Part I: Anthrax and Pneumonic Plague
Author: Kevin M. Coonan, MD, Department of Emergency Medicine, Madigan Army Medical Center, Fort Lewis, WA.
Peer Reviewer: Steven Winograd, MD, FACEP, Attending Physician, Department of Emergency Medicine, Jeannette District Memorial Hospital, Jeannette, PA; St. Clair Memorial Hospital, Pittsburgh, PA, University of Pittsburgh Medical Center.
The events of September and October 2001 have changed the United States forever. As a country, we learned we are vulnerable to attack in many different arenas. Hospitals, emergency departments (EDs), and public health agencies have partnered together to develop strategies to minimize the vulnerability of our communities and our country. Tremendous amounts of information regarding biological warfare have been disseminated, not all of which are true. On the anniversary of this terrible tragedy, it is time for ED physicians to stop, analyze what we’ve learned from the experiences of the past year and use that information to further strengthen our EDs and communities. The possibility of biological warfare has not decreased; in fact, the threats have continued. The anthrax cases that presented last fall (although, thankfully, only a few patients were affected) can teach us many valuable lessons: What delays were associated with fatalities? What radiographic findings were present in all of the patients? What antibiotics were utilized?
The importance of the ED cannot be underestimated as the frontline for any future attacks. It is critical that every ED physician be aware of the infrastructure developments that have occurred over the last year, not only to facilitate the accurate and timely diagnosis of a biological warfare agent, but also to provide care for suspected exposures in non-ED settings. This two-part series is devoted to providing the ED physician with the most current information on resources and the management of patients with suspected exposure, known exposure, or evidence of a disease secondary to a biological warfare agent. This article addresses anthrax and pneumonic plague. Part II of this series will cover smallpox, viral hemorrhagic fevers, and botulinum toxins.—The Editor
Anthrax Attack in the United States, 2001
The vulnerability of the U.S. civilian population to bioterrorism became apparent Oct. 4, 2001.1 The first cases of inhalational anthrax seen in the United States since 1976 were linked to the intentional delivery of a highly virulent, highly refined, dried spore preparation distributed through the mail.2-4 There were 11 cases of inhalational anthrax, five of which were fatal. The initial nine cases were directly related to handling mail tainted with anthrax spores from two known contaminated letters.5,6 The two other cases, both fatal, have raised great concern about the existence of a technologically advanced preparation that produces secondary aerosols.7
Eight of the first 10 cases of inhalational anthrax presented during their initial phase of illness, with a median duration of symptoms of 3.5 days (range 1-7). Of these eight, six received antibiotics active against Bacillus anthracis on their first visit; all six survived. All four patients who had a delay in the initiation of antibiotics died. Twelve additional cases of cutaneous anthrax have been described, all of which recovered with antibiotic therapy.8
Fortunately, the total number of patients (22 total) with clinical disease was small, compared to the 34,000 patients placed on protracted courses of prophylactic antibiotics.9 Although it is difficult to make firm conclusions with such a small population, several features were unanticipated or differed considerably from prior experience.
The clinical presentation of these patients was similar to prior reports. Table 1 shows the frequency of various clinical features. Advances in antibiotic therapy, rapid diagnosis, and supportive care appear to have played a substantial role in reducing mortality. All survivors received multi-drug regimens, usually consisting of a fluoroquinolone (most often ciprofloxacin), rifampin, and clindamycin.6,9 Unfortunately, all patients who required intubation or vasopressor therapy died, underscoring the critical importance of initiating prompt, effective, empiric antibiotic therapy.6 Non-contrast chest computed tomography (CT) emerged as a rapid, sensitive diagnostic tool that appears to have improved management in at least five of the patients.10,11
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Thoracentesis or tube thoracostomy was used 18 times in eight patients. Other interventions required included blood transfusions, tracheal intubation, continuous arterial-venous hemofiltration, bronchoscopy, endoscopy for management of gastrointestinal bleeding, plasmapheresis, pulmonary artery catheterization, and echocardiography.6, 12-14 Clearly, this degree of support would not be possible if an aerial release occurred, with predictions of hundreds of thousands of similarly critically ill patients.9
Other features pointed to the difficulty in making a correct, timely diagnosis. In spite of the fact that every patient had an abnormal initial plain chest radiograph, three of the inhalational anthrax patients had missed, subtle findings on the initial plain film. Two of them died, two were misinterpreted as community-acquired pneumonia, and one was thought to show congestive heart failure (CHF).6,15
