Smallpox (Variola Virus), Pediatric

Basics

Description

- 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.

- 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

- Modified smallpox - Milder than ordinary smallpox - Accelerated course - Lesions are not as deep

- 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

- 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

- 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.

- 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.

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 smallpoxModified smallpoxFlat smallpoxHemorrhagic smallpoxVariola 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 casesHospital-based health care teams responsible for assessing and caring for suspected smallpox cases
Vaccine efficacy95% efficacious in preventing disease if given prior to exposureMay prevent smallpox or decrease severity if given 1 " 3 days after exposureMay 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 administrationA 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 disorderImmunosuppressionPregnancy or breastfeedingClose contact of someone who is pregnant, immunosuppressed, or has skin diseaseAllergy to vaccine componentModerate or severe acute illnessInflammatory eye diseaseHeart disease (myocardial infarction, stroke, cardiomyopathy, heart failure, or angina) or ≥3 risk factors for heart diseaseAge <1 yearThese 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 lossAccidental inoculation with blister formationModerate to severe generalized rashEczema vaccinatumEncephalitisCongenital or generalized vacciniaMyopericarditisProgressive vaccinia/vaccinia gangrenosumBacterial 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 swellingInfections 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 smallpoxIncubation 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 rashOften starts on face and spreads to rest of body within 24 " 48 hoursOn 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 smallpoxMilder than ordinary smallpoxAccelerated courseLesions are not as deep
Flat smallpoxCharacterized by soft, flat, semiconfluent or confluent rash that does not evolve to pustules but can still result in significant skin loss
Hemorrhagic smallpoxShorter incubation timeSkin becomes duskyBleeding in skin and mucous membranesCan be difficult to diagnose unless exposure to variola virus is known
Variola sine eruptioneMay be asymptomatic or cause an influenza-like illnessNoncontagiousSeen 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 criteriaFebrile 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 painClassic 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 criteriaCentrifugal distribution with greatest concentration of lesions on face and extremitiesFirst lesions appear on the oral mucosa, palate, face, or forearms.Patient appears toxic or moribundSlow evolution: Lesions evolve from macules to papules to pustules over days (each stage lasts 1 " 2 days).Lesions on the palms and solesHigh risk of smallpoxFebrile prodrome and classic lesions in same stage of developmentModerate risk of smallpoxFebrile prodrome and either 1 other major criterion or ≥4 minor criteriaLow risk of smallpoxNo 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 testingShould not be performed in low- and moderate-risk cases because of risk of false positivesShould only be performed in designated high-containment facilitiesLesion 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 zosterHerpes simplex virusMeaslesRubellaMonkeypox, cowpox, and tanapoxViral exanthema including enterovirusDisseminated molluscum contagiosumImpetigo, insect bites, or scabiesPost-smallpox vaccine rash (vaccinia)Secondary syphilisAcne and contact dermatitisDrug reactions including erythema multiformeMeningococcemia 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]