The librarian returned to Dr. Wooten's table with the other references. Both were contributions to the New England Journal of Medicine. One was entitled "Skin Changes of Nutritional Origin," and had been written by Harold Jeghers, an associate professor of medicine at the Boston University School of Medicine, in 1943. The other was the work of three faculty members of the Harvard Medical School—Peter Reich, Harry Shwachman, and John M. Craig—and was entitled "Lycopenemia: A Variant of Carotenemia." It had appeared in 1960. Dr. Wooten looked first at "Skin Changes of Nutritional Origin." It was a comprehensive survey, and it read, in part:
The carotenoid group of pigments color the serum and fix themselves to the fat of the dermis and subcutaneous tissues, to which they impart the yellow tint. . . . Edwards and Duntley showed by means of spectrophotometric analysis of skin color in human beings that carotene is present in every normal skin and is one of the five basic pigments that determine the skin color of every living person. Clinically, therefore, carotenemia refers to the presence of an excess over normal of carotene in the skin and serum. ... In most cases carotenemia results simply from excess use of foods rich in the carotenoid pigments. Individuals probably vary in the ease with which carotenemia develops, which is evidenced by the fact that many vegetarians do not develop it. It is said to develop more readily in those who sweat profusely. Except for the yellow color produced, it appears to be harmless, even though present for months. It eventually disappears over several weeks to months when the carotene consumption is reduced.
Dr. Wooten moved on to the third report. ("This investigation concerns a middle-aged woman whose prolonged and excessive consumption of tomato juice led to the discoloration of her skin.") He read it slowly through from beginning to end, and then turned back and reread certain passages:
Although carotenemia due to the ingestion of foods containing a high concentration of beta carotene is a commonly described disorder, a similar condition secondary to the ingestion of tomatoes and associated with high serum levels of lycopene has not previously been reported. . . . Lycopene is a common carotenoid pigment widely distributed through nature. It is most familiar as the red pigment of tomatoes, but has been detected in many animals and vegetables. ... It is also frequently found in human serum and liver, especially when tomatoes are eaten. But lycopene is not well known medically because, unlike beta carotene, it is physiologically inert and has not been involved in any form of illness.
Dr. Wooten closed the volume. Turner was not only a heavy eater of carrots. He was also a heavy drinker of tomato juice. Carrots are rich in carotene and tomatoes are rich in lycopene. Carotene is a yellow pigment and lycopene is red. And yellow and red make orange.
Dr. Wooten completed his record of the case with a double diagnosis: pseudocyst of the pancreas and carotenemia- lycopenemia. The results of the X-ray examination of Turner's colon were normal ("Terminal ileum was visualized. No pathology was demonstrated in the colon"), and the carotene test showed a high concentration of serum carotenoids (495 micrometers per hundred milliliters, compared to a normal concentration of 50 to 350 micrometers per hundred milliliters). The diagnosis of lycopenemia was made from the clinical evidence. Turner was discharged from the hospital on December 17. His instructions were to avoid abdominal blows, carrots (and other yellow vegetables), and tomatoes in any form. Four months later, on April 16, 1961, he reported to Dr. Wooten that his skin had recovered its normal ruddiness. Two years later, in 1963, he returned again to Memphis and dropped in on Dr. Wooten for a visit. His abdominal symptoms had long since disappeared, and a comprehensive examination showed no sign of the pseudocyst.
Elmo Turner was the first recorded victim of the condition known as carotenemia-lycopenemia. He is not, however, the only one now on record. Another victim turned up in 1964. She was a woman of thirty-five, a resident of Memphis, and a patient of Dr. Wooten's. He had been treating her for a mild diabetes since 1962, and had put her at that time on the eighteen-hundred-calorie diet recommended by the American Diabetes Association. She had faithfully followed the diet, but in order to do so had eaten heavily of low-calorie vegetables, and (as she confirmed, with some surprise, when questioned) the vegetables she ate most heavily were carrots and tomatoes. She ate at least two cups of carrots and at least two whole tomatoes every day. Dr. Wooten was unaware of this until she walked into his office one October day in 1964 for her semi-annual consultation. He greeted her as calmly as he could, and asked her to sit down. He would be back in just a moment. He stepped along the hall to Dr. Hughes's office and looked in. Dr. Hughes was alone.
