Letters and Corrections
Letters submitted for possible publication must be identified as such and submitted with a signed transfer-of-copyright form (see Table of Contents for location). Text length must not exceed 400 words. No more than five references may be used; reference format must be that specified in "Information for Readers and Authors." Letters must have no more than three authors. All parts of letters must be typed double-spaced, including references. Letters not typed double-spaced will not be considered for publication. Tables and figures will not be published. Acceptance of letters for publication depends on several factors: newness of information, relevance to current topics and recent content of this journal, clarity of statement, distribution of topics within this section, conformity to acceptable formats, and space available; only about half of the letters submitted can be published. The Editor reserves the right to shorten letters and make changes to our style. Authors of letters to be published will be notified of their acceptance. Unpublished letters are returned only on request.
Hyperkalemia Associated with Diarrhea To the Editor: Severe hyperkalemia, which may produce muscle weakness and cardiac arrhythmias, is a recognized complication of renal failure. We report two cases of life-threatening hyperkalemia in patients on chronic dialysis in whom profuse diarrhea was the dominant symptom. Hemofiltration was begun in a 61-year-old woman with reflux nephropathy because of hypotension during hemodialysis. At each hemofiltration one-third of her body weight was replaced with fluid containing an intended 1 m m o l / L KC1. Immediately after the first treatment she developed nausea, vomiting, abdominal pain, and profuse diarrhea that resolved before her next treatment. Similar symptoms, lasting 24 to 36 hours, occurred after each subsequent hemofiltration. Shortly after her sixth treatment she also had chest pain, dyspnea, and palpitations, and collapsed at home. At admission to the hospital an electrocardiogram showed a broad complex tachycardia with peaked T-waves and runs of ventricular tachycardia. Her plasma potassium was 9.5 m m o l / L . Hemodialysis against a 1-mM KC1 dialysate lowered her plasma potassium to 3.8 m m o l / L with prompt relief of symptoms, however, recurrent hyperkalemia necessitated two further dialyses in the next 48 hours. Her diarrhea
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ceased at admission and a fecal sample was not available for some days. A 69-year-old man with end-stage renal failure of unknown origin had been on hemofiltration for six consecutive sessions over 2 weeks. He also described mild nausea and profuse diarrhea occurring after each hemofiltration treatment, associated with severe progressive weakness and recurrent palpitations. A physical examination was normal and an electrocardiogram showed only peaked T-waves. His plasma potassium was 9.1 m m o l / L and fell to 4.2 m m o l / L after 3.5 hours of hemodialysis against a 1-mmol/L KC1 dialysate. However, two more dialyses were needed in the next 36 hours to control hyperkalemia. During this period his symptoms resolved completely. As with the first patient, his diarrhea ceased after dialysis. It was later discovered that, through a manufacturer's error, these patients had received a hemofiltration replacement fluid with 10.5 to 11.6 m m o l / L KC1. Thus they would have received acute potassium loads of 180 mmol (Patient 1) to 200 mmol (Patient 2) in the course of each hemofiltration session to cumulative loads of 1080 to 1200 mmol, respectively. The striking feature of their clinical presentation was the occurrence of profuse diarrhea after each hemofiltration. N o other cause was found and the diarrhea ceased immediately when the hyperkalemia was corrected. No family members or other patients in the unit reported similar symptoms. Although colonic potassium excretion rises in response to chronic total body potassium excess and may act to maintain potassium balance in uremia ( 1 ) , acute diarrhea associated with acute hyperkalemia has not been previously reported. In animal studies, however, hyperkalemia has been reported (2) to stimulate an increase in gut motility. We suggest that the diarrhea our patients had was caused by acute hyperkalemia and may have protected them from an otherwise potentially fatal potassium load. Alpha S. Yap, B Med Sci, MB BS Gregory I. Hockings, MB BS Philip D. Boyle, MB BS Royal Brisbane Hospital Brisbane, Queensland, Australia 4029
References 1. Hayslett JP, Binder HJ. Mechanism of potassium adaptation. Am J Physiol. 1982;243:F103-12. 2. Daniel EE. Pharmacology of the gastrointestinal tract. In: Code CF, ed. Handbook of Physiology, v 4. Washington DC: American Physiological Society; 1968:2267-324.
