Quinine-Induced TTP-HUS in a 42 Year-Old Woman
Melissa went to the emergency room (ER) on a Sunday evening, because of fever and chills, nausea, vomiting, and bloody diarrhea. Very early the previous morning, at 2:00 a.m. Saturday, Melissa had the sudden onset of nausea and vomiting with fever and chills. Melissa says, “I thought it was food poisoning,” from a fast-food restaurant where she had ordered chicken on Friday evening. That night, around midnight, she recalls having bad leg cramps. Melissa says her primary care physician had prescribed quinine sulfate tablets for her a year earlier for episodes of leg cramps. Melissa explains that when she had taken quinine tablets before, she had become ill with nausea and even vomited. She describes, “When I took the quinine, I felt bad, like having a knot in my stomach. I didn’t like it so I stopped taking them.” She had been given another medicine, flexeril, for back pain and it also may help leg cramps. Melissa says, “At midnight, about an hour after I went to bed, I had leg cramps. I went to the medicine cabinet and reached in to get some muscle relaxers (flexeril).” At the time, Melissa thought she had gotten the flexeril. However she later learned that “I grabbed the quinine instead.” This was confirmed by Melissa’s daughter, who counted the quinine tablets. It turned out that Melissa had taken two quinine tablets that night instead of flexeril. The quinine bottle was next to her bottle of flexeril, and it was dark, and her cramps were bad. Melissa continued to feel nauseated and vomited throughout Saturday. The following day, Sunday, she had diarrhea that became bloody. She also noticed blood in her urine, although she also recalls that she had very little urine that Sunday.
When Melissa came to the ER, she continued to vomit and she was jaundiced. She couldn’t hold anything down. Melissa had a blood count that showed an elevated white blood count of 14,500 (the normal value is from 4,500 to 11,000) and an extremely low platelet count of 16,000 (normal is over 150,000). Her hematocrit, a measure of the red blood cells, was normal at 38%. Other tests were very abnormal: her LDH was 5026 (the upper limit of normal is 200), indicating very severe damage to blood or muscle tissue. Her creatinine level was 7.9 (normal is 0.6-1.2), indicating very severe kidney failure. Also she was making no urine. Melissa was urgently admitted to the hospital.
Because Melissa had fever and chills, an elevated white blood cell count, nausea and vomiting, bloody diarrhea, and kidney failure, the initial diagnosis was a severe infection in the blood stream known as sepsis. Intravenous antibiotics were started. An infection in the blood can cause severe organ failure and can be fatal. However, the following day the cultures of her blood showed no signs of infection. Therefore, 24 hours after Melissa came to the emergency room, the diagnosis of sepsis was changed to thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS), because of her low platelet count, rapidly developing anemia with evidence of broken red blood cells (her hematocrit had fallen to 20%), and severe kidney failure. It was only at this time that Melissa was asked about quinine and the story of her leg cramps and quinine pills were suspected as the cause of her severe illness. With the diagnosis of TTP-HUS, a catheter was inserted into a blood vessel in her right groin, and the first plasma exchange treatment was given to Melissa at that time.
When Melissa was told that she had a condition known as TTP-HUS she felt confused; she was not aware of what TTP-HUS was. Mentally, Melissa was not normal. She had trouble focusing and remembering the things that she was told and the events that were going on. She says, “Nothing was clear at the time. I didn’t know what was going on for sure.” Also, she felt very weak.
In the investigation for potential causes of the bloody diarrhea and the acute TTP-HUS, Melissa’s doctor took her stool sample and had it analyzed for E. coli 0157 and Shiga toxin. Incompletely cooked meat or vegetables can carry this dangerous strain of E. coli, and these Shiga toxin-producing E. coli can cause TTP-HUS. When the tests came back with no evidence for E. coli 0157, the explanation of food poisoning was excluded and the suspicion that quinine had caused the TTP-HUS increased.
On the following day, after one plasma exchange treatment, Melissa felt more alert and talkative. However, she still had very little urine. A kidney ultrasound test showed that the size of her kidneys was normal with no scarring; therefore there was no evidence of chronic kidney disease. She continued to be treated with daily plasma exchange with fresh frozen plasma through the catheter. After 4 days, the temporary catheter in Melissa’s right groin was replaced with a new catheter in her subclavian vein, which is located under her collar bone. This is a safer location for the catheter, with less risk of causing infection, and it allowed Melissa to be out of bed and to walk around. Melissa’s recovery from the severely low platelet count began after the fourth plasma exchange treatment. Her platelet count returned to normal and the plasma exchanges were stopped after 9 daily treatments.
