Smallpox

SMALLPOX

SUMMARY

Signs and Symptoms: Clinical manifestations begin acutely with malaise, fever, rigors, vomiting, headache, and backache. 2-3 days later lesions appear which quickly progress from macules to papules, and eventually to pustular vesicles. They are more abundant on the extremities and face, and develop synchronously.

Diagnosis: Electron and light microscopy are not capable of discriminating variola from vaccinia, monkeypox or cowpox. The new PCR diagnostic techniques may be more accurate in discriminating between variola and other Orthopoxviruses.

Treatment: At present there is no effective chemotherapy, and treatment of a clinical case remains supportive.

Prophylaxis: Immediate vaccination or revaccination should be undertaken for all personnel exposed. Vaccinia immune globulin (VIG) is of value in post-exposure prophylaxis of smallpox when given within the first week following exposure.

Isolation and Decontamination: Droplet and Airborne Precautions for a minimum of 16-17 days following exposure for all contacts. Patients should be considered infectious until all scabs separate.

OVERVIEW

Variola virus causes smallpox. It is an Orthopox virus and occurs in at least two strains, variola major and the milder disease, variola minor. Despite the global eradication of smallpox and continued availability of a vaccine, the potential weaponization of variola continues to pose a military threat. This threat can be attributed to the aerosol infectivity of the virus, the relative ease of large-scale production, and an increasingly Orthopoxvirus-naive populace. Although the fully-developed cutaneous eruption of smallpox is unique, earlier stages of the rash could be mistaken for varicella. Secondary spread of infection constitutes a nosocomial hazard from the time of onset of a smallpox patient's exanthem until scabs have separated. Quarantine with respiratory isolation should be applied to secondary contacts for 17 days post-exposure. Vaccinia vaccination and vaccinia immune globulin each possess some efficacy in post-exposure prophylaxis.

HISTORY AND SIGNIFICANCE

Endemic smallpox was declared eradicated in 1980 by the World Health Organization (WHO). Although two WHO-approved repositories of variola virus remain at the Centers for Disease Control and Prevention (CDC) in Atlanta and the Institute for Viral Preparations in Moscow, the extent of clandestine stockpiles in other parts of the world remains unknown. In January 1996, WHO’s governing board recommended that all stocks of smallpox be destroyed by 30 June, 1999.

The United States stopped vaccinating its military population in 1989 and civilians in the early 1980s. These populations are now susceptible to variola major, although recruits immunized in 1989 may retain some degree of immunity. Variola may have been used by the British Army against native Americans by giving them contaminated blankets from the beds of smallpox victims during the eighteenth century. Japan considered the use of smallpox as a BW weapon in World War II and it has been considered as a possible threat agent against US forces for many years.

CLINICAL FEATURES

The incubation period of smallpox averaged 12 days, and contacts were quarantined for a minimum of 16-17 days following exposure. Clinical manifestations began acutely with malaise, fever, rigors, vomiting, headache, and backache; 15% of patients developed delirium. Approximately 10% of light-skinned patients exhibited an erythematous rash during this phase. Two to three days later, an enanthem appeared concomitantly with a discrete rash about the face, hands and forearms.

Following eruptions on the lower extremities, the rash spread centrally to the trunk over the next week. Lesions quickly progressed from macules to papules, and eventually to pustular vesicles. Lesions were more abundant on the extremities and face, and this centrifugal distribution is an important diagnostic feature. In distinct contrast to varicella, lesions on various segments of the body remained generally synchronous in their stage of development. From 8 to 14 days after onset, the pustules formed scabs which leave depressed depigmented scars upon healing. Although variola concentrations in the throat, conjunctiva, and urine diminished with time, virus could readily be recovered from scabs throughout convalescence. Therefore, patients should be isolated and considered infectious until all scabs separate.

For the past century, two distinct types of smallpox were recognized. Variola minor was distinguished by milder systemic toxicity and more diminutive pox lesions, and caused 1% mortality in unvaccinated victims. However, the prototypical disease variola major caused mortality of 3% and 30% in the vaccinated and unvaccinated, respectively. Other clinical forms associated with variola major, flat-type and hemorrhagic-type smallpox, were notable for severe mortality. A naturally occurring relative of variola, monkeypox, occurs in Africa, and is clinically indistinguishable from smallpox with the exception of notable enlargement of cervical and inguinal lymph nodes.

