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Smallpox Differential Diagnoses

  • Author: Aneela Naureen Hussain, MD, MBBS, FAAFM; Chief Editor: Mark R Wallace, MD, FACP, FIDSA  more...
 
Updated: Nov 17, 2015
 
 

Diagnostic Considerations

The rash of chickenpox was frequently mistaken for that of smallpox during the days of natural infection. Both conditions can result in pustular scarring lesions that involve the face. Varicella typically does not have a prodromal phase, and the evolution of the rash from its appearance to scab separation takes approximately 7 days in varicella. Often, individuals who were previously vaccinated had only a mild prodrome without any rash.

The fever and vesicular rash of herpes zoster and erythema multiforme also were often confused with those of variola major.

Hemorrhagic smallpox, seen in the image below, develops fulminantly and was most often confused with meningococcemia or severe acute leukemia.

Hemorrhagic-type variola major lesions. Death usuaHemorrhagic-type variola major lesions. Death usually ensued before typical pustules developed. Reprinted with permission from the World Health Organization (WHO). 1988; 10-14, 35-36.

Contact dermatitis, although often vesicular, is distinguishable from smallpox lesions because contact dermatitis is pruritic and is not accompanied by fever or constitutional symptoms.

Conditions to consider in the differential diagnosis of smallpox include the following:

  • Rocky Mountain spotted fever
  • Syphilis
  • Varicella-zoster virus
  • Drug eruptions
  • Insect bites
  • Kawasaki disease
  • Measles, rubeola
  • Monkeypox
  • Rubella
  • Generalized vaccinia and eczema vaccinatum
  • Insect bites
  • Viral hemorrhagic fevers (may be confused with hemorrhagic smallpox)
  • Varicella virus
  • Acne
  • Atypical measles
  • Coxsackievirus
  • Acute leukemia
  • Secondary syphilis
  • Rat-bite fever
  • Infectious mononucleosis
  • Toxic erythemas
  • Parvovirus B19
  • Cytomegalovirus
  • Erythema multiforme (Stevens-Johnson syndrome)
  • Molluscum contagiosum
  • Scarlet fever

Differential Diagnoses

 
 
Contributor Information and Disclosures
Author

Aneela Naureen Hussain, MD, MBBS, FAAFM Diplomate, American Board of Family Medicine; 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, MBBS, FAAFM is a member of the following medical societies: American Academy of Family Physicians, American Medical Association, American Medical Womens Association, Medical Society of the State of New York, Society of Teachers of Family Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Fazal Hussain, MD, MBBS Associate Professor, College of Medicine, Alfaisal University College of Medicine, Saudi Arabia

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, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Dennis J Cleri, MD, FACP, FIDSA, FAAM Chairman, Graduate Medical Education Committee, Professor of Medicine, Associate Professor of Infectious Diseases, Seton Hall University; Director, Internal Medicine Residency Program, St Francis Medical Center

Disclosure: Nothing to disclose.

Chief Editor

Mark R Wallace, MD, FACP, FIDSA Clinical Professor of Medicine, Florida State University College of Medicine; Clinical Professor of Medicine, University of Central Florida College of Medicine

Mark R Wallace, MD, FACP, FIDSA is a member of the following medical societies: American College of Physicians, American Medical Association, American Society for Microbiology, Infectious Diseases Society of America, International AIDS Society, Florida Infectious Diseases Society

Disclosure: Nothing to disclose.

Acknowledgements

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.

David F Butler, MD Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic

David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Jeffrey P Callen, MD Professor of Medicine (Dermatology), Chief, Division of Dermatology, University of Louisville School of Medicine

Jeffrey P Callen, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and American College of Rheumatology

Disclosure: Amgen Honoraria Consulting; Abbott Honoraria Consulting; Electrical Optical Sciences Consulting fee Consulting; Celgene Honoraria Safety Monitoring Committee; GSK - Glaxo Smith Kline Consulting fee Consulting; TenXBioPharma Consulting fee Safety Monitoring Committee

Dirk M Elston, MD Director, Ackerman Academy of Dermatopathology, New York

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Michael D Gober, MD Resident Physician, Department of Dermatology, Hospital of the University of Pennsylvania

Michael D Gober, MD is a member of the following medical societies: American Academy of Dermatology and American Medical Association

Disclosure: Nothing to disclose.

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.