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Ulcerative Colitis and Marijuana To the Editor: The apparent protective effect of cigarette smoking on ulcerative colitis (1) suggests that inhaled plant products might affect the disease process. We report a case suggesting a relation between ulcerative colitis and smoking marijuana. In 1972, a 23-year-old woman developed abdominal pain, diarrhea, and rectal bleeding. Sigmoidoscopy to 15 cm revealed diffuse cobblestone ulcerations, and a single-contrast barium enema showed numerous small marginal irregularities in the distal sigmoid and rectum. Ulcerative colitis was diagnosed, and her symptoms waxed and waned despite treatment with sulfasalazine, librax, and intermittent prednisone. Discouraged, she stopped all medications in 1975. In 1976, she noted that smoking marijuana resulted in fewer stools, more stable body weight, and fewer, milder exacerbations. Her typical intake was a pipeful once or twice daily, which she maintained despite her dislike for its euphoric effects. Cessation repeatedly resulted in exacerbations within a few weeks; resumption led to some improvement in a day or two, with maximal effect after several weeks. She was smoking marijuana daily when, after having 2 months of symptoms, she was hospitalized at the Mary Hitchcock Memorial Hospital in 1983. She was febrile and had an erythrocyte sedimentation rate of 103 m m / h . Sigmoidoscopy to 16 cm showed diffuse small friable ulcerations with granularity. A biopsy of the lower rectal fold showed marked chronic inflammation extending into the submucosa without granulomas. She improved promptly with prednisone. At home she resumed taking marijuana. Over 15 months her prednisone dose was tapered and sulfasalazine therapy begun. Sigmoidoscopy to 20 cm was normal, and a single-contrast barium enema showed a diffuse granular pattern with a "pipe-like" appearance, compatible with inactive colitis. In 1986 she stopped both sulfasalazine and marijuana but within 2 months became symptomatic. Sulfasalazine was resumed with minimal relief, and 2 months later she resumed taking marijuana. Her symptoms improved within about a week, and in 2 months she was again in remission through 1988. The patient had started smoking cigarettes before the onset of the ulcerative colitis. She noted no relation to her symptoms and stopped smoking in 1982 for "health reasons." She thought her symptoms. worsened with coffee or alcohol and rarely drank either beverage. This case suggests marijuana may ameliorate ulcerative colitis, although an alternative explanation is the natural variation in the severity of its symptoms. It is not clear how tobacco or marijuana might have a beneficial effect. Suggested mechanisms for cigarettes include enhanced catecholamine release, disturbed prostaglandin production, and immunologic changes ( 1 ) . Cigarettes increase colonic motility and marijuana in large doses may cause diarrhea ( 2 ) , although it is difficult to relate these observations to ulcerative colitis. A few systemic effects are similar for both drugs. Both have been associated with T-cell suppression ( 3 ) , but
the relation of ulcerative colitis with immune disturbances is weak ( 4 ) . Interference with the pituitaryovarian axis can occur from either drug (2, 5); for tobacco, this interference seems to cause relative estrogen deficiency in women ( 5 ) . Through effects on estrogen receptors in the colon or changes in bile composition, such hormonal changes could conceivably affect the colon. Although an ameliorative effect of marijuana smoking on ulcerative colitis, if verified, would probably have little direct clinical relevance, it might lead to new therapy and help elucidate the disease. John A. Baron, MD, MS, MSc Richard D. Folan, MD Maurice L. Kelley Jr., MD Dartmouth-Hitchcock Medical Center Hanover, N H 03756 References 1. Cope EF, Heatley RV, Kelleher J, Lee PN. Cigarette smoking and inflammatory bowel disease: a review. Hum Toxicol. 1987;6:189-93. 2. Nahas GG. Toxicology and pharmacology. In: Nahas GG, ed. Marihuana in Science and Medicine. New York: Raven Press; 1984. 3. Holt PG, Keast D. Environmentally induced changes in immunological function: acute and chronic effect of inhalation of tobacco smoke and other atmospheric contaminants in man and experimental animals. Bacteriol Rev. 1977;41:205-16. 4. Kirsner JB, Shorter RG. Recent developments in nonspecific inflammatory bowel disease, part 2. NEnglJMed. 19*82;306:837-48. 5. Baron J A. Smoking and estrogen-related disease. Am J Epidemiol. 1984;119:9-22.
Parenteral Nutrition and Cancer Chemotherapy To the Editor: The Chief of Pharmacy eagerly presented me with a copy of a position paper by the American College of Physicians ( 1 ) . He needed an explanation because his impression from reading the article was that nutritional support had no place in the management of patients with cancer. I pointed out that although the first sentence in the "Rationale" section recognized malnutrition or a significant comorbidity in some patients with cancer, the first sentence of the second paragraph in the "Recommendations," stated, "Most patients in the studies reviewed were not severely malnourished." I explained that parenteral nutrition does not treat cancer. It treats or prevents progressive malnutrition associated with the compromise of normal nutriture either by direct infiltration or as the result of adjuvant therapy (24 ) . Its indication is to keep a patient alive who has a chance for cure or palliation, not allowing that patient to deteriorate and suffer potentially life-threatening complications of progressive malnutrition. He immediately understood and asked why a position taken by an august group like the American College of Physicians was based squarely on a false premise. I could not explain why and therefore request that the authors respond. Mitchell V. Kaminski Jr., MD Terri Haase, PA St. Mary of Nazareth Hospital Center Chicago, IL 60622
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References 1. American College of Physicians. Parenteral nutrition in patients receiving cancer chemotherapy. Ann Intern Med. 1989;110:734-6. 2. Muller JM, Dienst C, Brenner U, Pichlmaier H. Preoperative parenteral feeding in patients with gastrointestinal carcinoma. Lancet. 1982;1:68-71. 3. Bellantone R, Doglietto GB, Bossola M, et al. Preoperative parenteral nutrition in the high risk surgical patient. J PEN. 1988; 12:1957. 4. Muller JM, Keller HW, Brenner U, et al. Indications and effects of preoperative parenteral nutrition. World J Surg. 1986;10:53.
Allan 5. Detsky, MD, PhD University of Toronto Toronto, Ontario M 5 G 2C4 Reference 1. American College of Physicians. Parenteral nutrition in patients receiving cancer chemotherapy. Ann Intern Med. 1989;110:734-6.
