COLUMN ONE : Tracking Disease the Old Way : Physicians use detective work, instinct and some incredible luck. Recall of tryptophan products is the result.
SANTA FE, N.M. — Over the summer, the 37-year-old woman had been sail boarding and winning tennis tournaments. Then she began to experience insidious pains in the temples and jaws. Later the pain spread throughout her body. It became so intense that “it hurt to put my sunglasses on,” she recalled.
Her doctors had found extremely high numbers of the uncommon white blood cell known as the eosinophil in her blood stream. But despite an exhaustive medical workup, including exploratory abdominal surgery, they “were completely baffled.”
When Dr. William Blevins, a Taos oncologist, reviewed the case at St. Vincent Hospital in late October, he was struck by a tantalizing clue: From July until September, the woman had taken supplements of the essential amino acid L-tryptophan each night to help her sleep.
At the same time, a 44-year-old Los Alamos housewife and a 37-year-old Santa Fe restaurant hostess were seeking medical treatment for severe muscle pains. They too had been taking tryptophan pills for insomnia and were found to have strikingly high eosinophil counts.
Within days, Blevins and three other physicians--a medical school classmate who was treating the Los Alamos housewife, a rheumatologist who was consulting on two of the three cases, and a Mayo Clinic immunologist who is a leading authority on eosinophils--had made the connection between preparations of the amino acid and a potentially fatal condition, now known as the eosinophilia-myalgia syndrome.
Physicians increasingly rely on complex technology and testing procedures to diagnose disease. But the eosinophilia-myalgia syndrome illustrates how some clinical advances are still made the old-fashioned way--by talking to patients and carefully piecing together their histories. Like many medical discoveries, this one combined instinct, detective work, and some incredible strokes of luck.
As of Nov. 22, there had been 427 reported cases nationwide of the previously unrecognized disorder, including 69 in California, and two confirmed deaths, according to the Centers for Disease Control. About a third of the first 85 reported patients have been hospitalized.
The U.S. Food and Drug Administration has ordered a recall of products in which tryptophan is the sole or major component, and several states, including California, have banned tryptophan sales. The public has been warned not to take tryptophan capsules or tablets until it is determined if the amino acid itself, a chemical or microbiological impurity, or perhaps a predisposition for some individuals to develop the disorder is to blame for the epidemic.
Medical progress, such as the discovery of the AIDS virus or the tick-borne bacterium that causes Lyme disease, often results from exhaustive epidemiological and laboratory research. But these developments were possible because connections were made between puzzling patients--the gay men in Los Angeles in 1981 with the unusual lung infections or the cluster of children with rashes and arthritis in the region of Lyme, Conn., in 1975.
On the other hand, many apparent clusters of illnesses, such as cancers, turn out to be coincidences and not true associations. As a result, sometimes potential clues to new knowledge are prematurely dismissed as “red herrings,” while in other instances, physicians or the public cling to discredited relationships.
In New Mexico, “it was clear at the outset that something unusual was going on,” said Dr. Phillip Hertzman, the Los Alamos family practitioner. “But I think it was luck that we talked to each other.” Otherwise, Hertzman said the connection might have gone unrecognized for “months.”
“I have been in this game a while and when I see lightning strike once, I get a little suspicious, twice, more suspicious, and three times, we better take it very seriously,” said Dr. Gerald J. Gleich, the Mayo Clinic immunologist who discussed the cases by telephone with the New Mexico doctors and first notified New Mexico and federal health officials of the illness cluster.
The majority of cases have been in women, who appear more likely to take tryptophan-containing products than men. Because some estimate that tens of thousands to hundreds of thousands of people may be using the supplements, health officials expect many more cases to develop.
Tryptophan supplements have been increasingly used during the 1980s, not only for insomnia and premenstrual syndrome, but also for depression and stress reduction, attention deficits in children, and weight loss.
Most of the illnesses seem to have developed since July, although there have been sporadic reports of problems that began earlier. Some patients had only taken tryptophan for a matter of weeks before they became ill; others had taken it for several years.
“The problem has probably been going on at a low-grade level and for some reason spurted this summer,” said Dr. Henry Falk, director of the CDC’s environmental hazards and health effects division. Recent studies in New Mexico, Minnesota and Oregon “appear to have very strongly linked the actual taking of these tablets and capsules with the disease.”
