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From the Centers for Disease Control and Prevention
November 7, 2001

Recognition of Illness Associated With the Intentional Release of a Biologic Agent

JAMA. 2001;286(17):2088-2090. doi:10.1001/jama.286.17.2088-JWR1107-2-1

MMWR. 20001;50:893-897

On September 11, 2001, following the terrorist incidents in New York City and Washington, D.C., CDC recommended heightened surveillance for any unusual disease occurrence or increased numbers of illnesses that might be associated with the terrorist attacks. Subsequently, cases of anthrax in Florida and New York City have demonstrated the risks associated with intentional release of biologic agents.1 This report provides guidance for health-care providers and public health personnel about recognizing illnesses or patterns of illness that might be associated with intentional release of biologic agents.

Health-Care Providers

Health-care providers should be alert to illness patterns and diagnostic clues that might indicate an unusual infectious disease outbreak associated with intentional release of a biologic agent and should report any clusters or findings to their local or state health department. The covert release of a biologic agent may not have an immediate impact because of the delay between exposure and illness onset, and outbreaks associated with intentional releases might closely resemble naturally occurring outbreaks. Indications of intentional release of a biologic agent include (1) an unusual temporal or geographic clustering of illness (e.g., persons who attended the same public event or gathering) or patients presenting with clinical signs and symptoms that suggest an infectious disease outbreak (e.g., ≥2 patients presenting with an unexplained febrile illness associated with sepsis, pneumonia, respiratory failure, or rash or a botulism-like syndrome with flaccid muscle paralysis, especially if occurring in otherwise healthy persons); (2) an unusual age distribution for common diseases (e.g., an increase in what appears to be a chickenpox-like illness among adult patients, but which might be smallpox); and (3) a large number of cases of acute flaccid paralysis with prominent bulbar palsies, suggestive of a release of botulinum toxin.

CDC defines three categories of biologic agents with potential to be used as weapons, based on ease of dissemination or transmission, potential for major public health impact (e.g., high mortality), potential for public panic and social disruption, and requirements for public health preparedness.2 Agents of highest concern are Bacillus anthracis (anthrax), Yersinia pestis (plague), variola major (smallpox), Clostridium botulinum toxin (botulism), Francisella tularensis (tularemia), filoviruses (Ebola hemorrhagic fever, Marburg hemorrhagic fever); and arenaviruses (Lassa [Lassa fever], Junin [Argentine hemorrhagic fever], and related viruses). The following summarizes the clinical features of these agents.36

Anthrax. A nonspecific prodrome (i.e., fever, dyspnea, cough, and chest discomfort) follows inhalation of infectious spores. Approximately 2-4 days after initial symptoms, sometimes after a brief period of improvement, respiratory failure and hemodynamic collapse ensue. Inhalational anthrax also might include thoracic edema and a widened mediastinum on chest radiograph. Gram-positive bacilli can grow on blood culture, usually 2-3 days after onset of illness. Cutaneous anthrax follows deposition of the organism onto the skin, occurring particularly on exposed areas of the hands, arms, or face. An area of local edema becomes a pruritic macule or papule, which enlarges and ulcerates after 1-2 days. Small, 1-3 mm vesicles may surround the ulcer. A painless, depressed, black eschar usually with surrounding local edema subsequently develops. The syndrome also may include lymphangitis and painful lymphadenopathy.

Plague. Clinical features of pneumonic plague include fever, cough with muco-purulent sputum (gram-negative rods may be seen on gram stain), hemoptysis, and chest pain. A chest radiograph will show evidence of bronchopneumonia.

Botulism. Clinical features include symmetric cranial neuropathies (i.e., drooping eyelids, weakened jaw clench, and difficulty swallowing or speaking), blurred vision or diplopia, symmetric descending weakness in a proximal to distal pattern, and respiratory dysfunction from respiratory muscle paralysis or upper airway obstruction without sensory deficits. Inhalational botulism would have a similar clinical presentation as foodborne botulism; however, the gastrointestinal symptoms that accompany foodborne botulism may be absent.

