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Plague as a Biological Weapon
Medical and Public Health Management
Thomas V. Inglesby, MD;
David T. Dennis, MD, MPH;
Donald A. Henderson, MD, MPH;
John G. Bartlett, MD;
Michael S. Ascher, MD;
Edward Eitzen, MD, MPH;
Anne D. Fine, MD;
Arthur M. Friedlander, MD;
Jerome Hauer, MPH;
John F. Koerner, MPH, CIH;
Marcelle Layton, MD;
Joseph McDade, PhD;
Michael T. Osterholm, PhD, MPH;
Tara O'Toole, MD, MPH;
Gerald Parker, PhD, DVM;
Trish M. Perl, MD, MSc;
Philip K. Russell, MD;
Monica Schoch-Spana, PhD;
Kevin Tonat, DrPH, MPH;
for the Working Group on Civilian Biodefense
JAMA. 2000;283:2281-2290.
ABSTRACT
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Objective The Working Group on Civilian Biodefense has developed consensus-based recommendations for measures to be taken by medical and public health professionals following the use of plague as a biological weapon against a civilian population.
Participants The working group included 25 representatives from major academic medical centers and research, government, military, public health, and emergency management institutions and agencies.
Evidence MEDLINE databases were searched from January 1966 to June 1998 for the Medical Subject Headings plague, Yersinia pestis, biological weapon, biological terrorism, biological warfare, and biowarfare. Review of the bibliographies of the references identified by this search led to subsequent identification of relevant references published prior to 1966. In addition, participants identified other unpublished references and sources. Additional MEDLINE searches were conducted through January 2000.
Consensus Process The first draft of the consensus statement was a synthesis of information obtained in the formal evidence-gathering process. The working group was convened to review drafts of the document in October 1998 and May 1999. The final statement incorporates all relevant evidence obtained by the literature search in conjunction with final consensus recommendations supported by all working group members.
Conclusions An aerosolized plague weapon could cause fever, cough, chest pain, and hemoptysis with signs consistent with severe pneumonia 1 to 6 days after exposure. Rapid evolution of disease would occur in the 2 to 4 days after symptom onset and would lead to septic shock with high mortality without early treatment. Early treatment and prophylaxis with streptomycin or gentamicin or the tetracycline or fluoroquinolone classes of antimicrobials would be advised.
INTRODUCTION
This is the third 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.1-2 The working group has identified a limited number of agents that, if used as weapons, could cause disease and death in sufficient numbers to cripple a city or region. These agents also comprise the top of the list of "Critical Biological Agents" recently developed by the Centers for Disease Control and Prevention (CDC).3 Yersinia pestis, the causative agent of plague, is one of the most serious of these. Given the availability of Y pestis around the world, capacity for its mass production and aerosol dissemination, difficulty in preventing such activities, high fatality rate of pneumonic plague, and potential for secondary spread of cases during an epidemic, the potential use of plague as a biological weapon is of great concern.
CONSENSUS METHODS
The working group comprised 25 representatives from major academic medical centers and research, government, military, public health, and emergency management institutions and agencies.
MEDLINE databases were searched from January 1966 to June 1998 using the Medical Subject Headings (MeSH) plague, Yersinia pestis, biological weapon, biological terrorism, biological warfare, and biowarfare. Review of the bibliographies of the references identified by this search led to subsequent identification of relevant references published prior to 1966. In addition, participants identified other unpublished references and sources in their fields of expertise. Additional MEDLINE searches were conducted through January 2000 during the review and revisions of the statement.
The first draft of the consensus statement was a synthesis of information obtained in the initial formal evidence-gathering process. Members of the working group were asked to make formal written comments on this first draft of the document in September 1998. The document was revised incorporating changes suggested by members of the working group, which was convened to review the second draft of the document on October 30, 1998. Following this meeting and a second meeting of the working group on May 24, 1999, a third draft of the document was completed, reviewed, and revised. Working group members had a final opportunity to review the document and suggest revisions. The final document incorporates all relevant evidence obtained by the literature search in conjunction with consensus recommendations supported by all working group members.
