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clues

from the inexplicably dead

BY MITCH LESLIE

A SUCCESSOR TO AIDS COULD ALREADY BE SIMMERING UNDETECTED IN THE UNITED STATES, QUIETLY CLAIMING A VICTIM HERE AND A VICTIM THERE. * If unrecognized infectious diseases are lurking in this country, David Relman, MD, hopes to flush them into the open with the tools of molecular biology. Relman, an assistant professor of medicine and of microbiology and immunology, is one of only a few academic researchers participating in the Unexplained Illnesses and Deaths Surveillance project, a pilot program to identify new pathogens by investigating mysterious deaths.

Begun four years ago, the project is part of the Centers for Disease Control and Prevention's worldwide Emerging Infectious Diseases program, which aims to identify disease outbreaks and, if possible, stamp them out before they grow into epidemics.

The good news is that, so far, the unexplained deaths project has found no new pathogens skulking in the corners of America. The bad news is that many of the more than 100 cases the group has investigated remain unsolved.

Recent history provides the rationale for the project, Relman says. The appearance of new, deadly illnesses like AIDS, as well as the resurgence of old killers elsewhere in the world like malaria and diphtheria, rattled the medical and public health communities, which had grown complacent to the threat from infectious disease.

Yet retrospective analyses showed that many of these "new" diseases had actually been killing on a small scale for decades. Consider AIDS. By testing stored tissues of patients who died from unknown causes, scientists know that AIDS was abroad in Europe in the mid-1960s,15 years before the disease was formally described. Legionnaire's disease, which seemed to burst on the scene by killing 29 people during the 1976 American Legion convention in Philadelphia, was not new either. Outbreaks of pneumonia attributed to Legionella pneumophila, the microbe responsible, have been traced as far back as 1947.

Epidemiologists don't want to get caught flat-footed again. They want to catch the next new disease before it becomes a major killer. In hope of nabbing vital early cases, the unexplained deaths project takes a two-pronged approach, combining epidemiological surveillance with thorough laboratory investigations of undiagnosed illnesses and unsolved deaths.

Given the advances in diagnostic technology, the number of mystery cases is surprisingly high. By crude estimates, nearly 3,000 Americans die each year from unidentified infectious diseases, Relman says. In most cases, run-of-the-mill microbes are probably responsible. But new and deadly diseases could be lurking among them.

"We are looking for deaths that were unexpected -- for people who died but shouldn't have died," Relman says. More specifically, the investigators are seeking cases in which previously healthy people between the ages of 1 and 49 became critically ill or perished from what appears to be an infectious disease. To qualify, a case must also meet another criterion: negative results from the usual battery of laboratory tests.

To keep the amount of work manageable, the search is initially focusing on only two states -- Minnesota and Oregon -- along with the city and county of New Haven, Conn., and the San Francisco Bay Area counties of Alameda, Contra Costa and San Francisco. These areas were selectedbecause they already had set up particularly strong epidemiology groups for the Emerging Infectious Disease program. Public health officials and clinicians in each area keep an eye out for suspicious cases and forward the files -- along with blood or other clinical samples that could be screened for microbial fingerprints -- to relevant state health departments and to the CDC.

If the case meets the project's criteria after further review, samples are parceled out to particular labs for analysis. Relman's lab gets samples from patients with the hallmarks of bacterial infection. He and his colleagues use the polymerase chain reaction to make multiple copies of any bacterial genetic material in the sample. To determine whether a new pathogen is present, the researchers can then sequence the organism's genes and compare them with the sequences from known pathogens.

To date, every solved case has involved an already-known microbe that had eluded conventional detection methods, Relman says.

The project's success depends on the quality of information and clinical specimens forwarded by the doctors. We know about the early AIDS patients, for instance, only because some doctors had the foresight to preserve tissues from enigmatic cases, hoping that future medical technology might someday solve the mystery.

But although the project has gotten the word out to anyone who might see a mystery illness -- ICU managers, emergency room staff, residents -- Relman and his colleagues suspect a certain amount of reluctance to cooperate among doctors.

SEVERAL REASONS MAY lie behind this reluctance, Relman speculates. Doctors may not have the time to do the work involved in reporting a case, or the existence of the project may just slip their minds during hectic emergency-room situations. Some doctors may be concerned that the project means greater governmental intrusion into medicine. And some may be unwilling to comply because they are loath to confront their own failures of diagnosis. If the cause of death turns out to be an ordinary and treatable pathogen that was simply overlooked, the doctor might believe he or she could be inviting a malpractice suit.

A new pathogen could be lurking among the project's file of unsolved cases. But, as Relman points out, some rather ordinary obstacles to diagnosis often keep a case from being solved. There may be no clinical specimens from the case, or the specimens may have been taken from the wrong part of the body to allow identification of the pathogen. The cause of death might not be an infectious disease. Microbial toxins, for which we lack good identification methods, may be responsible. Or our diagnostic methods may not be sensitive enough.

In fact, improved diagnosis may be the most tangible result of the project. Even if no new diseases turn up, Relman says that the project is serving as a testing ground for new diagnostic techniques. Some of these are being developed here at Stanford, including cell biosensors to detect microbial toxins and new methods detecting microbes using high-density DNA microarrays. SM