Remaining questions about clinical variola major.

After the recent summary of World Health Organization-authorized research on smallpox, several clinical issues remain. This policy review addresses whether early hemorrhagic smallpox is disseminated intravascular coagulation and speculates about the cause of the high mortality rate among pregnant women and whether ocular smallpox is partly the result of trachoma or vitamin A deficiency. The joint destruction common in children with smallpox might be prevented by antiviral drugs, but intraarticular infusion of antiviral drugs is unprecedented. Development of highly effective antiviral drugs against smallpox raises the issue of whether postexposure vaccination can be performed without interference by an antiviral drug. Clinicians should consider whether patients with smallpox should be admitted to general hospitals. Although an adequate supply of second-generation smallpox vaccine exists in the United States, its use is unclear. Finally, political and ethical forces suggest that destruction of the remaining stocks of live smallpox virus is now appropriate.

Evaluating public health responses to reintroduced smallpox via dynamic, socially structured, and spatially distributed metapopulation models.

The risk of smallpox reintroduction has motivated preparations in potential target countries. After reproducing the spatiotemporal pattern after the 1972 importation into Yugoslavia via coupled, biologically realistic systems of ordinary differential equations, we developed dynamic population models with current US age distributions and typical spatially distributed social structures. Surveillance and containment (S&C) coupled with vaccination of 95% of hospital-based health care workers (HCWs) within 2 days after the first diagnosis (estimated to be 18 days after aerosol release) were modeled after simulated exposure of 10, 50, or 10,000 people in various settings. If 90% of patients were isolated within days after symptom onset and 75% of contacts were vaccinated and monitored, S&C would reduce cases by 82%-99%. Preemptive immunization of HCWs, closing of schools, and even vaccination of as many as 80% within 1 week would have small marginal benefits. Preparations should emphasize stockpiling vaccine, training HCWs, improving laboratory capacity, and fostering an understanding of S&C.

Myocarditis, pericarditis, and dilated cardiomyopathy after smallpox vaccination among civilians in the United States, January-October 2003.

Myocarditis was reported after smallpox vaccination in Europe and Australia, but no association had been reported with the US vaccine. We conducted surveillance to describe and determine the frequency of myocarditis and/or pericarditis (myo/pericarditis) among civilians vaccinated during the US smallpox vaccination program between January and October 2003. We developed surveillance case definitions for myocarditis, pericarditis, and dilated cardiomyopathy after smallpox vaccination. We identified 21 myo/pericarditis cases among 37,901 vaccinees (5.5 per 10,000); 18 (86%) were revacinees, 14 (67%) were women, and the median age was 48 years (range, 25-70 years). The median time from vaccination to onset of symptoms was 11 days (range, 2-42 days). Myo/pericarditis severity was mild, with no fatalities, although 9 patients (43%) were hospitalized. Three additional vaccinees were found to have dilated cardiomyopathy, recognized within 3 months after vaccination. We describe an association between smallpox vaccination, using the US vaccinia strain, and myo/pericarditis among civilians.

Smallpox.

The WHO declared smallpox eradicated in 1980. However, concern over its potential use by terrorists or in biowarfare has led to striking growth in research related to this much-feared disease. Modern molecular techniques and new animal models are advancing our understanding of smallpox and its interaction with the host immune system. Rapid progress is likewise being made in smallpox laboratory diagnostics, smallpox vaccines, and antiviral medications. WHO and several nations are developing stockpiles of smallpox vaccine for use in the event the disease is reintroduced. National and international public-health agencies have also drawn up plans to help with early detection of and response to a smallpox outbreak. These plans hinge on physicians' ability to recognise the clinical features of smallpox and to distinguish it from other illnesses characterised by rashes.

Development of a risk-priority score for category A bioterrorism agents as an aid for public health policy.

In developing public health policy and planning for a bioterrorist attack or vaccination of military personnel, the most common method for assigning priority is using the probability of attack with a particular agent as the single criterion. Using this approach, smallpox is often dismissed as an unlikely threat. We aimed to develop an evidence-based, systematic, multifactorial method for prioritizing the level of risk of each category A bioterrorism agent. Using 10 criterion, anthrax scored the highest, followed by smallpox. Tularemia was the lowest scoring agent. We suggest that such a system would be useful for developing public policy, stockpiling of vaccines and therapeutics, vaccination of military personnel, and planning for public health responses to a bioterrorist attack.

Generalized vaccinia, progressive vaccinia, and eczema vaccinatum are rare following smallpox (vaccinia) vaccination: United States surveillance, 2003.

