NEW ORLEANS - A surveillance effort by the Center for Disease Control and Prevention (CDC), the Unexplained Deaths and Critical Illnesses project, is trying to characterize severe illnesses and deaths from unknown infections. The project is collaborating medical reports and new technologies to identify organisms that cause these diseases, which represent "a substantial and surprising burden," said an investigator.
Bradley Perkins, MD, chief of the Meningitis and Special Pathogens Branch in the Division of Bacterial and Mycotic Diseases, National Center for Infectious Diseases, CDC, Atlanta, said the effort started in 1995 "to identify and build capacity for detection of new infectious diseases, to identify poorly recognized known infectious diseases and to define the burden of unexplained critical illness and death."
Speaking here at the Infectious Diseases Society of America 38th Annual Meeting, Perkins said, "This is a pilot effort to try to systematically recognize new infectious diseases earlier than they have been in the past, but I think there's considerable value to this effort beyond that single goal."
Perkins said the project is founded on two infectious disease revolutions. First is the changing world view of infectious diseases, from one where diseases could be controlled by vaccines and antibiotics to a recognition that diseases' ever-changing nature requires "a continuous, high-level health public health effort to be prepared for earlier protection of diseases like hepatitis C and HIV."
Second, he said, improvements in molecular techniques now provide tools to identify infectious agents without the burden of in vitro cultivation. A publication from 1990 showed the kind of progress in molecular technology, one particularly relevant to this project, Perkins said, where uncultured pathogens could be identified by polymerase chain reaction (PCR) primer codes, allowing phylogenetic classification of sequences and identification of new organisms. Citing another article, Perkins said these molecular methods "fire up the hunt" for emerging pathogens, combining an early warning system with genetic techniques.
Investigators in the Unexplained Deaths and Critical Illnesses project started with a case definition, Perkins said. In a population-based manner, they tried to identify previously healthy people, 1 to 49 years old, who had a life-threatening illness, probably from an infectious disease, but no etiology was identified. For case findings, they used physicians, infection control practitioners, intensive care unit nurses and death certificates. All clinical specimens were saved and banked.
The surveillance populations were four CDC Emerging Infections Program (EIP) sites, with 7.8 million children and adults. In the project's first 3 1/2 years, 526 cases were reported and 137 were enrolled, for an annual rate of 0.5 per 100,000 people. There were 41 deaths, a case fatality rate of 30%. Autopsies were performed in 73% of the deaths, well above the national average.
"This represents a substantial and surprising burden," Perkins said, "and if this rate were extrapolated to the rest of the United States, this would describe about 2,000 previously healthy 1-to-49 year olds who became critically ill with an unexplained infectious disease, 640 of whom would die from that unexplained presumed infectious disease."
Among the 389 excluded patients, 34% had an underlying condition, 25% had an etiology identified after inclusion in the project and 17% were not residents of surveillance area.
The most common clinical syndromes were respiratory (30%), central nervous system (meningitis, encephalitis) (29%) and cardiac (myocarditis, pericarditis) (16%). The case-fatality rate of those with neurologic syndromes was 18%; it was 46% in those with cardiac syndromes.
To help organize the results, Perkins said, the investigators needed a new classification system to show whether a patient's etiology was explained or unexplained after extensive laboratory testing. The divided all laboratory test results into those providing direct evidence of disease causation, providing indirect evidence and that give a possible etiology but were not linked to causation.
Of the 137 enrolled cases, clinical specimens in 122 were tested extensively. "It's astonishing that such a low proportion of those cases were able to be subsequently defined: only 34 of the 122 cases," he said. "Almost 80% remain unexplained, and with only nine of those did we have any possible idea what was going on."
Perkins said they learned a number of important lessons. First, the initial system had a complex case-finding methodology that was quite challenging to the state department and other partners. Second, they weren't getting the degree of collaboration "we thought was optimal among clinicians, pathologists and public health professionals at the local level." Third, they weren't getting the quality clinical specimens; and, finally, they needed a more systematic way to evaluate diagnostic technologies.
As a result, he said they have "re-engineered this project as a family of projects." One is a core population-based surveillance for deaths from known infections and possible infectious causes among children and young adults. This project allows investigators to develop networks around particular syndromes. Another is an encephalitis project started two years ago.
While Perkins thinks "substantial progress" has been made in creating a capacity to detect these pathogens, he said it is important to continue to seek better diagnostic technologies as well as to continue to create networks of syndrome-based investigators.
For more information:
- Perkins, B. Can surveillance for unexplained deaths and critical illnesses be used as a public health approach for early recognition of new pathogens. Session 65: Emerging Pathogens. Presented at the Infectious Diseases Society of America 38th Annual Meeting. September 7-10. New Orleans.
- The Unexplained Deaths & Critical Illnesses project Web site: http://www.cdc.gov/ncidod/dbmd/diseaseinfo/unexplaineddeaths_t.htm.
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