Smallpox

Background

This disease has re-emerged to frontpage status with the threat of biological terrorism. Smallpox was eliminated from the world after the last case was reported in Somalia in 1977. This was a concerted effort by the World Health Organization. After this last case, routine vaccination against smallpox in the general population was discontinued. After the September 11, 2001 attacks in the United States, the United States government began a concerted effort at mass immunization due to the heightened threat of smallpox being used as a terrorist weapon.

Smallpox is an extremely contagious and sometimes fatal disease. Patients are covered with raised bumps and pustules, occurring over the face and body of an infected person.

OUTLINE

Disease Associations

Pathogenesis

Gross Appearance and Clinical Variants

Treatment

Commonly Used Terms

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DISEASE ASSOCIATIONS CHARACTERIZATION

ALLERGIES

Smallpox vaccination and risk of allergy and asthma.

Bager P, Westergaard T, Rostgaard K, Nielsen NM, Melbye M, Aaby P.

Department of Epidemiology Research, Danish Epidemiology Science Centre, Statens Serum Institut.

J Allergy Clin Immunol. 2003 Jun;111(6):1227-31. Abstract quote
BACKGROUND: It has been proposed that childhood vaccinations may influence the development of allergy. Atopy and allergic diseases have increased after routine smallpox vaccination was stopped in the 1970s.

OBJECTIVE: We examined whether administration of smallpox vaccination during childhood was associated with a decreased risk of atopy, allergic rhinitis, and asthma.

METHODS: The occurrence of atopy, allergic rhinitis, and asthma was studied in nearly 2000 women participating in a national birth cohort study. Detailed information on smallpox vaccination was available from school health records. Atopic status was assessed serologically by a specific response to 11 common inhalant allergens by using serum samples obtained from the women during the period 1997 to 2001. Information on allergic rhinitis and asthma was available from telephone interviews.

RESULTS: We found no association between having been vaccinated against smallpox in childhood and risk of atopy or allergic rhinitis. Smallpox vaccination was associated with a slightly decreased risk of asthma. There was no association between age at smallpox vaccination and risk of atopy, allergic rhinitis, or asthma. Adjusting for birth cohort, sibship size, age of the woman's mother at birth, and social class in childhood did not change these results.

CONCLUSION: Our findings do not suggest that childhood vaccination against smallpox, even if given early in life, influences the development of atopy or allergic rhinitis. The association with asthma should be interpreted with caution and needs further study.

PATHOGENESIS CHARACTERIZATION

SCARS

The scarring mechanism of smallpox.

Regan TD, Norton SA

J Am Acad Dermatol. 2004 Apr;50(4):591-4. Abstract quote

BACKGROUND: Smallpox is notorious for leaving its survivors with disfiguring scars, but it is unclear how these scars are produced. Modern dermatopathology textbooks report that smallpox produced epidermal lesions, yet the process of scarring requires dermal involvement.

OBJECTIVES: Our goal was to uncover past theories on the mechanism of smallpox scarring.

METHODS: We conducted a comprehensive review of English-language textbooks and English-translations of textbooks in general medicine, dermatology, pathology, and dermatopathology from the past 150 years as well as relevant journal publications for the same time period.

RESULTS: We identified five different theories to explain the scarring of smallpox. The five proposals are that scarring resulted from: the extension of suppuration into the dermis; the extension of suppuration into the dermis along with inappropriate treatment and scratching; secondary bacterial ecthyma; the destruction of elastic fibers; or the destruction of sebaceous glands.

CONCLUSION: The theory that best fits clinical and histological observations is that smallpox caused scars through the destruction of sebaceous glands, first proposed by Gerrit Bras in 1952. Although this explanation is not found in any dermatopathology text, it is supported by today's leading authorities on smallpox. However, since variola virions have never actually been identified in sebaceous glands, or even in the dermis, further study of preserved tissue is warranted. Until then, the mechanism of scar formation remains speculative.

GROSS APPEARANCE/
CLINICAL VARIANTS CHARACTERIZATION

GENERAL

VARIOLA MAJOR Overall fatality rate of about 30%
Flat and hemorrhagic smallpox usually are fatal

ORDINDARY
Most frequent type, accounting for 90% of cases

MODIFIED
Mild and occurring in previously vaccinated persons

FLAT

HEMORRHAGIC
Rare and very severe

VARIOLA MINOR
Less common presentation of smallpox
Less severe disease with death rates historically of 1% or less

VARIANTS

FOLLICULITIS

Focal and generalized folliculitis following smallpox vaccination among vaccinia-naive recipients.

Talbot TR, Bredenberg HK, Smith M, LaFleur BJ, Boyd A, Edwards KM.

