patient with generalized pustules , which were deep seated , monomorphic , dome shaped , and firm and were distributed densely on forearms and abdomen . c ) umbilicated papulopustules in the same stage of evolution ; no herpetiform clusters or red areolae are seen around the lesions . at our hospital , his oral temperature fluctuated dramatically , from 89.3f to 101.3f , with rectal confirmation < 95f ( < 35c ) , indicating hypothermia ( 5 ) . we performed a tzanck preparation , which showed multinucleated giant keratinocytes with nuclear molding and margination ( appendix figure ) . a direct fluorescent antibody ( dfa ) test was positive for varicella zoster virus ( vzv ) . a biopsy specimen showed epithelial necrosis with cellular ballooning and multinucleated giant cells , plus intranuclear inclusion bodies ( figure 2 , panels a and b ) . subsequently , special immunohistochemical stains were positive for herpes simplex virus ( hsv ) ( figure 2 , panel c ) , and a viral culture grew hsv type 2 . his illness was diagnosed with disseminated hsv concurrent with underlying atopic dermatitis ( i.e. , eczema herpeticum ) . c ) positive immunohistochemical stain for herpes simplex virus . within minutes of the tzanck smear evaluation , our patient was given intravenous acyclovir . when cutaneous improvement was evident , he was switched to oral valacyclovir . within days , his skin lesions largely resolved without conspicuous crusting or scarring , but he remained intermittently hypothermic for several weeks . this patient was markedly ill on admission and had a distinctive varioliform eruption with lesions in a uniform stage of evolution . tzanck preparation promptly confirmed herpetic etiology , but we nevertheless used cdc s algorithm for evaluating agvpri , and our patient s illness stratified to high risk . cdc has 3 major diagnostic criteria to designate a case as high risk for smallpox ( table ) ( 6 ) . the first is febrile prodrome , which typically lasts 14 days before cutaneous lesions appear and must include > 1 of the following : prostration , headache , backache , chills , vomiting , or severe abdominal pain . although our patient s illness eventually met the fever criterion , his 101f temperature occurred only after he began antiviral treatment . prolonged hypothermia is associated with severe illness ( 7 ) and is equivalent to fever in determining critical illness ( 8) , which we believe satisfies cdc s first major criterion . the second criterion requires classic cutaneous lesions that are deep seated , firm , round , well - circumscribed vesicles or pustules that may become umbilicated or confluent . the third criterion requires the same stage for most cutaneous lesions on an affected area . our patient s illness met all 3 criteria ; however , laboratory tests confirmed herpesvirus infection . smallpox was declared eradicated by the world health organization in 1977 ; nevertheless , some health organizations consider this illness a bioterrorism threat . clinical smallpox typically starts with a prodrome of high fever , headache , myalgia , backache , nausea , vomiting , and diarrhea . an oropharyngeal enanthem is followed by cutaneous eruption of erythematous macules that quickly become papules . the papules evolve over days into vesicles and then pustules , often developing central umbilication . classic smallpox lesions occur in the same stage of evolution on a body segment , which differentiates it from varicella . smallpox pustules have been called  pearls of pus  to help distinguish them from the more delicate histopathologically , cutaneous smallpox lesions may resemble herpetic lesions except that smallpox has intracytoplasmic inclusions ( guarnieri bodies ) instead of intranuclear inclusions ( lipschutz bodies ) of herpetic lesions . also , multinucleated giant keratinocytes are uncharacteristic of smallpox ( 9 ) . eczema herpeticum , described by kaposi in 1887 , is most common in patients with atopic dermatitis but can occur in other conditions that disrupt epidermal integrity . in eczema herpeticum , lesions are typically monomorphic vesicles that evolve into pustules ( 10 ) . fever , malaise , lymphadenopathy , and tender skin may accompany cutaneous eruption ( 11 ) . fever is a well - recognized sign of infection ; however , hypothermia can also signal serious disease , including bacterial sepsis or viral encephalitis ( 12 ) , and may be more dire than fever in severely ill hospitalized patients ( 13 ) . we propose that our patient s hypothermic temperature dysregulation is equivalent to fever , thus serving as a major diagnostic criterion . when a patient with agvpri is evaluated for possible smallpox , rapid laboratory tests are necessary . viral culture does not yield results quickly enough to avert infection control measures expected with a smallpox case . indeed , cdc reports 7 incidents when patients with agvpri prompted emergency department diversions or hospital closures ( 1 ) . also , rapid confirmation of nonvariola etiology can help avert public panic , a potential problem in a suspected smallpox outbreak and a probable intended consequence of a terrorist attack . the tzanck smear must be performed by someone experienced in using the technique and interpreted by someone who can confidently and correctly distinguish herpesvivus nuclear inclusions from poxvirus cytoplasmic inclusions . dfa for hsv and vzv is relatively rapid , but in our case , the dfa result was positive for vzv , although viral culture and immunohistochemical staining later showed that the patient s infection was due to hsv-2 . had we been unable to confirm a nonvariola etiology , we would have proceeded to poxvirus testing . with no commercially available tests for smallpox , the algorithm advises close coordination among local , state , and federal public health authorities . some state and federal reference laboratories can provide confirmatory tests , including pcr , for orthopoxviruses such as smallpox and monkeypox . although not performed in this case , we recommend such testing if a simultaneous infection with an orthopoxvirus can not be ruled out .
eczema herpeticum can clinically resemble smallpox . on the basis of the algorithm for rapid evaluation of patients with an acute generalized vesiculopustular rash illness , our patient met criteria for high risk for smallpox . 
 the tzanck preparation was critical for rapid diagnosis of herpetic infection and exclusion of smallpox .