Role of Hospital Emergency Departments
Emergency physicians will continue to play a critical role in the detection of and response to biological weapons.16 Due to the precipitous and severe nature of most of the agents, infected patients will present predominantly to hospital EDs.17 There often will be no prior knowledge of an attack, and the only warning may be a sudden surge of critically ill patients or a large insurge of patients with an unusual disease. Environmental detection, containment, and decontamination play little role.18 Contemporary HAZMAT models do not apply.19 The "first responders" to a biological attack will continue to be ED personnel.20 The emphasis will be on diagnosis, treatment, prophylaxis, and epidemiology.21 It is absolutely critical that anyone participating in patient care know how to contact their local public health officials and to have in place contingency plans for possible outbreaks of intentional or naturally occurring infectious diseases.22
Biological weapons cause epidemics. Early recognition of a rapidly crescendoing epidemic is the critical event in detection. Preparation and response to these events will be difficult due to several factors.18 Hospitals are ill-prepared to care for a large number of patients presenting in a short period of time, especially if respiratory isolation is required. Hospital laboratories do not routinely have the capability to handle hazardous microorganisms without a significant risk of technicians becoming infected. There is currently a significant shortage of inpatient and critical care capacity in most metropolitan areas. There is a very limited supply of both the smallpox and anthrax vaccines, with no other vaccines even remotely accessible for any large-scale event. Antibiotic stockpiles are limited, but improving due to ongoing efforts of the Centers for Disease Control and Prevention (CDC).23
The essential clinical tool in combating biological weapons is an improved public health infrastructure, which includes a close collaboration between specialists in emergency medicine, infectious disease, and public health. While this is likely to be a new relationship, given the increasing impact of emerging infectious diseases on the health of our nation, it will result in long-term benefits that far exceed those of the current crisis.24,25 Emergency physicians are going to be increasingly involved in real-time syndrome surveillance and reporting.26-30 Furthermore, EDs likely will be the focal point for urgent distribution of postexposure prophylaxis and treatment.
A multi-tiered public health laboratory system (Laboratory Response Network, or LRN) has been implemented, involving capabilities of existing diagnostic laboratories (level A), with additional capability at local and state public health laboratories to include additional diagnostic testing (level B), plus advanced and specialized testing (level C), and three national research and reference centers (level D).31,32
Hospital and other clinical laboratories must be notified if samples submitted are suspected of harboring agents of biological warfare to assure that the correct diagnostic tests are applied and to reduce the risk of infection of laboratory personnel.33 Serious consideration should be given to submitting diagnostic samples directly to a level B or C laboratory through the local health agencies for both confirmatory and rapid diagnostic testing.34,35 They have methods that are more rapid and reliable than local resources may be able to provide. In addition, they have additional biosafety containment capacity and the ability to rapidly expand capacity to accommodate large fluxes of samples.36,37
Emergency physicians and infectious disease consultants will continue to be the primary health care providers involved with detection of biological weapons use.38 Any cases suggesting intentional infection or infection with one of the category A or B agents should be reported immediately to local law enforcement and public health agencies, who then will contact the appropriate federal agencies (the Federal Bureau of Investigation [FBI] and the CDC). Contact with other EDs is essential, as the heightened index of suspicion may allow timely diagnosis and initiation of time-sensitive therapy. Public health officials are available to assist in investigation of unusual diseases and likely will play an increasingly visible role in supporting daily activities of hospital EDs.22,24,39,40
Environmental samples, especially suspicious materials, should be handled exclusively by law enforcement agencies and should not involve emergency medical services (EMS) agencies, hospitals, or health departments.41,42
Additional consultation and diagnostics, particularly isolation of viral agents, can be made by a variety of research and reference centers. (See Table 2.) (This is usually done in conjunction with local public health officials.) The United States Army Medical Research Institutes for Infectious Diseases (USAMRIID) (1-888-USA-RIID) and the CDC (1-770-488-7100 for emergency response) maintain 24-hour hotlines for physician and public health official consultation. Additional assistance may be obtained from the National Response Center (1-800-424-8802 or 1-202-267-2675), or Johns Hopkins Center for Civilian Bio-Defense Strategies (1-410-223-1667).