Departments of Medicine, Pediatrics, Preventive Medicine, and Pathology, Vanderbilt University School of Medicine, Nashville, Tenn.

JAMA. 2003 Jun 25;289(24):3290-4. Abstract quote
CONTEXT: With the reintroduction of smallpox vaccination, detailed contemporary descriptions of adverse reactions to the vaccine are needed to adequately inform the public and clinicians. During a multicenter, randomized controlled trial investigating the efficacy of various dilutions of smallpox vaccine, we observed the appearance of a papulovesicular eruption (focal and generalized) in study volunteers.

OBJECTIVE: To characterize the papulovesicular eruptions by clinical, virologic, and histopathological characteristics.

DESIGN, SETTING, AND PARTICIPANTS: Prospective case series of papulovesicular eruptions following smallpox vaccination in healthy, vaccinia-naive adult participants compared with noncases conducted from October 2002 to March 2003. Variables potentially related to these eruptions were collected retrospectively through chart review. Eruptions were described based on viral culture, clinical examination, and histopathological evaluation (1 biopsy specimen from 1 case).

MAIN OUTCOME MEASURE: Cases of papulovesicular eruptions following vaccination.

RESULTS: During the trial, of 148 volunteers (56% women; mean age 23.6 years), 4 participants (2.7%) developed generalized eruptions and 11 (7.4%) noted focal eruptions. Viral cultures of sample lesions were negative for vaccinia. The result of a skin biopsy sample from 1 case of generalized rash revealed suppurative folliculitis without evidence of viral infection. All lesions resolved without scarring. In the cohort, cases and noncases did not show significant differences in terms of sex, in the use of nonsteroidal anti-inflammatory drugs or oral or depo contraceptives, in medication allergies, in the incidence of fever or lymphadenopathy after vaccination, or in the dilution of vaccine received.

CONCLUSIONS: Folliculitis is a common and benign eruption observed in vaccinia-naive adult volunteers following smallpox vaccination. This eruption may be seen in volunteers receiving the vaccine in the newly instituted vaccination programs and may be met with heightened anxiety, potentially being confused with generalized vaccinia. This description of folliculitis using clinical, virologic, and histopathological findings should allay these concerns and provide additional insight into this eruption.

MYOPERICARDITIS

Myopericarditis Following Smallpox Vaccination Among Vaccinia-Naive US Military Personnel.

Halsell JS, Riddle JR, Atwood JE, Gardner P, Shope R, Poland GA, Gray GC, Ostroff S, Eckart RE, Hospenthal DR, Gibson RL, Grabenstein JD, Arness MK, Tornberg DN.

The University of Virginia, Charlottesville, Brooke Army Medical Center, Fort Sam Houston, Tex.
JAMA. 2003 Jun 25;289(24):3283-9. Abstract quote
CONTEXT: In the United States, the annual incidence of myocarditis is estimated at 1 to 10 per 100 000 population. As many as 1% to 5% of patients with acute viral infections involve the myocardium. Although many viruses have been reported to cause myopericarditis, it has been a rare or unrecognized event after vaccination with the currently used strain of vaccinia virus (New York City Board of Health).

OBJECTIVE: To describe a series of probable cases of myopericarditis following smallpox vaccination among US military service members reported since the reintroduction of vaccinia vaccine.Design, Setting,

PARTICIPANTS: Surveillance case definitions are presented. The cases were identified either through sentinel reporting to US military headquarters surveillance using the Defense Medical Surveillance System or reports to the Vaccine Adverse Event Reporting System using International Classification of Diseases, Ninth Revision. The cases occurred among individuals vaccinated from mid-December 2002 to March 14, 2003.

MAIN OUTCOME MEASURE: Elevated serum levels of creatine kinase (MB isoenzyme), troponin I, and troponin T, usually in the presence of ST-segment elevation on electrocardiogram and wall motion abnormalities on echocardiogram.

RESULTS: Among 230 734 primary vaccinees, 18 cases of probable myopericarditis after smallpox vaccination were reported (an incidence of 7.8 per 100 000 over 30 days). No cases of myopericarditis following smallpox vaccination were reported among 95 622 vaccinees who were previously vaccinated. All cases were white men aged 21 years to 33 years (mean age, 26.5 years), who presented with acute myopericarditis 7 to 19 days following vaccination. A causal relationship is supported by the close temporal clustering (7-19 days; mean, 10.5 days following vaccination), wide geographic and temporal distribution, occurrence in only primary vaccinees, and lack of evidence for alternative etiologies or other diseases associated with myopericarditis. Additional supporting evidence is the observation that the observed rate of myopericarditis among primary vaccinees is 3.6-fold (95% confidence interval, 3.33-4.11) higher than the expected rate among personnel who were not vaccinated. The background incidence of myopericarditis did not show statistical significance when stratified by age (20-34 years: 2.18 expected cases per 100 000; 95% confidence interval [CI], 1.90-2.34), race (whites: 1.82 per 100 000; 95% CI, 1.50-2.01), and sex (males: 2.28 per 100 000; 95% CI, 2.04-2.54).