William D James, MD Paul R Gross Professor of Dermatology, University of Pennsylvania School of Medicine; Vice-Chair, Program Director, Department of Dermatology, University of Pennsylvania Health System

William D James, MD is a member of the following medical societies: American Academy of Dermatology and Society for Investigative Dermatology

Disclosure: elsevier Royalty Other; american college of physicians Honoraria Other

Julie R Kenner, MD, PhD Consultant, Clinical Research, Medical Affairs, VaxGen, Inc; Private Practice, Kenner Dermatology Center

Julie R Kenner, MD, PhD is a member of the following medical societies: American Academy of Dermatology and American Society of Tropical Medicine and Hygiene

Disclosure: Nothing to disclose.

Michelle Pelle, MD Clinical Assistant Professor, Division of Dermatology, Department of Medicine, University of California at San Diego

Michelle Pelle, MD is a member of the following medical societies: American Academy of Dermatology, California Medical Association, Medical Dermatology Society, and Pennsylvania Medical Society

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Victoria P Werth, MD Professor of Dermatology and Medicine, University of Pennsylvania School of Medicine; Chief, Division of Dermatology, Philadelphia Veterans Affairs Medical Center

Victoria P Werth, MD is a member of the following medical societies: American Academy of Dermatology, American College of Physicians, American College of Rheumatology, Medical Dermatology Society, Phi Beta Kappa, and Society for Investigative Dermatology

Disclosure: Nothing to disclose.

References
  1. Duraffour S, Meyer H, Andrei G, Snoeck R. Camelpox virus. Antiviral Res. 2011 Nov. 92(2):167-86. [Medline].

  2. Bera BC, Shanmugasundaram K, Barua S, et al. Zoonotic cases of camelpox infection in India. Vet Microbiol. 2011 Aug 26. 152(1-2):29-38. [Medline].

  3. Carroll DS, Emerson GL, Li Y, et al. Chasing Jenner's vaccine: revisiting cowpox virus classification. PLoS One. 2011. 6(8):e23086. [Medline]. [Full Text].

  4. Wahl-Jensen V, Cann JA, Rubins KH, et al. Progression of pathogenic events in cynomolgus macaques infected with variola virus. PLoS One. 2011. 6(10):e24832. [Medline]. [Full Text].

  5. Medaglia ML, Pereira Ade C, Freitas TR, Damaso CR. Swinepox virus outbreak, Brazil, 2011. Emerg Infect Dis. 2011 Oct. 17(10):1976-8. [Medline].

  6. Mohamed MR, Rahman MM, Lanchbury JS, et al. Proteomic screening of variola virus reveals a unique NF-kappaB inhibitor that is highly conserved among pathogenic orthopoxviruses. Proc Natl Acad Sci U S A. 2009 Jun 2. 106(22):9045-50. [Medline]. [Full Text].

  7. Altmann SE, Jones JC, Schultz-Cherry S, Brandt CR. Inhibition of Vaccinia virus entry by a broad spectrum antiviral peptide. Virology. 2009 Jun 5. 388(2):248-59. [Medline]. [Full Text].

  8. Loveless BM, Mucker EM, Hartmann C, Craw PD, Huggins J, Kulesh DA. Differentiation of Variola major and Variola minor variants by MGB-Eclipse probe melt curves and genotyping analysis. Mol Cell Probes. 2009 Jun-Aug. 23(3-4):166-70. [Medline].

  9. Singh RK, Balamurugan V, Bhanuprakash V, Venkatesan G, Hosamani M. Emergence and reemergence of vaccinia-like viruses: global scenario and perspectives. Indian J Virol. 2012 Jun. 23(1):1-11. [Medline]. [Full Text].

  10. Frey SE, Winokur PL, Salata RA, El-Kamary SS, Turley CB, Walter EB Jr, et al. Safety and immunogenicity of IMVAMUNE® smallpox vaccine using different strategies for a post event scenario. Vaccine. 2013 Jun 24. 31(29):3025-33. [Medline]. [Full Text].

  11. Milton DK. What was the primary mode of smallpox transmission? Implications for biodefense. Front Cell Infect Microbiol. 2012. 2:150. [Medline]. [Full Text].

  12. Breman JG, Henderson DA. Diagnosis and management of smallpox. N Engl J Med. 2002 Apr 25. 346 (17):1300-8. [Medline].

  13. Espy MJ, Cockerill III FR, Meyer RF, et al. Detection of smallpox virus DNA by LightCycler PCR. J Clin Microbiol. 2002 Jun. 40(6):1985-8. [Medline]. [Full Text].

  14. Ropp SL, Jin Q, Knight JC, Massung RF, Esposito JJ. PCR strategy for identification and differentiation of small pox and other orthopoxviruses. J Clin Microbiol. 1995 Aug. 33(8):2069-76. [Medline]. [Full Text].

