By Thomas V. Inglesby, MD

Tara O’Toole, MD, MPH

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.

Clinical Case

Three previously healthy, patients of varying age, from different places in the community present to the hospital Emergency Department with similar symptoms which include chest discomfort, fever, malaise, myalgias and nausea. In the hours after admission, each shows evidence of worsening sepsis requiring critical care unit support despite initiation of empiric antibiotics. There are no revealing findings on physical examination. CSF from the first patient shows evidence of hemorrhagic meningitis. CXR on the second patient shows widened mediastinum. Labs are unrevealing. On the following day, the microbiology laboratory reports that blood cultures from the first patient are growing a Bacillus species; despite continued broad spectrum antibiotics, the patient dies four hours later.

Clinical Questions

• What is a biological weapon?

• How does biological terrorism pertain to medicine?

• Who should be contacted if biological terrorism is suspected?

• When should a physician suspect biological terrorism?

• What are the most serious biological weapons?

• What are the clinical and epidemiological features of smallpox, inhalational anthrax, and pneumonic plague?

What is biological weapon?

A biological weapon is a device used to intentionally cause disease through dissemination of bacteria, virus or microbial toxin. Depending on the microbe or toxin, resulting disease may or may not be contagious. Biological terrorism, then, is the use of a biological weapon against civilian populations for purposes of creating terror. The result of the use of a biological weapon is an epidemic.

Until recently, biological weapons have generally been considered a concern of the military. There is a growing concern, however, that biological weapons will be used as a terrorist weapon in the US. The microbial agents used to make some of the most lethal biological weapons are widely available, and the associated technology is also obtainable given its legitimate use for agricultural, pharmaceutical or other purposes. Food, water or insects are each potential vehicles of transmission for biological weapons, though it is aerosol dissemination that has the greatest capacity to cause widespread disease.

How does biological terrorism pertain to medicine?

An act of biological terrorism would require significant and sustained response from experts throughout the hospital community. First, it is important to review the significant distinctions between chemical and biological terrorism. Chemical terrorism would result in illness minutes to hours after attack in persons close to the location of weapon release. Paramedics, firefighters and police and emergency rescue workers would be the first to respond, would need personal protective equipment to prevent becoming ill themselves, would cordon off the affected area, decontaminate patients, and administer antidotes if appropriate.

In contrast, biological terrorism would most likely result in illness days to weeks after attack and in persons widely dispersed from the site of release. Affected persons would present to clinics and emergency departments with undiagnosed illness. If no warning has been made, bioterrorism may first be suspected by physicians who notice an unusual illness or pattern of illnesses. Once discovered, an act of bioterrorism would rarely require decontamination of persons and the environment; vaccines and antibiotics, not antidotes, would be needed; and, depending on the disease, patient isolation may be required.

Many of the responsibilities for the management of the consequences of bioterrorism are those of physicians. They would provide medical treatment the sick and dying–depending on the scale and character of the event, many persons could rapidly and simultaneously require critical care. Since bioterrorism results in an ongoing epidemic, the challenges facing the hospital environment would also occur over weeks to months. During this period, physicians would be asked to provide crucial hospital and community leadership in bringing the epidemic to an end.

Who should be contacted if biological terrorism is suspected?

If a physician suspects bioterrorism is responsible for a patient’s illness or for a cluster of illnesses, immediate contact should be made with a public health official of the local health department and with the hospital epidemiologist or infection control specialist. Once contacted, the health department would initiate rapid investigation of the event, and, if bioterrorism is suspected or confirmed, provide guidance to physicians, hospitals and the affected community. The health department would also establish communication and cooperation with other government agencies.

When should a physician suspect biological terrorism?

A physician should consider the possibility of biological terrorism following the clinical or microbiological diagnosis of a single case of a rare or non-naturally occurring infectious disease. While regulations vary between states, each state has a list of immediately reportable diseases that, when suspected or diagnosed, are grounds for immediate verbal reporting to the health department. While these lists generally are used as a surveillance mechanism for naturally occurring infectious disease and may not include all pathogens that could be used as biological weapons, in most states the list does (or soon will) include the agents of highest concern with respect to biological terrorism.

A physician should also consider the possibility of biological terrorism as the cause of an unexplained cluster of illnesses. A large clustering of unusually severe or lethal viral or lower respiratory illness in previously well persons, for example, should prompt the consideration of anthrax or plague, respectively.