"Have you got a minute, John?" Dr. Wooten said.
"Sure," Dr. Hughes said. "What is it?"
"I'd like you to come into my office," Dr. Wooten said. "I'd like to show you something."
[1967]
CHAPTER 10
The Dead Mosquitoes
Dr. John P. Conrad, Jr., a senior associate in a suburban pediatric group practice in Fresno, California, excused himself to the mother of the young patient in his consultation room and crossed the hall to take a telephone call in his office. The call was a request from a general practitioner on the other side of town named Robert Lanford to refer a patient to Dr. Conrad for immediate hospitalization and treatment. That morning—it was now around four o'clock in the afternoon (on October 4, 1961)—an eight-year- old boy whom I'll call Billy Cordoba had been brought to Dr. Lanford's office by his mother. Billy had been sent home sick from school. He was pale, his eyes had a glassy look, and his heart was a little fast. Dr. Lanford had examined him, found nothing significantly out of order, and sent him home to rest. But Billy was now back in his office, and there was no longer any doubt that he was sick. The manifestations of his illness now included a ghastlier pallor, a glassier look, a notably faster heart, rapid and irregular breathing, muscle twitches, diarrhea, nausea, vomiting, and abdominal pain. He was also confused in mind and almost comatose. Something about this inharmonious symphony of symptoms had prompted Dr. Lanford to make a urine-sugar test, and the results were strongly positive. That suggested a frightening possibility. He was afraid that Billy was a hitherto unsuspected diabetic on the brink of diabetic coma. In any event, he said, the boy was in urgent need of sophisticated help. Dr. Conrad agreed. He told Dr. Lanford that he shared his sense of urgency, and that he would arrange at once for Billy's admittance to Valley Children's Hospital.
Mrs. Cordoba drove her son to the hospital. Billy was admitted there at five o'clock. He was put to bed, and a sample of blood was taken for immediate laboratory analysis to confirm or deny the presence of diabetes. That had been ordered by Dr. Conrad when he made the admittance arrangements. When he himself reached the hospital, at a little before six, the results of the blood studies had been noted on Billy's chart. Dr. Conrad read them with a momentary lift of spirit. The relevant values (blood glucose, blood carbon dioxide, blood sodium, blood potassium, blood pH) were close enough to normal to make it comfortably certain that despite the earlier positive urinalysis the boy was not a diabetic. But that was all. Or practically all; the studies did show a morbid elevation in the white-blood-cell count. Other than that, the studies had no positive diagnostic significance. Dr. Conrad replaced the chart and went into Billy's room to take his first look at his patient. It was anything but reassuring. The boy was clearly sicker than he had been two hours before. Dr. Conrad sat down and began with care the standard physical examination. His findings were even more discordant than those recorded by Dr. Lanford. Billy's pulse was fast, his breathing was fast, his temperature was 100 degrees, his skin was pale and clammy, the pupils of his glassy eyes had shrunk to pinpoints, his face and arms were twitching, he was drooling saliva, and he appeared to be in almost constant abdominal pain. Twice during the short examination the pain was so great that he screamed. He was still confused, still comatose, still nauseated, still diarrheic. Dr. Conrad finished the examination and sorted out his impressions. They led in two distinctly different directions. One possi
bility was shigellosis, or bacillary dysentery The other was chemical poisoning.
"I didn't particularly favor the idea of shigellosis," Dr. Conrail says. "It was simply suggested by some of the clinical evidence- the high white-cell count and the gastrointestinal symptoms. And I didn't favor it at all for very long. A shigella infection produces a rather distinctive kind of damage that can be detected by microscopic examination of a stool specimen. It isn't conclusive, but it's reliable enough to be useful. Well, I asked the laboratory for a report and the answer came back in a matter of minutes. Negative. I wasn't much surprised. Chemical poisoning had always been by far the stronger possibility. The very bizarreness of the symptoms was suggestive of poison. Certain particular symptoms were even more suggestive. Stupor. Abdominal pain. Salivation. But the real tipoff was those pinpoint pupils. What I had in mind was an insecticide—specifically, one containing an organic phosphate. That isn't as inspired as it may sound. Fresno County is a big agricultural county. It produces everything from cantaloupes to cotton, and it uses tons of highly toxic chemicals. Including organic phosphates. Then Mrs. Cordoba said something that seemed to make my hunch a certainty. I was asking her the usual questions for Billy's personal history, and she remembered a remark that Billy made when he came home sick from school. The Cordobas live on the edge of town, and there are cultivated fields all around the stop where Billy waits for the bus. That morning, Billy said, there was a spray rig working in one of the fields and a spray plane flying back and forth overhead. Organic phosphates can enter the body in various ways, but the commonest route is absorption through the skin. Also, they work very fast. Symptoms can begin within a couple of hours of exposure. And it doesn't take much of the stuff to cause a lot of trouble. The fatal skin dose is only about five drops.
