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Smallpox as a Biological Weapon
Medical and Public Health Management
Donald A. Henderson, MD, MPH;
Thomas V. Inglesby, MD;
John G. Bartlett, MD;
Michael S. Ascher, MD;
Edward Eitzen, MD, MPH;
Peter B. Jahrling, PhD;
Jerome Hauer, MPH;
Marcelle Layton, MD;
Joseph McDade, PhD;
Michael T. Osterholm, PhD, MPH;
Tara O'Toole, MD, MPH;
Gerald Parker, PhD, DVM;
Trish Perl, MD, MSc;
Philip K. Russell, MD;
Kevin Tonat, PhD;
for the Working Group on Civilian Biodefense
JAMA. 1999;281:2127-2137.
ABSTRACT
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Objective To develop consensus-based recommendations for measures to be taken by medical and public health professionals following the use of smallpox as a biological weapon against a civilian population.
Participants The working group included 21 representatives from staff of major medical centers and research, government, military, public health, and emergency management institutions and agencies.
Evidence The first author (D.A.H.) conducted a literature search in conjunction with the preparation of another publication on smallpox as well as this article. The literature identified was reviewed and opinions were sought from experts in the diagnosis and management of smallpox, including members of the working group.
Consensus Process The first draft of the consensus statement was a synthesis of information obtained in the evidence-gathering process. Members of the working group provided formal written comments that were incorporated into the second draft of the statement. The working group reviewed the second draft on October 30, 1998. No significant disagreements existed and comments were incorporated into a third draft. The fourth and final statement incorporates all relevant evidence obtained by the literature search in conjunction with final consensus recommendations supported by all working group members.
Conclusions Specific recommendations are made regarding smallpox vaccination, therapy, postexposure isolation and infection control, hospital epidemiology and infection control, home care, decontamination of the environment, and additional research needs. In the event of an actual release of smallpox and subsequent epidemic, early detection, isolation of infected individuals, surveillance of contacts, and a focused selective vaccination program will be the essential items of an effective control program.
INTRODUCTION
This is the second article in a series entitled Medical and Public Health Management Following the Use of a Biological Weapon: Consensus Statements of the Working Group on Civilian Biodefense.1 The working group has identified a limited number of widely known organisms that could cause disease and deaths in sufficient numbers to cripple a city or region. Smallpox is one of the most serious of these diseases.
If used as a biological weapon, smallpox represents a serious threat to civilian populations because of its case-fatality rate of 30% or more among unvaccinated persons and the absence of specific therapy. Although smallpox has long been feared as the most devastating of all infectious diseases,2 its potential for devastation today is far greater than at any previous time. Routine vaccination throughout the United States ceased more than 25 years ago. In a now highly susceptible, mobile population, smallpox would be able to spread widely and rapidly throughout this country and the world.
CONSENSUS METHODS
Members of the working group were selected by the chairman in consultation with principal agency heads in the Department of Health and Human Services (DHHS) and the US Army Medical Research Institute of Infectious Diseases (USAMRIID).
The first author (D.A.H.) conducted a literature search in conjunction with the preparation of another publication on smallpox2 as well as this article. The literature was reviewed and opinions were sought from experts in the diagnosis and management of smallpox, including members of the working group.
The first draft of the working group's consensus statement was the result of synthesis of information obtained in the evidence-gathering process. Members of the working group were asked to make written comments on the first draft of the document in September 1998. Suggested revisions were incorporated into the second draft of the statement. The working group was convened to review the second draft of the statement on October 30, 1998. Consensus recommendations were made and no significant disagreements existed at the conclusion of this meeting. The third draft incorporated changes suggested at the conference and working group members had an additional opportunity to suggest final revisions. The final statement incorporates all relevant evidence obtained by the literature search in conjunction with final consensus recommendations supported by all working group members.
This article is intended to provide the scientific foundation and initial framework for the detailed planning that would follow a bioterrorist attack with smallpox. This planning must encompass coordinated systems approaches to bioterrorism, including public policies and consequence management by local and regional public and private institutions. The assessment and recommendations provided herein represent the best professional judgment of the working group at this time based on data and expertise currently available. The conclusions and recommendations need to be regularly reassessed as new information becomes available.