Smallpox (variola). The acute clinical symptoms of smallpox resemble other acute viral illnesses, such as influenza, beginning with a 2-4 day nonspecific prodrome of fever and myalgias before rash onset. Several clinical features can help clinicians differentiate varicella (chickenpox) from smallpox. The rash of varicella is most prominent on the trunk and develops in successive groups of lesions over several days, resulting in lesions in various stages of development and resolution. In comparison, the vesicular/pustular rash of smallpox is typically most prominent on the face and extremities, and lesions develop at the same time.

Inhalational tularemia. Inhalation of F. tularensis causes an abrupt onset of an acute, nonspecific febrile illness beginning 3-5 days after exposure, with pleuropneumonitis developing in a substantial proportion of cases during subsequent days.7

Hemorrhagic fever (such as would be caused by Ebola or Marburg viruses). After an incubation period of usually 5-10 days (range: 2-19 days), illness is characterized by abrupt onset of fever, myalgia, and headache. Other signs and symptoms include nausea and vomiting, abdominal pain, diarrhea, chest pain, cough, and pharyngitis. A maculopapular rash, prominent on the trunk, develops in most patients approximately 5 days after onset of illness. Bleeding manifestations, such as petechiae, ecchymoses, and hemorrhages, occur as the disease progresses.8

Clinical Laboratory Personnel

Although unidentified gram-positive bacilli growing on agar may be considered as contaminants and discarded, CDC recommends that these bacilli be treated as a "finding" when they occur in a suspicious clinical setting (e.g., febrile illness in a previously healthy person). The laboratory should attempt to characterize the organism, such as motility testing, inhibition by penicillin, absence of hemolysis on sheep blood agar, and further biochemical testing or species determination.

An unusually high number of samples, particularly from the same biologic medium (e.g., blood and stool cultures), may alert laboratory personnel to an outbreak. In addition, central laboratories that receive clinical specimens from several sources should be alert to increases in demand or unusual requests for culturing (e.g., uncommon biologic specimens such as cerebrospinal fluid or pulmonary aspirates).

When collecting or handling clinical specimens, laboratory personnel should (1) use Biological Safety Level II (BSL-2) or Level III (BSL-3) facilities and practices when working with clinical samples considered potentially infectious; (2) handle all specimens in a BSL-2 laminar flow hood with protective eyewear (e.g., safety glasses or eye shields), use closed-front laboratory coats with cuffed sleeves, and stretch the gloves over the cuffed sleeves; (3) avoid any activity that places persons at risk for infectious exposure, especially activities that might create aerosols or droplet dispersal; (4) decontaminate laboratory benches after each use and dispose of supplies and equipment in proper receptacles; (5) avoid touching mucosal surfaces with their hands (gloved or ungloved), and never eat or drink in the laboratory; and (6) remove and reverse their gloves before leaving the laboratory and dispose of them in a biohazard container, and wash their hands and remove their laboratory coat.

When a laboratory is unable to identify an organism in a clinical specimen, it should be sent to a laboratory where the agent can be characterized, such as the state public health laboratory or, in some large metropolitan areas, the local health department laboratory. Any clinical specimens suspected to contain variola (smallpox) should be reported to local and state health authorities and then transported to CDC. All variola diagnostics should be conducted at CDC laboratories. Clinical laboratories should report any clusters or findings that could indicate intentional release of a biologic agent to their state and local health departments.

Infection-Control Professionals

Heightened awareness by infection-control professionals (ICPs) facilitates recognition of the release of a biologic agent. ICPs are involved with many aspects of hospital operations and several departments and with counterparts in other hospitals. As a result, ICPs may recognize changing patterns or clusters in a hospital or in a community that might otherwise go unrecognized.

ICPs should ensure that hospitals have current telephone numbers for notification of both internal (ICPs, epidemiologists, infectious diseases specialists, administrators, and public affairs officials) and external (state and local health departments, Federal Bureau of Investigation field office, and CDC Emergency Response office) contacts and that they are distributed to the appropriate personnel.9 ICPs should work with clinical microbiology laboratories, on- or off-site, that receive specimens for testing from their facility to ensure that cultures from suspicious cases are evaluated appropriately.