Discerning that an outbreak is occurring is the first challenge, but one that might be met by physicians who notice an unusual or suspicious pattern of illness in the emergency department or hospital-wide. Determining the specific cause of the outbreak is likely to require specific resources and expertise; such an investigation is the responsibility of the health department working in consultation with the hospital epidemiologist. Even if unusual or suspicious illness is not the result of bioterrorism, a health department and medical epidemiology investigation is appropriate given the health department’s charge to analyze naturally occurring disease outbreaks in a community.

What are the most serious biological weapons?

While many agents or toxins could be made into biological weapons, three have been identified that stand above all others and which require the highest level of concern: smallpox (caused by Variola virus), anthrax (caused by Bacillus anthracis), and plague (caused by Yersinia pestis). Few US physicians would recognize these diseases, but biological terrorism employing any of these would have the capacity to cause widespread, potentially catastrophic epidemics and would require immediate medical and public health intervention. Even a single case of smallpox, anthrax or plague appearing in the US today would constitute a medical and public health emergency and must be reported immediately to local health authorities.

The next most serious group of potential biological weapons includes botulism (caused by botulinum toxin that is produced by Clostridium botulinum), tularemia (caused by Francisella tularensis) and the some of the viral hemorrhagic fever syndromes. Specific and substantial public health interventions would be needed in response to these diseases following the use of a biological weapon, though the public health preparedness efforts made for smallpox, anthrax and plague would provide much of the needed resources and infrastructure to respond to these and other threats.

What are the clinical and epidemiological features of smallpox, inhalational anthrax, pneumonic plague?

Twelve to 14 days following exposure to the smallpox virus, fever and macular rash develop. Over 1 to 2 days, the rash becomes vesicular and then pustular. In a modern outbreak, smallpox may be misdiagnosed as a case of ‘adult chickenpox,’ but important distinctions exist between the two diseases. In smallpox, pustules evolve concurrently and the rash begins and is most dense on the face, soon spreading to the extremities and trunk. In chickenpox, however, the vesicles and pustules evolve in crops and start on the chest and back.

In diagnosing smallpox, the rash is the best clue; no routine laboratory studies are useful. Once the disease is suspected, rapid confirmatory testing would be facilitated by the state health department and performed by the Centers for Disease Control and Prevention (CDC).

There is no evidence that antiviral agents alter the natural history of the smallpox. Therapy for smallpox, therefore, is supportive. The expected mortality rate would be 30% for those not previously vaccinated. Clinical sequelae related to sepsis, in some cases encephalitis, and, more rarely, bacterial superinfection, would be expected.

Direct contacts of smallpox patients have a high risk of acquiring the disease via respiratory droplet. Smallpox patients are considered contagious from the time they develop rash until all scabs have formed and fallen off. In order to prevent further transmission, a direct contact should be quarantined immediately if he develops fever in the 2 weeks following smallpox exposure. In addition, all persons with direct contact with smallpox patients should be urgently vaccinated. If administered within 3 to 4 days of smallpox exposure, vaccine is usually protective against a fatal outcome though it may not prevent the onset of a milder form of disease.

In the US, routine vaccination was discontinued in 1972 so that essentially no persons under the age of 27 have been vaccinated in the US. Further, it is expected that only a minority of those vaccinated prior to 1972 could be expected to be fully protected against the disease. Efforts are underway to increase the limited reserve of US smallpox vaccine.

Vaccination can result in serious complications. Some groups are at higher risk: persons with eczema or exfoliative conditions; persons with malignancy or undergoing treatment with immunosuppressive agents; persons with HIV infection; and persons with hereditary immune disorders. The risk of vaccination of individuals with special risk would need to be carefully measured against the risk of developing smallpox.

Anthrax

A biological weapon disseminating an anthrax aerosol primarily would result in cases of inhalational anthrax. Symptoms and signs of inhalational anthrax would be expected to develop between 2 and 43 days after exposure, with the majority of cases occurring in the two weeks following exposure. Symptoms of inhalational anthrax include fever, dyspnea, cough, headache, vomiting, chills, weakness, abdominal and chest pain; the signs are non-specific. Up to half of patients with inhalational anthrax will develop hemorrhagic meningitis.

