Smallpox Case File

Smallpox Case File

Eugene C.Toy, MD, Cynthia Debord, PHD, Audrey Wanger, PHD, Gilbert Castro, PHD, James D. Kettering, PHD, Donald Briscoe, MD

CASE 37

You are asked to consider being vaccinated with smallpox vaccine to serve as a first-responder in the event of a biological warfare attack. After considering the risks and benefits, you consent. You are given the vaccine by the standard technique—a small, bifurcated needle is used to create multiple punctures in the skin overlying your deltoid. The area is covered, and you are instructed not to touch the actual site. In 2 days, a small papule and erythema appear at the vaccine site. A few days later, multiple vesicles are noted. These progress to form larger pustules. In approximately 2 weeks, the whole vaccine site has formed a scab and this subsequently falls off in another week. When complete recovery has occurred, you have a scar left at the vaccine site.

◆ What is the actual virus used as the smallpox vaccine?

◆ Why must the virus used in the vaccine carry or encode its own enzymes for DNA and mRNA synthesis?

ANSWERS TO CASE 37: SMALLPOX

Summary: A physician has received the smallpox vaccine.

◆ Actual virus used as the smallpox vaccine: Vaccinia, which is a form of the cowpox virus.

◆ Reason variola carries or encodes its own enzymes for DNA and mRNA synthesis: Variola virus must produce its own enzymes for DNA and mRNA synthesis because viral replication occurs entirely in host cell cytoplasm, and therefore it cannot use the enzymes located in the host nucleus.

CLINICAL CORRELATION

Variola, the virus that causes smallpox, is a member of the poxvirus family. Smallpox is a highly contagious and severe disease that once caused high mortality in human populations. It was discovered in 1796 by Edward Jenner that the closely related but less virulent cowpox virus could confer resistance to smallpox. This discovery, along with the fact that humans were the only reservoir for variola, eventually led to an effective global vaccination program, using the vaccinia virus as the live viral vaccine. Vaccinia shares antigenic determinants with variola but primarily causes clinical disease in nonhuman animals. Rare, but potentially severe, adverse events such as postvaccinial encephalitis, progressive vaccinia necrosum, or fetal vaccinia can occur after vaccination, primarily in persons with suppressed immunity, severe allergies, eczema, or pregnant women. Additionally, smallpox vaccination is also contraindicated for persons in close contact with individuals with the conditions listed.

Because of worldwide vaccination and disease control efforts, the last case of indigenously acquired smallpox was seen in Somalia in 1977. The World Health Organization declared that smallpox was eradicated in 1980. Routine smallpox vaccination was discontinued after 1980, as the risk of vaccination was thought to outweigh the risk of acquiring smallpox. Concerns about the risk of smallpox being used as a bioterror weapon have led to the reinstitution of vaccination programs, primarily among military, public health, and safety workers.

APPROACH TO SUSPECTED SMALLPOX INFECTION

Objectives

1. Be able to describe the characteristics of the virus.
2. Be able to describe the strategies for prevention and treatment of the infection.

Definitions

Bifurcated needle: A specialized needle that forks into two prongs at its distal end; the prongs use capillary action to administer a specific amount of smallpox vaccine via multiple inoculations at the same site.

Maculopapular: The clinical presentation combination of both macules (rash) with papules (lesions).

Guarnieri’s inclusion bodies: Electron-dense intracytoplasmic acidophilic inclusions within infected cells which serve as assembly sites for new smallpox virions.

DISCUSSION

Characteristics of Smallpox That Impact Transmission

Variola is a member of the poxvirus family, and a member of the genera Orthopoxvirus. There are several diseases caused by orthopoxviruses: variola, vaccinia, cowpox, and monkeypox. Variola is the causative agent of smallpox, a virulent human virus that causes high mortality, while cowpox and monkeypox are zoonotic viruses causing accidental cutaneous infections in humans. Vaccinia is a form of the cowpox virus and has been used effectively as a live viral vaccine against smallpox disease. Poxviruses are the largest and most complex viruses known. Poxviruses are enveloped and contain a linear, double-stranded DNA genome, which is fused at both ends. They are the only DNA viruses, which replicate entirely in the host cell cytoplasm. Because of this, poxviruses must carry and/or encode all of the proteins required for both DNA and mRNA synthesis.

Transmission of the smallpox virus occurs via inhalation of infected respiratory droplets, exposure to infectious skin lesions, or through contact with contaminated fomites. Once inhaled, initial replication of the virus occurs in the respiratory tract, where the virus binds to a target cell surface receptor and the envelope fuses with the cell membrane. The core of the virus is then released into the cellular cytoplasm where DNA replication and transcription takes place. New virions are assembled in cytoplasmic inclusions, referred to as Guarnieri inclusion bodies. Unlike other enveloped viruses, poxviruses assemble their own viral membranes around these viral inclusions instead of acquiring them from host membranes. The new viral particles are then released either by cell lysis or exocytosis. After initial infection of the respiratory tract occurs, the virus spreads through lymphatic channels causing primary viremia and infection of reticuloendothelial cells. Viral replication in these cells causes a secondary viremia and results in clinical manifestations of the skin and internal organs. Variola virus exists as at least two strains—variola major and variola minor. Variola major is associated with high mortality rates (20–50 percent), whereas variola minor is associated with a mortality rate of less than 1 percent.