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Considerable effort has been made to provide timely, widely disseminated information. Consensus statements by a Working Group on Civilian Bio-Defense convened as a collaboration of the Departments of Defense and Health and Human Services have been published for the CDC Category A agents and are available online from the Journal of the American Medical Association website (http://pubs.ama-assn.org/bioterr.html).9,43-48
Other useful references available online include the Textbook of Military Medicine Medical Aspects of Chemical and Biological Warfare (www.nbc-med.org), the CDC recommendations (www.cdc.gov/mmwr/indexbt.html), and the CDC’s Public Health Preparedness site (www.bt.cdc.gov/).
Management of Asymptomatic Patients Who Present with Possible Contamination
EDs must have policies and procedures in place to reduce the threat from contaminated patients.49 While the risk to health care providers and other patients is minimal, a suspected contaminated patient can result in extensive disruption of the ED function.49,50 ED staff, particularly registration, security, and triage personnel, should redirect any persons requesting testing of material suspected to be a chemical, biological, or radiologic weapon. If someone does bring such material to the hospital, he should be directed outside of the building, with instructions on double-bagging and hand-washing. He then should shower and change clothing, preferably at home. Law enforcement agencies then should investigate. Identification of such substances is solely the responsibility of law enforcement agencies, and health care facilities should eschew any participation.51 Finally, it is essential to maintain the chain of custody of any suspicious materials to avoid disrupting a potential criminal investigation.
Although the risk of generating a secondary aerosol is low, patients who present with a concern that they may have been exposed to a biological agent need to wash their hands and faces, shower, and change—preferably at home, unless the patient is symptomatic or otherwise requires medical intervention.50 Prior experience with anthrax hoaxes have shown a wide range of inappropriate responses and revealed both the inappropriate application of HAZMAT response protocols and inadequate education of care providers.16 The very fine (1-5 mcg/M) particles used in aerosol attacks are unlikely to be present on the surface of a victim in large numbers, and would not be an efficient generator of respirable particles. While dilute hypochlorite solutions (typically a 1:10 dilution of household bleach) previously have been advised and widely used, they are largely unnecessary and may cause some minor irritation of skin and mucous membranes.52 With the exception of T-2 mycotoxin and situations involving heavy contamination (e.g., visible), decontamination of patients with hypochlorite solutions is unnecessary and no longer recommended as a routine procedure.19 Nonporous personal items and contaminated surfaces should, however, be decontaminated with an appropriate sporicidal disinfectant.53 Simply changing clothing and showering would reduce the level of contamination by a factor of 10,000, well below that required for generation of infectious aerosols.19 Only cutaneous anthrax, smallpox, and Q fever have been documented to be transmitted via contaminated clothing.54-56 Clothing items should be double-bagged and retained for forensic investigation.19
It is likely that any public announcement of a biological weapons release would trigger ED presentation of large numbers of "worried well."57,58 It is highly desirable to direct possibly contaminated individuals away from EDs, as urgent medical intervention is not required. These patients should be provided directions on self-decontamination, recommendations on prophylaxis, and indications of infection/intoxication. Recommendations on testing and prophylaxis will come from public health and law enforcement agencies, as well as efforts at risk assessment and agent identification. Impulsive use of antibiotics in the absence of a clear threat is unwise. However, in the face of a credible threat, it may be prudent to initiate prophylaxis pending testing results. As exposed patients will not yet manifest disease, there is adequate time to determine a reasonable approach, coordinated with public health departments.18
Collection of samples to detect contamination within 24 hours of exposure (as opposed to diagnosis) should be handled by public health departments or law enforcement agencies. In addition, direct referral of patients to public health authorities, who have access to level B and level C laboratories, will facilitate rapid diagnosis, agent confirmation, and sensitivity testing, as well as follow up.34,35 If samples are collected in the ED, synthetic swabs are preferred, and should be refrigerated.37 While most hospital laboratories can process and identify anthrax, tularemia, brucella, and plague, these agents rapidly could overwhelm available resources and expose laboratory workers to infection. Viral agent isolation should be done only by a reference center, due to the extreme biohazard risk posed by these agents.