"I was practically certain that Billy had been poisoned by some organic-phosphate insecticide. I was sure enough to start treatment on that assumption. I followed the standard procedure. I ordered intravenous fluids to restore the loss of body fluids through sweating, salivation, and diarrhea, and a regimen of atropine—one milligram injected intramuscularly every two hours. Atropine is a lifesaving drug in organic-phosphate poisoning, because it relieves the threatening symptoms. It doesn't, however, get at the source. It doesn't eliminate the poison. The next step in the treatment involves a drug called pam—pralidoxime chloride. But I couldn't take that step—not until I was absolutely certain. pam is a little too specific to prescribe on mere suspicion. The definitive test for organic-phosphate poisoning is a blood test that measures the levels in the plasma and the red cells of an enzyme called cholinesterase. Cholinesterase is a kind of neural moderator. Its presence controls the accumulation of an ester that governs the transmission of impulses of the parasympathetic nervous system. Organic phosphates destroy cholinesterase, and the destruction of cholinesterase allows an excessive accumulation of the ester. The result is a powerful overstimulation of the parasympathetic nerves. The cholinesterase test is too elaborate for the average small hospital laboratory. The only laboratory equipped to do that kind of thing here is in the Poison Control Center at Fresno Community Hospital, down in the center of town. I drew a sample of blood and rounded up a messenger and got on the telephone to Dr. Bocian—Dr. J. J. Bocian, the director there. That was around seven o'clock. Dr. Bocian called me back around eight-thirty. He had the results of the test. Billy's plasma cholinesterase level was only forty percent of normal, and his red-cell level was a scant seventeen. His illness was definitely organic-phosphate poisoning.
"It was gratifying to know that I'd made a good guess. And that I'd been able to make it in time. But the really gratifying thing was Billy's response to atropine. By the time I had Dr. Bocian's definite diagnosis, Billy was just as definitely out of danger. His vital signs were all good. Moreover, he was beginning to look more alert. His pupils were coming back to normal size. And he wasn't salivating the way he had been. I was so satisfied that I decided to hold off on pam. Atropine would continue to counteract the potentially dangerous neuromuscular symptoms, and time would do the rest. It would gradually bring the cholinesterase levels back to normal. I stayed at the hospital until about ten o'clock, and went home feeling pretty good. I had diagnosed the nature of Billy's illness, and he was responding well to treatment. And I thought I knew just how his illness had come about.
"But I was wrong about that. It wasn't the spray rig or the spray plane at the bus stop. It couldn't have been either of them. Mrs. Cordoba or her husband or somebody made some inquiries. Those rigs weren't spraying an organic phosphate. Or any kind of insecticide. The fields they were working were cotton fields, and they were spraying a defoliant to strip the plants for mechanical picking. But I wasn't mistaken about Billy. He continued to do just fine. I kept him on atropine and intravenous fluids for a total of forty-eight hours. His symptoms all subsided and his serum cholinesterase levels began to improve. At the end of the second hospital day, he showed a plasma level of forty-two per cent of normal and a red-cell level of almost thirty-two. By the sixth day, the plasma level had risen to ninety-two per cent of normal. The red-cell concentration is always slower to recover. It requires the formation of new cells. But it was up to forty per cent. There was no reason to keep him in the hospital any longer. I could follow him the rest of the way as an out-patient. So I ordered his discharge."
Billy was discharged from Valley Children's Hospital to convalesce at home on October 9. That was a Monday. He remained at home, sleeping and eating and resting, until the following Monday, October 16. That afternoon, by prearrangement, Mrs. Cordoba drove him back across town to Dr. Conrad's office for what was expected to be a final physical examination and dismissal. Their appointment was for four o'clock, and they were on time.