Diagnosis

Diagnosis of smallpox is typically made by clinical presentation. Clinical smallpox has an incubation period of approximately 2 weeks, followed by an abrupt onset of malaise, fever, chills, and myalgia. A few days post-onset, a characteristic maculopapular rash begins to develop and progresses in a centrifugal pattern over the head and extremities. During approximately a 2-week period, the rash progresses to a single crop of maculopapular lesions to firm vesicles, then to pustules that scab and slowly heal. The high mortality associated with this smallpox results from either the overwhelming primary viral infection or from potential secondary bacterial superinfection.

Highly suspected cases of smallpox should be referred immediately to the Centers for Disease Control, where new variola and orthopox PCR tests are available.

Treatment and Prevention

As previously discussed, successful global vaccination efforts have eliminated naturally acquired cases of smallpox worldwide, with routine smallpox vaccinations ending in 1980 in the United States. However, new concerns of biological weapons development have led to the testing of old vaccine stocks and the development of new stocks for use primarily among military, public health, and safety workers. Chemotherapeutic agents such as methisazone or cidofovir may have some efficacy as prophylaxis against smallpox infection; however, currently there are no treatments available for use in established smallpox disease.

COMPREHENSION QUESTIONS

[37.1] Which of the following statements describes a characteristic that enabled the worldwide eradication of smallpox in 1980?

A. The inactivated smallpox vaccine is easily prepared and safe.

B. Smallpox has no known reservoir outside of humans.

C. Mass vaccination of the world was possible as a result of easy administration of the vaccine in the field.

D. Subclinical smallpox infections were also inhibited through worldwide mass vaccinations.

E. All stocks of smallpox virus were destroyed worldwide in 1979.

[37.2] Due to the potential of a bioterrorist threat, emergency health-care responders in New York City are being considered for smallpox vaccination. Which of the following would be a candidate for vaccination?

A. Household contact is breast-feeding

B. Mild asthma

C. Is pregnant

D. Has eczema

E. Household contact is HIV-positive

[37.3] A college student is reading about the Middle Ages and notices that many people during that era contracted a deadly disease with similar symptoms including acute fever, chills, and myalgia followed by a characteristic rash with small blister-like lesions. Those that did not die from the illness were left with disfiguring scars. The inciting agent has a double-stranded linear DNA genome that replicates in the cytoplasm. Which of the following agents is the most likely culprit?

A. Varicella virus

B. Herpes simplex virus

C. Rubeola virus

D. Papilloma virus

E. Variola virus

Answers

[37.1] B. Smallpox has no known reservoir outside of humans, which was one of the factors which enabled its eradication; answers A, C, D, and E are all incorrect: the vaccination for smallpox consists of a live vaccinia virus and does not contain smallpox virus; mass vaccination of the world was not performed or required because there are no known nonhuman reservoirs of smallpox and subclinical infections do not occur. Thus, large numbers of vaccinations occurring in many populations, such as in the United States, along with strict epidemiologic reporting of smallpox cases worldwide allowed for immunization of those exposed and the elimination of smallpox disease. Not all stocks of smallpox virus were destroyed, and there are still two locations where smallpox virus strains are held: one in Atlanta, and one in Moscow.

[37.2] B. Smallpox is a live attenuated vaccine and is contraindicated for individuals or those who are household contacts who are immunocompromised or who may be susceptible to the adverse effects of the vaccine. Those with eczema and similar skin conditions, infection with HIV, transplant patients, those on high dose corticosteroids, those patients who are pregnant or who are breast-feeding are a partial listing of patients for whom the vaccine is contraindicated.

[37.3] E. Smallpox (variola virus) killed many people during the Middle Ages. The clinical presentation was that of fever, malaise, and myalgia followed by pus-filled or vesicular rash, which often left disfiguring scars.

MICROBIOLOGY PEARLS ❖ Variola is a poxvirus and etiologic agent of smallpox. ❖ Vaccinia is a form of the cowpox virus and has been used effectively as a live viral vaccine against smallpox disease. ❖ Clinical manifestations of smallpox: a severe rash followed by a single crop of maculopapular lesions that transition into vesicles and pustules, and then slowly crust and heal. The lesions are at the same stage. ❖ Contraindications for vaccinia vaccination: suppressed immunity, severe allergies, eczema, pregnancy, or close contact with such persons.

REFERENCES

Brooks GF, Butel JS, Morse SA. Jawetz, Melnick, & Adelberg’s Medical Microbiology, 23rd ed. New York: McGraw-Hill, 2004:561–6. 

Cono J, Casey CG, Bell DM: Smallpox vaccination and adverse reactions. Guidance for clinicians. MMWR Recomm Rep 2003;52(RR-4):1. 

Ryan JR, Ray CG. Sherris Medical Microbiology, 4th ed. New York: McGraw-Hill, 2004:525–7. 

Centers for Disease Control and Prevention. Acute, generalized vesicular or pustular rash illness testing protocol in the United States. http://www.bt.cdc.gov/agent/smallpox/ diagnosis/rashtestingprotocol.asp

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