Basics
Description
- Smallpox is a life-threatening, acute, eruptive, contagious disease caused by variola virus.
- The disease is characterized by a febrile prodrome followed by the development of 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:
- Variola minor is a less common and less severe form of disease.
- There are 5 types of variola major, the more common and serious form of disease.
- Ordinary smallpox
- Modified smallpox
- Flat smallpox
- Hemorrhagic smallpox
- Variola sine eruptione
Epidemiology
- The last documented case of endemic smallpox was in Somalia in 1977.
- The last case in the United States was in the late 1940s.
- Smallpox was declared eradicated by the World Health Organization in 1979.
- Historically in unvaccinated individuals, ordinary smallpox accounted for 90% of cases, hemorrhagic smallpox for 7% of cases, and flat and modified smallpox for the remainder.
- Modified smallpox was rare in unvaccinated individuals but accounted for 25% of cases of disease in vaccinated individuals.
General Prevention
- Prior to 1972, all U.S. children were vaccinated.
- Vaccines were produced from the vaccinia virus, a closely related orthopoxvirus to variola.
- 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 other viruses.
- Newer smallpox vaccines are developed from vaccinia clones grown in tissue culture and therefore are free of contamination from bacteria and other viruses.
- Only laboratories in the United States and Russia currently have stockpiles of smallpox virus.
- Due to concern for use of smallpox as an agent of bioterrorism, the U.S. Strategic National Stockpile still stores smallpox vaccine.
- The only currently FDA-licensed smallpox vaccine, ACAM2000 (which replaced Dryvax), is used for active immunization of persons determined to be at highest risk for infection.
- The Advisory Committee on Immunization Practices recommends smallpox vaccination for the following:
- Public health response teams responsible for investigating suspected smallpox cases
- Hospital-based health care teams responsible for assessing and caring for suspected smallpox cases
- 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
- Vaccination is estimated to provide protective immunity for 3 " 10 years but may decrease the severity of disease for 10 " 20 years.
- Vaccine administration
- A skin abrasion is created using a bifurcated needle dipped in 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, which evolves into a vesicle followed by a pustule; after a few weeks, a scab forms, then falls off leaving a scar.
- Contraindications to vaccine:
- Atopic dermatitis or exfoliative skin disorder
- Immunosuppression
- Pregnancy or breastfeeding
- Close contact of someone who is pregnant, immunosuppressed, 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) or ≥3 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 first time.
- A mild rash occurs in ’ Ό8% of cases.
- Less common vaccine reactions:
- Vaccinia keratitis and/or vision loss
- Accidental inoculation with blister formation
- Moderate to severe generalized rash
- Eczema vaccinatum
- Encephalitis
- Congenital or generalized vaccinia
- Myopericarditis
- Progressive vaccinia/vaccinia gangrenosum
- Bacterial superinfection
Pathophysiology
- The virus infects the upper respiratory tract and replicates; rarely, primary infections can occur via skin, conjunctival, or placental routes.
- The virus enters the bloodstream (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 reenters the bloodstream and infects organs.
- Can cause epidermal necrosis and swelling
- Infections of the bone marrow, kidneys, liver, lymph nodes, spleen, and other organs result in coagulopathy and multiorgan system failure.
- Exact mechanisms of viral toxicity are not understood but may involve both viral cytopathic effects and inflammatory pathology.
Etiology
- Variola virus is a member of the poxvirus family and (Orthopox genus).
- Variola is a double-stranded DNA virus most commonly transmitted during face-to-face contact via respiratory aerosols or direct contact with infected skin lesions.
- Transmission of the virus via air in enclosed settings or via infected fomites is uncommon.
- Humans are the only vectors.
Diagnosis
- Ordinary smallpox
- Incubation period lasts 7 " 17 days, followed by a 1 " 4 day febrile prodrome characterized by high fever, headache, back pain, chills, abdominal pain, and emesis.
- Eruptive phase begins with lesions of the mouth, tongue, and oropharynx.
- The rash
- Often starts on face and spreads to rest of body within 24 " 48 hours
- On day 1, rash is macular.
- On day 2, rash becomes papular.
- On days 4 and 5, rash becomes vesicular.
- By day 7, rash becomes pustular.
- By 2 " 3 weeks, scabs form.
- Scabs fall off and leave pockmarks.
- Modified smallpox
- Milder than ordinary smallpox
- Accelerated course
- Lesions are not as deep
- Flat smallpox
- Characterized by soft, flat, semiconfluent or confluent rash that does not evolve to pustules but can still result in significant skin loss
- Hemorrhagic smallpox
- Shorter incubation time
- Skin becomes dusky
- Bleeding in skin and mucous membranes
- Can be difficult to diagnose unless exposure to variola virus is known
- Variola sine eruptione
- May be asymptomatic or cause an influenza-like 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.
