Syndromic Surveillance and Bioterrorism-related Epidemics

James W. Buehler, Ruth L. Berkelman, David M. Hartley, Clarence J. Peters


Emerging Infectious Diseases. 2003;9(10) 

In This Article

Detecting Specific Bioterrorism Epidemics and Agents

The attributes of the CDC category A bioterrorism agents that affect their detection, as well as the benefits of early detection, are summarized below, on the basis of potential bioterrorism-related epidemic profiles developed by experts.[12,22,23,26,27,28] These profiles reflect current knowledge of these diseases; their epidemiology might differ if novel modes of dissemination or preparation were employed. Each disease has attributes that could increase or decrease the likelihood of early outbreak recognition through either clinical diagnosis or syndromic surveillance.

The distribution of the incubation period for inhalational anthrax can be relatively broad as observed in Sverdlovsk (2-43 days); most cases occur within 1-2 weeks after exposure.[24] In the 2001 U.S. outbreak, the distribution of incubation periods was more limited, 4-6 days, although later-onset cases may have been averted by antibiotic prophylaxis.[25] The nonspecific prodrome for anthrax may last from several hours to several days. Taken together, these data suggest that the initial slope of an epidemic curve may be comparatively gradual during the first week, leading to slower recognition through syndromic surveillance than for other infections caused by bioterrorist agents with pulmonary manifestations, such as tularemia or pneumonic plague.[22,28] In contrast, mediastinal widening on chest x-ray or computed tomographic scan or Gram stain of cerebrospinal or pleural fluid should lead an alert and knowledgeable physician to consider the diagnosis of anthrax, even though these tests may not be conducted until relatively late in the clinical course. B. anthracis is likely to be detected quickly in cultures, favoring clinical recognition. Retrospective analysis of data from 2001 showed that inhalational anthrax can be distinguished from influenzalike illness or community-acquired pneumonia by using an algorithm that combines clinical and laboratory findings,[20] although the practical utility of this approach is untested. In addition to permitting antibiotic use among ill persons, early recognition would enable postexposure antibiotic prophylaxis.[12,25]

The typical incubation period for tularemia is relatively narrow after a person is exposed to aerosolized F. tularensis, with abrupt onset of nonspecific febrile illness, with or without respiratory symptoms, in 3-5 days (range 1-14 days), followed by rapid progression to life-threatening pneumonitis.[22] This relatively narrow incubation period for most patients and rapid progression to severe disease would lead to a rapid increase in cases after a large and acute exposure. Finding a number of such cases in a short interval should trigger both syndromic surveillance alarms and clinical suspicion. F. tularensis is a slow-growing and fastidious organism and may take up to 5 days after inoculation to be detectable, if it is detected at all, in a routinely processed blood culture. The use of special laboratory techniques may be required, delaying the likelihood of detection in the absence of clinical suspicion. After an epidemic is recognized, specific antibiotic therapy is recommended for exposed persons in whom a febrile illness develops.[22]

Exposure to aerosolized Yersinia pestis results in pneumonic plague, which has a typical incubation period of 2 to 4 days (range 1-6 days). The disease has a relatively short prodrome, followed by rapidly progressive pneumonia,[28] which would lead to a rapid increase in cases at the onset of an epidemic. Standard clinical laboratory findings are nonspecific, which alone might not prompt clinical suspicion, but microscopic examination of a sputum smear may show characteristic findings, which should prompt consideration of the diagnosis. Cultures of blood or sputum are apt to show growth within 24 to 48 hours, but routine procedures may misidentify Y. pestis unless the diagnosis is suspected and special attention is given to specimen processing. Confirming the diagnosis depends on special tests available through reference laboratories. Treatment the first day of symptoms is generally considered necessary to prevent death in pneumonic plague, so early recognition of an aerosol plague attack would enable life-saving use of antibiotics in febrile patients and prophylaxis of contacts.[28]

Foodborne botulism typically has a relatively narrow incubation period (12-72 hours), which may vary from 2 hours to 8 days, depending on the inoculum. For the three known cases of inhalational botulism attributed to a relatively low exposure to aerosolized toxin, the incubation period was approximately 72 hours.[26] The characteristic clinical picture of descending paralysis should prompt consideration of botulism, and this unique pattern among bioterrorism agents lends itself to a specific syndrome category. However, the illness may be misdiagnosed, as observed in a large foodborne outbreak of botulism in 1985; 28 persons who had eaten at a particular restaurant and in whom botulism had developed were assigned other diagnoses before the geographically dispersed outbreak was recognized and publicized in the media.[26,29] Symptoms of inhalational botulism, with choking, dysphagia, and dysarthria dominating the clinical picture, may differ from those associated with ingestion of toxin and complicate recognition of the disease. Specialized testing for botulinum toxin is available at a limited number of state laboratories and CDC. Postexposure prophylaxis is limited by the scarcity of, and potential for, allergic reactions to botulinum antitoxin, leading to recommendations that exposed persons be observed carefully for early signs of botulism, which should prompt antitoxin use.[26] Antitoxin should be given as early as possible, another fact that highlights the importance of early detection. Depending on the level of exposure and the geographic dispersion of affected persons, syndromic surveillance for characteristic neurologic symptoms could aid outbreak detection, or the occurrence of an epidemic might be obvious to clinicians.