Patients who have been exposed to a known release or who are otherwise at risk (e.g., postal workers in facilities handling contaminated mail) may present to EDs for initiation of prophylactic therapy. While it may be reasonable to send a surface culture (e.g., a nasal swab) prior to initiation of prophylactic therapy, such cultures have no role in decisions about an individual patient. Culture results can help detect and characterize agents used in an attack, but absolutely do not indicate whether a patient was exposed to an infectious dose of a biological agent or has become infected. Studies in mill workers have shown it is possible to have a positive nasal swab for an agent, yet not have inhaled a sufficient inoculum to establish infection.59 Similarly, it is possible to have a lethal infection without recovering any organism from body surfaces, including the nose. Thus, the decision to initiate prophylactic therapy is based solely on a credible history of exposure, which is based on results of the forensic investigation by law enforcement agencies.4
Prophylaxis with either a fluoroquinolone (ciprofloxacin, levofloxacin, ofloxacin, moxifloxacin, or gatifloxacin) or a tetracycline (doxycycline or minocycline) is thought to be effective against anthrax, plague, tularemia, brucella, and Q fever. Prophylaxis for anthrax exposure should be continued for four weeks following initiation of vaccination, or at least eight weeks if immunization is unavailable. Penicillins (Pen VK or amoxicillin) or erythromycin also may be effective for anthrax, but should be used only if other agents are contraindicated. Prophylaxis for plague should continue for at least seven days after exposure. Prophylaxis for Q fever should begin 8-12 days after exposure, as earlier initiation is associated with delayed onset of disease. Prophylaxis for brucellosis should be continued for six weeks and many experts recommend the addition of rifampin. Macrolides are effective prophylaxis for Q fever.60
Vaccination against smallpox is effective in preventing disease if given within 2-3 days of exposure. If given within 4-5 days, it may offer incomplete protection, but has an improved survival benefit.61 Vaccinia immune globulin (VIG) may be beneficial in cases in which vaccination is contraindicated. Botulinum immune globulin (BIG) is an equine antitoxin against types A, B, and E, and is available from the CDC. USAMRIID has an investigational new drug (IND), F(ab´)2 heptavalent antitoxin, that appears to be less reactive and more active than the previous agent. Both are effective only if given prior to symptom onset.43,62,63
Management of Patient Who Presents with an Illness Consistent with Biological Terrorism/Warfare Agent
Future terrorist attacks on United States civilian targets will likely continue to be unannounced. Indications of a biological attack may be subtle or elusive. The diagnosis of an atypical infection is likely to be the initial discovery of a covert assault with biological weapons. Given the severity and acuity with which these diseases usually present, initial evaluations will be predominantly in the hospital ED. Emergency physicians must maintain a high index of suspicion in conjunction with ongoing public health surveillance to allow timely diagnosis and detection.
Any unusual temporal or spatial clustering of infectious diseases, particularly if serious pulmonary symptoms or hemorrhagic diathesis is prominent, should prompt urgent public health consultation. Emergency physicians are familiar with the large influx of patients that can follow a large outbreak of food poisoning. The same principle applies: multiple patients presenting with a similar disease over a short course of time, with rapid peak attack rates and some geographic or vector association. Thus, consultation with infectious disease specialists or public health practitioners is warranted with any increase in the number of acute febrile illnesses with clinical syndromes that are consistent with any of the agents of concern and not known to be due to community-acquired viral agents (e.g., influenza).64
In addition, communication with other EDs is critical to alert other practitioners of a possible epidemic of an unusual disease. This has played a crucial role in prior naturally occurring botulism outbreaks, as victims often present simultaneously to multiple hospitals.65
Other causes for concern and discussion with public health officials include multiple presentations of sepsis or fulminant pneumonia in otherwise healthy patients, suggesting plague, anthrax, or tularemia. Outbreaks of acute flaccid paralysis with prominent bulbar symptoms, suggesting botulism, mandates immediate public heath notification. Any clinical diagnosis or suspicion of smallpox is an international public health emergency and is almost certain to be due to intentional release. Similarly, diagnosis of infection with any of the agents of concern, isolation of pathognomonic organism (e.g., variola virus, agents of viral hemorrhagic fever, engineered or highly drug-resistant B. anthracis, or Yersinia pestis) or isolation of genetically identical organisms from multiple regions indicates either an emerging epidemic or intentional release warranting public health and infectious disease consultation. Unexpected animal illness or deaths also are considered to be possible indicators of biological weapons use, and have been important predictors of naturally occurring outbreaks such as the plague epidemic in India, the West Nile encephalitis outbreak in New York, and equine encephalitis outbreaks elsewhere in the United States.66 However, it is unlikely that emergency physicians will be aware of such events, and this highlights the current information infrastructure deficit in our public health system.38,67
In spite of their high infectivity by aerosol route, most agents do not pose a significant risk for person-to-person spread. Notable exceptions are plague pneumonia, smallpox, and the viral hemorrhagic fever agents, which are very contagious and require isolation of the patient in a negative pressure room and respiratory protection of any care givers. Simple droplet precautions (e.g., surgical mask) may be sufficient for protection from the plague.68-70 Due to the significant delay in disease onset, with the exception of T-2 mycotoxin, there is no role for decontamination of symptomatic patients, as it is very unlikely that any viable organisms remain.