At the hospital, Melissa’s diet was normal; however, she was told to “watch my fluid intake.” She had to watch the amount of fluid intake because she was excreting very little urine due to her kidney failure. It was frustrating because for about two weeks, “I had urges to go, but I couldn’t.” Because her kidneys were not working Melissa began hemodialysis, which is like an artificial kidney to clean the blood, on her ninth hospital day. Melissa says, “I was afraid that I would have to be on dialysis for the rest of my life.” She also notes, “Kidney dialysis wore me out and I just went to sleep.” A kidney biopsy was discussed to determine if her kidney function would recover, but after the second hemodialysis, Melissa’s kidneys resumed their function and a biopsy was not needed.
Melissa stayed in the hospital for 18 days. The first two weeks were for treatment of her TTP-HUS, but the third week was for a serious infection that had developed around the large intravenous catheter in her subclavian vein. Even with the precaution of changing the catheter from her groin to her shoulder, infection remained a serious risk. The infection was complicated by the development of blood clots around the catheter that caused painful swelling of her shoulder. Also, blood clots were obstructing the catheter. “Because of the infection and complications that had developed, the doctors took out the catheter,” says Melissa. She also recalls, “It was a Staph infection and the doctors treated it with antibiotics.” Specifically, Melissa was treated with vancomycin for the infection and also intravenous heparin (later switched to coumadin) for the venous blood clot where the catheter had been. Fortunately, Melissa did not need any additional plasma exchange treatments; therefore, insertion of a new catheter was not needed. A Staph infection is serious and can be life-threatening; this is a major complication of the large catheters required for plasma exchange and dialysis treatments.
When Melissa went home, her kidney function was returning to normal and she was producing a normal volume of urine each day. Also her TTP-HUS was in remission. Her kidney function became completely normal one month later, and her anemia recovered completely in 3 months.
Although she had recovered from TTP-HUS, Melissa had not regained her strength and stamina. Melissa went on short-term disability from her job for 3 months to regain her strength. She eventually returned to work, part-time on light duty. But when she returned home from her job as an electronic bench tech, Melissa says, “I was worn out. I was too tired to do anything else. I would come home and sleep for a couple of hours.” During her second week at work, Melissa returned to working 8 hours a day. Again, she says, “When I came home in the afternoon, I would sleep for about an hour.” Melissa recalls, “It took me about a year to get back to almost normal strength and back to feeling stronger and doing the things I did before TTP.”
When Melissa was released from the hospital, she was being treated with coumadin for the venous blood clot. Because coumadin is a blood thinner, Melissa was advised to be careful not to fall and hurt herself, as she could bleed easily. Unfortunately, when she was out at a park, she lost her balance, fell, and bled – but not seriously. Luckily, she recovered and did not have another unfortunate mishap. Now, Melissa has no restrictions with her activities and has resumed her normal routines.
Especially for the first year after her TTP-HUS, Melissa had a hard time focusing and remembering things, names, and events. She says, “I couldn’t focus on anything too long, and I would have to do a lot more concentration when I read. Also I was drowsy all the time. Half-way through a conversion, I would be wanting to go to sleep.” With her memory, Melissa notes, “I couldn’t remember names of medicines. And sometimes, I wanted to tell my husband something, but I didn’t remember what I had wanted to tell him.” Her focus and memory are improving, but not yet at the level where she was before TTP-HUS. She says that, “Some days are better than others.”
When asked what has been most helpful in her experience with TTP-HUS, Melissa replies, “The Oklahoma Blood Institute (OBI) and my hematologist. Both the OBI and my hematologist gave me a lot of information about TTP-HUS, and also, they sent all the information and my records to my family doctor, who sees me on a regular basis. My hematologist was great and told me how I was going to get back to feeling better.” Also, Melissa has participated in the TTP-HUS support group at the OBI. She says, “It was fun. I was nervous at first, but it was great. There were lots of people who had lots to say about TTP-HUS.” She enjoyed the support group because “they talked about how people got along and how they coped with TTP-HUS.” Melissa’s husband bought her a dog to keep her company a couple of weeks after she was released from the hospital. “My dog makes me do things to take care of her, which keeps me busy,” says Melissa.