State Health Departments

State health departments should implement plans for educating and reminding health-care providers about how to recognize unusual illnesses that might indicate intentional release of a biologic agent. Strategies for responding to potential bioterrorism include (1) providing information or reminders to health-care providers and clinical laboratories about how to report events to the appropriate public health authorities; (2) implementing a 24-hour-a-day, 7-day-a-week capacity to receive and act on any positive report of events that suggest intentional release of a biologic agent; (3) investigating immediately any report of a cluster of illnesses or other event that suggests an intentional release of a biologic agent and requesting CDC's assistance when necessary; (4) implementing a plan, including accessing the Laboratory Response Network for Bioterrorism, to collect and transport specimens and to store them appropriately before laboratory analysis; and (5) reporting immediately to CDC if the results of an investigation suggest release of a biologic agent.

Reported by:

National Center for Infectious Diseases; Epidemiology Program Office; Public Health Practice Program Office; Office of the Director, CDC.

CDC Editorial Note:

Health-care providers, clinical laboratory personnel, infection control professionals, and health departments play critical and complementary roles in recognizing and responding to illnesses caused by intentional release of biologic agents. The syndrome descriptions, epidemiologic clues, and laboratory recommendations in this report provide basic guidance that can be implemented immediately to improve recognition of these events.

After the terrorist attacks of September 11, state and local health departments initiated various activities to improve surveillance and response, ranging from enhancing communications (between state and local health departments and between public health agencies and health-care providers) to conducting special surveillance projects. These special projects have included active surveillance for changes in the number of hospital admissions, emergency department visits, and occurrence of specific syndromes. Activities in bioterrorism preparedness and emerging infections over the past few years have better positioned public health agencies to detect and respond to the intentional release of a biologic agent. Immediate review of these activities to identify the most useful and practical approaches will help refine syndrome surveillance efforts in various clinical situations.

Information about clinical diagnosis and management can be found elsewhere.19 Additional information about responding to bioterrorism is available from CDC at http://www.bt.cdc.gov; the U.S. Army Medical Research Institute of Infectious Diseases at http://www.usamriid.army.mil/education/bluebook.html; the Association for Infection Control Practitioners at http://www.apic.org; and the Johns Hopkins Center for Civilian Biodefense at http://www.hopkins-biodefense.org.

References
1.
Not Available, Update: investigation of anthrax associated with intentional exposure and interim public health guidelines, October 2001. MMWR Morb Mortal Wkly Rep. 2001;50889- 93
2.
Not Available, Biological and chemical terrorism: strategic plan for preparedness and response. MMWR. 2000;49 ((RR-4)) 1- 14
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Arnon  SSSchechter  RInglesby  TV  et al.  Botulinum toxin as a biological weapon: medical and public health management. JAMA. 2001;2851059- 70Article
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Inglesby  TVDennis  DTHenderson  DA  et al.  Plague as a biological weapon: medical and public health management. JAMA. 2000;2832281- 90Article
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Henderson  DAInglesby  TVBartlett  JG  et al.  Smallpox as a biological weapon: medical and public health management. JAMA. 1999;2812127- 37Article
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Inglesby  TVHenderson  DABartlett  JG  et al.  Anthrax as a biological weapon: medical and public health management. JAMA. 1999;2811735- 963Article
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Dennis  DTInglesby  TVHenderson  DA  et al.  Tularemia as a biological weapon: medical and public health management. JAMA. 2001;2852763- 73Article
8.
Peters  CJ Marburg and Ebola virus hemorrhagic fevers. Mandell  GLBennett  JEDolin  Reds.Principles and practice of infectious diseases. 5th ed. New York, New York Churchill Livingstone2000;21821- 3
9.
APIC Bioterrorism Task Force and CDC Hospital Infections Program Bioterrorism Working Group, Bioterrorism readiness plan: a template for healthcare facilities. Available at http://www.cdc.gov/ncidod/hip/Bio/bio.htm. Accessed October 2001.
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