Generalized vaccinia (GV), progressive vaccinia (PV), and eczema vaccinatum (EV) are adverse reactions following smallpox vaccination. We investigated all reports suggestive of GV, PV, or EV among United States civilian smallpox vaccinees during 2003 and applied standard case definitions. We identified 29 reports of possible GV among 38,440 vaccinees; 2 (7%) of the reports met the case definition. One case of GV was confirmed by identifying vaccinia from a lesion distant from the vaccine site using polymerase chain reaction. The other case was classified as probable GV, because confirmatory testing was not done. We identified 3 potential EV cases and 7 potential PV cases, none of which met the standard case definition. GV, PV, and EV were rare or absent following smallpox vaccination after careful screening of potential vaccinees. GV may be difficult to distinguish from other rashes, and confirmatory testing is recommended. Careful prevaccination screening probably contributed to the low incidence of these adverse reactions following smallpox vaccination.

Evaluation of 21st-century risks of smallpox vaccination and policy options.

The United States stopped vaccinating against smallpox in 1972 because the risks were judged to outweigh the benefits. The possibility of a terrorist attack using smallpox has led to renewed interest in a vaccination program. Smallpox vaccination carries considerable risks, which may be of greater concern today than in the late 1960s because of the increased prevalence of immunosuppression and atopy in the population. This paper reviews the clinical presentations of major adverse events after vaccination and the rates of occurrence of these events observed in the 1960s. The normal dynamics of the spread of smallpox is slow, and usually only persons who have had close personal contact with an overtly ill patient are affected. There are several preattack vaccination policy options, but immunization of medical workers, especially those who might have close contact with infected patients, is sufficient in the absence of a known threat of a bioterrorist attack or the identification of a smallpox-infected person.

Neurologic adverse events associated with smallpox vaccination in the United States, 2002-2004.

CONTEXT: Neurologic illness is an infrequent but severe adverse event associated with smallpox vaccination. The reinstatement of smallpox vaccination in the United States in response to possible bioterrorism renewed concerns about vaccine-related adverse neurologic events. OBJECTIVE: To determine rates and describe the clinical features of neurologic events associated with smallpox vaccination. DESIGN AND SETTING: We assessed reports of adverse events obtained through active case reporting and review of data reported to the Vaccine Adverse Event Reporting System among 665,000 persons vaccinated against smallpox by the Departments of Defense (n = 625,400 [corrected]) and Health and Human Services (n = 39,400 [corrected]) during the 2002-2004 US Smallpox Vaccination Program. MAIN OUTCOME MEASURE: Adverse neurologic events temporally associated with smallpox vaccination. RESULTS: Between December 16, 2002, and March 11, 2004, 214 neurologic adverse events temporally associated with smallpox vaccination were reported; 111 reports involved Department of Health and Human Services and 103 involved Department of Defense vaccinees. Fifty-four percent of these events occurred within 1 week of vaccination, and 53% were among primary vaccinees. The most common neurologic adverse event was headache (95 cases), followed by nonserious limb paresthesias (n = 17) or pain (n = 13) and dizziness or vertigo (n = 13). Serious neurologic adverse events included 13 cases of suspected meningitis, 3 cases of suspected encephalitis or myelitis, 11 cases of Bell palsy, 8 seizures (including 1 death), and 3 cases of Guillain-Barré syndrome. Among these 39 events, 27 (69%) occurred in primary vaccinees and all but 2 occurred within 12 days of vaccination. CONCLUSIONS: During the 2002-2004 smallpox vaccination campaign, reported neurologic events were generally mild and self-limited, and no neurologic syndrome was identified at a rate above baseline estimates. Serious neurologic adverse events, such as postvaccinal encephalitis, Bell palsy, and Guillain-Barré syndrome, occurred in accordance with expected ranges.

Clinical efficacy of intramuscular vaccinia immune globulin: a literature review.

BACKGROUND: Numerous literature reports describe clinical efficacy of intramuscular vaccinia immune globulin (VIG) for complications of smallpox vaccination, prophylaxis of individuals with contraindications to vaccination, and prevention of smallpox among close contacts of patients with smallpox. METHODS: We reviewed the literature regarding VIG treatment and prophylaxis of smallpox vaccine complications and the use of VIG as a preventative measure for close contacts of patients with smallpox. RESULTS: Data regarding intramuscular administration of VIG for treatment of smallpox vaccine complications occurred in 16 articles, none of which reported formal controlled trials. The indications for treatment include generalized vaccinia, progressive vaccinia, eczema vaccinatum, and certain accidental implantations. Six publications suggest VIG efficacy for prophylaxis of vaccinial superinfection of eczema, burns, chickenpox, immunosuppression, pregnancy, or certain skin conditions. Prophylactic VIG has also been used in healthy military recruits to reduce the incidence of postvaccinial encephalitis. The use of intramuscular administration of VIG to prevent smallpox in contacts of patients with documented cases of smallpox is reported in 4 studies that compare contacts who received intramuscular administration of VIG with those who did not and in 1 observational study, with varying but promising results. CONCLUSIONS: Although controlled clinical trials do not exist to support the use of VIG for treatment of vaccinia-related complications or prophylaxis among individuals with contraindications to smallpox vaccination, available data suggest that VIG reduces morbidity and mortality associated with progressive vaccinia (vaccinia necrosum) and eczema vaccinatum. Furthermore, VIG seems to prevent vaccinial superinfection in patients with inflammatory skin diseases or burns, given the low incidence of vaccina-related complications associated with these conditions.

