To the Editor: We report a case in which a man presented witha papulovesicular rash with centrifugal distribution (Figure 1)that had been preceded by four days of headache, backache,fever, nausea, and vomiting. Because the rash started on theface, evolved slowly, and was in the same stage of developmenton any one part of the body, smallpox was considered in thedifferential diagnosis. Urgent consultation was obtained, andhealth departments and the Centers for Disease Control and Prevention(CDC) were contacted. Limited specimens sent to the hospitallaboratory tested positive for varicella–zoster virus(VZV) IgG, negative for VZV on direct fluorescent-antibody staining,and negative for the human immunodeficiency virus on serologicanalysis. Digital photographs were e-mailed to the CDC. Specimenswere collected according to CDC guidelines1 and sent to theCDC. A culture performed at the CDC was positive for herpessimplex virus (HSV) type 2.
Figure 1. Multiple Hemorrhagic Vesicles and Crusted Papules in the Same Stage of Development on the Face and Scalp.
Once smallpox was considered, limited laboratory tests to ruleout VZV were performed. If direct fluorescence antibody testsfor HSV had been performed, we could have avoided sending specimensto the CDC. Our hospital has instituted a protocol for the rapidevaluation of patients presenting with illnesses involving feverand rash that includes smallpox in the differential diagnosis.Persons presenting with a rash that is consistent with classicsmallpox will be evaluated in conjunction with health departments,as occurred in this case. In persons presenting with a suspiciousrash that is deemed to represent a low or moderate risk in thealgorithm for evaluation of smallpox,2,3 direct fluorescenceantibody testing for HSV and VZV will be performed, as wellas a test for syphilis. These tests and the need for a digitalcamera should be considered at other hospitals.
The collection and shipping of specimens were more complex thanwe had anticipated. Not all items listed by the CDC1 as necessaryfor the collection of specimens are generally available in hospitals,so it is worth reviewing this list ahead of time. Collectingthe appropriate specimens took about 90 minutes. By the timethat was done, there was very little time left to get the specimensto the commercial carrier. Hospitals should review shippingpolicies for biologic specimens. Commercial carriers that acceptbiologic specimens may do so only at certain stations. Detailedpaperwork must be completed and sent with the specimen. Thecollection, packaging, and transport of specimens to the commercialcarrier can take a great deal of time.
Twenty-five hours elapsed from the time that health departmentswere contacted to the time negative results that ruled out smallpoxwere received. Had this event not occurred during normal businesshours, the process could have taken even longer. These problemsshould be taken into consideration in emergency response plans.
Jennifer A. Hanrahan, D.O. Marta Jakubowycz, M.D. Bryan R. Davis, M.D. MetroHealth Medical Center Cleveland, OH 44109 jhanrahan{at}metrohealth.org
This letter was published at www.nejm.org on December 19, 2002.
The CDC offers the following reply: The case study presentedby Hanrahan et al. offers an excellent example of the type ofpartnership that is required between health care providers andlocal, state, and federal public health personnel in smallpox-responseefforts. As predicted by the algorithm for the evaluation offebrile rash,1,2 smallpox was not the final diagnosis in thiscase because only one or two major criteria were met and thepatient was thus classified as being at low risk for smallpox.Nevertheless, testing for smallpox was performed in order toprovide reassurance to a health care community that is not yetfamiliar with the use of the algorithm for the assessment ofrisk of smallpox in patients with febrile rash illnesses. Thiscase demonstrates the clinical usefulness of digital cameras,and it shows that public health laboratories have a need forrapid diagnostic tests for the full range of diseases includedin the differential diagnosis of smallpox. The appropriate diagnosiswould have been made hours earlier in this case if a test forHSV had been readily available. It is this level of preparednessthat the CDC is committed to achieving.
To provide rapid local testing for infectious causes of illnessesinvolving rashes that could be confused with smallpox, bothdirect fluorescence antibody and polymerase-chain-reaction (PCR)testing for varicella have been made available at all laboratoriesof the Laboratory Response Network for Bioterrorism (LRN). PCRtesting capabilities for HSV, such as those used by the CDCin this case, may also be useful. LRN laboratories can currentlyevaluate clinical specimens for vaccinia, a step that may becomenecessary in certain cases of smallpox-vaccine–relatedadverse events. In addition, a subgroup of LRN laboratorieswith appropriate technical, biosafety, and biosecurity measureswill have diagnostic laboratory tests to screen for smallpox.As Hanrahan et al. demonstrate, transportation of specimensintroduces a delay in obtaining laboratory confirmation. Tominimize such delays, guidelines for the collection and shippingof specimens should be reviewed (they can be found at http://www.cdc.gov/smallpox).When indicated, aircraft are available 24 hours a day, 7 daysa week, to move specimens to reference laboratories or physicianswho can assist in the evaluation of patients.
Inger Damon, M.D., Ph.D. Lisa Rotz, M.D. Jane Seward, M.B., B.S. James Hughes, M.D. Centers for Disease Control and Prevention Atlanta, GA 30333
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