Since the events of September 11, 2001, and the recent casualties due to inhalational anthrax, the threat that other biologic agents may be used as terrorist weapons has increased. Bioterrorism experts consider smallpox to be one of the most likely agents, given its high transmission (as many as 10–20 second-generation cases from a single index case) and case-fatality rates (30% among the unvaccinated).1 This is especially so during the winter.
Smallpox poses particularly serious threats, not only because of its aerosol infectivity, relative ease of large-scale production, and widespread susceptibility, but also because few practicing physicians have seen a case of smallpox, and almost none have been formally trained in its early diagnosis. The last smallpox cases in the United States occurred in 1949, and the last case of naturally acquired infection occurred in Somalia in 1977. The World Health Organization declared its global eradication in 1980.2
Our objectives are to review the current recommendations for diagnosis and prevention of smallpox, as well as its effects on pregnancy outcome.
Before its eradication, variola virus existed as two related strains: variola minor, which caused a clinically milder febrile rash (alastrim) with a mortality rate of less than 1%, and variola major (smallpox), with a case-fatality rate of up to 30% in susceptible populations and 3% in vaccinated populations.
Smallpox was transmitted from person to person, with no reservoir apart from infected individuals.3 Exposure occurred by inhaling airborne droplets containing the variola virus or by coming into direct contact with smallpox lesions. Viral invasion of oropharyngeal or respiratory mucosae was followed by multiplication in the lymphatic system and viremia. These pathogenic events corresponded to the incubation period, usually 12 days from exposure until the first symptoms appeared (range 7–17 days).4–8
Typically, the rash was preceded by fever (100–105 F), chills, severe headache, backache, and vomiting.9 Although this preeruption phase was very similar to severe influenza, only 15% of patients with smallpox complained of catarrhal symptoms (sore throat and dry cough), and rarely of runny nose, sneezing, or watering of the eyes.9 Delirium, which affected 15% of smallpox patients, usually cleared as the rash developed. Some of these cases progressed to encephalitis.9
Viremia was then followed by localization of viral particles in the small dermal vessels with subsequent development of skin lesions (2–3 days after the onset of symptoms). In the great majority of cases, these lesions progressed from macula to papule, papule to vesicle, vesicle to pustule (known as pock), and pustule to scabs, which then separated into pitted scars (Figures 1 and 2). The patients remained febrile throughout the progression of exanthema. Umbilication, a common feature of smallpox lesions, was not found on palms or soles.10 Smallpox lesions were more abundant and left more scars in the face than elsewere.10 During the first 2–3 days, the rash of smallpox is very similar to chickenpox. However, later on, there are some characteristics that help in their differential diagnosis (Table 1). Death secondary to smallpox resulted from viral pneumonitis, bacterial pneumonia, or sudden cardiovascular collapse, usually during the second week of the illness.6
A suspicious case of smallpox must be confirmed or ruled out by polymerase chain reaction11 in a laboratory with high-containment facilities (Centers for Disease Control and Prevention [CDC] and the US Army Medical Research Institute of Infectious Diseases' biosafety level 4 laboratories1,4). Vaccinated personnel should collect vesicular or pustular fluid and scabs into a vacutainer tube, which must be sealed and placed in a second watertight container and shipped immediately. Scrapings from macules and papules can also be obtained. Once smallpox has been recognized as the etiologic agent for an epidemic, typical cases would not require further laboratory confirmation.
