Smallpox (Variola Virus)

Smallpox (Variola Virus): Excerpt from The 5-Minute Pediatric Consult

Joanne N. Wood, MD

Smallpox - BASICS

Smallpox - description

• Smallpox is a life-threatening, acute eruptive, contagious disease caused by the variola virus.
• The disease is characterized by a febrile prodrome followed by the development of a rash.
• Rash evolves in a characteristic fashion: Macules → papules → vesicles → pustules. Scabs form and fall off leaving scars called pockmarks.
• There are 2 clinical forms of smallpox:
  • Smallpox minor is a less common and less severe form of the disease.
  • There are 5 types of smallpox major, the more common and serious form of the disease.
    • Ordinary smallpox
    • Modified smallpox
    • Flat smallpox
    • Hemorrhagic smallpox
    • Variola sine eruptione

Smallpox - general prevention

• Prior to 1972, all children in the US were vaccinated.
• Vaccines were produced from the vaccinia virus, an orthopoxvirus that is closely related to the variola virus.
• Historically, the vaccine was prepared from virus grown on the skin of animals and in some cases the vaccine was contaminated with animal proteins, bacteria, and adventitial viruses.
• 2nd-generation vaccines are developed from vaccinia clones grown in tissue culture and are free of contamination from bacteria and other viruses.
• 3rd-generation vaccines are being developed from attenuated strains of vaccinia.
• 2nd- and 3rd-generation vaccines have not been tested in humans against smallpox.
• Laboratories in the US and Russia have stockpiles of the variola virus. There is concern that scientists in the Soviet Union may have illegally transported samples of the variola virus to other nations.
• Due to concern regarding the possible use of smallpox as a bioterrorism weapon, the US has increased the production of smallpox vaccine.
• The Advisory Committee on Immunization Practices recommends smallpox vaccination for:
  • Public-health response teams responsible for investigating suspected smallpox cases.
  • Hospital-based health care teams responsible for assessing and caring for suspected smallpox cases.
• Health and emergency services workers are being vaccinated on a volunteer basis only.
• Vaccine efficacy:
  • 95% efficacious in preventing disease if given prior to exposure.
  • May prevent smallpox or decrease severity if given 1–3 days after exposure.
  • May decrease severity of disease if given 4–7 days after exposure.
• Length of immunity after vaccination is estimated to be 3–10 years. Vaccine may decrease the severity of disease for 10–20 years.
• Vaccine administration:
  • A skin abrasion is created using a bifurcated needle dipped in the vaccine.
  • The vaccine site should be loosely covered to prevent the spread of virus to others.
  • After 3–4 days a red pruritic papule appears at the vaccination site. A vesicle and then a pustule forms. After a few weeks a scab forms that falls off leaving a scar.
• Contraindications to vaccine:
  • Atopic dermatitis or exfoliative skin disorder
  • Immunosupression
  • Pregnancy or breastfeeding
  • Close contact of someone who is pregnant, immunosupressed, or has skin disease
  • Allergy to vaccine component
  • Moderate or severe acute illness
  • Inflammatory eye disease
  • Heart disease (myocardial infarction, stroke, cardiomyopathy, heart failure, or angina)
  • 3 or more risk factors for heart disease
  • Age <1 year
  • These contraindications may be reevaluated if smallpox is reintroduced into the population.
• Common adverse reactions to vaccination:
  • Fever, swelling, lymphadenitis, and headache are seen in 2–16% of adults receiving the vaccine for the 1st time.
  • A mild rash occurs in ~8% of cases.
• Less common vaccine reactions:
  • Vaccinia keratitis and vision loss
  • Accidental inoculation with blister formation.
  • Moderate to severe generalized rash.
  • Eczema vaccinatum
  • Encephalitis
  • Congenital vaccinia and generalized vaccinia
  • Myopericarditis
  • Progressive vaccinia/vaccinia gangreosum
  • Bacterial superinfection

Smallpox - epidemiology

• The last documented case of endemic smallpox was in Somalia in 1977. The last case in the US was in the late 1940s.
• Smallpox was declared eradicated by the World Health Organization in 1980.
• Historically in unvaccinated individuals ordinary smallpox accounted for 90% of cases and hemorrhagic accounted for 7% of cases. Flat and modified smallpox accounted for the remainder of cases.
• Modified smallpox was rare in unvaccinated individuals but accounted for 25% of cases of disease in vaccinated individuals.