The incubation period of smallpox is usually 12-14 days but may range from 7 to 17 days. The early symptomatic phase includes a severe febrile illness and appearance of a nonspecific macular rash over a 2- to 4-day period, followed by evolution to a vesicular and then pustular rash over the next 4 to 5 days.[27] Thus, the initial phase of smallpox may lend itself to detection through surveillance of a febrile rash illness syndrome. Once smallpox is suspected, the virus can be rapidly detected by electron microscopic examination of vesicular or pustular fluid, if laboratory resources for electron microscopy are available, or by polymerase chain reaction, if the necessary primers are available. Contacts can be protected by vaccination up to 4 days after exposure. Discourse is substantial about the relative merits of pre-event versus postevent vaccination.[27,30,31,32,33] Syndromic surveillance may show an increase in febrile rash illness, although once the characteristic rash appears, the diagnosis should be quickly established.

This category includes multiple infectious agents that range from having a relatively broad to narrow incubation period (e.g., Ebola, 2-21 days; yellow fever 3-6 days). These diseases present with nonspecific prodromes that may have an insidious or abrupt onset. In severe cases, the prodrome is followed by hypotension, shock, central nervous system dysfunction, and a bleeding diathesis. The differential diagnosis includes a variety of viral and bacterial diseases. Establishing the diagnosis depends on clinical suspicion and the results of specific tests that must be requested from CDC or the U. S. Army Medical Research Institute of Infectious Diseases. The value of postexposure prophylaxis with antiviral medications is uncertain, and (with the exception of yellow fever, for which a vaccine is available) response measures are limited to isolation and observation of exposed persons, treatment with ribavarin (if the virus is one that responds to that antiviral drug), and careful attention to infection control measures.[23] Patients seen with symptoms during the prodromal phase may not clearly fit into a single syndrome category, but syndromic surveillance focused on the early signs of a febrile bleeding disorder would be more specific.

One of the biggest concerns about syndromic surveillance is its potentially low specificity, resulting in use of resources to investigate false alarms.[6,10] Specificity for distinguishing bioterrorism-related epidemics from more ordinary illness may be low because the early symptoms of bioterrorism-related illness overlap with those of many common infections. Specificity for distinguishing any type of outbreak from random variations in illness trends may be low if statistical detection thresholds are reduced to enhance sensitivity and timeliness. The likelihood that a given alarm represents a bioterrorism event will be low, assuming that probability of such an event is low in a given locality. Approaches used to increase specificity include requiring that aberrant trends be sustained for at least 2 days or that aberrant trends be detected in multiple systems.[2] Another approach to enhancing specificity would be to focus surveillance on the severe phases of disease, since the category A bioterrorism infections are more likely than many common infections to progress to life-threatening illness. For those diseases that are likely to progress rapidly, such as pneumonic plague, syndromic detection of severe disease (e.g., through emergency room visits, hospital admissions, or deaths) may be more feasible than detection aimed at early indicators before care is sought (e.g., purchases of over-the-counter medications) or when illness is less severe (e.g., primary care visits). Whether detection of syndromic late-stage disease offers an advantage over detection through clinical evaluation will depend on the attributes of the infections and diagnostic resources, as described above.

Predicting how the mix of relevant factors would combine in a given situation to affect the recognition of a bioterrorism-related epidemic is difficult, although mathematical models may provide further insight.[5] The most important factors affecting early detection are likely to be the rate of accrual of new cases at the outset of an epidemic, geographic clustering, the selection of syndromic surveillance methods, and the likelihood of making a diagnosis quickly in clinical practice.

Ongoing efforts to strengthen the public health infrastructure[34,35] and to educate healthcare providers about bioterrorism diseases and reporting procedures should strengthen the ability to recognize bioterrorism outbreaks. For example, in New Jersey in 2001, reporting of two early cases of cutaneous anthrax was delayed until publicity about other anthrax cases prompted physicians to consider the diagnosis and notify the health department, suggesting that opportunities for earlier use of postexposure prophylaxis were missed.[36] In addition, while the importance of new diagnostic tools, including rapid tests, should be emphasized,[37] the essential role of existing diagnostic techniques should not be overlooked. Clinical suspicion is critical, and a key prompt for arousing clinical suspicion may be the microscopic examination of a routinely collected specimen, as occurred in the index case of the 2001 anthrax outbreak, when a Gram stain of the cerebrospinal fluid led to the diagnosis.[15] However, as recently highlighted by the Institute of Medicine, the use of basic diagnostic tests has decreased because of efforts to reduce the costs of care, the increasing use of empiric broad-spectrum antibiotic therapy, and federal laboratory regulations, such as the Clinical Laboratory Improvement Amendments of 1988, which have discouraged laboratory evaluation in some clinical settings.[38]

While we have focused on the role of syndromic surveillance in detecting a bioterrorism-related epidemic, other uses of syndromic surveillance include detecting naturally occurring epidemics, providing reassurance that epidemics are not occurring when threats or rumors arise, and tracking bioterrorism-related epidemics regardless of the mode of detection.[4,6,10] Syndromic surveillance is intended to enhance, rather than replace, traditional approaches to epidemic detection. Evaluation of syndromic surveillance to consider the spectrum of potential uses is essential. A certain level of false alarms, as the result of either syndromic surveillance or calls from clinicians, will be necessary to ensure that opportunities for detection are not missed. Efforts to enhance the predictive value of syndromic surveillance will be offset by costs in timeliness and sensitivity, and defining the right balance in practice, particularly in the absence of an accurate assessment of bioterrorism risk, will be essential.

Two committees of the National Academies have recommended more careful evaluation of the usefulness of syndromic surveillance before it is more widely implemented.[5,38] Because the epidemiologic characteristics of different bioterrorism agents may vary in ways that affect the detection of epidemics, these evaluations should address the epidemiology of specific bioterrorism agents. Efforts to detect bioterrorism epidemics at an early stage should not only address the development of innovative new surveillance mechanisms but also strengthen resources for diagnosis and enhance relationships between clinicians and public health agencies-relationships that will ensure that clinicians notify public health authorities if they suspect or diagnose a possible bioterrorism-related disease.


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