Patients presenting with decompensated disease need immediate stabilization with consideration of intubation, fluid resuscitation, pressors, and antimicrobial therapy. However, any such patient, with the exception of botulinum intoxication, likely will die. Patients with a cough should have a surgical mask applied, until it is known that they do not pose a risk to others.
The decision to embark on an diagnostic work-up and empiric therapy for biological weapons is difficult to make.17 However, slight modifications of testing and antibiotic therapy currently used in evaluating ED patients will suffice for the majority, pending consultation with public health, law enforcement, and infectious disease colleagues. A lowered threshold for chest radiography in evaluating influenza-like illness clearly is indicated, and is likely to detect the effusions and mediastinal adenopathy of anthrax as well as the acute infiltrates of Q fever, plague, tularemia, and community-acquired pneumonias. In addition, blood cultures may be warranted in febrile patients who otherwise would not be subjected to diagnostic testing. If biological weapons use is a consideration, aggressive diagnostic testing in conjunction with empiric therapy is essential. Patients should not be placed on antibiotics "just in case" a biological weapons agent is involved without such testing and public health involvement.
It is difficult to distinguish community-acquired, influenza-like illnesses from the presentations of smallpox (prior to vesicle eruption), viral hemorrhagic fever (early), viral equine encephalitis (VEE), anthrax (early), tularemia, plague, brucella, and Q fever. Rapid diagnostic testing for respiratory viruses is widely available and may assist in identifying those patients who would benefit from specific anti-influenza therapy. However, this will not identify many self-limited viral infections other than the respiratory viruses (influenza, parainfluenza, and respiratory syncytial virus [RSV]) detected in commercially available rapid diagnostic tests, as well as several other life-threatening infections. There is no role for nasal swabs in treatment decisions in symptomatic patients, as culture results are neither sensitive nor timely enough to assist in intervention.71
Several diagnostic algorithms have been proposed, but have never been tested in a clinical setting.72,73 However, some generalizations may be useful. Table 3 summarizes clinical features of life-threatening acute febrile illness.
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Recommendations on antimicrobial therapy usually are based on naturally occurring disease, without consideration of engineered antimicrobial resistance, simultaneous release of multiple agents, or the need for coverage of typical community-acquired organisms with similar presentations. It would seem prudent to use multiple antibiotics in the face of a suspected biological weapons attack, to both account for possible drug resistance as well as to address the possibility of multiple agents being used simultaneously. A combination of a parenteral fluoroquinolone and aminoglycoside (streptomycin or gentamicin) would offer coverage for anthrax, plague, tularemia, Q fever, and brucellosis. These antimicrobial agents are familiar to emergency physicians, readily available, and are routinely used for life-threatening infections. The addition of clindamycin would extend coverage for complicated pneumonias, sepsis, abdominal catastrophe and bacterial mediastinitis. If plague is a consideration, lactam antibiotics should be avoided. Chloramphenicol and rifampin may be useful additions in the case of meningitis.
Patients suspected of having smallpox, viral hemorrhagic fever (VHF), and pneumonic plague must be isolated and quarantined. Patients who refuse admission should be held by order of the public health officer. It is unlikely that patients with pneumonic plague, VEE, viral hemorrhagic fevers, or smallpox would be well enough to be treated as outpatients, and most would require admission. Patients with suspicion of early inhalational anthrax may appear well enough to send home, but should be admitted for parenteral antibiotics until afebrile, culture results are returned, and the patient is tolerating oral therapy. Anyone with botulinum toxin exposure should be observed at least 24 hours after exposure or symptom onset to assess for disease progression. Tularemia, brucellosis, and Q fever often are treated as outpatients, and disposition should be based on clinical stability, social situation, and adequacy of follow up. It may be prudent to admit any suspected victim of a bioterrorism attack until the exact characteristics of the attack are known with sufficient certainty.
