When a death defies explanation

A method for flagging mysterious illnesses may be a useful tool in the battle against bioterrorism.

Even before last fall’s anthrax attacks, physicians and public health experts worried about the nation’s ability to identify and respond to outbreaks of infectious disease. In response to a 1992 report from the Institute of Medicine, the Centers for Disease Control and Prevention (CDC) had begun a surveillance strategy to detect new and unrecognized infectious diseases.

The project, called Surveillance for Unexplained Deaths and Critical Illnesses Due to Possibly Infectious Causes, grew out of two observations: new infectious diseases in this country were breaking out long before they were recognized, and the development of new molecular probes allowed infectious agents to be identified and characterized.

In 1995 the CDC, with partners at Yale and Stanford universities and in San Francisco, Minneapolis and Portland, Ore., began a population-based surveillance using diagnostic tests, death records and hospital discharge records to identify cases that would bear the label UNEX (for unexplained deaths and critical illnesses due to possibly infectious etiologies.) Preliminary results were published earlier this year in the journal Emerging Infectious Diseases.

“We found that in a population of 7.7 million, about 40 people are dying or becoming sick from unexplained illnesses each year,” said Andre N. Sofair, M.D., M.P.H., HS ’90, assistant professor of medicine and one of the authors of the study. “While this number might seem small, it is rather significant when it is put into perspective. Each year, in a well-served population, there are many young people who become critically ill or die without a diagnosis.”

The study, which is continuing, examined unexplained critical illnesses and deaths among people between the ages of 1 and 49 in the San Francisco Bay area, the state of Minnesota and New Haven County in Connecticut. It also looked for cases among people between the ages of 1 and 39 in Oregon. A UNEX case was defined as a previously healthy person who died or was hospitalized in an intensive care unit with a life-threatening illness bearing the hallmarks of an infectious disease for which no cause was identified. The study examined tissue or blood samples from 122 patients who died or became ill for unexplained reasons. The researchers divided patients into syndrome categories that represented their illness, such as a disease of lung or liver, and samples were tested accordingly, with each sample undergoing an average of 28 tests. No new infectious agents were discovered, but the cause of illness was determined in 28 percent of the patients tested.

This pilot study yielded numerous lessons, according to the authors. Future surveillance for UNEX, they found, could benefit from simplified case-finding methods, better quality of specimens and a more focused surveillance of specific syndromes. The authors believe their surveillance approaches will strengthen collaborations among clinicians, laboratory technicians and public health professionals and result in better detection of unexplained deaths and critical illnesses and better monitoring of emerging infectious diseases. “These preliminary findings are being used to direct programs to assist in bioterrorism preparedness and outbreak investigation,” said Sofair. “Having more sophisticated diagnostic testing would be helpful in finding a cause of death or illness.”

A tool for predicting mortality among older patients, across populations

Any one of 10 conditions—ranging from congestive heart failure to major stroke to diabetes—suggests that geriatric patients run a higher risk of dying within a year of being hospitalized, according to a Yale geriatrician. The list of conditions, said Sharon Inouye, M.D., associate professor of medicine and geriatrics, is not for application to individual cases. Instead, it should be used to make outcomes analysis uniform and to foster appropriate programs and policies for an aging population.

“It’s important to be able to compare how sick people are across populations, across hospitals and across studies,” said Inouye, senior author of the study published in March in the Journal of the American Geriatrics Society. Lead author Mayur Desai, Ph.D., working with Inouye and her colleagues, wanted to develop a risk assessment tool that would be easy to use without extensive physicals or detailed chart reviews and which would take into account the high burden of illness among the elderly. “We wanted to come up with a system that is based on administrative data that are readily available, identifies high-risk diagnoses and indicates which segments of the population are at a high risk for mortality. We’re hoping this will be useful to people who do research with older patients or develop new systems to care for older patients.”

Inouye and colleagues found that elderly patients with any of 10 conditions were at higher risk of dying within a year of being hospitalized. In descending order of risk, the conditions are congestive heart failure, pneumonia, chronic lung disease, solid tumor cancer that is localized, metastatic cancer, lymphoma/leukemia, major stroke, acute renal failure, chronic renal failure and diabetes with end-stage organ damage. This system is unique in being developed specifically for use with older persons, based on readily available hospital data.

“Given the potential for misuse or misinterpretation we do not advocate use of this index at the bedside for individual patients,” Inouye said. “The index is recommended for mortality prediction in patient groups or populations.”

A better take on beta blockers

A Yale study has debunked the myth that beta blockers—prescribed following a heart attack to guard against future episodes—commonly cause depression, fatigue and sexual dysfunction. Harlan M. Krumholz, M.D., senior author of a July paper in JAMA, found that there had been no systematic review of the alleged association and reviewed 15 clinical trials involving more than 35,000 patients. “We found no clear evidence that the use of beta blockers causes depression,” Krumholz said. There was a slight association with fatigue and sexual dysfunction, but Krumholz also found those symptoms among study subjects taking placebo. His conclusion? More patients than are now receiving the medication stand to benefit.

The kidneys and renal arteries are clearly visible in this spiral computed tomography image of the anatomy of a kidney donor. The donor decided to have his kidney removed using a minimally invasive procedure that is less painful and has a shorter recovery period than open surgery.

An easier operation for kidney donors, laparoscopy still carries a risk

When potential kidney donors meet transplant surgeons Marc I. Lorber, M.D., and Amy L. Friedman, M.D., many have already read on the Internet that laparoscopic nephrectomy is easier on the donor than the conventional open surgery. But according to Friedman and Lorber, the choice is seldom clear-cut. Among the 37 donors who chose to give a kidney at Yale during the first 11 months the advanced procedure was offered here (starting in June 2001), only eight chose the new approach.