Ethical Questions about Pay for Research In response: As outlined in our statement ( 1 ) , the investigators who did the randomized trials of parenteral nutritional support for patients undergoing intensive chemotherapy did so with the following rationale composed of three components: there was a known association between malnutrition and poor prognosis in cancer patients; patients undergoing intensive chemotherapy have a decreased tolerance for oral feeding; and, finally, parenteral nutritional support may maintain or improve the patients' nutritional status. It was hoped that maintenance or improvement in nutritional status might permit improved response to chemotherapy and protection from complications associated with malnutrition. As correctly pointed out by Dr. Kaminski and Ms. Haase, we do not believe that any of the trials were undertaken under the premise that nutritional support treats cancer. Unfortunately, the routine use of parenteral nutritional support for patients undergoing intensive chemotherapy was not associated with improved clinical outcomes in these trials and was associated with an increased risk of complications during the period of nutritional support. We believe that our analysis of these trials clearly shows this. The background paper that reviews the evidence in detail will be published shortly in the journal Nutrition. Dr. Kaminski and Ms. Haase note that "nutritional support is used to treat life-threatening degrees of malnutrition in patients with cancer at our institution." They correctly point out that our paper notes that most patients in studies reviewed were not severely malnourished. We did note that for these randomized trials the detrimental effects of parenteral nutritional support (that is, increased infections) seemed to be less in malnourished patients, and recommended that "in deciding to use such therapy in individual patients whose malnutrition is judged to be life-threatening, physicians should take into account possible exposure to increased risk." Thus, the recommendations do not preclude the use of parenteral nutritional support for patients who are malnourished before chemotherapy; unfortunately, we lack the data necessary to assess the overall effect of parenteral nutritional support during intensive chemotherapy in such patients. In addition, the recommendations do not preclude the use of nutritional support to treat life-threatening degrees of malnutrition for patients with cancer if the purpose of such support is to keep the patient alive while treating the patient with some other modality such as surgery for possible cure or palliation. Allison J. McGeer, MD Keith O'Rourke, MBA 472
To the Editor: Part 2 of The American College of Physicians' Ethics Manual (1) is first-rate throughout. Even I cannot find fault with it. I come from the school where a researcher was largely a "hired hand." I fear that not enough researchers will see the report; it needs wider distribution in purely scientifically oriented journals. One problem not discussed that needs guidelines is the question of pay for the scientific investigator. This problem is becoming bigger and bigger as more research is being financed by industry as well as through the usual sources. For example, should some investigators receive large stock options while others receive nothing? Must researchers patent their discoveries in order to receive some financial benefit instead of it all going to the company that manufactures a drug or apparatus? Is it sometimes ethical or acceptable to receive salaries from universities, government, and industry concurrently? These are all sticky subjects and I cannot blame the committee for keeping their distance. Someone must address these questions, however, and I hope it will be your very competent committee. Irvine H. Page, MD 100 Longwood Avenue Hyannis Port, M A 02647 Reference 1. American College of Physicians. American College of Physicians ethics manual. Part 2: The physician and society; research; lifesustaining treatment; other issues. Ann Intern Med. 1989;111:327-35.
Diclofenac Sodium and Bruising To the Editor: N o reports to date have described prolonged bleeding time and spontaneous bruising with the use of diclofenac sodium. A literature search {Index Medicus and Excerpta Medica) revealed a single study that described reversible inhibition of platelet aggregation without prolongation of bleeding time with the use of diclofenac sodium ( 1 ) . Moreover, the manufacturer (Geigy) reports no effect on bleeding time with its use ( 2 ) . We report a case of spontaneous bruising and prolongation of bleeding time temporally associated with the use of diclofenac sodium. An otherwise healthy 45-year-old woman complained of spontaneous bruising for 1 week. She denied any history of trauma or blood dyscrasias, but admitted to easy bruising in the past. The patient had been placed on diclofenac sodium (75 mg orally, twice a day) 5 months earlier for plantar fasciitis, which responded well to this therapy. She was on no other
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medication. She had extensive bruises over her abdomen and extremities. No petechiae or purpura was noted. Laboratory tests included a complete blood count, platelet count, prothrombin time, partial thromboplastin time, fibrinogen, fibrin split products, and bleeding time. The bleeding time was prolonged at 18.5 minutes (normal range, 2.3 to 9.5 min). The other laboratory values were within normal limits. A repeat bleeding time returned to normal (7.0 min) 36 hours after her last dose of diclofenac sodium. Diclofenac sodium was withdrawn with resolution of spontaneous bruising. Prolonged bleeding time and bruising have been demonstrated with other nonsteroidal antiinflammatory agents ( 3 ) . This case shows that these effects can also occur with diclofenac sodium. UriKhazan,MD Mary Toth, MD Anand Mutgi, MD Medical College of Ohio Toledo, O H 43699 References 1. Francis J L , Daws RF, Roath O S . The effect of diclofenac on platelet aggregation and post-operative bleeding. Hematol Rev Commun. 1988;2/3:283-91. 2. Physicians' Desk Reference. 43d ed. Oradel, New Jersey: Medical Economics Company; 1989:984-5. 3. Nadel J, Bruno J, Varady E J . Effect of naproxen and of aspirin on bleeding time and platelet aggregation. / Clin Pharmacol 1974;14:1975-82.
Heparin-Associated Thrombocytopenia and Immunoglobulin Therapy To the Editor: The report by Frame and associates (1) claims to "report the first case of severe heparinassociated thrombocytopenia complicated by intestinal bleeding and progressive thrombocytopenia that had intestinal bleeding stopped and normal platelet counts restored shortly after the administration of intravenous immunoglobulin." The patient, a 62-yearold woman who presented with deep venous thrombosis and pulmonary emboli, was subsequently found to have carcinoma of the colon. Her platelets were positive for P L A 1 antigen. Platelet and fibrinogen levels were low but fibrin split products were elevated. There were no data to rule in or out the diagnoses of heparinassociated thrombocytopenia or immune thrombocytopenia. Gastrointestinal bleeding (in this patient with colon carcinoma) occurred when she was on heparin, had been given warfarin, and while her platelet count was low. Recovery of the platelet count coincided with return of the fibrinogen level to normal. It is hard to reconcile the claims of the title and the first paragraph of this report with the data provided. It is impossible to define the role of the malignancy, parameters of disseminated intravascular coagulation, P L A 1 antigen, and heparin in this case. In addition, heparin-associated platelet aggregation remains positive for " m o n t h s " even after stopping heparin (2, 3) and could have been checked later in the course of this patient.