When asked what advice she has for people newly diagnosed with TTP-HUS, Melissa suggests, “Get the rest you need and don’t push it. Take care of yourself. Rest and watch what you eat and drink. People will give you the worst scenarios.” For Melissa she says, “I had 25-50% function of my kidneys and I was on dialysis. But now they are working normally.” She adds, “Listen to what your doctors tell you. Also read and do something to keep yourself busy, but nothing real strenuous.”
Currently, Melissa lives at home with her husband and her dog. She is feeling a lot better than a year ago and getting much stronger. Work has resumed to normal, and she has again become a real asset to her company.
Melissa Update: February 2007
We recently spoke with Melissa to update her patient perspective for our website. Because we follow all of our former patients closely, we knew that she had not had any more episodes of quinine-induced TTP-HUS. Melissa says that her health is good, “except for getting old,” she says laughing. She stays away from anything containing quinine, and she always reads all medicine labels to avoid inadvertently ingesting it. “I also stop taking any medications that have side effects that don’t make me feel good. This is because when I took the quinine tablets for my leg cramps the first time, I didn’t like the way the medicine made me feel. In fact, I was never going to take the quinine again because it made me feel so bad. Unfortunately, I took the quinine accidentally because it was beside my muscle relaxers in the medicine cabinet.” We hope Melissa’s vigilance for things containing quinine will prevent her from experiencing any additional episodes of TTP-HUS.
Dr. George's comments:
Melissa's story is very important because her illness demonstrates how reactions to quinine can be so severe and so dangerous.
I first saw Melissa on Monday evening, after she had been in the hospital for one day. When Melissa was first seen in the emergency room, the initial diagnosis was that she had a serious blood stream infection, described as sepsis. This is a much more common critical illness than TTP-HUS. It is important for antibiotics to be started immediately and therefore this was an appropriate initial impression. However when cultures of the blood did not reveal any infection, then TTP-HUS was considered because of the severely low platelet count, the severe renal failure, the rapidly developing anemia, and the evidence that her red blood cells were being destroyed very quickly.
I suspected that quinine sensitivity was the cause for Melissa's illness because of how suddenly her illness began early Saturday morning, after taking medicine for leg cramps late the previous evening. Melissa first told me that she had taken flexeril, not quinine. But my suspicion remained when she told me that she had quinine tablets in the medicine chest, just next to the bottle of flexeril tablets. My suspicion increased when she told me that she had had stomach cramps when she had taken quinine previously. And then with the investigation by her daughter, we concluded that indeed Melissa had mistakenly taken quinine rather than flexeril.
Quinine is a very common medicine, the traditional treatment for the very common symptom of night-time leg cramps. Over 60 years ago, publications in medical journals discussed the use of quinine for leg cramps. But even for 100 years before that, quinine had been used as a remedy for various aches and pains. Quinine is a natural product from the bark of the South American cinchona tree. It had been used by the native peoples of South America for centuries as treatment for malaria. It was the first effective treatment for malaria throughout the world following the Spanish conquest of South America.
As widely used as quinine is, the reactions are frequent and severe. Because of these bad reactions, and because the evidence supporting effectiveness of quinine in the treatment of leg cramps is weak, the US Food and Drug Administration (FDA) removed quinine from over-the-counter drug store sales in 1994 and required a doctor's prescription to dispense quinine. This may have limited the use of quinine and may have decreased the frequency of bad reactions, but still quinine use is extremely common. Leg cramps remain a common and troublesome symptom; prescriptions from doctors are easily obtained. Furthermore, quinine is available in lower concentrations in various remedies marketed for leg cramps and other symptoms. Internet "chat rooms" for people with leg cramps frequently discuss all of these alternative remedies and describe exactly how much needs to be taken to be equivalent to a prescription quinine tablet.
For patients who have serious reactions to quinine, such as Melissa had, even the small amount in quinine in beverages such as tonic water and Schweppes bitter lemon are enough to trigger a severe reaction. We suspect that sometimes the parent substance, the natural cinchona bark, may also trigger severe reactions in sensitive people, but we have not yet documented this. Cinchona is a common preparation in a variety of remedies sold in nutrition stores and other markets.