No currently known, naturally occurring organism possesses all the characteristics needed for the "ideal" weapon.74 It is quite plausible that a terrorist would choose agents based on factors other than their potential as weapons, including ease of obtaining, risk to the offender, or use of agents with wide-spread public recognition, such as HIV, rabies, or "flesh-eating" streptococcus.
The CDC has categorized various microorganisms and toxins into three threat levels based on ease of dissemination, person-to-person transmission, lethality, public health impact, ease of prophylaxis, and treatability. High priority (Category A) agents include variola major (smallpox), B. anthracis (anthrax), Yersinia pestis (plague), botulinum toxin, Francisella tularensis, filovirus, and arenaviruses capable of causing VHF.31
Category B agents include a subset of water- or food-borne agents, as well as more conventional inhalational agents, including Coxiella burnetii (Q fever), Brucella species (brucellosis), Burkholderia mallei, Burkholderia pseudomallei, equine encephalitis viruses (Venezuelan equine encephalitis [VEE], eastern equine encephalitis [EEE], and western equine encephalitis [WEE]), ricin toxin, Clostridium perfringens e-toxin, Salmonella species, Shigella species, E. coli O157:H7, Vibrio cholerae, and Cryptosporidium parvum.31
There are extensive numbers of other agents considered potential, but less concerning, threats (Category C). These include a variety of toxins (abrin, aflatoxin, conotoxins, tricothecene mycotoxins, saxitoxin, ciguatoxin and tetrodotoxin), as well as a wide range of infectious agents which include Chlamydia psittaci (psittacosis), Rickettsia rickettsii (Rocky Mountain spotted fever), Rickettsia prowazekii and Rickettsia typhi (typhus), Vibrio cholerae (cholera), Coccidioides immitis, Crimean-Congo hemorrhagic fever (CCHF) virus, tick-borne encephalitis viruses, influenza virus, Rift Valley fever virus, yellow fever virus, hantavirus, Nipah virus, and multidrug-resistant tuberculosis (MDR Tb).31,75,76
Inhalational Anthrax
Clinical Features. The infectious dose of inhaled anthrax spores is not known with certainty, and estimates of 2500-55,000 (likely 8000-10,000) spores are based on a dose causing infection in 50% of a population, rather than individuals.47,77 Predisposed individuals may become infected with a significantly lower dose, and a small percentage of people could become infected with only a few spores.9
Anthrax’s clinical presentation is dependent on the route of inoculation. Inhalational anthrax appears to have a propensity for the elderly or those with underlying pulmonary disease.77-80
During the initial period of early replication and local lymphatic involvement in inhalational anthrax, the patient experiences a nonspecific, influenza-like illness with retrosternal discomfort, nonproductive cough, low-grade fever, malaise, myalgias, and fatigue.77,81 Some patients may experience a brief quiescent period with apparent improvement ranging from just hours to 2-3 days, followed by the abrupt onset of cyanosis, edema, respiratory distress, obtundation, meningismus, seizures, temperature instability, and irreversible shock. Massive facial and upper thoracic edema may be seen, especially when there is pharyngeal infection. Historically, death occurs within 24-36 hours after onset of the terminal phase in 60-90% of patients, in spite of aggressive therapy.82 Improved survival after early initiation of antibiotics has been reported, but hinges on a high index of suspicion with effective empiric therapy.6,9
Cutaneous anthrax occurs when spores are inoculated through injured skin or, possibly, via insect vector. After an incubation period of 1-7 days, a small, pruritic papule develops and evolves into a large vesicle or becomes ringed with smaller vesicles in a day or two. Edema of surrounding tissues commonly is seen, and may be extensive. If aspirated, the vesicle fluid is serous or serosanguineous, with many bacilli but few leukocytes. Typically, after a week, the vesicles necrose, leaving the characteristic black eschar, which separates with minimal scarring in one to two weeks. Most patients experience headache, malaise, lymphadenopathy, and low-grade fever. Dissemination with bacteremia and fatal sepsis occurs in approximately one-fifth of the cases. Treatment with antibiotics prior to dissemination is very effective, with fewer than 1% of patients developing systemic infection.82
Diagnosis. A previously healthy patient with severe respiratory distress and sepsis without evidence of pneumonia, but with mediastinal adenopathy, should strongly suggest the possibility of inhalational anthrax, as would hemorrhagic meningitis. Hemorrhagic pleural effusions and edema of the chest and neck also are highly suggestive. Early clinical diagnosis is difficult, as the presentation may be indistinguishable from influenza and other community-acquired respiratory infections, such as mycoplasma pneumonia and other viral influenza-like illnesses.71 Inhalational anthrax has fewer upper respiratory symptoms (rhinorrhea, sore throat), and gastrointestinal symptoms may be more frequent, which offer scant clinical differentiation from common community-acquired viral and mycoplasmal infections.64,71 Other biological warfare agents may have similar presentations, at least early on, including brucellosis, tularemia, VEE, and Q fever.73
Chest radiographs most frequently reflect the massive mediastinal lymphadenopathy and associated effusions. None of the 11 described inhalational anthrax cases had normal initial films (giving plain films a sensitivity with a 95% confidence interval of 76-100%).6,7,42,83-85 Chest CT may add additional sensitivity. Leukocytosis is not a prominent feature, even with fulminant disease.6,86 In the setting of a septic patient, the findings of mediastinal adenopathy, hemorrhagic pleural effusions, or hemorrhagic meningitis is strongly suggestive of disseminated anthrax and warrants immediate public health and law enforcement involvement.