Finally, was informed consent obtained from this patient as she was given a previously untried therapy for her "heparin-associated thrombocytopenia"? Sucha Nand, MD Loyola University Stritch School of Medicine Maywood, IL 60153 Edward Hines Jr., Hospital Veterans Affairs Hines, IL 60141 References 1. Frame J N , Mulvey KP, Phares J C , Anderson M J . Correction of severe heparin-associated thrombocytopenia with intravenous immunoglobulin. Ann Intern Med. 1989;111:946-7. 2. King DJ, Kelton J G . Heparin-associated thrombocytopenia. Ann Intern Med. 1984;100:535-40. 3. Gall us AS, Goodall KT, Beswick W, Chesterman CN. Heparinassociated thrombocytopenia. Case report and prospective study. AustNZJMed. 1980;10:25-31.
In response: We welcome the opportunity to respond to Dr. Nand's comments about our recent report ( 1 ) . We believe there is reasonable clinical evidence to support a diagnosis of heparin-associated thrombocytopenia as we outlined and referenced ( 1 ) . Further evidence to support this diagnosis arises from the development of thrombocytopenia on heparin rechallenge for recurrent thrombotic episodes later in the patient's clinical course ( 2 ) . We agree with Dr. Nand that platelet aggregation testing may remain positive after withdrawal of heparin in this disorder. This test has been reported (3) to be negative, however, in a significant number of patients, thus limiting its clinical usefulness as a diagnostic tool. Because heparinassociated thrombocytopenia remains a clinical diagnosis of exclusion, we are not aware of data that absolutely require in-vitro demonstration of an underlying immune mechanism for the thrombocytopenia or tests for platelet aggregation to establish this diagnosis. Although the mechanism of this disorder is under investigation, there is growing evidence, as referenced in our report, of an immune-mediated mechanism for heparin-associated thrombocytopenia. We believe such data warranted the consideration of this possibility in our patient. Dr. Nand addresses a broader issue for defining the role of the malignancy, parameters of disseminated intravascular coagulation, P L A 1 antigen, and heparin. Gastrointestinal bleeding during anticoagulant therapy may be a harbinger of an underlying lesion in the gastrointestinal tract ( 4 ) . This proved to be the case in our patient. The patient's underlying colon carcinoma, however, may have been unmasked by the complicating thrombocytopenia. As we cited in our report ( 1 ) , hypofibrinogenemia and increased fibrin degradation products have been reported in some patients with heparin-associated thrombocytopenia. Although the mechanism of these abnormalities is open to speculation ( 5 ) , we do not believe this sufficiently detracts from a diagnosis of heparin-associated thrombocytopenia. The presence of the P L A 1 antigen excludes the diagnosis of " P L A 1 antigen-negative" post-transfusion
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purpura. The role of heparin in this patient has been previously discussed. We do not share Dr. Nand's difficulty in reconciling our findings. That a platelet transfusion was administered after the initial dose of immunoglobulin and subsequent doses of immunoglobulin alone were given does not exclude a causal role for intravenous immunoglobulin given the temporal relationship of the reported observations. We are cautious in interpreting the results from a single patient and support further study into the nature of these clinical findings. Informed consent was obtained. The views expressed in this letter are those of the authors and do not reflect the official policy or position of the Department of the Navy, the Department of Defense, or the U.S. Government. James N. Frame, MD Kevin P. Mulvey, MD John C. Phares, MD Michael J. Anderson, MD National Naval Medical Center Bethesda, M D 20814-5000 References 1. Frame JN, Mulvey KP, Phares JC, Anderson MJ. Correction of severe heparin-associated thrombocytopenia with intravenous immunoglobulin. Ann Intern Med. 1989;111:946-7. 2. Sheridan D, Carter C, Kelton JG. A diagnostic test for heparininduced thrombocytopenia. Blood. 1986;67:27-30. 3. King DJ, Kelton JG. Heparin-associated thrombocytopenia. Ann Intern Med. 1984;100:535-40. 4. Mosley DH, Schatz IJ, Breneman GH, Keyes JW. Long-term anticoagulant therapy: complications and control in a review of 978 cases. JAMA. 1963;186:914-6. 5. Bell WR, Tamasulo PA, Alving BA, Duffy TP. Thrombocytopenia occurring during the administration of heparin. Ann Intern Med. 1976;85:155-60.