CONCLUSION: Among US military personnel vaccinated against smallpox, myopericarditis occurred at a rate of 1 per 12 819 primary vaccinees. Myopericarditis should be considered an expected adverse event associated with smallpox vaccination. Clinicians should consider myopericarditis in the differential diagnosis of patients presenting with chest pain 4 to 30 days following smallpox vaccination and be aware of the implications as well as the need to report this potential adverse advent.

TREATMENT CHARACTERIZATION

GENERAL

VACCINATION

US Military Smallpox Vaccination Program Experience.

Grabenstein JD, Winkenwerder W Jr.

Military Vaccine Agency, US Army Medical Command, Falls Church, Va, Pentagon, Washington, DC.
JAMA. 2003 Jun 25;289(24):3278-82. Abstract quote
CONTEXT: The United States recently implemented smallpox vaccination of selected military personnel in a national program of preparedness against use of smallpox as a biological weapon. The resumption of smallpox vaccinations raises important questions regarding implementation and safety.

OBJECTIVE: To describe the US military smallpox vaccination program.

DESIGN: Descriptive study of the vaccination program from its inception on December 13, 2002, through May 28, 2003.

SETTING: US Department of Defense (DoD) fixed and field medical treatment facilities on multiple continents and ships at sea.

SUBJECTS: US service members and DoD civilian workers eligible for smallpox vaccination.

MAIN OUTCOME MEASURES: Numbers of vaccinations and rates of vaccination exemptions, symptoms, and adverse events. Data were collected via reports to headquarters and rigorous surveillance for sentinel events.

RESULTS: In 5.5 months, the DoD administered 450 293 smallpox vaccinations (70.5% primary vaccinees and 29.5% revaccinees). In 2 settings, 0.5% and 3.0% of vaccine recipients needed short-term sick leave. Most adverse events occurred at rates below historical rates. One case of encephalitis and 37 cases of acute myopericarditis developed after vaccination; all cases recovered. Among 19 461 worker-months of clinical contact, there were no cases of transmission of vaccinia from worker to patient, no cases of eczema vaccinatum or progressive vaccinia, and no attributed deaths.

CONCLUSIONS: Mass smallpox vaccinations can be conducted safely with very low rates of serious adverse events. Program implementation emphasized human factors: careful staff training, contraindication screening, recipient education, and attention to bandaging. Our experience suggests that broad smallpox vaccination programs may be implemented with fewer serious adverse events than previously believed.

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Eight Edition. Mosby 1996.
Sternberg S. Diagnostic Surgical Pathology. Third Edition. Lipincott Williams and Wilkins 1999.
Robbins Pathologic Basis of Disease. Sixth Edition. WB Saunders 1999.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

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Last Updated 4/13/2004

Disease Associations
Pathogenesis
Gross Appearance and Clinical Variants
Treatment
Commonly Used Terms
Internet Links