The assessment and recommendations provided herein represent the best professional judgment of the working group 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 BIOTERRORIST AGENT
In AD 541, the first recorded plague pandemic began in Egypt and swept across Europe with attributable population losses of between 50% and 60% in North Africa, Europe, and central and southern Asia.4 The second plague pandemic, also known as the black death or great pestilence, began in 1346 and eventually killed 20 to 30 million people in Europe, one third of the European population.5 Plague spread slowly and inexorably from village to village by infected rats and humans or more quickly from country to country by ships. The pandemic lasted more than 130 years and had major political, cultural, and religious ramifications. The third pandemic began in China in 1855, spread to all inhabited continents, and ultimately killed more than 12 million people in India and China alone.4 Small outbreaks of plague continue to occur throughout the world.4-5
Advances in living conditions, public health, and antibiotic therapy make future pandemics improbable. However, plague outbreaks following use of a biological weapon are a plausible threat. In World War II, a secret branch of the Japanese army, Unit 731, is reported to have dropped plague-infected fleas over populated areas of China, thereby causing outbreaks of plague.6 In the ensuing years, the biological weapons programs of the United States and the Soviet Union developed techniques to aerosolize plague directly, eliminating dependence on the unpredictable flea vector. In 1970, the World Health Organization (WHO) reported that, in a worst-case scenario, if 50 kg of Y pestis were released as an aerosol over a city of 5 million, pneumonic plague could occur in as many as 150,000 persons, 36,000 of whom would be expected to die.7 The plague bacilli would remain viable as an aerosol for 1 hour for a distance of up to 10 km. Significant numbers of city inhabitants might attempt to flee, further spreading the disease.7
While US scientists had not succeeded in making quantities of plague organisms sufficient to use as an effective weapon by the time the US offensive program was terminated in 1970, Soviet scientists were able to manufacture large quantities of the agent suitable for placing into weapons.8 More than 10 institutes and thousands of scientists were reported to have worked with plague in the former Soviet Union.8 In contrast, few scientists in the United States study this disease.9
There is little published information indicating actions of autonomous groups or individuals seeking to develop plague as a weapon. However, in 1995 in Ohio, a microbiologist with suspect motives was arrested after fraudulently acquiring Y pestis by mail.10 New antiterrorism legislation was introduced in reaction.
EPIDEMIOLOGY
Naturally Occurring Plague
Human plague most commonly occurs when plague-infected fleas bite humans who then develop bubonic plague. As a prelude to human epidemics, rats frequently die in large numbers, precipitating the movement of the flea population from its natural rat reservoir to humans. Although most persons infected by this route develop bubonic plague, a small minority will develop sepsis with no bubo, a form of plague termed primary septicemic plague. Neither bubonic nor septicemic plague spreads directly from person to person. A small percentage of patients with bubonic or septicemic plague develop secondary pneumonic plague and can then spread the disease by respiratory droplet. Persons contracting the disease by this route develop primary pneumonic plague.11
Plague remains an enzootic infection of rats, ground squirrels, prairie dogs, and other rodents on every populated continent except Australia.4 Worldwide, on average in the last 50 years, 1700 cases have been reported annually.4 In the United States, 390 cases of plague were reported from 1947 to 1996, 84% of which were bubonic, 13% septicemic, and 2% pneumonic. Concomitant case fatality rates were 14%, 22%, and 57%, respectively.12 Most US cases were in New Mexico, Arizona, Colorado, and California. Of the 15 cases following exposure to domestic cats with plague, 4 were primary pneumonic plague.13 In the United States, the last case of human-to-human transmission of plague occurred in Los Angeles in 1924.14-15
Although pneumonic plague has rarely been the dominant manifestation of the disease, large outbreaks of pneumonic plague have occurred.16 In an outbreak in Manchuria in 1910-1911, as many as 60,000 persons developed pneumonic plague; a second large Manchurian pneumonic plague outbreak occurred in 1920-1921.16-17 As would be anticipated in the preantibiotic era, nearly 100% of these cases were reported to be fatal.16-17 Reports from the Manchurian outbreaks suggested that indoor contacts of affected patients were at higher risk than outdoor contacts and that cold temperature, increased humidity, and crowding contributed to increased spread.14-15 In northern India, there was an epidemic of pneumonic plague with 1400 deaths reported at about the same time.15 While epidemics of pneumonic plague of this scale have not occurred since, smaller epidemics of pneumonic plague have occurred recently. In 1997 in Madagascar, 1 patient with bubonic plague and secondary pneumonic infection transmitted pneumonic plague to 18 persons, 8 of whom died.18
Plague Following Use of a Biological Weapon
The epidemiology of plague following its use as a biological weapon would differ substantially from that of naturally occurring infection. Intentional dissemination of plague would most probably occur via an aerosol of Y pestis, a mechanism that has been shown to produce disease in nonhuman primates.19 A pneumonic plague outbreak would result with symptoms initially resembling those of other severe respiratory illnesses. The size of the outbreak would depend on factors including the quantity of biological agent used, characteristics of the strain, environmental conditions, and methods of aerosolization. Symptoms would begin to occur 1 to 6 days following exposure, and people would die quickly following onset of symptoms.16 Indications that plague had been artificially disseminated would be the occurrence of cases in locations not known to have enzootic infection, in persons without known risk factors, and in the absence of prior rodent deaths.