A serious diagnostic problem would arise if after a bioterrorist attack the index case manifests as one of three “atypical” varieties of smallpox: malignant (flat), hemorrhagic, or modified. Before its eradication, smallpox was seldom suspected in such cases, until more cases with the typical rash were seen, and it was then recognized that a smallpox outbreak was in progress.5
A dense, confluent macular rash with no progression to papules or pustules (flat smallpox), high transmission, and mortality rates characterized the “malignant” variety of smallpox. In India, between 1961 and 1972, malignant smallpox affected 7% of the unvaccinated with a case-fatality rate of 95%, and 1.3% of the vaccinated with a case-fatality rate of 66%.9
Petechiae, ecchymosis, and bloody pustules on skin and mucosae characterized the “hemorrhagic” variety of smallpox, also known as “purpura variolosa.” This subtype represented 2–4% of all smallpox cases. Subconjuctival hemorrhages were the most common, but bleeding from gums, epistaxis, hematemesis, hemoptysis, hematuria, as well as vaginal bleeding occurred.9 These cases were frequently confused with meningococcemia or acute leukemia.5,9 This subtype had even a higher mortality, with case-fatality rates of 99% and 94% among the unvaccinated and vaccinated, respectively.9 For reasons poorly understood, hemorrhagic smallpox affected pregnant women more frequently9 (see below).
The “modified” variety occurred in individuals vaccinated more than 5 years before exposure and was characterized by milder constitutional syndrome, quicker progression of the rash (usually without pustules that crusted as early as the 7th day of eruption), and very low mortality.
No specific treatment exists for smallpox other than supportive care. Vaccination and containment of smallpox by quarantine are crucial interventions to avoid spread of the infection.4,8,12 Strict universal precautions are required as well as patient isolation in negative pressure rooms equipped with special filter systems. All patient contacts up to 17 days before the onset of symptoms (including physicians and nursing staff) should remain in isolation until a definitive diagnosis is made. If a smallpox diagnosis is confirmed, vaccination and 17 days of quarantine are mandatory. It is estimated that there would be at least 10–20 secondary cases for every case in the first wave.1,12,13 If the initial cases could not be contained or if a large population was initially exposed, the only logical approach would be a mass vaccination, an option that would not be possible with current vaccine availability (see below).
Vaccination within 2–3 days of the initial exposure affords almost complete protection against disease or reduces symptomatology. Vaccination as late as 4–5 days after exposure may prevent death.1,6 Antibiotics are needed if secondary infection of the skin lesions develops.
The Advisory Committee in Immunization Practices from the CDC has recently published its recommendations on smallpox vaccination.4 Permanent evaluation and update of these guidelines, as well as other important clinical resources on smallpox can be found on http://www.cdc.gov/nip/smallpox/Providers.htm.
The smallpox vaccine that is currently Food and Drug Administration licensed and available in the United States is Dryvax (Wyeth Laboratories, Lancaster, PA). Dryvax is the lyophilized (freeze-dried), heat-stable formulation of live attenuated vaccinia virus. Vaccinia is a stable hybrid virus related both to smallpox and cowpox virus. Wyeth Laboratories discontinued production of Dryvax in 1982 (the United States discontinued routine vaccination in 1971). The vaccine was manufactured from harvesting fluid of vesicles/pustules of calf or sheep skin infected with the New York City Board of Health strain of the vaccinia virus. This vaccine contains trace amounts of streptomycin, chlortetracycline, neomycin, and polymyxin B sulfate. The vaccination method is by inoculation using a double prong (bifurcated) needle (Wyeth Laboratories).
Current availability of the vaccine is limited. The CDC is the only source of the vaccine for civilians. As of 1999, only 15.4 million doses of smallpox vaccine existed in the United States.14 There is also a limited supply of the specific diluent and special bifurcated needles.14 On September 20, 2000, the CDC contracted Ora Vax (Cambridge, MA) to produce a new smallpox vaccine. Similar to the Dryvax vaccine, this investigational drug contains the live vaccinia virus, but it is now produced in cell cultures. An initial delivery of 40 million doses is anticipated for 2004.15
The reaction to primary vaccination is a flat vesicle of about 1 cm in diameter, with an inflammatory surrounding zone. The vesicle is maximal around the 10th day and dries to a crust that separates in 3 weeks.16 Successful vaccination completely protects against smallpox for approximately 5 years and will modify an attack for a further 5–10 years.16
The CDC's Advisory Committee in Immunization Practices recommendations for vaccination against smallpox are as follows4:
In a nonemergency scenario, pre-exposure vaccination is not recommended for any group other than the research or laboratory staff that handles cultures or animals contaminated or infected with variola-related viruses. This limited recommendation is based on the risk of complications from vaccination and our limited vaccine and vaccinia immune globulin (VIG) stocks.