DIAGNOSIS

Smallpox must be distinguished from other vesicular exanthems, such as chickenpox, erythema multiforme with bullae, or allergic contact dermatitis. Particularly problematic to infection control measures would be the failure to recognize relatively mild cases of smallpox in persons with partial immunity. An additional threat to effective quarantine is the fact that exposed persons may shed virus from the oropharynx without ever manifesting disease. Therefore, quarantine and initiation of medical countermeasures should be promptly followed by an accurate diagnosis so as to avert panic.

The usual method of diagnosis is demonstration of characteristic virions on electron microscopy of vesicular scrapings. Under light microscopy, aggregations of variola virus particles, called Guarnieri bodies, are found. Another rapid but relatively insensitive test for Guarnieri bodies in vesicular scrapings is Gispen's modified silver stain, in which cytoplasmic inclusions appear black.

None of the above laboratory tests are capable of discriminating variola from vaccinia, monkeypox or cowpox. This differentiation classically required isolation of the virus and characterization of its growth on chorioallantoic membrane. The development of polymerase chain reaction diagnostic techniques promises a more accurate and less cumbersome method of discriminating between variola and other Orthopoxviruses.

MEDICAL MANAGEMENT

Medical personnel must be prepared to recognize a vesicular exanthem in possible biowarfare theaters as potentially variola, and to initiate appropriate countermeasures. Any confirmed case of smallpox should be considered an international emergency with immediate report made to public health authorities. Droplet and Airborne Precautions for a minimum of 16-17 days following exposure for all persons in direct contact with the index case, especially the unvaccinated. Patients should be considered infectious until all scabs separate. Immediate vaccination or revaccination should also be undertaken for all personnel exposed to either weaponized variola virus or a clinical case of smallpox.

The potential for airborne spread to other than close contacts is controversial. In general, close person-to-person proximity is required for transmission to reliably occur. Nevertheless, variola's potential in low relative humidity for airborne dissemination was alarming in two hospital outbreaks. Smallpox patients were infectious from the time of onset of their eruptive exanthem, most commonly from days 3-6 after onset of fever. Infectivity was markedly enhanced if the patient manifested a cough. Indirect transmission via contaminated bedding or other fomites was infrequent. Some close contacts harbored virus in their throats without developing disease, and hence might have served as a means of secondary transmission.

Vaccination with a verified clinical "take" (vesicle with scar formation) within the past 3 years is considered to render a person immune to smallpox. However, given the difficulties and uncertainties under wartime conditions of verifying the adequacy of troops' prior vaccination, routine revaccination of all potentially exposed personnel would seem prudent if there existed a significant prospect of smallpox exposure.

Antivirals for use against smallpox are under investigation. Cidofovir has been shown to have significant in vitro and in vivo activity in experimental animals.

PROPHYLAXIS

Vaccine: Smallpox vaccine (vaccinia virus) is most often administered by intradermal inoculation with a bifurcated needle, a process that became known as scarification because of the permanent scar that resulted. Vaccination after exposure to weaponized smallpox or a case of smallpox is effective in preventing disease if given within 3-7 days after exposure. A vesicle typically appears at the vaccination site 5-7 days post-inoculation, with surrounding erythema and induration. The lesion forms a scab and gradually heals over the next 1-2 weeks.

Side effects include low-grade fever and axillary lymphadenopathy. The attendant erythema and induration of the vaccination vesicle is frequently misdiagnosed as bacterial superinfection. More severe first-time vaccine reactions include secondary inoculation of the virus to other sites such as the face, eyelid, or other persons (~ 6/10,000 vaccinations), and generalized vaccinia, which is a systemic spread of the virus to produce mucocutaneous lesions away from the primary vaccination site (~3/10,000 vaccinations).

Vaccination is contraindicated in the following conditions: immunosuppression, HIV infection, history or evidence of eczema, or current household, sexual, or other close physical contact with person(s) possessing one of these conditions. In addition, vaccination should not be performed during pregnancy.

Despite the above caveats, most authorities state that, with the exception of significant impairment of systemic immunity, there are no absolute contraindications to post-exposure vaccination of a person who experiences bona fide exposure to variola. However, concomitant VIG administration is recommended for pregnant and eczematous persons in such circumstances.

Passive Immunoprophylaxis: Evidence indicates that vaccinia immune globulin is of value in post-exposure prophylaxis of smallpox when given within the first week following exposure, and concurrently with vaccination. Vaccination alone is recommended for those without contraindications to the vaccine, unless greater than one week has elapsed after exposure. At this time, administration of both products, if available, is recommended.

The U.S. Army maintains a supply of VIG. The dose for prophylaxis or treatment is 0.6 ml/kg intramuscularly. VIG should be available when using vaccinia vaccine for treatment of adverse reactions.