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

Establishing a Diagnosis

Two pathways to establishing a diagnosis are described by the scenarios below and in Figure 1, using a single, clandestine dissemination of an anthrax aerosol as an example.

Figure 1.

Number of cases of syndromic illness by time in a hypothetical bioterrorism attack and two pathways to establishing a diagnosis: syndromic surveillance coupled with public health investigation (upper pathway) and clinical and diagnostic evaluation of patients with short-incubation period disease (lower pathway). A, scenario favoring earlier detection by means of clinical evaluation. B, scenario favoring earlier detection by means of syndromic surveillance.

The early signs of inhalational anthrax include nonspecific symptoms that may persist for several days before the onset of more severe disease.[12] Patients with prodromal illnesses seek outpatient care and are assigned nonspecific diagnoses such as "viral syndrome." Data on patients fitting various syndromic criteria are transferred to the health department and tested for aberrant trends. This process "flags" that a statistical detection threshold has been exceeded. Epidemiologists conclude that a preliminary investigation is warranted and collect blood for culture from several patients. Within 18 hours, one culture yields a presumptive diagnosis of anthrax, prompting a full-scale response.

Some persons in whom inhalational anthrax develops will have short incubation periods and prodromes.[12] Respiratory distress occurs in one such person, and he is hospitalized. Routine admission procedures include blood cultures. Within 18 hours, a presumptive diagnosis of anthrax is made. The patient's physician informs the local health department, prompting a full-scale response.

In practice, how a bioterrorism attack might be detected and diagnosed will probably be more complex. Published descriptions of 11 persons with inhalational anthrax in the United States in 2001[13,14,15,16,17,18,19] provide some insight into this issue ( Table 1 and Figure 2),[1] even though that epidemic was too small and geographically diffuse to be detectable by syndromic surveillance. For six patients with known dates of exposure, the median duration between exposure and symptom onset was 4 days (range 4-6 days). The median duration between onset and the initial healthcare visit was 3 days[20] (range 1-7 days), and the median duration between onset of symptoms and hospitalization was 4 days (range 3-7 days). Two of the 11 patients visited emergency departments and were sent home with diagnoses of gastroenteritis or viral syndrome 1 day before admission. In one patient, a blood culture obtained in the emergency room was read as positive for gram-positive bacilli the following day, which prompted recall of the patient. The culture was subsequently confirmed as positive for Bacillus anthracis. Two other patients were seen by primary care physicians and sent home with diagnoses of viral syndrome or bronchitis 2-3 days before admission, including one patient who was begun on empiric antibiotic therapy. For seven other patients, initial emergency room or hospital visits led directly to admission. In addition to the patient whose blood culture was obtained in an emergency room, seven others had not received prior antibiotic therapy, and B. anthracis was presumptively identified from blood within 24 hours of culture. One of these seven patients was the index patient, in whom B. anthracis was also recognized in cerebrospinal fluid within 7 hours of specimen collection. Three other patients had received antibiotics before blood cultures were taken (one as an outpatient and two at the time of hospital admission), requiring alternative diagnostic methods.

Figure 2.

Timeline to presumptive anthrax diagnosis, 11 patients with inhalational anthrax, 2001, United States. Abbreviations: Dx, diagnosis; OutPt, outpatient visit followed by discharge home; ER, emergency room visit followed by discharge home. *Diagnosis delayed-initial blood cultures were negative in three patients who received antibiotic therapy before culture specimens were collected, requiring use of special diagnostic tests. For patients 1-10, case numbers correspond to those in report by Jernigan et al.;[13] patient 11 reported by Barakat et al.[14] A, timeline begins with presumed date of anthrax exposure, available for six patients. B, timeline begins with day of illness onset for five patients without recognized date of exposure.