Epidemiologic studies have demonstrated that a high level of protection against smallpox and other related viruses persists close to 5 years after primary vaccination, and substantial but waning immunity can persist for more than 10 years.16–18 Scheduled routine nonemergency revaccination of orthopoxviruses research personnel is recommended for every 10 years. For those working with more virulent orthopoxviruses (eg, monkeypox virus), revaccination has been empirically recommended for every 3 years19 but not during pregnancy.
During routine nonemergency circumstances, contraindications to smallpox vaccination include pregnancy, immunodeficiency (hereditary or acquired immune deficiency disorders, patients with leukemia, lymphoma, or generalized malignancy who are receiving therapy with alkylating agents, antimetabolites, radiation, or large doses of corticosteroids), persons with eczema (regardless of disease state) or other exfoliative skin conditions (atopic dermatitis, impetigo, shingles, or burns), and allergies to vaccine components.4
In an emergency scenario (after intentional release of variola virus has been confirmed), vaccination will be initially recommended for: 1) people who were exposed to the initial release of the virus; 2) people who had face-to-face, household, or close proximity contact (less than 6.5 ft or 2 m) with a confirmed or suspected smallpox patient at any time between the onset of the patient's fever until all scabs have separated; 3) personnel involved in the direct medical or public health evaluation, care, or transportation of confirmed or suspected smallpox patients; 4) laboratory personnel involved in the collection or processing of clinical specimens from confirmed or suspected smallpox patients; and 5) other persons who have an increased likelihood of contact with infectious materials from a smallpox patient (eg, personnel responsible for medical waste disposal, linen disposal, or room disinfection in a facility where smallpox patients are present),4 unless vaccinated in the previous 5 years. Smallpox mandatory vaccination for civilian population was stopped more than 30 years ago. It is estimated that less than 10% of the vaccinees before 1970 retains any protection from vaccination.
There are no absolute contraindications to vaccination of an individual with a high-risk exposure to smallpox. This is because people at the greatest risk for developing serious vaccination complications are also at the greatest risk of death from smallpox.1,4,18 If a relative contraindication to vaccination exists, the risk of serious vaccination complications must be weighed against the risk of a potentially fatal smallpox infection.
Smallpox vaccination produces complications more often than any other viral vaccine and for this reason should be carried out only when definitely indicated. The most serious nondermal side effect is postvaccinal encephalitis, which occurred at a rate of 12 per million vaccines20 (mostly infants less than 1 year old); 40% of the cases are fatal, and some patients are left with permanent neurologic damage. There are several dermal complications. Mild generalized vaccinia occurred at a rate of one per 25,000 people vaccinated. Eczema vaccinatum was sometimes fatal and occurred as a superinfection of eczema with the vaccinia virus. Progressive vaccinia and severe generalized vaccinia occurred among the immunosuppressed. The former was also known as vaccinia gangrenosa caused by the extensive local necrosis at the site of vaccination. The latter was the most fatal dermal complication, unless patients were treated with VIG.4
Currently, VIG is the medication used as prophylaxis in individuals at risk of serious vaccination complications and/or treatment of smallpox complications. If people with contraindications have been in close contact with someone infected with smallpox or the individual is at risk for occupational reasons, prophylactic VIG (if available) should be given simultaneously with the vaccination in a dose of 0.3 mL/kg of body weight to prevent complications; this does not alter vaccine efficacy.21 Currently, there is a limited amount of VIG doses that are being reserved for the treatment of life-threatening postvaccinial complications. Also, VIG provides no benefit in the treatment of postvaccinial encephalitis, and it is contraindicated in cases of postvaccinial keratitis. Even if VIG is not available, vaccine administration may still be warranted, given that the risk of an adverse outcome from smallpox infection far outweighs the risk from vaccination (see below for pregnancy scenario).1 For therapeutic purposes, the recommended dose is 0.6 mL/kg.21
SMALLPOX EFFECTS ON PREGNANCY
Variola virus caused severe problems in pregnant women and was associated with significant perinatal and maternal morbidity and mortality.