B. anthracis can be identified by traditional microbiological methods. However, positive cultures may be dismissed as contaminants or misidentified by some automated systems.37,87 Definitive identification often requires specialized testing that is available through community public health department laboratories.32 Rapid detection and identification methods are becoming more prevalent, but are not yet widely available.88 Sputum cultures are seldom positive, even with advanced disease. Due to the extremely high level of bacteremia, blood cultures and even Gram stains usually are positive. In the recent attack, all of the eight patients who had not received prior antibiotic therapy were positive, even in the early stages of disease.5,6
Treatment. Penicillins and tetracyclines have long been recommended for first-line therapy, and there is substantial clinical experience with these drugs.51,82 Streptomycin and gentamicin are highly effective and may have synergistic effects with penicillins. The fluoroquinolones are highly active in vitro, and experience with ciprofloxacin is well-described.85,89 Levofloxacin and ofloxacin also are active and recommended.41,81 Other effective drugs include clindamycin, rifampin, vancomycin, chloramphenicol, and possibly the macrolides.51,82,90,91 Survival in the recent attack appears to be associated with use of ciprofloxacin plus rifampin (which achieves high concentrations in the macrophages harboring the organism), often in conjunction with clindamycin (for possible toxin suppression).6,9,85
Engineered strains resistant to penicillin, doxycycline, chloramphenicol, rifampin and erythromycin have been described.92 B. anthracis is predictably resistant to extended spectrum cephalosporins and trimethoprim-sulfamethoxazole. Naturally occurring strains may express an inducible ß-lactamase.90,93,94 Resistance to tetracycline class antibiotics occurs more often than to fluoroquinolones, which only has been anecdotally described.95 This, coupled with limited animal data, have led to the recommendation of a fluoroquinolone for empiric therapy.47,51
Oral therapy with penicillin or doxycycline for cutaneous anthrax is very effective at preventing dissemination, but does not hasten clinical resolution. Edema may progress the first day or two of treatment. Treatment should be extended from the usual 7-10 days to a full 60 days as inhalation of spores must be presumed.81
Since dried secretions may sporulate, it is recommended that all secretions and bodily fluids be carefully disposed of, although the risk of generating an aerosol from such materials is unlikely. Cutaneous infections contracted from patients and dressing materials have been described, but appear rare.82 Universal precautions with prompt disposal (after autoclaving, incinerating, or soaking in sporicidal solutions) of secretions and bodily fluids appears adequate.81,96
Vaccination with the U.S. Food and Drug Administration-approved Anthrax Vaccine Absorbed (AVA) is protective.97,98 However, due to manufacturing problems, it is in limited supply.99 Mild to moderate localized inflammatory reactions are seen in approximately one-third of vaccine recipients; such reactions respond well to oral nonsteroidal anti-inflammatory drugs and ice packs. Systemic reactions rarely are seen, and there are no known long-term adverse effects.100-102
Not all inhaled spores germinate simultaneously, and may lay dormant beyond typical antibiotic courses. Animal studies have shown that infection may ensue even after a prolonged course of antibiotics, if vaccination is not simultaneously administered.89 Current recommendations specify an eight-week course of antibiotics following known or suspected exposure.51
Pneumonic Plague
Clinical Features. Pneumonic plague is greatly feared, as it has a precipitous, fulminant course and is very contagious. Human-to-human transmission has been important in explosive outbreaks, but has not been seen in the United States in the past 50 years.103-105 Aerosol dispersal resulting in primary pneumonic plague remains a substantial concern for use as a biological weapon.48,106