HISTORY AND POTENTIAL AS A BIOWEAPON
Smallpox probably was first used as a biological weapon during the French and Indian Wars (1754-1767) by British forces in North America.3 Soldiers distributed blankets that had been used by smallpox patients with the intent of initiating outbreaks among American Indians. Epidemics occurred, killing more than 50% of many affected tribes. With Edward Jenner's demonstration in 1796 that an infection caused by cowpox protected against smallpox and the rapid diffusion worldwide of the practice of cowpox inoculation (ie, vaccination),4 the potential threat of smallpox as a bioweapon was greatly diminished.
A global campaign, begun in 1967 under the aegis of the World Health Organization (WHO), succeeded in eradicating smallpox in 1977.1 In 1980, the World Health Assembly recommended that all countries cease vaccination.5 A WHO expert committee recommended that all laboratories destroy their stocks of variola virus or transfer them to 1 of 2 WHO reference laboratories—the Institute of Virus Preparations in Moscow, Russia, or the Centers for Disease Control and Prevention (CDC) in Atlanta, Ga. All countries reported compliance. The WHO committee later recommended that all virus stocks be destroyed in June 1999, and the 1996 World Health Assembly concurred.6 In 1998, possible research uses for variola virus were reviewed by a committee of the Institute of Medicine (IOM).7 The IOM committee concluded, as did the preceding WHO committee, that there were research questions that might be addressed if the virus were to be retained. However, the IOM committee did not explore the costs or relative priority to be assigned to such an effort, and that committee was not asked to weigh the possible benefits resulting from such research activities contrasted with the possible benefits resulting from an international decision to destroy all virus stocks. These considerations will be weighed and decided by the 1999 World Health Assembly.
Recent allegations from Ken Alibek, a former deputy director of the Soviet Union's civilian bioweapons program, have heightened concern that smallpox might be used as a bioweapon. Alibek8 reported that beginning in 1980, the Soviet government embarked on a successful program to produce the smallpox virus in large quantities and adapt it for use in bombs and intercontinental ballistic missiles; the program had an industrial capacity capable of producing many tons of smallpox virus annually. Furthermore, Alibek reports that Russia even now has a research program that seeks to produce more virulent and contagious recombinant strains. Because financial support for laboratories in Russia has sharply declined in recent years, there are increasing concerns that existing expertise and equipment might fall into non-Russian hands.
The deliberate reintroduction of smallpox as an epidemic disease would be an international crime of unprecedented proportions, but it is now regarded as a possibility. An aerosol release of variola virus would disseminate widely, given the considerable stability of the orthopoxviruses in aerosol form9 and the likelihood that the infectious dose is very small.10 Moreover, during the 1960s and 1970s in Europe, when smallpox was imported during the December to April period of high transmission, as many as 10 to 20 second-generation cases were often infected from a single case. Widespread concern and, sometimes, panic occurred, even with outbreaks of fewer than 100 cases, resulting in extensive emergency control measures.2
EPIDEMIOLOGY
Smallpox was once worldwide in scope, and before vaccination was practiced, almost everyone eventually contracted the disease. There were 2 principal forms of the disease, variola major and a much milder form, variola minor (or alastrim). Before eradication took place, these forms could be differentiated clinically only when occurring in outbreaks; virological differentiation is now possible.11-12 Through the end of the 19th century, variola major predominated throughout the world. However, at the turn of the century, variola minor was first detected in South Africa and later in Florida, from whence it spread across the United States and into Latin America and Europe.13 Typical variola major epidemics such as those that occurred in Asia resulted in case-fatality rates of 30% or higher among the unvaccinated, whereas variola minor case-fatality rates were customarily 1% or less.2
Smallpox spreads from person to person,10, 14 primarily by droplet nuclei or aerosols expelled from the oropharynx of infected persons and by direct contact. Contaminated clothing or bed linens can also spread the virus.15 There are no known animal or insect reservoirs or vectors.
Historically, the rapidity of smallpox transmission throughout the population was generally slower than for such diseases as measles or chickenpox. Patients spread smallpox primarily to household members and friends; large outbreaks in schools, for example, were uncommon. This finding was accounted for in part by the fact that transmission of smallpox virus did not occur until onset of rash. By then, many patients had been confined to bed because of the high fever and malaise of the prodromal illness. Secondary cases were thus usually restricted to those who came into contact with patients, usually in the household or hospital.