During the smallpox era, it seemed that successful vaccination (presence of inoculation scar) did not completely protect the pregnant from death caused by smallpox. Maternal mortality was reported disproportionately high compared with that of the overall population, particularly in developing countries. Rao has described the largest series of smallpox during pregnancy (n = 389).9 During the early 1960s, this author reported that in India the overall case-fatality rate in pregnant women with smallpox was 33%, with 27% among the vaccinated and 61% among the unvaccinated. He also reported that when smallpox was acquired before 24 weeks' gestation, around 75% of these pregnancies either aborted or delivered prematurely, either during the course of the infection (42%), or during the convalescence period (35%). When smallpox was acquired between 24 and 37 weeks' gestation, around 55% of these pregnancies delivered prematurely, either during the course of the infection (42%), or during the convalescence period (13%). When smallpox was acquired at full term, about 9% of women died before delivery, and about 45% of the survivors delivered during the acute phase of disease.9
The other aspect of smallpox in pregnant women was its influence on severity of disease. Hemorrhagic smallpox was seven times more frequent in pregnant women than in men and nonpregnant women, regardless of vaccination status. The incidence of hemorrhagic smallpox was 25% among the unvaccinated pregnant women and 13% among the vaccinated.22 The case-fatality rate in hemorrhagic smallpox was reported to be 100% among pregnant Indian women.22
The rate of preterm stillbirths was nearly 48% and 10% after 37 weeks' gestation. Nearly 55% of the live births died within 15 days after birth (the majority during the first 72 hours of life). Some of these neonatal deaths were probably secondary to viral infection not clinically manifested and others to the precarious neonatal care. The rate of congenital smallpox among the live births was 9%; all of them died. In these cases, the “maternal fever-to-neonatal fever period” was 9–12 days.9
VACCINATION EFFECTS DURING PREGNANCY
The vaccinia virus has not been documented to be teratogenic,23,24 and fetal vaccinia is a rare complication of vaccination.25 Nineteen cases of fetal vaccinia were found between 1932 and 1978 in the English literature.* Cases of fetal vaccinia presented lesions to the skin, mucous membranes, and the placenta independent of the duration of pregnancy at the time of vaccination. Fetal vaccinia has resulted in abortion, stillbirth, or neonatal death after both primary vaccination and revaccination.5 Therefore, in nonemergency circumstances, smallpox vaccination is contraindicated at all stages of pregnancy, but if inadvertently performed in early pregnancy is not grounds for termination.26 Nonpregnant vaccination candidates must be advised of potential complications and should not become pregnant for 3 months after vaccination, as it is recommended after vaccination with other live virus vaccines.27,28 Scheduled revaccination should be postponed if the previously vaccinated researcher is pregnant or wants to become pregnant. It may be cautious but prudent to recommend to the wives of recently vaccinated research personnel that they should also avoid becoming pregnant.29 The risk of transmitting the vaccinia virus from the site of inoculation was reported to be 27 infections per million vaccinations.20
In the event of a woman being at risk from smallpox (direct victim of bioterrorist attack or a close contact of an index case), the risks to the mother and fetus from experiencing clinical smallpox, especially hemorrhagic smallpox, substantially outweigh any potential risks regarding vaccination. Vaccination and VIG may be given simultaneously,21 if available. During the smallpox era, the ACOG recommended: “the safest procedure for primary smallpox vaccination during pregnancy is to administer a simultaneous, separate injection of VIG. But when VIG is not available and vaccination is mandatory, during epidemics …, vaccine should not be withheld.”30 Revaccination did not require prophylactic VIG.
