eMedicine Specialties > Infectious Diseases > Viral Infections

Smallpox: Differential Diagnoses & Workup

Author: Aneela Naureen Hussain, MD, FAAFM, Assistant Professor, Department of Family Medicine, State University of New York Downstate Medical Center; Consulting Staff, Department of Family Medicine, University Hospital of Brooklyn
Coauthor(s): Fazal Hussain, MD, MBBS, Director, Clinical Research, King Faisal Cancer Centre; Maqsood Alam, MD, Fellow, Department of Infectious Diseases, State University of New York Downstate Medical Center; Dennis J Cleri, MD, FACP, FAAM, FIDSA, Chairman, Graduate Medical Education Committee, Professor of Medicine, Associate Professor of Infection Disease, Seton Hall University; Director, Internal Medicine Residency Program, St Francis Medical Center
Contributor Information and Disclosures

Updated: Oct 20, 2008

Differential Diagnoses

Enteroviruses
Meningococcemia
Erythema Multiforme (Stevens-Johnson Syndrome)
Molluscum Contagiosum
Herpes Simplex
Poxviruses
Herpes Zoster
Rickettsialpox
Impetigo
Rocky Mountain Spotted Fever
Influenza
Syphilis
Malaria
Vaccinia
Meningitis
Varicella-Zoster Virus

Other Problems to Be Considered

Monkeypox
Acne
Chickenpox (varicella-zoster virus)
Drug eruptions
Generalized vaccinia and eczema vaccinatum
Insect bites
Viral hemorrhagic fevers (may be confused with hemorrhagic smallpox)

Workup

Laboratory Studies

  • Smallpox infection may be confirmed based on the presence of brick-shaped virions viewed with electron microscopy examination of vesicular or pustular fluid or scabs.
    • Although smallpox and all other viruses in the Orthopoxvirus genus exhibit identically appearing brick-shaped virions, the clinical aspects of these diseases generally suffice for distinguishing cowpox and vaccinia from smallpox.
    • Monkeypox virions may also be indistinguishable from smallpox virions, but naturally occurring monkeypox is typically limited to tropical rain forest areas of Africa.
  • Variola virus can be detected with electron microscopy, virus culture from live cells, or DNA analysis using polymerase chain reaction (PCR).1,2
    • Cell culture is seldom used because it is not as effective as the other methods and because it requires the use of live virus, which, in turn, requires the use of a biosafety level 4 (BSL-4) laboratory.
    • PCR and electron microscopy can be used to examine inactivated samples and therefore do not require such high levels of isolation and can be performed in local laboratories.
    • Electron microscopy can help identify the virus as a member of the Orthopoxvirus genus, but it cannot help determine the exact species.
    • PCR can be used to identify the species (variola) and can even distinguish minor genetic variations in the different strains. PCR is a relatively new technology and has been used to identify variola only twice previously, and never in a clinical situation. PCR can amplify small and specific lengths of DNA and can accurately differentiate variola virus DNA from other species in the genus. The sensitivity is 5-10 copies of DNA. PCR can be useful to distinguish between chickenpox and smallpox.
  • Smallpox skin specimen should be collected with precautions in place.
    • Gloves should be worn during collection. Fluid from lesions can be harvested on a cotton swab; prior to shipping specimens, state and local health department laboratories should be contacted for specific instructions.
    • The CDC recommends the following procedures for handling specimens obtained from a patient thought to be infected with the smallpox virus:
      • Specimens should be collected by someone who has recently been vaccinated (or who is vaccinated that day) and who wears gloves and a mask.
      • To obtain vesicular or pustular fluid, the lesions may need to be opened with the blunt edge of a scalpel. The fluid can then be harvested on a cotton swab. Scabs can be picked off with forceps.
      • Specimens should be deposited in a Vacutainer tube. The tube should be sealed with adhesive tape at the juncture of the stopper and the tube. This tube, in turn, should be enclosed in a second durable and watertight container.
      • State or local health department laboratories should be contacted immediately for proper specimen shipping protocols.
  • Laboratory examination should be performed only in designated BSL-4 laboratories. Once established that an epidemic is caused by the smallpox virus, clinically similar cases would not require further laboratory testing.

More on Smallpox

Overview: Smallpox
Differential Diagnoses & Workup: Smallpox
Treatment & Medication: Smallpox
Follow-up: Smallpox
Multimedia: Smallpox
References
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Further Reading

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Keywords

smallpox, Poxvirus variolae, variola virus, variola, variola vera, variola major, variola minor, orthopoxvirus, poxvirus, hemorrhagic smallpox, ordinary smallpox, flat smallpox, modified smallpox, alastrim, amass, cottonpox, milkpox, whitepox, Cuban itch, Kaffir, biological agent, bioterrorism, bio-terrorism, biological attack, pox virus, malignant smallpox, fulminant smallpox, variola sine eruptione, variola sine exanthemata, smallpox vaccination, vaccinia immune globulin, vaccinia immunoglobulin, VIG, VIGIV, osteomyelitis variolosa, variola residua, fetal vaccinia

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Contributor Information and Disclosures

Author

Aneela Naureen Hussain, MD, FAAFM, Assistant Professor, Department of Family Medicine, State University of New York Downstate Medical Center; Consulting Staff, Department of Family Medicine, University Hospital of Brooklyn
Aneela Naureen Hussain, MD, FAAFM is a member of the following medical societies: American Academy of Family Physicians, American Medical Association, American Medical Women's Association, Medical Society of the State of New York, and Society of Teachers of Family Medicine
Disclosure: Nothing to disclose.

Coauthor(s)

Fazal Hussain, MD, MBBS, Director, Clinical Research, King Faisal Cancer Centre
Fazal Hussain, MD, MBBS is a member of the following medical societies: American College of Radiology
Disclosure: Nothing to disclose.

Maqsood Alam, MD, Fellow, Department of Infectious Diseases, State University of New York Downstate Medical Center
Maqsood Alam, MD is a member of the following medical societies: American Medical Association and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Dennis J Cleri, MD, FACP, FAAM, FIDSA, Chairman, Graduate Medical Education Committee, Professor of Medicine, Associate Professor of Infection Disease, Seton Hall University; Director, Internal Medicine Residency Program, St Francis Medical Center
Disclosure: Nothing to disclose.

Medical Editor

Duane R Hospenthal, MD, PhD, Chief, Infectious Disease Service, San Antonio Military Medical Center, Brooke Army Medical Center; Professor of Medicine, Uniformed Services University of the Health Sciences
Duane R Hospenthal, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Society for Microbiology, American Society of Tropical Medicine and Hygiene, Armed Forces Infectious Diseases Society, Association of Military Surgeons of the US, Infectious Diseases Society of America, International Society for Infectious Diseases, International Society of Travel Medicine, and Medical Mycology Society of the Americas
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

John L Brusch, MD, FACP, Assistant Professor of Medicine, Harvard Medical School; Consulting Staff, Department of Medicine and Infectious Disease Service, Cambridge Health Alliance
John L Brusch, MD, FACP is a member of the following medical societies: American College of Physicians and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

CME Editor

Eleftherios Mylonakis, MD, Clinical and Research Fellow, Department of Internal Medicine, Division of Infectious Diseases, Massachusetts General Hospital
Eleftherios Mylonakis, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Society for Microbiology, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Chief Editor

Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital
Burke A Cunha, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

 
 
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