Smallpox - pathophysiology

• The virus infects the upper respiratory tract and replicates. Rarely, primary infections via skin, conjunctiva or placenta can occur.
• The virus then enters the bloodstream causing primary viremia and is taken up by macrophages.
  • Patient is asymptomatic during this time.
• Next the virus enters the reticuloendothelial system where it continues to replicate.
• Secondary viremia occurs as the virus enters the bloodstream and the organs.
  • Virus enters the epidermis causing necrosis and swelling.
  • Virus infects the bone marrow, kidneys, liver, lymph nodes, spleen, and other organs.
  • The virus causes coagulopathy and multiorgan system failure,
• Exact mechanism of viral toxicity is not understood but may involve both direct viral cytopathic effects and inflammatory mediators.

Smallpox - etiology

• The variola virus, a member of the poxvirus family and the orthopox genus, causes smallpox.
• Variola is a double-stranded DNA virus. Usually transmitted during face-to-face contact via respiratory aerosol or direct contact with the virus via skin lesions.
• Transmission of the virus via air in enclosed settings or via infected fomites is uncommon.
• Humans are the only vectors.

Smallpox - DIAGNOSIS

Smallpox - signs & symptoms

• Ordinary smallpox:
  • Incubation period of 7–17 days is followed by febrile prodrome lasting 1–4 days.
    • The prodrome is characterized by high fever, headache, back pain, chills, abdominal pain, and emesis.
  • Eruptive phase begins with lesions of the mouth, tongue and oropharynx.
  • Then the rash develops:
    • Often starts on face and spreads to rest of body within 24–48 hours.
    • On day 1 the rash is macular.
    • On day 2 the rash becomes papular.
    • On days 4–5 the rash is vesicular.
    • By day 7 the rash has become pustular.
    • By 2–3 weeks the scabs have formed.
    • Scabs fall off and leave scars.
• Modified smallpox:
  • Milder than ordinary smallpox
  • Accelerated course
  • Lesions are not as deep.
• Flat smallpox:
  • Characterized by a soft, flat, semiconfluent or confluent rash that does not progress to pustules
  • Can result in significant skin loss
• Hemorrhagic smallpox:
  • Shorter incubation time.
  • Skin becomes dusky.
  • Bleeding occurs in the skin and mucous membranes.
  • Can be difficult to diagnose unless exposure to variola virus is known
• Variola Sine Eruptione:
  • May be asymptomatic or cause a febrile influenzalike illness
  • Noncontagious
  • Seen in infants with protective maternal antibodies and in vaccinated individuals
• If there has not been a release or circulation of smallpox the CDC Protocol for evaluating patients for smallpox can be used to guide the assessment of a suspicious rash illness.
• CDC protocol for evaluating patients for smallpox:
  • If a patient has an acute, generalized rash on the body, with vesicles or pustules:
    • Use the major and minor criteria to assess the likelihood of smallpox.
  • Major criteria:
    • Febrile prodrome: 1–4 days prior to rash onset including a temperature ≥101°F and 1 or more of the following: Prostration, headache, backache, chills, vomiting or severe abdominal pain
    • Classic smallpox lesions: Deep-seated, firm/hard, round, well-circumscribed vesicles or pustules. Can become umbilicated or confluent as they evolve.
    • On any one part of the body (e.g., the face or arm) all the lesions are in the same stage of development.
  • Minor criteria:
    • Centrifugal distribution: Greatest concentration of lesions on face and extremities
    • 1st lesions appear on the oral mucosa, palate, face, or forearms.
    • Patient appears toxic or moribund.
    • Slow evolution: Lesions evolve from macules to papules to pustules over days (each stage lasts 1–2 days).
    • Lesions on the palms and soles
  • High risk of smallpox:
    • Febrile prodrome and classic smallpox lesions in same stage of development
  • Moderate risk of smallpox:
    • Febrile prodrome and 1 other major smallpox criterion
    • Or febrile prodrome and ≥4 minor smallpox criteria
  • Low risk of smallpox:
    • No febrile prodrome
    • Or febrile prodrome and <4 minor smallpox criteria
• Online tool for evaluation risk of smallpox is available at http://www.bt.cdc.gov/agent/smallpox/diagnosis/riskalgorithm/