When the level of exposure risk is undetermined, the decision to vaccinate should be made after assessment by the clinician and patient of the potential risks versus the benefits of the smallpox vaccination.
The possibility of a bioterrorist attack is real. If such an attack occurs, health care providers are the first line of defense by identifying the index case, preventing spread of the disease by vaccination, and proper isolation of contacts. As the primary care provider for pregnant and nonpregnant women, we will be faced with an addition to our differential diagnosis in women with severe flu-like symptoms or a febrile exanthema, such as chicken-pox. We must learn to correctly prevent and, in the event of a bioterrorist attack, to correctly diagnose, treat, and avoid spread of the infection. Our degree of preparedness and quickness to diagnose and respond to a bioterrorism attack are extremely important to avert a great tragedy.
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2. World Health Organization. The global eradication of smallpox. Final report of the global commission for the certification of smallpox eradication. Geneva: World Health Organization, 1980.
3. Neff JM. Variola (smallpox) and monkeypox viruses. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and practice of infectious diseases. Philadelphia, PA: Churchill Livingstone, 2000:1555–6.
4. Centers for Disease Control and Prevention. Vaccinia (smallpox) vaccine recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2001;50:1–25.
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10. Institute of Medicine. Assessment of future scientific needs for live variola virus. Washington, DC: National Academy Press, 1999:25–31.
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13. Henderson DA. The looming threat of bioterrorism. Science 1999;283:1279–82.
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15. LeDuc JW, Jahrling PB. Strengthening national preparedness for smallpox: An update. Emerg Infect Dis 2001;7:155–7.
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17. World Health Organization Expert Committee on Smallpox Eradication. Second report. World Health Organ Tech Rep Ser 1972;493:1–64.
18. Public Health Service. Recommendations of the Public Health Service Advisory Committee on Immunization Practices: Smallpox vaccine. Washington, DC: Public Health Service, 1972.
19. Centers for Disease Control and Prevention. Human monkeypox—Kasai Oriental, Zaire, 1996–1997. MMWR Morb Mortal Wkly Rep 1997;46:304–7.
20. Lane JM, Ruben FL, Neff JM, Millar JD. Complications of smallpox vaccination, 1968: Results of ten statewide surveys. J Infect Dis 1970;122:303–9.
21. Goldstein JA, Neff JM, Lane JM, Koplan JP. Smallpox vaccination reactions, prophylaxis, and therapy of complications. Pediatrics 1975;55:342–7.
22. Rao AR, Prahlad I, Swaminathan M, Lakshmi A. Pregnancy and smallpox. J Indian Med Assoc 1963;40:353–63.
23. Naderi S. Smallpox vaccination during pregnancy. Obstet Gynecol 1975;46:223–6.
24. Greenberg M, Yankauer A Jr, Krugman S, Osborn JJ, Ward RS, Dancis J. The effect of smallpox vaccination during pregnancy on the incidence of congenital malformations. Pediatrics 1949;3:456–67.
25. Levine MM, Edsall G, Bruce-Chwatt LJ. Live-virus vaccines in pregnancy. Risks and recommendations. Lancet 1974;2:34–8.
26. Waterson AP. Virus infections (other than rubella) during pregnancy. BMJ 1979;2:564–6.
27. Centers for Disease Control and Prevention Advisory Committee on Immunization Practices. Rubella prevention. MMWR Morb Mortal Wkly Rep 1984;33:301–18.
28. American College of Obstetricians and Gynecologists. Immunization during pregnancy. ACOG technical bulletin no. 160. Washington, DC: American College of Obstetricians and Gynecologists, 2001:546–55.
29. Centers for Disease Control and Prevention. Contact spread of vaccinia from a recently vaccinated marine—Louisiana. MMWR Morb Mortal Wkly Rep 1984;33:37–8.
30. American College of Obstetricians and Gynecologists. Immunization during pregnancy. ACOG technical bulletin no. 20. Washington, DC: American College of Obstetricians and Gynecologists, 1973.