MICROBIOLOGY AND VIRULENCE FACTORS
Y pestis is a nonmotile, gram-negative bacillus, sometimes coccobacillus, that shows bipolar (also termed safety pin) staining with Wright, Giemsa, or Wayson stain (Figure 1).20 Y pestis is a lactose nonfermenter, urease and indole negative, and a member of the Enterobacteriaceae family.21 It grows optimally at 28°C on blood agar or MacConkey agar, typically requiring 48 hours for observable growth, but colonies are initially much smaller than other Enterobacteriaceae and may be overlooked. Y pestis has a number of virulence factors that enable it to survive in humans by facilitating use of host nutrients, causing damage to host cells, and subverting phagocytosis and other host defense mechanisms.4, 11, 21-22
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Figure 1. Peripheral Blood Smear From Patient With Septicemic Plague
Smear shows characteristic bipolar staining of Yersinia pestis bacilli (Wright-Giemsa stain; magnification, x1000). Figure from Centers for Disease Control and Prevention, Division of Vector-Borne Infectious Diseases, Fort Collins, Colo.
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PATHOGENESIS AND CLINICAL MANIFESTATIONS
Naturally Occurring Plague
In most cases of naturally occurring plague, the bite by a plague-infected flea leads to the inoculation of up to thousands of organisms into a patient's skin. The bacteria migrate through cutaneous lymphatics to regional lymph nodes where they are phagocytosed but resist destruction. They rapidly multiply, causing destruction and necrosis of lymph node architecture with subsequent bacteremia, septicemia, and endotoxemia that can lead quickly to shock, disseminated intravascular coagulation, and coma.21
Patients typically develop symptoms of bubonic plague 2 to 8 days after being bitten by an infected flea. There is sudden onset of fever, chills, and weakness and the development of an acutely swollen tender lymph node, or bubo, up to 1 day later.23 The bubo most typically develops in the groin, axilla, or cervical region (Figure 2, A) and is often so painful that it prevents patients from moving the affected area of the body. Buboes are 1 to 10 cm in diameter, and the overlying skin is erythematous.21 They are extremely tender, nonfluctuant, and warm and are often associated with considerable surrounding edema, but seldom lymphangitis. Rarely, buboes become fluctuant and suppurate. In addition, pustules or skin ulcerations may occur at the site of the flea bite in a minority of patients. A small minority of patients infected by fleas develop Y pestis septicemia without a discernable bubo, the form of disease termed primary septicemic plague.23 Septicemia can also arise secondary to bubonic plague.21 Septicemic plague may lead to disseminated intravascular coagulation, necrosis of small vessels, and purpuric skin lesions (Figure 2, B). Gangrene of acral regions such as the digits and nose may also occur in advanced disease, a process believed responsible for the name black death in the second plague pandemic (Figure 2, C).21 However, the finding of gangrene would not be expected to be helpful in diagnosing the disease in the early stages of illness when early antibiotic treatment could be lifesaving.