Danazol and Idiopathic Thrombocytopenic Purpura To the Editor: Does long-term treatment with danazol really benefit patients with autoimmune thrombocytopenia? Unfortunately, Dr. Ahn and colleagues (1) have not answered this question convincingly because their study did not incorporate controls who were not treated with danazol. The improved platelet counts observed in this uncontrolled "before and after" experiment could possibly have been due to factors other than danazol alone, for example, spontaneous improvement, placebo response, potentiation of the effects of glucocorticoids, or a combination of these effects. A study incorporating a placebo control group would answer these objections and would also be completely ethical because all subjects could receive therapy of proven value for the disease (glucocorticoids or splenectomy, or b o t h ) . In the absence of a long-term prospective randomized double-blind placebo-controlled study, the authors have yet to show that danazol is superior to placebo in the treatment of autoimmune thrombocytopenia. Because treatment with danazol may be accompanied by severe adverse effects, including amenorrhea 474
and masculinization in females and cholestatic jaundice (2), the authors' recommendations regarding the use of this experimental drug in autoimmune thrombocytopenia should be received with caution. Michael Phillips, MD St. Vincent's Medical Center of Richmond Staten Island, N Y 10310-1699 References 1. Ahn YS, Rocha R, Mylvaganam R, Garcia R, Duncan R, Harrington WJ. Long-term danazol therapy in autoimmune thrombocytopenia: unmaintained remission and age-dependent response in women. Ann Intern Med. 1989;111:723-9. 2. Androgens. In: McEvoy GK, ed. American Hospital Formulary Service Drug Information 89. Bethesda, Maryland: American Society of Hospital Pharmacists. 1989:1685-7.
In response: We have cared for approximately 2000 patients with idiopathic thrombocytopenic purpura. In our clinic, we do not include under the designation "idiopathic" the postviral syndrome of childhood or thrombocytopenia seen in such diverse settings as collagen vascular diseases, lymphomas, or drug sensitivities. Idiopathic thrombocytopenic purpura is usually a lifelong disorder with a generally predictable clinical course. It usually improves with therapy and relapses on its withdrawal. Spontaneous remissions in adults with chronic idiopathic thrombocytopenic purpura are rare. In the series we described ( 1 ) , because glucocorticoids were tapered off completely in 8 0 % of the patients, potentiation of glucocorticoid effect does not apply. The time for responses to danazol also assumed a definite pattern: in early responders ( 7 1 % ) it took 0.5 to 2 months whereas in late responders ( 2 7 % ) it took 4 to 10 months ( 1 ) . Late responses are also seen in paroxysmal nocturnal hemoglobinuria and cyclic thrombocytopenia (2) where complete cessation of transfusion requirement and amelioration of cycling of thrombocytopenia followed about 10 months of therapy. Could a tripling of platelet counts in a predictable time after treatment in 58 of 96 patients, most of whom were entirely weaned away from glucocorticoids and who had had idiopathic thrombocytopenic purpura for decades be due to "placebo effect" or "spontaneous" remission? A carefully controlled study is required for treatments with marginal therapies but is not a prerequisite for treatments with obvious clinical efficacy. Digitalis in heart failure was not proved by a controlled study nor glucocorticoids in idiopathic thrombocytopenic purpura or rheumatoid arthritis. For a controlled study, prognostic factors must be controlled in the design or in the analysis. Prognostic factors for this disorder have not been systematically investigated, although our study showed that age, sex, and status of splenectomy are determining factors. There must be other unknown factors (for example, immunologic variables, target antigens, H L A type). Without knowing such prognostic factors in the con-
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trol population, a "controlled study" is not really controlled. We cited (1) nine other papers that independently confirmed our positive results with danazol in this disorder. We observed no "severe adverse effects"; if they were incipient, they were reversible ( 1 ) . Our observations were consistent with an earlier study on longterm danazol therapy in patients with angioneurotic edema ( 3 ) ; abnormal liver function associated with danazol therapy is dose-related and reversible. Benefits included freedom from the inevitable side effects of glucocorticoids and life-threatening hemorrhage. Further, many patients now have been in complete remission for up to 5 years (that is, without further treatment). Indeed, perhaps the most remarkable result of our study is the finding of unmaintained lasting remission in autoimmune disease after prolonged danazol therapy. Similar observations have been made in patients with endometriosis (4) and autoimmune hemolytic anemia ( 5 ) . Elucidation of the mechanism of action of danazol and further refinements in its use would be of great value in the management of idiopathic thrombocytopenic purpura and other autoimmune diseases. Yeon S. Ahn, MD William J. Harrington, MD Robert C. Duncan, PhD University of Miami School of Medicine Miami, F L 33136 References 1. Ahn YS, Mylvaganam R, Rocha R, Garcia R, Duncan R, Harrington WJ. Long-term danazol therapy in autoimmune thrombocytopenia: unmaintained remission and age-dependent response in women. Ann Intern Med. 1989;111:723-9. 2. Rocha R, Ahn YS, Mylvaganam R, Harrington WJ. Danazol therapy for cyclic thrombocytopenia [Abstract]. Blood. 1988;72:1254a. 3. Hosea SW, Santaella ML, Brown EJ, Berger M, Katusha K, Frank MM. Long-term therapy of hereditary angioneurotic edema with danazol. Ann Intern Med. 1980;93:809-12. 4. Madanes AE, Farber M. Danazol. Ann Intern Med. 1982;96:625-30. 5. Ahn YS, Rocha R, Antunez J, Garcia R, Mylvaganam R, Harrington WJ. Long term danazol therapy for idiopathic secondary autoimmune hemolytic anemias [Abstract 700]. Blood. 1989;74:187a.