The seasonal occurrence of smallpox was similar to that of chickenpox and measles—its incidence was highest during winter and early spring.16 This pattern was consonant with the observation that the duration of survival of orthopoxviruses in the aerosolized form was inversely proportional to both temperature and humidity.9 Likewise, when imported cases occurred in Europe, large outbreaks sometimes developed during the winter months, rarely during the summer.17
The patient was most infectious from onset of rash through the first 7 to 10 days of rash (Figure 1).17-18 As scabs formed, infectivity waned rapidly. Although the scabs contained large amounts of viable virus, epidemiological and laboratory studies indicate that they were not especially infectious, presumably because the virions were bound tightly in the fibrin matrix.19
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Figure 1. Typical Temperature Chart of Patient With Smallpox Infection
Chart shows approximate time of appearance, evolution of the rash, and magnitude of infectivity relative to the number of days after acquisition of infection.3, 26, 29
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The age distribution of cases depended primarily on the degree of smallpox susceptibility in the population. In most areas, cases predominated among children because adults were protected by immunity induced by vaccination or previous smallpox infection. In rural areas that had seen little vaccination or smallpox, the age distribution of cases was similar to the age distribution of the population. The age distribution pattern of cases in the United States presumably would be such if smallpox were to occur now because vaccination immunity in the population has waned so substantially.
MICROBIOLOGY
Smallpox, a DNA virus, is a member of the genus orthopoxvirus.20 The orthopoxviruses are among the largest and most complex of all viruses. The virion is characteristically a brick-shaped structure with a diameter of about 200 nm. Three other members of this genus (monkeypox, vaccinia, and cowpox) can also infect humans, causing cutaneous lesions, but only smallpox is readily transmitted from person to person.2 Monkeypox, a zoonotic disease, presently is found only in tropical rain forest areas of central and western Africa and is not readily transmitted among humans.21 Vaccinia and cowpox seldom spread from person to person.
PATHOGENESIS AND CLINICAL PRESENTATION
Natural infection occurs following implantation of the virus on the oropharyngeal or respiratory mucosa.2 The infectious dose is unknown but is believed to be only a few virions.10 After the migration of virus to and multiplication in regional lymph nodes, an asymptomatic viremia develops on about the third or fourth day, followed by multiplication of virus in the spleen, bone marrow, and lymph nodes. A secondary viremia begins on about the eighth day and is followed by fever and toxemia. The virus, contained in leukocytes, then localizes in small blood vessels of the dermis and beneath the oral and pharyngeal mucosa and subsequently infects adjacent cells.
At the end of the 12- to 14-day incubation period (range, 7-17 days), the patient typically experiences high fever, malaise, and prostration with headache and backache.2 Severe abdominal pain and delirium are sometimes present. A maculopapular rash then appears on the mucosa of the mouth and pharynx, face, and forearms, and spreads to the trunk and legs (Figure 2).2 Within 1 to 2 days, the rash becomes vesicular and, later, pustular. The pustules are characteristically round, tense, and deeply embedded in the dermis; crusts begin to form on about the eighth or ninth day of rash. As the patient recovers, the scabs separate and characteristic pitted scarring gradually develops. The scars are most evident on the face and result from the destruction of sebaceous glands followed by shrinking of granulation tissue and fibrosis.2
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Figure 2. Typical Case of Smallpox Infection in a Child
Figure shows the appearance of the rash at days 3, 5, and 7 of evolution. Note that lesions are more dense on the face and extremities than on the trunk; that they appear on the palms of the hand; and that they are similar in appearance to each other. If this were a case of chickenpox, one would expect to see, in any area, macules, papules, pustules, and lesions with scabs. Reproduced with permission from the World Health Organization.2
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The lesions that first appear in the mouth and pharynx ulcerate quickly because of the absence of a stratum corneum, releasing large amounts of virus into the saliva.22 Virus titers in saliva are highest during the first week of illness, corresponding with the period during which patients are most infectious. Although the virus in some instances can be detected in swabs taken from the oropharynx as many as 5 to 6 days before the rash develops,22 transmission does not occur during this period.