- The CDC risk evaluation tool can be found at http://www.bt.cdc.gov/agent/smallpox/diagnosis/riskalgorithm/
- 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 are deep-seated, firm/hard, round, well-circumscribed vesicles or pustules that 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 with greatest concentration of lesions on face and extremities
- First 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 lesions in same stage of development
- Moderate risk of smallpox
- Febrile prodrome and either 1 other major criterion or ≥4 minor criteria
- Low risk of smallpox
- No febrile prodrome, or febrile prodrome and <4 minor criteria
Diagnostic Tests & Interpretation
Diagnostic Procedures/Other
- 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.
- Testing will be performed at an approved laboratory prior to other tests.
- 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 is made after testing, ensure adequacy of specimen and have consultants reevaluate.
- If smallpox still cannot be ruled out, then classify case as high-risk case.
- If low risk of smallpox, and history and physical exam 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 designated high-containment facilities
- Lesion specimens (fluid, cells, and scabs) are preferred for testing, but blood, tonsillar swabs, and biopsy specimens may be used.
- Serologic studies and electron microscopy cannot distinguish between the variola virus and other orthopoxviruses.
- Polymerase chain reaction (PCR) assays can distinguish variola virus from other orthopoxviruses.
- Variola virus can be cultured.
Differential Diagnosis
- Multiple rash illnesses, including the following, can be confused with smallpox:
- Varicella and herpes zoster
- Herpes simplex virus
- Measles
- Rubella
- Monkeypox, cowpox, and tanapox
- Viral exanthema including enterovirus
- Disseminated molluscum contagiosum
- Impetigo, insect bites, or scabies
- Post-smallpox vaccine rash (vaccinia)
- Secondary syphilis
- Acne and contact dermatitis
- Drug reactions including erythema multiforme
- Meningococcemia can be confused with hemorrhagic smallpox.
Alert
- Varicella can be confused with smallpox.
- Varicella lesions present in different stages, are superficial, and concentrate on the trunk and face, sparing the palms and soles.
- Smallpox lesions all present in the same stage, are deep, and concentrated on the face and limbs, often involving the palms and soles.
Treatment
Medication
- Patients suspected of having smallpox should be vaccinated against smallpox, especially if they are in the early stages of the disease.
- The efficacy of antiviral drugs are not known; however, cidofovir has shown efficacy in reducing smallpox virus replication in vitro and in animal studies, and tecovirimat (ST-246) shows promise and is currently in clinical trials.
- The use of vaccinia immune globulin (VIG) can be considered for complications from vaccinia immunization but not for smallpox therapy or postexposure prophylaxis.
- Cidofovir or VIG are available through the Strategic National Stockpile.
Additional Treatment
General Measures
- Suspected cases of smallpox require notification of state and local authorities, who should then notify the CDC.
- For patients with acute, generalized vesicular or pustular rash, institute airborne and contact precautions and alert infection control.
- If high risk, report to state and local public health agency immediately.
- Individuals recently exposed (within 3 " 4 days) to someone with contagious smallpox (e.g., someone with oral or skin lesions) should receive postexposure vaccination, as this offers the potential to limit disease and also provides significant protection from death.
- Individuals with smallpox may be contagious during the febrile prodrome, are contagious during the early rash phase, and remain contagious until all the scabs have fallen off.
Ongoing Care
Prognosis
- 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 immunodeficiency.
- Long-term sequelae include pockmarks, vision loss, and limb deformities.
Complications
- Dehydration and electrolyte abnormalities can occur during the vesicular and pustular stages and should be corrected.
- Secondary bacterial superinfections may require antibiotic treatment.
- Corneal ulcers or keratitis, arthritis, or encephalitis may develop.
Additional Reading
- 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. [View Abstract]
- Breman JG, Henderson DA. Diagnosis and management of smallpox. N Engl J Med. 2002;346(17):1300 " 1308. [View Abstract]
- Moore ZS, Seward JF, Lane JM. Smallpox. Lancet. 2006;367(9508):425 " 435. [View Abstract]
Codes
ICD09
- 050.9 Smallpox, unspecified
- 050.0 Variola major
- 050.2 Modified smallpox
ICD10
SNOMED
- 67924001 Smallpox (disorder)
- 47452006 Variola major (disorder)
- 51423006 Modified smallpox (disorder)
- 86497005 Flat-type smallpox (disorder)