Amino acids are the building blocks of proteins. Tryptophan is one of the essential amino acids that is a necessary part of the diet because it cannot be synthesized by humans.
In adults, the average daily dietary intake of tryptophan is slightly more than one gram (0.04 ounces). The amino acid is contained in proteins found in meat, eggs, dairy products and other foods. The syndrome has developed in people who were taking from as little as 200 milligrams of tryptophan supplements daily to as much as 18 grams a day, according to Falk. The average amount has been about two grams.
Many researchers are suspicious that some form of contamination will eventually be identified, perhaps involving one of a handful of Japanese companies that make virtually all of the tryptophan contained in products that have been sold in the United States or some of the many American companies that repackage and distribute the products.
Of the tryptophan users who have become sick, a few--like the Santa Fe woman who was hospitalized--have been more seriously ill than others. Some “basically have sore flesh” while others “have serious organ damage,” according to Dr. Joseph Duffy, a consultant in rheumatology at the Mayo Clinic in Rochester, Minn., where about a dozen patients with the syndrome have been treated.
All the patients, however, appear to share common features--high eosinophil counts and marked muscle inflammation caused by an invasion of muscle tissue by eosinophils. Other causes of high eosinophil counts, such as parasite infections or tumors, have been excluded.
The sicker patients include those whose nerves, skin, or heart muscle have been afflicted, Duffy said. One Mayo Clinic patient with severe impairment of her breathing muscles has been on a respirator for more than 10 days. A patient who died in New York had such severe nerve and muscle damage that she became a quadriplegic, and eventually her heart stopped beating.
The severe cases of the illness resemble “toxic-oil syndrome,” a disease that was epidemic in Spain in 1981. Toxic-oil syndrome was caused by a denatured cooking oil that was sold for food use, although it was intended for industrial use. Nearly 20,000 cases and 315 deaths were reported over a one-year period.
Some patients seem to improve when they discontinue tryptophan and are prescribed high doses of steroids, which are powerful anti-inflammatory medications. But Duffy cautioned that many of the sickest patients have not had a “dramatic response” to steroid therapy and those that improve may relapse if the dose is reduced. The long-term prognosis of the syndrome and its biological mechanism are not known.
This illness can “potentially be fatal in extreme cases,” said Hertzman of Los Alamos. “Hopefully, if you catch it early it can be reversed.”
While the three northern New Mexico women may not have been the first to become ill, in the lexicon of disease investigators, they are the “index” cases that allowed other cases of eosinophilia-myalgia syndrome to be quickly identified.
The first case involved a woman who always had been healthy and athletic until she developed the debilitating muscle ailment.
After she was hospitalized in Santa Fe in early October, her condition deteriorated and her abdomen and lungs filled with fluid. Her doctors thought she might have some rare southwestern fungus, an exotic parasite, Lyme disease or perhaps leukemia, she recalled in an interview last week.
On Oct. 25, the woman’s physician went on vacation and turned her care over to Blevins, the Taos oncologist. Just the day before, he had been thinking about tryptophan because a physician had recommended it to his wife for premenstrual syndrome and he had read the pamphlet that she brought home.
When Blevins reviewed the perplexing case, “he immediately hit on it” and “decided it was an interesting thing to pursue,” the woman said.
Blevins said: “I spent a lot of time with her. Every test had turned out negative, she had even had surgery and there was no explanation. So it was one clue that maybe drugs (were involved). . . . I kind of suspected it but I didn’t know, I didn’t have another case.”
But Blevins was concerned enough that he called his wife and said “don’t take the L-tryptophan. There is a case at the hospital which has this bizarre allergic phenomenon and I presume it is the drug.”
The next day, Hertzman referred his patient to Dr. James W. Mayer, a Santa Fe rheumatologist. Over the course of a month, the housewife had developed incapacitating muscle aches, mouth ulcers and severe fatigue and was “feeling worse and worse,” Hertzman recalled.
Mayer, it turned out, was also consulting on Blevins’ patient. Immediately, he noticed “the possibility of similarities.” Mayer telephoned both Blevins and Hertzman, telling them that “we have another patient who is also on L-tryptophan, maybe something is going on.”