Except for the lesions in the skin and mucous membranes and reticulum cell hyperplasia, other organs are seldom involved. Secondary bacterial infection is not common, and death, which usually occurs during the second week of illness, most likely results from the toxemia associated with circulating immune complexes and soluble variola antigens.2 Encephalitis sometimes ensues that is indistinguishable from the acute perivascular demyelination observed as a complication of infection due to vaccinia, measles, or varicella.23
Neutralizing antibodies can be detected by the sixth day of rash and remain at high titers for many years.24 Hemagglutinin-inhibiting antibodies can be detected on about the sixth day of rash, or about 21 days after infection, and complement-fixing antibodies appear approximately 2 days later. Within 5 years, hemagglutinin-inhibiting antibodies decline to low levels and complement-fixing antibodies rarely persist for longer than 6 months.2
Although at least 90% of smallpox cases are clinically characteristic and readily diagnosed in endemic areas, 2 other forms of smallpox are difficult to recognize—hemorrhagic and malignant. Hemorrhagic cases are uniformly fatal and occur among all ages and in both sexes, but pregnant women appear to be unusually susceptible. Illness usually begins with a somewhat shorter incubation period and is characterized by a severely prostrating prodromal illness with high fever and head, back, and abdominal pain. Soon thereafter, a dusky erythema develops, followed by petechiae and frank hemorrhages into the skin and mucous membranes. Death usually occurs by the fifth or sixth day after onset of rash.23
In the frequently fatal malignant form, the abrupt onset and prostrating constitutional symptoms are similar. The confluent lesions develop slowly, never progressing to the pustular stage but remaining soft, flattened, and velvety to the touch. The skin has the appearance of a fine-grained, reddish-colored crepe rubber, sometimes with hemorrhages. If the patient survives, the lesions gradually disappear without forming scabs or, in severe cases, large amounts of epidermis might peel away.23
The illness associated with variola minor is generally less severe, with fewer constitutional symptoms and a more sparse rash.25 A milder form of disease is also seen among those who have residual immunity from previous vaccination. In partially immune persons, the rash tends to be atypical and more scant and the evolution of the lesions more rapid.15
There is little information about how individuals with different types of immune deficiency responded to natural smallpox infection. Smallpox was eradicated before human immunodeficiency virus (HIV) was identified and before suitable techniques became available for measuring cell-mediated immunity. However, it is probable that the underlying cause of some cases of malignant and hemorrhagic smallpox resulted from defective immune responses. Vaccination of immune-deficient persons sometimes resulted in a continually spreading primary lesion, persistent viremia, and secondary viral infection of many organs. One such case is documented to have occurred in a vaccinated soldier who had HIV infection.26
DIAGNOSIS
The discovery of a single suspected case of smallpox must be treated as an international health emergency and be brought immediately to the attention of national officials through local and state health authorities.
The majority of smallpox cases present with a characteristic rash that is centrifugal in distribution, ie, most dense on the face and extremities. The lesions appear during a 1- to 2-day period and evolve at the same rate. On any given part of the body, they are generally at the same stage of development. In varicella (chickenpox), the disease most frequently confused with smallpox, new lesions appear in crops every few days and lesions at very different stages of maturation (ie, vesicles, pustules, and scabs) are found in adjacent areas of skin. Varicella lesions are much more superficial and are almost never found on the palms and soles. The distribution of varicella lesions is centripetal, with a greater concentration of lesions on the trunk than on the face and extremities.
The signs and symptoms of both hemorrhagic and malignant smallpox were such that smallpox was seldom suspected until more typical cases were seen and it was recognized that a smallpox outbreak was in progress. Hemorrhagic cases were most often initially identified as meningococcemia or severe acute leukemia. Malignant cases likewise posed diagnostic problems, most often being mistaken for hemorrhagic chickenpox or prompting surgery because of severe abdominal pain.
Laboratory confirmation of the diagnosis in a smallpox outbreak is important. Specimens should be collected by someone who has recently been vaccinated (or is vaccinated that day) and who wears gloves and a mask. To obtain vesicular or pustular fluid, it is often necessary to open lesions with the blunt edge of a scalpel. The fluid can then be harvested on a cotton swab. Scabs can be picked off with forceps. Specimens should be deposited in a vacutainer tube that should be sealed with adhesive tape at the juncture of stopper and tube. This tube, in turn, should be enclosed in a second durable, watertight container. State or local health department laboratories should immediately be contacted regarding the shipping of specimens. Laboratory examination requires high-containment (BL-4) facilities and should be undertaken only in designated laboratories with the appropriate training and equipment. Once it is established that the epidemic is caused by smallpox virus, clinically typical cases would not require further laboratory confirmation.