The donors’ sophistication poses a challenge to Lorber and Friedman. True, laparoscopic nephrectomy offers advantages to people who wish to give a healthy kidney to a relative or friend in need. The technique minimizes scarring because the surgery is done through smaller incisions, including one for a tiny camera that surgeons use to watch their work on a monitor. Laparoscopy can speed recovery and reduce pain. But the technique may also pose risks, including an increased chance of damage to the intestines and spleen, intra-abdominal scarring and, rarely, bleeding. Whether it’s the best choice depends partly on the anatomy of the donor and partly on the donor’s decision regarding risks and benefits, according to Friedman, who performs laparoscopic nephrectomies with urologic surgeon Kevin R. Anderson, M.D.

Although laparoscopy may attract new donors, it won’t resolve the overwhelming kidney shortage. With 52,000 Americans waiting for kidneys—including 434 on Yale’s list—the rate of 14,000 transplants per year falls short. Last year, 2,800 Americans died awaiting kidneys. At Yale and nationwide, most kidneys come from people who are brain-dead following a stroke or trauma (including 25 of 62 kidneys transplanted at Yale from June 2001 through April 2002). Yet only about half of Americans consent to donate the kidneys of a relative who dies.

The pressing issue, says Friedman, is not which type of surgery donors should choose. “The real problem is that we have all these patients who should be helped with a transplant, and we don’t have kidneys for them.”

A new tool for autism treatment

Risperidone, an antipsychotic drug, has proven effective for the treatment of behavioral problems in autistic children, according to a Yale study published in July in The New England Journal of Medicine. The clinical trial targeted not the core symptoms of autism, including impaired relations with others and delayed language, but related problems such as self-injury, aggression and tantrums, said Lawrence D. Scahill, M.S.N., M.P.H. ’89, Ph.D. ’97, an associate professor at the Yale Child Study Center and lead author of the study. More than two-thirds of the children randomly assigned to risperidone showed a positive response, compared with 12 percent in the placebo group. No previous study on autism has shown this large a treatment effect.

Scientist sees a connection between endometriosis and tampon use, orgasm

Tampons and sex appear to protect women from endometriosis, a painful condition that afflicts about 10 million American women and can cause infertility, according to research by a Yale physician.

The finding came as the result of a study exploring whether sexual behaviors, orgasm, tampon use and douching during menstruation modified the risk of endometriosis. “To our surprise, sexual behavior, orgasm and tampon use during menstruation were found to be less frequent among women with endometriosis compared to controls,” said Harvey J. Kliman, M.D., Ph.D., a research scientist in the Department of Obstetrics and Gynecology and lead author of the study published in the June issue of Gynecological and Obstetric Investigation. “It may be that uterine contractions that are part of the female orgasm induce more effective menstrual-fluid clearance of the uterine cavity, which in turn may facilitate cervical outflow. Further, the use of tampons may be more efficient at the removal of menstrual fluid compared to the use of pads.”

Women with endometriosis have endometrial tissue, which normally grows only in the uterus and is shed during menstruation, growing on the Fallopian tubes, ovaries, other sites in the pelvis or, in rare cases, outside the pelvic area. It is typically found in women who are childless or who have children later in life.

The study has provoked some controversy. “To state that women aren’t getting endo because they’re having sex—when it’s just as likely that they are not having sex because they are experiencing the pain of endo—is jumping to conclusions,” the Endometriosis Association stated on its website. Kliman claims that objections to his conclusions are related to a long-held belief that dioxin in tampons is the real culprit but, he said, “our study refutes this.”

According to Kliman, a backup of menstrual fluid in the pelvic cavity is believed to play a prominent role in the pathogenesis of endometriosis. At the start of his research Kliman held to the conventional wisdom that tampon use, douching and sexual activity, especially with orgasm, at the time of menstruation would heighten the chances of developing endometriosis. Instead, he found that douching did not appear to lessen the risk of endometriosis, but sexual activity, orgasm and tampon use did.

“Our study has an important public health message for women, especially at a time when many women seeking infertility care have endometriosis as their primary diagnosis,” said Kliman. “Our study suggests that tampon use could be one of the strongest protectors against endometriosis.”

Et Cetera

Old drug, new treatment

A postoperative pain reliever has a new role in the delivery room, according to a study by Yale doctors. When diluted, the drug hydromorphone, also known as Dilaudid, provides pain relief during labor and reduces the need for localized numbing agents, according to Raymond S. Sinatra, M.D., Ph.D., professor of anesthesiology and lead author of a study published in the May issue of the journal Anesthesia & Analgesia. “By decreasing the amount of local anesthetics in the epidural, women are able to push more vigorously and can actually feel the baby being born without feeling pain,” Sinatra said. On the basis of these findings, and clinical experience gained over several years, “hydromorphone is the epidural opioid of choice for labor and delivery analgesia at our institution,” said Sinatra.

Employment and well-being

Being out of a job increases one’s chances of dying, according to a Yale scientist. “Employment is the essential element of social status and it establishes a person as a contributing member of society,” said M. Harvey Brenner, Ph.D., a visiting professor in the Global Health Division at the Department of Epidemiology and Public Health. “Employment also has important implications for self-esteem. When that is taken away, people become susceptible to depression, cardiovascular disease, AIDS and many other illnesses that increase mortality.”

Brenner’s study found that mortality rose when unemployment rose and declined when unemployment declined. Low levels of unemployment also led to an increased community sense of well-being. The results of the study, the largest of its kind on mortality patterns in Europe and the United States, were presented to members of the European Parliament in May. The European Union commissioned the study to give a human context to unemployment rates over the last 10 to 55 years in 16 countries.


			Originally published in Yale Medicine, Autumn 2002. Copyright © 2002 Yale University School of Medicine. All rights reserved.