  15. Peterson BW, Damon IK. Orthopoxviruses: vaccinia (smallpox vaccine), variola (smallpox), monkeypox, and cowpox. Bennett JE, Dolin R, Blaser MJ, eds. Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. 8th ed. Philadelphia: Elsevier; 2014.

  16. Bray M, Martinez M, Smee DF, Kefauver D, Thompson E, Huggins JW. Cidofovir protects mice against lethal aerosol or intranasal cowpox virus challenge. J Infect Dis. 2000 Jan. 181(1):10-9. [Medline].

  17. De Clercq E. Cidofovir in the treatment of poxvirus infections. Antiviral Res. 2002 Jul. 55(1):1-13. [Medline].

  18. Smee DF, Bailey KW, Sidwell RW. Treatment of lethal vaccinia virus respiratory infections in mice with cidofovir. Antivir Chem Chemother. 2001 Jan. 12(1):71-6. [Medline].

  19. Smee DF, Bailey KW, Wong MH, Sidwell RW. Effects of cidofovir on the pathogenesis of a lethal vaccinia virus respiratory infection in mice. Antiviral Res. 2001 Oct. 52(1):55-62. [Medline].

  20. Wells TS, LeardMann CA, Smith TC, Smith B, Jacobson IG, Reed RJ, et al. Self-reported adverse health events following smallpox vaccination in a large prospective study of US military service members. Hum Vaccin. 2008 Mar-Apr. 4(2):127-33. [Medline].

  21. Neff J, Modlin J, Birkhead GS, et al. Monitoring the safety of a smallpox vaccination program in the United States: report of the joint Smallpox Vaccine Safety Working Group of the advisory committee on immunization practices and the Armed Forces Epidemiological Board. Clin Infect Dis. 2008 Mar 15. 46 Suppl 3:S258-70. [Medline].

  22. Talbot TR, Stapleton JT, Brady RC, et al. Vaccination success rate and reaction profile with diluted and undiluted smallpox vaccine: a randomized controlled trial. JAMA. 2004 Sep 8. 292(10):1205-12. [Medline].

  23. Kennedy JS, Frey SE, Yan L, et al. Induction of human T cell-mediated immune responses after primary and secondary smallpox vaccination. J Infect Dis. 2004 Oct 1. 190(7):1286-94. [Medline].

  24. Baggs J, Chen RT, Damon IK, et al. Safety profile of smallpox vaccine: insights from the laboratory worker smallpox vaccination program. Clin Infect Dis. 2005 Apr 15. 40(8):1133-40. [Medline].

  25. Ryan MA, Seward JF. Pregnancy, birth, and infant health outcomes from the National Smallpox Vaccine in Pregnancy Registry, 2003-2006. Clin Infect Dis. 2008 Mar 15. 46 Suppl 3:S221-6. [Medline].

  26. Shchelkunov SN. An increasing danger of zoonotic orthopoxvirus infections. PLoS Pathog. 2013 Dec. 9(12):e1003756. [Medline].

  27. Quenelle DC, Kern ER. Treatment of Vaccinia and Cowpox Virus Infections in Mice with CMX001 and ST-246. Viruses. 2010 Dec. 2(12):2681-95. [Medline]. [Full Text].

  28. Greenberg RN, Kennedy JS. ACAM2000: a newly licensed cell culture-based live vaccinia smallpox vaccine. Expert Opin Investig Drugs. 2008 Apr. 17(4):555-64. [Medline].

  29. Monath TP, Caldwell JR, Mundt W, et al. ACAM2000 clonal Vero cell culture vaccinia virus (New York City Board of Health strain)--a second-generation smallpox vaccine for biological defense. Int J Infect Dis. 2004 Oct. 8 Suppl 2:S31-44. [Medline].

  30. US Food and Drug Administration. Package Insert. Dryvax (Smallpox Vaccine, Dried, Calf Lymph Type). Wyeth Laboratories. Washington, DC:

  31. Simmons BJ, Falto-Aizpurua LA, Griffith RD, Nouri K. Smallpox: 12 000 years from plagues to eradication: a dermatologic ailment shaping the face of society. JAMA Dermatol. 2015 May 1. 151 (5):521. [Medline].

  32. Smee DF. Orthopoxvirus inhibitors that are active in animal models: an update from 2008 to 2012. Future Virol. 2013 Sep. 8 (9):891-901. [Medline].

  33. Nalca A, Zumbrun EE. ACAM2000: the new smallpox vaccine for United States Strategic National Stockpile. Drug Des Devel Ther. 2010 May 25. 4:71-9. [Medline].