Despite the small number of patients, their experience offers four lessons for detecting an epidemic of inhalational anthrax. First, a key objective of syndromic surveillance is to detect early-stage disease, but fewer than half of these patients sought care before hospitalization was necessary, and the interval between such care and admission was relatively narrow (1-3 days). This finding suggests that syndromic surveillance data must be processed, analyzed, and acted upon quickly if such data are to provide a clue to diagnosis in advance of late-stage disease. Second, emergency room data are a common source for syndromic surveillance, but detecting an increase in visits coincident with hospital admission may not provide an early warning because the time needed to process surveillance data and investigate suspected cases would be at least as long as the time for admission blood cultures to be positive for B. anthracis. Blood cultures are likely to be routine for patients admitted with fever and severe respiratory illness, regardless of whether anthrax is considered as a diagnostic possibility, and B. anthracis grows readily in culture in the absence of prior antibiotic therapy, as observed in most of these patients. Thus, if emergency room data are to be useful in early detection of an anthrax epidemic, those data would need to be for visits that occur before hospital care is required-a pattern observed in only two patients. Third, the four patients who received early care and were discharged to their homes were assigned three different diagnoses, which suggests that syndromic surveillance systems must address the potential variability in how patients with the same infection may be diagnosed during the prodrome phase. Fourth, rapid diagnosis after hospitalization was possible only in those patients who had not received antibiotics before cultures were taken. This finding emphasizes the importance of judicious use of antibiotics in patients with nonspecific illness.

In addition to the specific attributes of individual bioterrorism agents, multiple considerations will shape the recognition of a bioterrorism-related epidemic. Five of these attributes follow.

Syndromic surveillance would not detect outbreaks too small to trigger statistical alarms. Size would be affected by the virulence of the agent, its potential for person-to-person transmission, the extent and mode of agent dissemination, whether dissemination occurs in more than one time or place, and population vulnerability.

How persons change locations after an exposure will affect whether disease occurs in a concentrated or wide area, and thus whether clustering is apparent to clinicians or detectable through syndromic surveillance at specific sites.

The more knowledgeable providers are about bioterrorism agents, the greater the likelihood of recognition. Routine diagnostic practices or access to reference laboratories may affect the timeliness of diagnosis for some diseases. Familiarity with reporting procedures would increase prompt reporting of suspected or diagnosed cases.

Syndromic surveillance will be affected by the selection of data sources, timeliness of information management, definition of syndrome categories, selection of statistical detection thresholds, availability of resources for followup, recent experience with false alarms, and criteria for initiating investigations.

A fifth key attribute is seasonality. An increase in illness associated with a bioterrorism attack may be more difficult to detect if it occurs during a seasonal upswing in naturally occurring disease.

Agent- and disease-specific attributes may be among the most important factors affecting detection and diagnosis ( Table 2 ). The incubation period and its distribution in the population will affect the rate at which new cases develop[21] and thus how quickly an alarm threshold is exceeded or whether clinicians recognize a temporal and geographic cluster. If a disease has a short prodrome, the chance is increased that a patient would be hospitalized and a definitive evaluation initiated before an increase in cases triggered a surveillance alarm. Alternatively, if a disease has a relatively long prodrome, chances are greater that prediagnostic events (e.g., purchase of medications or use of outpatient care for nonspecific complaints) would accrue to levels that exceed syndromic surveillance thresholds, before definitive diagnostic evaluations are completed among patients with more severe disease. Arousing clinical suspicion for a particular diagnosis will depend on the specificity of both the early and late stages of illness as well as the presence or absence of a typical feature that should alert clinicians to the diagnosis, such as mediastinal widening in inhalational anthrax.[12] If a routinely performed test is apt to be diagnostic in a short time (e.g., the blood culture in anthrax), a rapid diagnosis is likely, even in the absence of clinical suspicion. If routine tests are unlikely to yield a rapid diagnosis (e.g., the blood culture for the cause of tularemia, Francisella tularensis[22]), or if the diagnosis requires a special test (e.g., the hemorrhagic fever viruses[23]), a diagnosis may be delayed if not immediately considered.

The public health benefit resulting from early detection of an epidemic is likely to vary by disease. If a disease has a relatively wide distribution of potential onsets, early recognition provides greater opportunity to administer prophylaxis to exposed persons. For example, based on data from the Sverdlovsk incident,[24] Brookmeyer and Blades estimated that use of antibiotic prophylaxis during the 2001 anthrax outbreak prevented nine cases of inhalational disease among exposed persons.[25] If the incubation period of a disease has a relatively narrow distribution, early recognition may offer little opportunity for postexposure prophylaxis, although a potential benefit would remain for alerting healthcare providers and informing their care of others with similar symptoms. This pattern of illness is apt to result from exposure to an F. tularensis aerosol, which would likely result in an explosive epidemic with an abrupt onset and limited duration.[22]


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