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
GENERAL
VARIOLA MAJOR	Overall fatality rate of about 30% Flat and hemorrhagic smallpox usually are fatal
ORDINDARY	Most frequent type, accounting for 90% of cases
MODIFIED	Mild and occurring in previously vaccinated persons
FLAT
HEMORRHAGIC	Rare and very severe
VARIOLA MINOR	Less common presentation of smallpox Less severe disease with death rates historically of 1% or less
VARIANTS
FOLLICULITIS
Focal and generalized folliculitis following smallpox vaccination among vaccinia-naive recipients. Talbot TR, Bredenberg HK, Smith M, LaFleur BJ, Boyd A, Edwards KM. Departments of Medicine, Pediatrics, Preventive Medicine, and Pathology, Vanderbilt University School of Medicine, Nashville, Tenn.	JAMA. 2003 Jun 25;289(24):3290-4. Abstract quote CONTEXT: With the reintroduction of smallpox vaccination, detailed contemporary descriptions of adverse reactions to the vaccine are needed to adequately inform the public and clinicians. During a multicenter, randomized controlled trial investigating the efficacy of various dilutions of smallpox vaccine, we observed the appearance of a papulovesicular eruption (focal and generalized) in study volunteers. OBJECTIVE: To characterize the papulovesicular eruptions by clinical, virologic, and histopathological characteristics. DESIGN, SETTING, AND PARTICIPANTS: Prospective case series of papulovesicular eruptions following smallpox vaccination in healthy, vaccinia-naive adult participants compared with noncases conducted from October 2002 to March 2003. Variables potentially related to these eruptions were collected retrospectively through chart review. Eruptions were described based on viral culture, clinical examination, and histopathological evaluation (1 biopsy specimen from 1 case). MAIN OUTCOME MEASURE: Cases of papulovesicular eruptions following vaccination. RESULTS: During the trial, of 148 volunteers (56% women; mean age 23.6 years), 4 participants (2.7%) developed generalized eruptions and 11 (7.4%) noted focal eruptions. Viral cultures of sample lesions were negative for vaccinia. The result of a skin biopsy sample from 1 case of generalized rash revealed suppurative folliculitis without evidence of viral infection. All lesions resolved without scarring. In the cohort, cases and noncases did not show significant differences in terms of sex, in the use of nonsteroidal anti-inflammatory drugs or oral or depo contraceptives, in medication allergies, in the incidence of fever or lymphadenopathy after vaccination, or in the dilution of vaccine received. CONCLUSIONS: Folliculitis is a common and benign eruption observed in vaccinia-naive adult volunteers following smallpox vaccination. This eruption may be seen in volunteers receiving the vaccine in the newly instituted vaccination programs and may be met with heightened anxiety, potentially being confused with generalized vaccinia. This description of folliculitis using clinical, virologic, and histopathological findings should allay these concerns and provide additional insight into this eruption.
MYOPERICARDITIS
Myopericarditis Following Smallpox Vaccination Among Vaccinia-Naive US Military Personnel. Halsell JS, Riddle JR, Atwood JE, Gardner P, Shope R, Poland GA, Gray GC, Ostroff S, Eckart RE, Hospenthal DR, Gibson RL, Grabenstein JD, Arness MK, Tornberg DN. The University of Virginia, Charlottesville, Brooke Army Medical Center, Fort Sam Houston, Tex.	JAMA. 2003 Jun 25;289(24):3283-9. Abstract quote CONTEXT: In the United States, the annual incidence of myocarditis is estimated at 1 to 10 per 100 000 population. As many as 1% to 5% of patients with acute viral infections involve the myocardium. Although many viruses have been reported to cause myopericarditis, it has been a rare or unrecognized event after vaccination with the currently used strain of vaccinia virus (New York City Board of Health). OBJECTIVE: To describe a series of probable cases of myopericarditis following smallpox vaccination among US military service members reported since the reintroduction of vaccinia vaccine.Design, Setting, PARTICIPANTS: Surveillance case definitions are presented. The cases were identified either through sentinel reporting to US military headquarters surveillance using the Defense Medical Surveillance System or reports to the Vaccine Adverse Event Reporting System using International Classification of Diseases, Ninth Revision. The cases occurred among individuals vaccinated from mid-December 2002 to March 14, 2003. MAIN OUTCOME MEASURE: Elevated serum levels of creatine kinase (MB isoenzyme), troponin I, and troponin T, usually in the presence of ST-segment elevation on electrocardiogram and wall motion abnormalities on echocardiogram. RESULTS: Among 230 734 primary vaccinees, 18 cases of probable myopericarditis after smallpox vaccination were reported (an incidence of 7.8 per 100 000 over 30 days). No cases of myopericarditis following smallpox vaccination were reported among 95 622 vaccinees who were previously vaccinated. All cases were white men aged 21 years to 33 years (mean age, 26.5 years), who presented with acute myopericarditis 7 to 19 days following vaccination. A causal relationship is supported by the close temporal clustering (7-19 days; mean, 10.5 days following vaccination), wide geographic and temporal distribution, occurrence in only primary vaccinees, and lack of evidence for alternative etiologies or other diseases associated with myopericarditis. Additional supporting evidence is the observation that the observed rate of myopericarditis among primary vaccinees is 3.6-fold (95% confidence interval, 3.33-4.11) higher than the expected rate among personnel who were not vaccinated. The background incidence of myopericarditis did not show statistical significance when stratified by age (20-34 years: 2.18 expected cases per 100 000; 95% confidence interval [CI], 1.90-2.34), race (whites: 1.82 per 100 000; 95% CI, 1.50-2.01), and sex (males: 2.28 per 100 000; 95% CI, 2.04-2.54). CONCLUSION: Among US military personnel vaccinated against smallpox, myopericarditis occurred at a rate of 1 per 12 819 primary vaccinees. Myopericarditis should be considered an expected adverse event associated with smallpox vaccination. Clinicians should consider myopericarditis in the differential diagnosis of patients presenting with chest pain 4 to 30 days following smallpox vaccination and be aware of the implications as well as the need to report this potential adverse advent.