Primary pneumonic plague presents after a 24-60 hour incubation, with an abrupt, non-specific, influenza-like illness with high fever, chills, headache, myalgias, dyspnea, and cough that rapidly progresses to a fulminant pneumonia, delirium, and sepsis. With large inoculum death may ensue more rapidly.107 Blood-tinged, watery- to purulent-sputum with possible frank hemoptysis is a frequent and often early feature. Abdominal pain appears to be a frequent, early complaint and may result in a delay in diagnosis.108,109 Pharyngitis may occur as a feature of pneumonic plague, or in isolation. Cervical lymphadenitis characteristic for bubonic plague may be seen in inhalational disease, but otherwise physical examination is unrevealing. The disease progresses rapidly, often with acral ecchymosis and gangrene, respiratory failure, shock, and death in 1-5 days from symptom onset.48,64,106
Diagnosis. Chest radiography typically shows patchy infiltrates, but less often shows pleural effusion, cavitation, lobar consolidation, and mediastinal lymphadenitis.107,110,111 Sputum samples often will show a positive direct fluorescent antibody (DFA) or the Gram stain may show negative coccobacilli or rods with a stereotypical "safety pin" appearance. Rapid tests are of insufficient accuracy to be used as sole diagnostic tools, but strongly support the clinical suspicion.112-114 Y. pestis can be isolated and identified with routine laboratory procedures from blood in more than 80% of patients with plague, and usually is present in sputum of patients with pneumonia.
Treatment. Primary plague pneumonia is uniformly fatal if effective antibiotic therapy is not initiated within a day of presentation, with overall mortality of 40-60%.107,115 In one small series, all patients who died of plague had been seen by a physician prior to their final presentation, and none had received antibiotics effective against plague. All survivors initially had received antibiotics effective against Y. pestis. Initial therapy with lactam antibiotics, presumably due to a failure to diagnose the presenting illness as plague, is associated with mortality as high as 60%.
Antibiotic therapy, to be effective, must be initiated within the first day of clinical illness.116 Experience with antibiotics other than streptomycin (30 mg/kg/day in two divided IM doses) is somewhat limited. Gentamicin (or tobramycin) is recommended by all authorities as an alternative aminoglycoside, and can be given intravenously.48,64,107,117 Patients typically improve and are afebrile within the first 72 hours of aminoglycoside therapy. Chloramphenicol (initial dose 25 mg/kg followed by 15 mg/kg q6h IV/PO) is similarly effective, and is the only anti-plague antibiotic with significant CNS penetration. Tetracyclines also are effective, but require a two-week course. In vitro susceptibility and in vivo animal models suggest that the fluoroquinolones may become the first-line therapeutic agents, although there are no human clinical studies on which to base decision making.118-120
Although most strains are susceptible to third-generation cephalosporins, clinical experience and animal models suggest they may be associated with increased mortality.118,121 trimethoprim-sulfamethoxazole is effective, but has been associated with treatment failures and should be considered only if all other agents are contraindicated. Imipenem and rifampin have sufficient naturally occurring resistance to preclude their use.120 Susceptibility testing of any strain suspected of use as a weapon is essential and a public health priority. Given the ease of genetic modification, it would be possible to engineer a virulent strain with considerable resistance to all frequently used agents.
Pneumonic plague is highly contagious. Patients should be isolated or quarantined, with a cohort of high airflow and respiratory protection for all care givers.96 Current recommendations are for surgical face masks, which reduce the spread of large respiratory droplets.122 Others have questioned this practice, given the highly fatal nature of the disease and relative ease of use of N95 face masks and negative airflow rooms.69 Patients should be isolated until treated for four days and they are afebrile. Anyone within two meters of patients with a cough or who potentially were exposed to the initial agent release should be placed on prophylactic antibiotics and observed for fever.106
Conclusion
Bioterrorism is a continued threat to the United States. ED physicians need to be aware of local and national resources and indications to report cases that provoke suspicion of a possible agent of biologic warfare. Anthrax and pneumonic plague require a high degree of suspicion to facilitate an early diagnosis and the prompt initiation of therapy.
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