"Billy looked fine," Dr. Conrad says. "And he was fine. Blood count, blood pressure, chest, pupils—everything was completely normal. So that was the happy ending of that. I walked Billy and his mother out to the waiting room and said goodbye and went back to my office and closed the case and rang for my next patient. I saw that patient and then the next, and then the receptionist called. She sounded almost frightened. Mrs. Cordoba was in the waiting room and she was practically hysterical. Billy was sick again. He was out in the car—too sick to even walk.
"It was true. I found Mrs. Cordoba and we went out to the car, and there he was, and he looked terrible. He looked shocky. His skin was cold and clammy with sweat, and he was salivating and breathing very fast, and he didn't seem to be able to move his legs. I didn't even go back in the building to say I was leaving. I just slid in beside Billy and told Mrs. Cordoba to head for the hospital. The hospital was only a block up the street, but on the way she told me what had happened. There wasn't much to tell. They had started home from my office, and they were almost there when all of a sudden Billy said he was sick. That was all she knew. She had turned around and driven right back to see me. But it was perfectly plain that this was the same thing all over again. Only worse—much worse. Dr. Bocian confirmed it later on in the evening. The serum cholinesterase levels were very low. The plasma level was down to twenty-seven per cent of normal, and the red-cell level was only twenty. I got Billy started on atropine and intravenous fluids, but he didn't respond as he had before. Two hours after I got him into the hospital, he was seized with severe abdominal cramps and began to vomit. Then he developed diarrhea. It was time for pam. I ordered an intravenous injection of five hundred milligrams. The next three hours were a little anxious, but then he began to improve. And the next morning he was very much better. He had had another five hundred milligrams of pam, and his cholinesterase levels were up enough to show that he was improving.
"That gave me a chance to think. Organic-phosphate poisoning is not a notifiable disease in California, so there had been no reason for me to report Billy's case to the Fresno County Public Health Department, but now I thought perhaps I should. I thought I had a lead that they might want to follow up. The lead was this: For a wee
k at home, Billy had been as good as well. Then he got up and drove over here to my office, and less than an hour later he was critically ill again with organic-phosphate poisoning. I'm not an epidemiologist, but it seemed to me that the probable source of his exposure wasn't far to look for. It almost had to be either something in the family car or something he was wearing. When I got to my office on Wednesday morning, I called the Health Department and talked to Mary Hayes. Dr. Hayes has since left the Department but she was then the acting health officer, and sin- was very interested in my story. She said she would have somebody look into it. She called me back on Friday afternoon. They had the answer—or part of it, anyway. The source was Billy's clothes—his blue jeans. They were brand new blue jeans that his mother had bought at a salvage store, and he had worn them only twice. He had worn them to school on the morning of October 4 and to my office on the afternoon of October 16. The Department had had the jeans tested and had found them contaminated with some form of organic phosphate.
"By that time, of course, Billy was recovering very nicely, and I could relax and begin to think about him as a case. It fascinated me. I'd never had a more dramatic experience in all my years of practice. Well, I'm on the staff at Fresno General Hospital and I make teaching rounds there on Monday, Wednesday, and Friday mornings, and I was so fascinated by Billy and his poisoned blue jeans that I told the interns and residents about them on my next rounds. That was on Monday—Monday, October 23. The next day, I got a call from one of the residents, a doctor named Merritt C. Warren. He had a new patient on his service—an eight-year-old boy. We can call him Johnny Morales. Johnny had become sick at school that morning and had been admitted to the hospital by his family physician around noon. His initial symptoms were sweating, dizziness, and vomiting. He reached the hospital in a stumbling, mindless stupor. His pulse was fast, his respiration was weak and shallow, his face was contorted by muscular twitches, and the pupils of his eyes were contracted to pinpoints. He also had abdominal cramps. The family physician had tentatively diagnosed Johnny's trouble as acute rheumatic fever. Dr. Warren thought differently. He said he thought it was another case of poisoned pants. That was the way he put it. I thought he was probably right. And he was. Dr. Bocian confirmed it by a serum cholinesterase test a couple of hours later."
The Medical Detectives Volume I Page 17