Measles Vaccine and Travelers To the Editor: The need for adequate immunity to measles in international travelers, outlined by Hill and Pearson (1) and von Reyn and Saviteer ( 2 ) , is clear cut. These authors have not adequately emphasized, however, the logistic or financial impact that the administration of a live-virus vaccine such as the measles vaccine will have on the pretravel immunization protocols used by travel clinics. Well-defined administration guidelines for the spacing of live-antigen preparations with other live-virus preparations or with immune globulin (a biological given to virtually all travelers to the developing world) will-with the addition of measles vaccine-ultimately lead to the inconvenience and expense of additional pretravel clinic visits for many persons. Unlike killed vaccines that can be administered at any time, live-virus vaccines like measles must gener-
ally be administered at least 2 weeks before or 3 months after immune globulin ( 3 ) . Two of the most commonly used live-virus "travel" vaccines-yellow fever and oral polio vaccines-are exceptions and can be administered at the same time as immune globulin. Therefore, many persons have up until now required only a single clinic visit before travel. The expense and inconvenience caused by the extra clinic visit required to administer measles vaccine must be added to the $18 cost Drs. Hill and Pearson (1) quoted for each dose. Our experience is that a large proportion of persons come to travel clinics a week or two before departure requesting an immune globulin shot and a prescription for malaria prophylaxis. Logistic and compliance issues will arise after these persons are informed that they must incur the cost and inconvenience of an extra clinic visit along with the cost of the actual measles vaccine and will have to wait 2 weeks to receive the immune globulin they originally came for. Alternatively, for travelers who come in less than 2 weeks before travel or who refuse a second visit, the measles vaccine can be administered at the same time as the immune globulin, realizing that a suboptimal response to measles will occur and they will have to be revaccinated against measles later. This approach not only entails an additional clinic visit but also the cost of a second dose of vaccine. Clearly, measles prophylaxis for international travel is indicated. Integrating this vaccine into the clinical practice of travel medicine, however, will not be as trivial as intimated in the editorial by Drs. Hill and Pearson. David O. Freedman, MD University of Alabama at Birmingham Travelers Health Clinic Birmingham, A L 35294 References 1. Hill DR, Pearson RD. Measles prophylaxis for international travel [Editorial]. Ann Intern Med. 1989;111:699-700. 2. von Reyn CF, Saviteer SM. Measles immunization for international travelers [Letter]. Ann In tern Med. 1989;111:766-7. 3. General recommendations on immunization. MMWR. 1989;38:20514, 219-27.
In response: We appreciate the letter from Dr. Freedman addressing our recommendations ( 1 ) . We obviously agree with Dr. Freedman's comment that "measles prophylaxis for international travel is indicated," but we strongly disagree that we have "trivialized" its integration into clinical practice. Indeed, in our editorial we carefully examined the data on measles in travelers in order to provide appropriate recommendations. These recommendations are in keeping with recent changes in measles immunization for all persons (2, 3 ) . Although the addition of the live, attenuated measles vaccine to pretravel immunizations requires careful planning on the part of both physician and traveler, we disagree that its administration will either be a major inconvenience or expense. Many, if not most,
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physicians in emporiatrics do not charge an additional consultation fee for travelers who need to return a second or third time to complete immunizations before a given trip. Dr. Freedman already agrees with us that the cost of the measles vaccine itself is justified as analyzed in our editorial. Therefore, only the potential inconvenience of a second visit for the proper spacing of vaccines is an issue. In our experience, nearly 5 0 % of travelers already return for a second visit because they need other immunobiologics or want to receive immune globulin close to their departure date. The importance of receiving optimal protection overrides this type of inconvenience for travelers. Dr. Freedman also questioned how best to handle travelers who wait until 2 weeks of departure before seeking advice. In the experience of the International Traveler's Medical Service at the University of Connecticut, where 2100 travelers have been seen, 2 9 % are first seen by the service within 2 weeks of travel. Of these, only 2 7 % , or 8% of all travelers, are candidates for measles vaccination by virtue of being born in 1957 or later. Some in this group are immune owing to natural measles whereas others have already received a second dose of the vaccine. Therefore, only a small percentage of travelers are faced with the dilemma of needing measles vaccination in close temporal proximity to immune globulin. In that situation, we explain to the patient the relative risks of measles (3 to 30 cases per 1 000 000 travelers) compared with hepatitis A (1 to 10 cases per 1000 travelers for a 3-week stay) ( 1 , 4 ) . In almost all instances, the traveler chooses to receive immune globulin. A traveler who waits until the last minute to seek pretravel medical advice cannot expect to always receive optimal prophylactic measures before his or her trip. The need for the spacing of immunobiologics applies to typhoid, rabies, hepatitis B, and other vaccines as well as measles. The scenario of a traveler presenting within 2 weeks of departure stresses the importance of primary care physicians, travel agents, and
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perhaps even airlines in informing patients of potential medical risks and encouraging them to plan ahead in order to obtain optimal pretravel preparation. DavidR. Hill, MD The University of Connecticut Health Center Farmington, CT 06032 Richard D. Pearson, MD University of Virginia Health Sciences Center Charlottesville, VA 22908 References 1. Hill DR, Pearson RD. Measles prophylaxis for international travel [Editorial]. Ann Intern Med. 1989;11:699-700. 2. Measles: reassessment of current immunization policy. American Academy of Pediatrics, Committee on Infectious Diseases. American Academy of Pediatrics News. 1989;5:6. 3. Measles prevention: recommendations of the Immunization Practices Advisory Committee ( A C I P ) . MMWR. 1989;38:(Suppl 9). 4. Steffen R, Rickenbach M, Wilhelm U, Helminger A, Schar M. Health problems after travel to developing countries. / Infect Dis. 1987;156:84-91.