Melissa's story demonstrates just how devastating quinine reactions can be. In her, the quinine reaction caused all typical features of TTP-HUS. Her kidneys completely shut down. Her platelets were rapidly destroyed. Her red blood cells were also rapidly destroyed. She did not have severe neurologic problems, only confusion, but in other patients quinine reactions have caused coma and death. Melissa's white blood cell count was not low, but other patients have had severely low white blood cell counts, also as a result of quinine sensitivity. Her liver function tests were moderately abnormal, which could also be caused by quinine sensitivity; other patients have had severe liver toxicity caused by quinine, often mistaken for infectious hepatitis. Melissa did have abnormal coagulation tests, and these can also be caused by quinine.
The importance of documenting quinine as the cause of Melissa's TTP-HUS is that we feel that she has no risk for any recurrent problems with TTP-HUS- unless she is exposed to quinine again. This is different from many other patients who may have multiple recurrent episodes of TTP-HUS, as demonstrated in Emily's story, Ralph’s story, and Bridget’s story in this website series.
When Melissa came to the hospital, her kidney function had completely stopped. The extremely high serum creatinine value suggested that she had had kidney trouble for a long time preceding this acute illness. This is because the serum creatinine is thought to only be able to increase about 0.5 mg/dL each day, and Melissa's level was 7.9 mg/dL after only about 36 hours of illness. Creatinine is a normal chemical in the blood that comes from normal breakdown and turnover of muscle tissue. Each day some new muscle tissue is made and old muscle tissue is turned into creatinine and excreted by the kidneys. When the kidneys cannot excrete creatinine, this increase of approximately 0.5 mg/dL each day occurs. However in Melissa's situation, her TTP-HUS caused clots obstructing small blood vessels throughout her body, and this can occur throughout all of the body's muscles. In a sense, this is like having a heart attack in all of the muscles of the body, not just in the heart muscle. As the muscles are deprived of their blood supply and do not get enough oxygen, the muscle cells break down more quickly and release more creatinine into the blood. This was the explanation for the extremely rapid increase of serum creatinine in Melissa. We can assume that her kidney function was normal before this acute illness because her kidney function returned completely to normal in approximately two months after this illness began.
The problem that Melissa had with the large venous catheter, required for both support of her kidneys by hemodialysis and plasma exchange to treat the TTP-HUS, is another major risk of this disease. These catheters are required for the rapid transfer of large volumes of blood that are needed for the dialysis and plasma exchange procedures. They are inserted into the large central veins of our body, and there is continual risk for infection, coming from the normal skin bacteria and getting into the bloodstream. This is what happened to Melissa. Even with ideal care, the best possible nursing supervision and dressing changes, these infections commonly occur. The Staphylococcus organism that was isolated from Melissa's blood at the time of her infection was the type of Staphylococcus that we all normally have on our skin. Melissa's infection was probably also related to the blood clot that formed in her catheter and in the vein around the catheter. This is another complication that commonly occurs and cannot easily be prevented. When the blood clot forms, it is a rich material for bacteria to grow in.
Whether plasma exchange treatment is actually required for treatment of quinine-induced TTP-HUS is unknown. What we do know is that essentially all patients with TTP-HUS died in the era before plasma exchange treatment was available, prior to 1975 to 1980. Although we may suspect that stopping the quinine is all that is needed, and that all of the blood abnormalities and organ damage will then spontaneously recover, we cannot be certain. Because nearly 90% of patients survive now with plasma exchange treatment, we feel that it is not appropriate to withhold plasma exchange treatment.
The good news is that Melissa recovered completely. Her platelet count recovered in only about one week. Her red blood cell count and kidney function recovered in several months. And her strength and energy recovered during the following year. Because we feel that all of her illness was caused by a reaction to quinine, we feel that she will never have this problem again. It is tragic when it is not recognized that a drug has caused a serious reaction, and repeated exposure to the drug causes an even more serious reaction. Therefore, doctors and their patients need to be very careful to consider whether a drug sensitivity may have been the cause for a serious illness, such as TTP-HUS. These reactions may not be only limited to regular prescriptions or over the counter medicines. These reactions may occur with herbal remedies, even foods. This is the lesson we learned from Melissa.
[First written July 2003. Last updated February 2007.]