Smallpox - tests

• Use the CDC smallpox evaluation protocol to guide testing.
  • If high risk of smallpox:
    • Consult infectious disease and or dermatology.
    • Public health agency will advise on management and collection of samples.
    • Variola testing will be performed at an approved laboratory prior to other testing.
  • If moderate risk of smallpox:
    • Consult infectious disease and/or dermatology.
    • Perform testing for varicella and other disorders including herpes simplex virus as indicated.
    • If no diagnosis made after testing and consultation ensure adequacy of specimen and have consultants reevaluate.
    • If still cannot rule out smallpox, then classify case as high-risk case.
  • If low risk of smallpox and history and examination are highly suggestive of varicella then varicella testing is optional.
  • If low risk of smallpox and diagnosis is uncertain then testing should be done for varicella and other disorders as indicated.
• Variola testing:
  • Should not be performed in low- and moderate-risk cases because of risk of false positives.
  • Should only be performed in high containment facilities designated by national authorities.
  • Lesion specimens (fluid, cells, and scabs) are preferred for testing but blood, tonsillar swabs, and biopsy specimens may be used.
  • Serology studies and electron microscopy cannot distinguish between the variola virus and other orthopoxviruses.
  • PCR assays can distinguish variola virus from other orthopoxviruses.
  • Variola virus can be cultured.
  • Historically variola was identified by the characteristic pocks it produced when grown on chorioallantoic membranes of chick embryos.

Smallpox - differencial diagnosis

• Multiple rash illness, including the following, can be confused with smallpox:
  • Varicella and herpes zoster
  • Herpes simplex virus
  • Measles, rubella, and monkeypox
  • Viral exanthema including enterovirus
  • Disseminated molluscum contagiosum
  • Impetigo, insect bites and scabies
  • Post smallpox vaccine rash (Vaccinia)
  • Secondary syphilis
  • Acne and contact dermatitis
  • Drug reactions, including erythema multiforme
• Meningococcemia can be confused with the hemorrhagic form of smallpox.

Varicella can be confused with smallpox.

• Lesions in varicella are in different stages, superficial, concentrated on the trunk and face, and often spare palms and soles.
• Lesions of smallpox are all at the same stage, deep, concentrated on face and limbs, and often involve palms and soles.

Smallpox - TREATMENT

Smallpox - general measures

• Use CDC smallpox evaluation protocol to guide reporting and infection control measures.
  • For all patients with acute, generalized vesicular or pustular rash:
    • Institute airborne and contact precautions.
    • Alert infection control at time of admission.
  • If high risk: Report to state and local public-health agency immediately.
• Individuals with smallpox may be contagious during the febrile prodrome and are most contagious during the early rash phase. They remain contagious until all of the scabs have fallen off.

Smallpox - medication

• Patients suspected of having smallpox should be vaccinated against smallpox, especially if they are in the early stages of the disease.
• No treatment has been proven to be effective.
• The efficacy of antivirals developed since the eradication of smallpox is unknown.
• Treat secondary bacterial infections.
• Cidofovir and vaccine immune globulin may be used for the treatment of some adverse effects from smallpox vaccination.

Smallpox - FOLLOW UP

Smallpox - complications

• Secondary bacterial infections: Skin, lung, joint, bone, sepsis, etc.
• Corneal ulcers and keratitis.
• Arthritis
• Encephalitis

Smallpox - prognosis

• The potential impact of improvements made in medical care over the past 20 years on the course of smallpox disease is unknown.
• The mortality rate for variola minor was <1%.
• Historically the overall mortality rate for variola major was 30% but was close to 100% for the flat and hemorrhagic forms of the disease.
• The highest mortality rates occurred among young children, pregnant women, elderly individuals and those with immunodeficiencies.
• Long-term sequelae include pockmarks, vision loss, and limb deformities.

Smallpox - bibliography

1. Breman JG, Henderson DA. Diagnosis and Management of Smallpox. N Engl J Med. 2002;346:1300–1308.
2. Besser JM, Crouch NA, Sullivan M. Laboratory diagnosis to differentiate smallpox, vaccinia, and other vesicular/pustular illnesses. J Lab Clin Med. 2003;142(4):246–251.
Centers for Disease Control and Prevention. Smallpox. Available at http://www.bt.cdc.gov/agent/smallpox/
3. Fulginiti Vam Papier A, Lane M, Neff JM, et al. Smallpox vaccination: A review, part I. CID. 2003;37:241–250.
4. Fulginiti Vam Papier A, Lane M, Neff JM, et al. Smallpox vaccination: A review, part II. CID. 2003;37:251–271.
5. Moore ZS, Seward JF, Lane JM. Smallpox. Lancet. 2006;367:425–435.

Smallpox - CODES

Smallpox - icd9

050.9 Smallpox, unspecified

Book Source Details

• Book Title: The 5-Minute Pediatric Consult
• Author(s): M. William Schwartz MD; et al.
• Year of Publication: 2008
• Copyright Details: The 5-Minute Pediatric Consult, Copyright © 2008 Lippincott Williams & Wilkins.

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More About This Book: Title: The 5-Minute Pediatric Consult Authors: M. William Schwartz MD; et al. Publisher: Lippincott Williams & Wilkins Copyright: 2008 ISBN: 0-7817-7577-9

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