Poison Pill


By LISA SANDERS, M.D.
13 april 2008 -
Symptoms
“You know, I really haven’t felt good since Christmas,” the 81-year-old woman remarked, a little sadly. “Must be getting old.” A brief smile softened the features of the patient’s tired, well-lined face. Dr. Anna Rae Ong, a resident in her first year of training, tried again. “But can you remember exactly what happened that made you come to the hospital two nights ago?” Ong reviewed the chart of the patient before coming into the room, and the story she found there seemed strangely incomplete.
The E.M.T.’s arrived at the patient’s Connecticut home that night to find her sitting on the edge of her bed, struggling to breathe. Her husband of 63 years hovered anxiously behind them. “She was fine when she went to bed,” he said. She felt lightheaded, she told them, and nauseated, and her right leg hurt. On the way to the hospital, she vomited.
In the emergency room her breathing became easier with oxygen, and she was starting to look a little better when her blood pressure suddenly plummeted and she spiked a temperature of 102. Then the lab called. Her infection-fighting white blood cells had dropped to a tiny fraction of their normal number, and the few that remained were mostly immature forms called bands. Usually, these cells are only sent out of the marrow early to provide backup in a fight against an active infection. This combination — fever, hypotension and the proliferation of bands — suggested that the patient was in septic shock, her system overwhelmed by some type of infection. A preliminary search for the source was unrevealing, so the emergency-room doctors started her on two strong antibiotics and sent the patient to the intensive-care unit, where she could be closely monitored. There she was given a medicine to increase the number of white blood cells. If this was an infection, she was going to need them.
The patient stayed in the I.C.U. nearly 48 hours. During that period she improved: her blood pressure came up; her fever went down. Her white-blood-cell count increased. Now she was being transferred to a regular hospital floor, and Ong was assigned to care for her. As she pored over the patient’s chart, Ong kept wondering just what made this woman sick and what — if anything — the doctors had done to make her better.
2. Investigation
Was her improvement due to the antibiotics fighting off some hidden infection? They still hadn’t found one: a chest X-ray and urine sample showed no signs of infection. There were no bacteria seen in her blood. Or could it be a virus, which had simply run its course? Both parvovirus B19 and the Epstein-Barr virus can cause fever and abnormalities in the blood. Yet tests for both were negative. She had an extensive work-up in the I.C.U. to look for clots and cancers and autoimmune disease. Nothing was found. Ong said she hoped that a more careful interview with the patient might provide some additional clues.
“You were feeling O.K. early in the evening,” Ong prompted the patient. That’s right, the patient told her. She went to bed as usual. But she didn’t sleep for long. Cramps in her legs awakened her. She began to describe the terrible charley horses that Ong knew were a common and distressing problem among the elderly. Nothing new there. The intern sighed inwardly. Maybe the only thing that happened that night was that she got sick.
But then the patient said something that grabbed the young doctor’s attention. Her regular doctor had given her some pills for these cramps. She had never taken them before; she took too many medications already. But on this particular night the cramps were so bad she thought she’d give the new pill a try. What was the pill? Ong asked. It was quinine, the patient told her.
Ong was very attentive now. She remembered seeing the drug on the patient’s medication list, but she didn’t realize the patient had taken it right before she started to feel bad. She didn’t know much about quinine — it’s rarely used these days — but she remembered that it was a medicine that could cause serious side effects. But, the patient added, she’d taken only one pill. Could such a small dose, the patient asked, do all this? Ong’s heart sank. It did seem unlikely. Plus, the patient vomited soon after — probably eliminating the pill before it was completely absorbed. A half-dozen doctors — including several specialists — had seen the patient and didn’t mention the quinine. They must have figured the reaction was too rapid, the exposure too limited for this drug to be the cause of all her symptoms.
Ong quickly examined the patient and wrote up her notes. Maybe this woman was going to be one of those patients who come to the hospital and get better, and no one ever figures out what made her sick in the first place. The pressure to get patients out of the hospital rapidly can focus medical attention on treatment rather than diagnosis. As a result, unusual illnesses can pass through unrecognized and uninvestigated.
The next morning Ong presented the case to the team at the patient’s bedside. Tentatively, she brought up the patient’s brief exposure to quinine. Could such a small quantity of quinine cause all this?
Dr. Stephen Holt, the resident in charge of the team, was intrigued. Like Ong, he had a vague memory that quinine was capable of causing all kinds of unusual side effects. After rounds he found a computer and looked up the unusual medication. Bingo.
3. Resolution
Since 1865 there have been occasional reports of serious allergic reactions to quinine. Patients — most of them women — taking quinine for leg cramps would suddenly develop fever, hypotension and blood abnormalities. Even a small dose could set off this devastating reaction. Over the past 30 years quinine has been linked to more than 200 deaths. In fact, in December 2006, not long after this patient was given this medication, the Food and Drug Administration banned the sale of quinine for leg cramps, restricting its use to the drug’s original purpose — the prevention and treatment of malaria.
It all fit perfectly — except for one tiny detail. For any allergic reaction to occur, there has to be a previous exposure to the medication. This woman said this was the first time she’d ever taken this drug. How could she develop an allergy if she’d never been exposed to it before?
Holt continued to read up on quinine. It was derived from the bark of the cinchona tree. The powder — astonishingly bitter in taste — was used by the Incas to treat the fevers of malaria. From South America, the drug made its way east to India, where soldiers in the British Army drank a dose of the bitter powder dissolved in carbonated water every day in order to ward off malaria. Eventually the mixture was combined with gin for the quintessential colonial beverage, the gin and tonic. Could this be how this patient had been unknowingly exposed to quinine?
Holt hurried back to talk with the patient. Did she drink gin and tonics? No, she was a Scotch drinker. Had been for years. He tried again; had she ever tried them — even once? Well, sure. She had tonic water before. She didn’t much care for it. She’d stick with Scotch.
Finally Holt could put together a story that made sense. The patient had probably developed an allergy from the small amount of quinine contained in tonic water. Maybe that’s why she didn’t care for it. He found a lab that could test her blood for evidence of such a reaction. And in fact, she was allergic.
Sir William Osler, the father of modern medicine, taught his students that the patient’s story will often contain the key to making a diagnosis. It was important advice at the turn of the 20th century, when few diagnostic tools were available. And it is still true, as research shows. Even now, 75 percent of diagnoses are based on the patient’s story alone. “Listen carefully to the patient,” Osler exhorted. “They will tell you the diagnosis.” You just have to pay attention.