Transmission of vaccinia virus and rationale for measures for prevention.

Currently, health care workers (HCWs) in the United States are being vaccinated against smallpox, and there is a possibility that this will be expanded to a more widespread vaccination program. Inadvertent transmission of vaccinia virus to patients with illnesses that are contraindications to vaccination is theoretically possible. Vaccinia virus is shed from the vaccination lesion of healthy primary vaccinees from approximately the third day to the end of the third week after vaccination; transmission of vaccinia virus is rare but does occur. Prudent management of the vaccination site by HCWs should virtually eliminate transmission. We recommend that vaccinated HCWs cover the site with loose gauze dressings and, when caring for patients with immunosuppression or extensive disruptive skin disorders, cover the dressings with semipermeable membranes. The evidence for respiratory spread of vaccinia virus is not compelling, and therefore droplet or airborne infection precautions should not be necessary, even for vaccinated HCWs who are caring for patients who experienced serious adverse events after smallpox vaccination in the past.

Myocarditis after smallpox vaccination: a case report.

A 20-year-old airman (US Air Force) developed myocarditis 8 days after smallpox vaccination. He was treated with nonsteroidal anti-inflammatory agents, and his symptoms promptly resolved. However, postvaccinial myocarditis can lead to serious complications and even death.

Smallpox vaccination: a review, part I. Background, vaccination technique, normal vaccination and revaccination, and expected normal reactions.

Because smallpox could be a factor in bioterrorism, the United States has provided guidelines for smallpox vaccination of certain members of the population, including health care workers and first responders, as well as military personnel. A plan for more extensive vaccination, if it is needed in the event of a bioterrorist attack, is being developed under the aegis of the Centers for Disease Control and Prevention. The characteristics of smallpox vaccine, the technique of administration, and the expected reactions to primary vaccination and revaccination are outlined in this article.

Smallpox vaccination: a review, part II. Adverse events.

Smallpox vaccination of health care workers, military personnel, and some first responders has begun in the United States in 2002-2003 as one aspect of biopreparedness. Full understanding of the spectrum of adverse events and of their cause, frequency, identification, prevention, and treatment is imperative. This article describes known and suspected adverse events occurring after smallpox vaccination.

Superinfection following smallpox vaccination (Vaccinia), United States: surveillance January 2003 through January 2004.

BACKGROUND: Superinfection is an adverse event following smallpox vaccination. The clinical presentation is similar to that of a large normal vaccine reaction or "robust take," and the frequency is unknown. METHODS: We retrospectively reviewed all reported severe local reactions consistent with superinfection among United States civilian smallpox vaccinees from January 2003 through January 2004. We applied a standard case definition and estimated the frequency of superinfection following smallpox vaccination. RESULTS: We identified 48 reported cases for further review among 39,350 [corrected] smallpox vaccinees. Two (4%) of the 48 reported cases met the case definition for superinfection; neither of the patients had a pathogenic organism isolated from their infection site. Both were treated with antibiotics and resolved their infection. Of the 46 cases determined not to be superinfection, 41 (89%) were temporally consistent with a large normal vaccine reaction. Thirty (75%) of 40 reported case patients for whom data were available received antibiotic therapy. CONCLUSIONS: Superinfection following smallpox vaccination is rare. Most of the reported superinfection cases were probably large normal smallpox vaccine reactions. Educating providers about the normal response to smallpox vaccine may decrease the overdiagnosis of superinfection and the unnecessary use of antimicrobials.

Adverse events occurring after smallpox vaccination.

We reviewed the literature on adverse events reported to occur after smallpox vaccination. Nearly one-half of the United States population is vaccinia-naïve and may be at risk for development of serious adverse events. We describe the clinical features of postvaccinial central nervous system disease, progressive vaccinia, eczema vaccinatum, accidental implantations, "generalized vaccinia," and the common erythematous and/or urticarial rashes. In the 1960s, death occurred approximately once in every million primary vaccinations, with fatalities resulting from progressive vaccinia, postvaccinial encephalitis, and eczema vaccinatum. Death in revaccinees occurred less commonly and almost entirely from progressive vaccinia. In today's population, death rates might be higher because of the increased prevalence of immune deficiency and atopic dermatitis.

Severe headaches following smallpox vaccination.

Headaches are common following smallpox vaccination; the re-introduction of civilian vaccination necessitates better understanding of the clinical features and outcome of postvaccination headache. We identified patients reporting headache following vaccination from among those reported to the U.S. Vaccine Adverse Events Reporting System to characterize demographic and clinical features. One-hundred and eight reports were obtained from among 627 smallpox vaccine-related reports, including 15 hospitalized persons. None had neurologic dysfunction or acute laboratory abnormalities; headache resolved in all except 2 hospitalized patients within 3 months. Severe headache following smallpox vaccination is generally transient, but debilitating headache may occur and further characterization is needed.