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Figure 2. Patients With Naturally Occurring Plague
A, Cervical bubo in patient with bubonic plague; B, petechial and ecchymotic bleeding into the skin in patient with septicemic plague; and C, gangrene of the digits during the recovery phase of illness of patient shown in B. In plague following the use of a biological weapon, presence of cervical bubo is rare; purpuric skin lesions and necrotic digits occur only in advanced disease and would not be helpful in diagnosing the disease in the early stages of illness when antibiotic treatment can be lifesaving. Figures from Centers for Disease Control and Prevention, Division of Vector-Borne Infectious Diseases, Fort Collins, Colo.
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Secondary pneumonic plague develops in a minority of patients with bubonic or primary septicemic plague—approximately 12% of total cases in the United States over the last 50 years.4 This process, termed secondary pneumonic plague, develops via hematogenous spread of plague bacilli to the lungs. Patients commonly have symptoms of severe bronchopneumonia, chest pain, dyspnea, cough, and hemoptysis.16, 21
Primary pneumonic plague resulting from the inhalation of plague bacilli occurs rarely in the United States.12 Reports of 2 recent cases of primary pneumonic plague, contracted after handling cats with pneumonic plague, reveal that both patients had pneumonic symptoms as well as prominent gastrointestinal symptoms including nausea, vomiting, abdominal pain, and diarrhea. Diagnosis and treatment were delayed more than 24 hours after symptom onset in both patients, both of whom died.24-25
Less common plague syndromes include plague meningitis and plague pharyngitis. Plague meningitis follows the hematogenous seeding of bacilli into the meninges and is associated with fever and meningismus. Plague pharyngitis follows inhalation or ingestion of plague bacilli and is associated with cervical lymphadenopathy.21
Plague Following Use of a Biological Weapon
The pathogenesis and clinical manifestations of plague following a biological attack would be notably different than naturally occurring plague. Inhaled aerosolized Y pestis bacilli would cause primary pneumonic plague. The time from exposure to aerosolized plague bacilli until development of first symptoms in humans and nonhuman primates has been found to be 1 to 6 days and most often, 2 to 4 days.12, 16, 19, 26 The first sign of illness would be expected to be fever with cough and dyspnea, sometimes with the production of bloody, watery, or less commonly, purulent sputum.16, 19, 27 Prominent gastrointestinal symptoms, including nausea, vomiting, abdominal pain, and diarrhea, might be present.24-25
The ensuing clinical findings of primary pneumonic plague are similar to those of any severe rapidly progressive pneumonia and are quite similar to those of secondary pneumonic plague. Clinicopathological features may help distinguish primary from secondary pneumonic plague.11 In contrast to secondary pneumonic plague, features of primary pneumonic plague would include absence of buboes (except, rarely, cervical buboes) and, on pathologic examination, pulmonary disease with areas of profound lobular exudation and bacillary aggregation.11 Chest radiographic findings are variable but bilateral infiltrates or consolidation are common (Figure 3).22
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Figure 3. Chest Radiograph of Patient With Primary Pneumonic Plague
Radiograph shows extensive lobar consolidation in left lower and left middle lung fields. Figure from Centers for Disease Control and Prevention, Division of Vector-Borne Infectious Diseases, Fort Collins, Colo.
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Laboratory studies may reveal leukocytosis with toxic granulations, coagulation abnormalities, aminotransferase elevations, azotemia, and other evidence of multiorgan failure. All are nonspecific findings associated with sepsis and systemic inflammatory response syndrome.11, 21
The time from respiratory exposure to death in humans is reported to have been between 2 to 6 days in epidemics during the preantibiotic era, with a mean of 2 to 4 days in most epidemics.16
DIAGNOSIS
Given the rarity of plague infection and the possibility that early cases are a harbinger of a larger epidemic, the first clinical or laboratory suspicion of plague must lead to immediate notification of the hospital epidemiologist or infection control practitioner, health department, and the local or state health laboratory. Definitive tests can thereby be arranged rapidly through a state reference laboratory or, as necessary, the Diagnostic and Reference Laboratory of the CDC and early interventions instituted.