Smallpox infection can be rapidly confirmed in the laboratory by electron microscopic examination of vesicular or pustular fluid or scabs. Although all orthopoxviruses exhibit identically appearing brick-shaped virions, history taking and clinical picture readily identify cowpox and vaccinia. Although smallpox and monkeypox virions may be indistinguishable, naturally occurring monkeypox is found only in tropical rain forest areas of Africa. Definitive laboratory identification and characterization of the virus involves growth of the virus in cell culture or on chorioallantoic egg membrane and characterization of strains by use of various biologic assays, including polymerase chain reaction techniques and restriction fragment-length polymorphisms.27-29 The latter studies can be completed within a few hours.
PREEXPOSURE PREVENTIVE VACCINATION
Before 1972, smallpox vaccination was recommended for all US children at age 1 year. Most states required that each child be vaccinated before school entry. The only other requirement for vaccination was for military recruits and tourists visiting foreign countries. Most countries required that the individual be successfully vaccinated within a 3-year period prior to entering the country. Routine vaccination in the United States stopped in 1972 and since then, few persons younger than 27 years have been vaccinated. The US Census Bureau reported that in 1998, approximately 114 million persons, or 42% of the US population, were aged 29 years or younger.30
In addition, the immune status of those who were vaccinated more than 27 years ago is not clear. The duration of immunity, based on the experience of naturally exposed susceptible persons, has never been satisfactorily measured. Neutralizing antibodies are reported to reflect levels of protection, although this has not been validated in the field. These antibodies have been shown to decline substantially during a 5- to 10-year period.24 Thus, even those who received the recommended single-dose vaccination as children do not have lifelong immunity. However, among a group who had been vaccinated at birth and at ages 8 and 18 years as part of a study, neutralizing antibody levels remained stable during a 30-year period.31 Because comparatively few persons today have been successfully vaccinated on more than 1 occasion, it must be assumed that the population at large is highly susceptible to infection.
In the United States, a limited reserve supply of vaccine that was produced by Wyeth Laboratories, Lancaster, Pa, in the 1970s is in storage. This supply is believed to be sufficient to vaccinate between 6 and 7 million persons. This vaccine, now under the control of the CDC, consists of vaccine virus (New York Board of Health strain) grown on scarified calves. After purification, it was freeze-dried in rubber-stoppered vials that contain sufficient vaccine for at least 50 doses when a bifurcated needle is used. It is stored at -20°C (James LeDuc, PhD, oral communication, 1998). Although quantities of vaccine have also been retained by a number of other countries, none have reserves large enough to meet more than their own potential emergency needs. WHO has 500,000 doses.32
There are no manufacturers now equipped to produce smallpox vaccine in large quantities. The development and licensure of a tissue cell culture vaccine and the establishment of a new vaccine production facility is estimated to require at least 36 months (Thomas Monath, MD, unpublished data, 1999).
Because of the small amounts of vaccine available, a preventive vaccination program to protect individuals such as emergency and health care personnel is not an option at this time. When additional supplies of vaccine are procured, a decision to undertake preventive vaccination of some portion of the population will have to weigh the relative risk of vaccination complications against the threat of contracting smallpox.
A further deterrent to extensive vaccination is the fact that presently available supplies of vaccinia immune globulin (VIG), also maintained by the CDC, are very limited in quantity. The working group recommends VIG for the treatment of severe cutaneous reactions occurring as a complication of vaccination.33-34 Vaccinia immune globulin has also been given along with vaccination to protect those who needed vaccination but who were at risk of experiencing vaccine-related complications.33 It has been estimated that if 1 million persons were vaccinated, as many as 250 persons would experience adverse reactions of a type that would require administration of VIG (James LeDuc, PhD, oral communication, 1998). How much VIG would be needed to administer with vaccine to those at risk is unknown.
POSTEXPOSURE THERAPY
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