  34. Kennedy JS, Gurwith M, Dekker CL, Frey SE, Edwards KM, Kenner J, et al. Safety and immunogenicity of LC16m8, an attenuated smallpox vaccine in vaccinia-naive adults. J Infect Dis. 2011 Nov. 204 (9):1395-402. [Medline].

  35. Frey SE, Winokur PL, Salata RA, El-Kamary SS, Turley CB, Walter EB Jr, et al. Safety and immunogenicity of IMVAMUNE® smallpox vaccine using different strategies for a post event scenario. Vaccine. 2013 Jun 24. 31 (29):3025-33. [Medline].

  36. LeDuc JW, Damon I, Relman DA, Huggins J, Jahrling PB. Smallpox research activities: U.S. interagency collaboration, 2001. Emerg Infect Dis. 2002 Jul. 8 (7):743-5. [Medline].

  37. Greenberg RN, Hurley MY, Dinh DV, Mraz S, Vera JG, von Bredow D, et al. Correction: A Multicenter, Open-Label, Controlled Phase II Study to Evaluate Safety and Immunogenicity of MVA Smallpox Vaccine (IMVAMUNE) in 18-40 Year Old Subjects with Diagnosed Atopic Dermatitis. PLoS One. 2015. 10 (11):e0142802. [Medline].

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Smallpox virion. Courtesy of US Centers for Disease Control and Prevention.
After exposure to the smallpox virus, a symptom-free incubation period follows. It normally lasts 10-12 days but may vary from 7-17 days. Smallpox begins with fever, headache, and severe backache. A rash appears after 2-4 days and progresses through characteristic stages of papules, vesicles, pustules, and, finally, scabs. The scabs desquamate at the end of the third or fourth week. Courtesy of the World Health Organization.
Smallpox rash at days 3, 5, and 7 of evolution. Lesions are denser on the face and extremities than on the trunk. They also appear on the palms of the hand and have a similar appearance. Courtesy of the World Health Organization.
Flat-type smallpox on day 6 of the rash. Courtesy of the US Centers for Disease Control and Prevention.
This patient with smallpox survived toxemia to succumb to secondary tissue damage days after this photo was taken. Courtesy of the US Centers for Disease Control and Prevention.
Smallpox vaccination with bifurcated needle. Reconstituted vaccine is held between the prongs of the needle and injected subcutaneously by multiple punctures; 15 rapid strokes, at right angles to the skin over the deltoid muscle, are made within a 5-mm area. Courtesy of the World Health Organization.
Smallpox vaccination. Evolving primary vaccination appearance. Courtesy of the US Centers for Disease Control and Prevention.
Typical temperature chart of a patient with smallpox infection (from Henderson, 1999).
Characteristic skin lesion of variola viral infection on the arms and the legs of an adolescent. Photo used with the permission of the World Health Organization (WHO).
Small child with pustular lesions due to variola viral infection. Photo used with the permission of the World Health Organization (WHO).
Infant with advanced lesions due to variola viral infection. Photo used with the permission of the World Health Organization (WHO).
Unvaccinated infant with the ordinary form of the variola major strain of smallpox has centrifugally distributed umbilicated pustules on day 3 in the course of the disease. Reprinted with permission from the World Health Organization (WHO).
Unvaccinated infant with the ordinary form of the variola major strain of smallpox has centrifugally distributed umbilicated pustules on day 5 in the course of the disease. Reprinted with permission from the World Health Organization (WHO).
Unvaccinated infant with the ordinary form of the variola major strain of smallpox has centrifugally distributed umbilicated pustules on day 7 in the course of the disease. Reprinted with permission from the World Health Organization (WHO).
The ordinary form of the variola minor strain of smallpox (alastrim) in an unvaccinated woman 12 days after the onset of skin lesions. The facial lesions are sparser and evolved more rapidly than the extremity lesions. Reprinted with permission from the World Health Organization (WHO).
The ordinary form of the variola minor strain of smallpox (alastrim) in an unvaccinated woman 12 days after the onset of skin lesions. The facial lesions are sparser and evolved more rapidly than the extremity lesions. Reprinted with permission from the World Health Organization (WHO).
The ordinary form of the variola minor strain of smallpox (alastrim) in an unvaccinated woman 12 days after the onset of skin lesions. The facial lesions are sparser and evolved more rapidly than the extremity lesions. Reprinted with permission from the World Health Organization (WHO).
Adult with variola major with hundreds of pustular lesions centrifugally distributed. Photo from Fitzsimmons Army Medical Center slide file.
Hemorrhagic-type variola major lesions. Death usually ensued before typical pustules developed. Reprinted with permission from the World Health Organization (WHO). 1988; 10-14, 35-36.
 
 
 
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