The early diagnosis of plague requires a high index of suspicion in naturally occurring cases and even more so following the use of a biological weapon. There are no effective environmental warning systems to detect an aerosol of plague bacilli.28
The first indication of a clandestine terrorist attack with plague would most likely be a sudden outbreak of illness presenting as severe pneumonia and sepsis. If there are only small numbers of cases, the possibility of them being plague may be at first overlooked given the clinical similarity to other bacterial or viral pneumonias and that few Western physicians have ever seen a case of pneumonic plague. However, the sudden appearance of a large number of previously healthy patients with fever, cough, shortness of breath, chest pain, and a fulminant course leading to death should immediately suggest the possibility of pneumonic plague or inhalational anthrax.1 The presence of hemoptysis in this setting would strongly suggest plague (Table 1). 22
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Table 1. Diagnosis of Pneumonic Plague Infection Following Use of a Biological Weapon
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There are no widely available rapid diagnostic tests for plague.28 Tests that would be used to confirm a suspected diagnosis—antigen detection, IgM enzyme immunoassay, immunostaining, and polymerase chain reaction—are available only at some state health departments, the CDC, and military laboratories.21 The routinely used passive hemagglutination antibody detection assay is typically only of retrospective value since several days to weeks usually pass after disease onset before antibodies develop.
Microbiologic studies are important in the diagnosis of pneumonic plague. A Gram stain of sputum or blood may reveal gram-negative bacilli or coccobacilli.4, 21, 29 A Wright, Giemsa, or Wayson stain will often show bipolar staining (Figure 1), and direct fluorescent antibody testing, if available, may be positive. In the unlikely event that a cervical bubo is present in pneumonic plague, an aspirate (obtained with a 20-gauge needle and a 10-mL syringe containing 1-2 mL of sterile saline for infusing the node) may be cultured and similarly stained (Table 1).22
Cultures of sputum, blood, or lymph node aspirate should demonstrate growth approximately 24 to 48 hours after inoculation. Most microbiology laboratories use either automated or semiautomated bacterial identification systems. Some of these systems may misidentify Y pestis.12, 30 In laboratories without automated bacterial identification, as many as 6 days may be required for identification, and there is some chance that the diagnosis may be missed entirely. Approaches for biochemical characterization of Y pestis are described in detail elsewhere.20
If a laboratory using automated or nonautomated techniques is notified that plague is suspected, it should split the culture: 1 culture incubated at 28°C for rapid growth and the second culture incubated at 37°C for identification of the diagnostic capsular (F1) antigen. Using these methods, up to 72 hours may be required following specimen procurement to make the identification (May Chu, PhD, CDC, Fort Collins, Colo, written communication, April 9, 1999). Antibiotic susceptibility testing should be performed at a reference laboratory because of the lack of standardized susceptibility testing procedures for Y pestis. A process establishing criteria and training measures for laboratory diagnosis of this disease is being undertaken jointly by the Association of Public Health Laboratories and the CDC.
VACCINATION
The US-licensed formaldehyde-killed whole bacilli vaccine was discontinued by its manufacturers in 1999 and is no longer available. Plans for future licensure and production are unclear. This killed vaccine demonstrated efficacy in preventing or ameliorating bubonic disease, but it does not prevent or ameliorate the development of primary pneumonic plague.19, 31 It was used in special circumstances for individuals deemed to be at high risk of developing plague, such as military personnel working in plague endemic areas, microbiologists working with Y pestis in the laboratory, or researchers working with plague-infected rats or fleas. Research is ongoing in the pursuit of a vaccine that protects against primary pneumonic plague.22, 32
THERAPY
Recommendations for the use of antibiotics following a plague biological weapon exposure are conditioned by the lack of published trials in treating plague in humans, limited number of studies in animals, and possible requirement to treat large numbers of persons. A number of possible therapeutic regimens for treating plague have yet to be adequately studied or submitted for approval to the Food and Drug Administration (FDA). For these reasons, the working group offers consensus recommendations based on the best available evidence. The recommendations do not necessarily represent uses currently approved by the FDA or an official position on the part of any of the federal agencies whose scientists participated in these discussions. Recommendations will need to be revised as further relevant information becomes available.
In the United States during the last 50 years, 4 of the 7 reported primary pneumonic plague patients died.12 |