Hertzman immediately telephoned Blevins, a medical school classmate whom he had not talked to in six years. Soon the three physicians were reviewing the situation with the Mayo Clinic’s Gleich, whose advice had been sought earlier in October by the physician Blevins was covering for.
The third case was identified when Blevins received a call on Oct. 30 from the Women’s Health Clinic in Santa Fe about a restaurant hostess with severe muscle pains and high numbers of eosinophils.
“I said is this patient on L-tryptophan?” Blevins recalled.
The answer was “Yes, she is. I immediately called Gleich.”
Gleich knew that very few eosinophilia cases would remain unexplained after the detailed evaluation that the first two patients had received. He “was already getting excited when he heard that there were two cases within 30 miles before anybody ever said a word about L-tryptophan,” Hertzman said. “And then there was a third case within three days and he was off the wall. He was calling five times a day.”
Still another case was identified the next day when Blevins was discussing eosinophilia over coffee in the doctor’s lounge at the hospital. “(An infectious disease specialist) overheard me and said, ‘I’ve got a case,’ ” Blevins said. “It was this networking, this collaboration.”
On Nov. 3, New Mexico health officials sent a computer message to other states alerting them to look for cases. On Nov. 7, the Albuquerque Journal ran a front-page story on the illness cluster.
Case reports soon began to flow in from across the state and across the country. Judy Kody Paulsen, an athletic 38-year-old Albuquerque woman with a similar problem, was on her way to the Mayo Clinic to see Duffy. After reading the paper, she packed her tryptophan tablets and called Duffy and Gleich from the airport.
Within days, it became clear that what appeared at first to be a northern New Mexico curiosity was in fact a national public health emergency. “We were beginning to collect patients daily,” Duffy said. It was “astonishing when they kept saying, yes, yes, yes (when asked about tryptophan use). We never expected that. It just had to be a cause/effect relationship.”
Researchers do not know how to explain isolated but apparently similar cases that have cropped up in previous years. One example is a 1986 case involving a woman taking “numerous self-prescribed vitamin and mineral supplements” that Duffy and two colleagues described in a January, 1988, article in the Mayo Clinic Proceedings.
At the time, the Mayo Clinic physicians had no specific reason to ask the woman specifically about tryptophan use. But when Duffy telephoned her earlier this month, he found out that she had been “on it for years” and was continuing to “do poorly.” Asked if he thought tryptophan products were to blame for the patient’s years of illness, Duffy said, “I would believe so.”
The three “index” New Mexico patients are all much improved. The patient who was hospitalized stopped taking tryptophan supplements before entering the hospital and her doctors started her on steroid therapy before they suspected the association with the amino acid product.
The fluid in her abdomen and lungs has disappeared and she is “getting stronger every day.” But she is apprehensive about the future. Physicians “don’t know whether this will turn itself off or whether I will relapse,” she said. “We really don’t know what will happen next.”
WHAT ARE EOSINOPHILS? Eosinophils, a type of white blood cell, are part of the body’s immune system. The cells are so named because of their marked affinity for the rose-colored stain called “eosin,” making them appear pink under the microscope.
Eosinophils play an important role in defense against infection, because they can kill many types of microscopic parasites and worms. On the other hand, in a variety of illnesses, including asthma, some skin ailments and some heart diseases, the cells release toxic proteins that may damage tissues.
“The eosinophil is a kamikaze cell,” said Dr. Gerald J. Gleich of the Mayo Clinic. “When it goes into tissue, it loses its (cellular) identity and blows up,” dispersing the highly toxic proteins.
This appears to be how disease is caused in the eosinophilia-myalgia syndrome. But researchers don’t understand why the body makes more eosinophils, and why they in turn attack the muscles and other tissues.
Eosinophilia is the medical name for conditions characterized by an elevated number of eosinophils in the blood stream. The list of such conditions is very long. It includes allergies, asthma, parasitic diseases, other infections, rheumatologic diseases, and tumors.
Normal eosinophil counts range from 50 to 350 cells per cubic millimeter, or just a few percent of all white blood cells in the circulation. By comparison, some of the patients with the eosinophilia-myalgia syndrome have had counts of 10,000 cells per cubic millimeter or more, or more than 50% of all white blood cells in their circulation.