Correction: Human Immunodeficiency Virus (HIV) Infection and the Kidney To the Editor: Please note the correct citation (1) for the work cited as unpublished observations (page 35, second paragraph) in our article (2) appearing in the 1 January 1990 issue. Richard J. Glassock, MD Harbor-UCLA Medical Center Torrance, C A 90509 References 1. Tang WW, Feinstein EI, Massry SG. Hyponatremia in patients with acquired immunodeficiency syndrome (AIDS) and the AIDS related complex ( A R C ) . Kidney Int. 1988;33:211. 2. Glassock RJ, Cohen AH, Danovitch G, Parsa KP. Human immunodeficiency virus (HIV) infection and the kidney. Ann Intern Med. 1990;112:35-49.
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Letters submitted for possible publication must be identified as such and submitted with a signed transfer-of-copyright form (see Table of Contents for location). Text length must not exceed 400 words. No more than five references may be used; reference format must be that specified in "Information for Readers and Authors." Letters must have no more than three authors. All parts of letters must be typed double-spaced, including references. Letters not typed double-spaced will not be considered for publication. Tables and figures will not be published. Acceptance of letters for publication depends on several factors: newness of information, relevance to current topics and recent content of this journal, clarity of statement, distribution of topics within this section, conformity to acceptable formats, and space available; only about half of the letters submitted can be published. The Editor reserves the right to shorten letters and make changes to our style. Authors of letters to be published will be notified of their acceptance. Unpublished letters are returned only on request.
Hyperkalemia Associated with Diarrhea To the Editor: Severe hyperkalemia, which may produce muscle weakness and cardiac arrhythmias, is a recognized complication of renal failure. We report two cases of life-threatening hyperkalemia in patients on chronic dialysis in whom profuse diarrhea was the dominant symptom. Hemofiltration was begun in a 61-year-old woman with reflux nephropathy because of hypotension during hemodialysis. At each hemofiltration one-third of her body weight was replaced with fluid containing an intended 1 m m o l / L KC1. Immediately after the first treatment she developed nausea, vomiting, abdominal pain, and profuse diarrhea that resolved before her next treatment. Similar symptoms, lasting 24 to 36 hours, occurred after each subsequent hemofiltration. Shortly after her sixth treatment she also had chest pain, dyspnea, and palpitations, and collapsed at home. At admission to the hospital an electrocardiogram showed a broad complex tachycardia with peaked T-waves and runs of ventricular tachycardia. Her plasma potassium was 9.5 m m o l / L . Hemodialysis against a 1-mM KC1 dialysate lowered her plasma potassium to 3.8 m m o l / L with prompt relief of symptoms, however, recurrent hyperkalemia necessitated two further dialyses in the next 48 hours. Her diarrhea
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ceased at admission and a fecal sample was not available for some days. A 69-year-old man with end-stage renal failure of unknown origin had been on hemofiltration for six consecutive sessions over 2 weeks. He also described mild nausea and profuse diarrhea occurring after each hemofiltration treatment, associated with severe progressive weakness and recurrent palpitations. A physical examination was normal and an electrocardiogram showed only peaked T-waves. His plasma potassium was 9.1 m m o l / L and fell to 4.2 m m o l / L after 3.5 hours of hemodialysis against a 1-mmol/L KC1 dialysate. However, two more dialyses were needed in the next 36 hours to control hyperkalemia. During this period his symptoms resolved completely. As with the first patient, his diarrhea ceased after dialysis. It was later discovered that, through a manufacturer's error, these patients had received a hemofiltration replacement fluid with 10.5 to 11.6 m m o l / L KC1. Thus they would have received acute potassium loads of 180 mmol (Patient 1) to 200 mmol (Patient 2) in the course of each hemofiltration session to cumulative loads of 1080 to 1200 mmol, respectively. The striking feature of their clinical presentation was the occurrence of profuse diarrhea after each hemofiltration. N o other cause was found and the diarrhea ceased immediately when the hyperkalemia was corrected. No family members or other patients in the unit reported similar symptoms. Although colonic potassium excretion rises in response to chronic total body potassium excess and may act to maintain potassium balance in uremia ( 1 ) , acute diarrhea associated with acute hyperkalemia has not been previously reported. In animal studies, however, hyperkalemia has been reported (2) to stimulate an increase in gut motility. We suggest that the diarrhea our patients had was caused by acute hyperkalemia and may have protected them from an otherwise potentially fatal potassium load. Alpha S. Yap, B Med Sci, MB BS Gregory I. Hockings, MB BS Philip D. Boyle, MB BS Royal Brisbane Hospital Brisbane, Queensland, Australia 4029
References 1. Hayslett JP, Binder HJ. Mechanism of potassium adaptation. Am J Physiol. 1982;243:F103-12. 2. Daniel EE. Pharmacology of the gastrointestinal tract. In: Code CF, ed. Handbook of Physiology, v 4. Washington DC: American Physiological Society; 1968:2267-324.