The clinical course of inhalational anthrax is rapid. In the two largest case series of inhalational anthrax, death typically occurred within 2 to 4 days of symptom onset and the associated case fatality rate was over 85%. A group of previously healthy persons dying of apparent sepsis and/or meningitis following flu-like illnesses should spur the consideration of anthrax as the cause of the outbreak.

In advanced disease, the chest radiograph may show a widened mediastinum, a finding that is nearly pathognomonic in this setting. Unspun blood smears of animals dying of inhalational anthrax have demonstrated Gram positive bacilli; similar findings could be expected in humans. Blood cultures should demonstrate growth of Gram positive bacilli, though current standard laboratory practices would be unlikely to make the final identification. Rapid diagnostic testing is available only at special reference centers such as the CDC, the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) and some state laboratories.

Rapid antibiotic administration is essential for treating anthrax infection. While naturally occurring anthrax infection could be treated effectively by a number of antibiotics, a number of specific concerns have led to the recommendation of the fluoroquinolone class of antibiotics as preferred treatment pending antibiotic susceptibility testing-alternatives and specific recommendations for children and pregnant women appear elsewhere. It is important to note that anthrax demonstrates naturally occurring resistance against the second and third generation cephalosporins, antibiotics often used for empiric treatment of pneumonia or sepsis.

Given the lethality and fulminant nature of inhalational anthrax infection, an attempt must be made to identify persons likely to have been exposed to the anthrax aerosol and to rapidly initiate postexposure antibiotic prophylaxis in this group. It is in this group of exposed but not yet symptomatic persons that antibiotic administration may have the greatest impact. Primate studies have shown that antibiotic prophylaxis started one day after anthrax exposure, but prior to symptom onset, provides significant protection against death.

The US anthrax vaccine is currently not available for civilian use. If the anthrax vaccine were available to civilians, postexposure vaccination of individuals exposed to an anthrax aerosol would both be high priority. Pre-exposure vaccination of essential service personnel would also be worth considering.

It is important to note that the disease does not spread from person to person. Standard barrier precautions should be used in carrying for patients, but no special isolation procedures are indicated.

Infection from a plague aerosol would result in pneumonic plague, not the more widely known and more frequently occurring bubonic form of disease. Patients with pneumonic plague develop evidence of illness 1 to 6 days following exposure. Characteristic symptoms include fever, dyspnea, cough, and serosanguinous or purulent sputum production; frank hemoptysis has been reported. Signs are non-specific but are consistent with a rapidly evolving bronchopneumonia. The clinical course is fulminant. Untreated mortality is high; survival rates where antibiotic therapy is readily available are uncertain. A group of previously healthy patients presenting with lethal bronchopneumonia, especially with hemoptysis, should raise a suspicion of pneumonic plague as a possible cause of the outbreak.

Lab studies are consistent with sepsis and not uncommonly demonstrate evidence of disseminated intravascular coagulation. A chest radiograph shows severe bronchopneumonia. Blood and sputum cultures are likely to reveal Gram negative bacilli. Using standard laboratory procedures, at least 2 to 3 days would be required to identify the organism from culture isolates. Rapid diagnostic testing is available only at national and some state reference centers.

Early antibiotic administration is essential for successful treatment of pneumonic plague. Gentamicin or streptomycin have been recommended as preferred therapy for all patients with pneumonic plague-alternatives and specific recommendations for children and pregnant women appear elsewhere. For those persons who are asymptomatic but who are determined to have been exposed to a plague aerosol, careful monitoring for fever or cough should be undertaken for the next seven days. If either develops during this time period, treatment for pneumonic plague should be empirically started.

Transmission of pneumonic plague can occur via respiratory droplet in those with face to face contact with infected patients at less than two meters distance. Therefore, protective masks should be worn by an infected patient’s health care workers, household members or others during close contact in order to prevent person to person spread. Unprotected face to fact contact with infected patients warrants antibiotic prophylaxis. No effective vaccine exists against pneumonic plague.

Key Points

• A biological weapon is a device used to intentionally cause disease through dissemination of bacteria, virus or microbial toxin. Depending on the microbe or toxin, resulting disease may or may not be contagious.

• The result of the use of a biological weapon is an epidemic. Affected persons will present to clinics and emergency departments as they do in other outbreaks.

• Physicians, along with other health care professionals, are likely to be the first to notice an outbreak caused by bioterrorism and therefore play a crucial role in early detection.

• Unusual outbreaks of disease should be promptly reported to the health department and hospital epidemiologist. While bioterrorism may or may not be the cause of unusual clusters of illnesses, the health department and hospital epidemiologist are charged with outbreak investigation.

• Smallpox, anthrax and plague merit special attention as biological weapons threats because of their capacity to cause widespread public health catastrophe. Other biological weapons of high concern are the agents responsible for botulism, tularemia and some of the viral hemorrhagic fever syndromes.

• Smallpox is highly contagious. Initial diagnosis would be through clinical recognition of the characteristic rash. Therapy is supportive. Isolation of patients and vaccination of contacts would be essential in bringing a smallpox epidemic under control.

• Inhalational anthrax is not contagious. Initial diagnosis would be through clinical or epidemiologic recognition of disease, microbiology laboratory isolation or post-mortem examination. Antibiotic treatment of the ill and postexposure antibiotic prophylaxis of the exposed are crucial public health interventions in an anthrax epidemic. Vaccine would be a useful public health tool but is not available to civilians.

• Pneumonic plague is contagious to close contacts by respiratory droplet–tight-fitting, disposable surgical masks are recommended for those in close contact with patients with pneumonic plague. Initial diagnosis would be through clinical or epidemiologic recognition of disease, microbiology laboratory or post-mortem examination. Antibiotic treatment for the ill and close observation for fever and cough in the exposed are crucial public health interventions in a pneumonic plague epidemic. There is no vaccine available that protects against pneumonic plague.

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.

Editorial Note

Information about clinical diagnosis and management can be found elsewhere(1-9) . 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. CDC. Update: investigation of anthrax associated with intentional exposure and interim public health guidelines, October 2001. MMWR 2001;50:889 -93.

2. CDC. Biological and chemical terrorism: strategic plan for preparedness and response. MMWR 2000;49(no. RR-4).

3. Arnon SS, Schechter R, Inglesby TV, et al. Botulinum toxin as a biological weapon: medical and public health management. JAMA 2001;285:1059-70.

4. Inglesby TV, Dennis DT, Henderson DA, et al. Plague as a biological weapon: medical and public health management. JAMA 2000;283:2281-90.

5. Henderson DA, Inglesby TV, Bartlett JG, et al. Smallpox as a biological weapon: medical and public health management. JAMA 1999;281:2127-37.

6. Inglesby TV, Henderson DA, Bartlett JG, et al. Anthrax as a biological weapon: medical and public health management. JAMA 1999;281:1735-963.

7. Dennis DT, Inglesby TV, Henderson DA, et al. Tularemia as a biological weapon: medical and public health management. JAMA 2001;285:2763-73.

8. Peters CJ. Marburg and Ebola virus hemorrhagic fevers. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and practice of infectious diseases. 5th ed. New York, New York: Churchill Livingstone 2000;2:1821-3.

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.

BIBLIOGRAPHY

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Summary: A primer on 10 biological warfare agents written by experts from the United States Army Medical Research Institute of Infectious Diseases.

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Summary: A description of the threats posed by biological terrorism and an overview of the public health resources and infrastructure necessary for to confront the challenges.

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Summary: Consensus recommendations are made regarding smallpox vaccination, therapy, postexposure isolation and infection control, hospital epidemiology, home care, environmental decontamination, and surveillance in the setting of an epidemic.

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Summary: Consensus recommendations are made regarding the diagnosis of anthrax, indications for vaccination, therapy, postexposure prophylaxis, decontamination of the environment and additional research needs.

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Summary: Consensus recommendations are made regarding the diagnosis of plague in the setting of bioterrorism, therapy, postexposure prophylaxis, infection control measures and additional research needs.

6. Inglesby TV, O’Toole T. Responding to Bioterrorism. N Engl J Med. (submitted for publication)

Summary: A review article that outlines the threat and challenges of biological terrorism, related federal funding initiatives, and the clinical and epidemiological features of smallpox, anthrax and plague.

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Summary: This article addresses the available epidemiologic data of the largest known epidemic of inhalational anthrax, which occurred in Sverdlovsk following an accident at a military facility.