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Ulcerative Colitis and Marijuana To the Editor: The apparent protective effect of cigarette smoking on ulcerative colitis (1) suggests that inhaled plant products might affect the disease process. We report a case suggesting a relation between ulcerative colitis and smoking marijuana. In 1972, a 23-year-old woman developed abdominal pain, diarrhea, and rectal bleeding. Sigmoidoscopy to 15 cm revealed diffuse cobblestone ulcerations, and a single-contrast barium enema showed numerous small marginal irregularities in the distal sigmoid and rectum. Ulcerative colitis was diagnosed, and her symptoms waxed and waned despite treatment with sulfasalazine, librax, and intermittent prednisone. Discouraged, she stopped all medications in 1975. In 1976, she noted that smoking marijuana resulted in fewer stools, more stable body weight, and fewer, milder exacerbations. Her typical intake was a pipeful once or twice daily, which she maintained despite her dislike for its euphoric effects. Cessation repeatedly resulted in exacerbations within a few weeks; resumption led to some improvement in a day or two, with maximal effect after several weeks. She was smoking marijuana daily when, after having 2 months of symptoms, she was hospitalized at the Mary Hitchcock Memorial Hospital in 1983. She was febrile and had an erythrocyte sedimentation rate of 103 m m / h . Sigmoidoscopy to 16 cm showed diffuse small friable ulcerations with granularity. A biopsy of the lower rectal fold showed marked chronic inflammation extending into the submucosa without granulomas. She improved promptly with prednisone. At home she resumed taking marijuana. Over 15 months her prednisone dose was tapered and sulfasalazine therapy begun. Sigmoidoscopy to 20 cm was normal, and a single-contrast barium enema showed a diffuse granular pattern with a "pipe-like" appearance, compatible with inactive colitis. In 1986 she stopped both sulfasalazine and marijuana but within 2 months became symptomatic. Sulfasalazine was resumed with minimal relief, and 2 months later she resumed taking marijuana. Her symptoms improved within about a week, and in 2 months she was again in remission through 1988. The patient had started smoking cigarettes before the onset of the ulcerative colitis. She noted no relation to her symptoms and stopped smoking in 1982 for "health reasons." She thought her symptoms. worsened with coffee or alcohol and rarely drank either beverage. This case suggests marijuana may ameliorate ulcerative colitis, although an alternative explanation is the natural variation in the severity of its symptoms. It is not clear how tobacco or marijuana might have a beneficial effect. Suggested mechanisms for cigarettes include enhanced catecholamine release, disturbed prostaglandin production, and immunologic changes ( 1 ) . Cigarettes increase colonic motility and marijuana in large doses may cause diarrhea ( 2 ) , although it is difficult to relate these observations to ulcerative colitis. A few systemic effects are similar for both drugs. Both have been associated with T-cell suppression ( 3 ) , but
the relation of ulcerative colitis with immune disturbances is weak ( 4 ) . Interference with the pituitaryovarian axis can occur from either drug (2, 5); for tobacco, this interference seems to cause relative estrogen deficiency in women ( 5 ) . Through effects on estrogen receptors in the colon or changes in bile composition, such hormonal changes could conceivably affect the colon. Although an ameliorative effect of marijuana smoking on ulcerative colitis, if verified, would probably have little direct clinical relevance, it might lead to new therapy and help elucidate the disease. John A. Baron, MD, MS, MSc Richard D. Folan, MD Maurice L. Kelley Jr., MD Dartmouth-Hitchcock Medical Center Hanover, N H 03756 References 1. Cope EF, Heatley RV, Kelleher J, Lee PN. Cigarette smoking and inflammatory bowel disease: a review. Hum Toxicol. 1987;6:189-93. 2. Nahas GG. Toxicology and pharmacology. In: Nahas GG, ed. Marihuana in Science and Medicine. New York: Raven Press; 1984. 3. Holt PG, Keast D. Environmentally induced changes in immunological function: acute and chronic effect of inhalation of tobacco smoke and other atmospheric contaminants in man and experimental animals. Bacteriol Rev. 1977;41:205-16. 4. Kirsner JB, Shorter RG. Recent developments in nonspecific inflammatory bowel disease, part 2. NEnglJMed. 19*82;306:837-48. 5. Baron J A. Smoking and estrogen-related disease. Am J Epidemiol. 1984;119:9-22.
Parenteral Nutrition and Cancer Chemotherapy To the Editor: The Chief of Pharmacy eagerly presented me with a copy of a position paper by the American College of Physicians ( 1 ) . He needed an explanation because his impression from reading the article was that nutritional support had no place in the management of patients with cancer. I pointed out that although the first sentence in the "Rationale" section recognized malnutrition or a significant comorbidity in some patients with cancer, the first sentence of the second paragraph in the "Recommendations," stated, "Most patients in the studies reviewed were not severely malnourished." I explained that parenteral nutrition does not treat cancer. It treats or prevents progressive malnutrition associated with the compromise of normal nutriture either by direct infiltration or as the result of adjuvant therapy (24 ) . Its indication is to keep a patient alive who has a chance for cure or palliation, not allowing that patient to deteriorate and suffer potentially life-threatening complications of progressive malnutrition. He immediately understood and asked why a position taken by an august group like the American College of Physicians was based squarely on a false premise. I could not explain why and therefore request that the authors respond. Mitchell V. Kaminski Jr., MD Terri Haase, PA St. Mary of Nazareth Hospital Center Chicago, IL 60622
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References 1. American College of Physicians. Parenteral nutrition in patients receiving cancer chemotherapy. Ann Intern Med. 1989;110:734-6. 2. Muller JM, Dienst C, Brenner U, Pichlmaier H. Preoperative parenteral feeding in patients with gastrointestinal carcinoma. Lancet. 1982;1:68-71. 3. Bellantone R, Doglietto GB, Bossola M, et al. Preoperative parenteral nutrition in the high risk surgical patient. J PEN. 1988; 12:1957. 4. Muller JM, Keller HW, Brenner U, et al. Indications and effects of preoperative parenteral nutrition. World J Surg. 1986;10:53.
Allan 5. Detsky, MD, PhD University of Toronto Toronto, Ontario M 5 G 2C4 Reference 1. American College of Physicians. Parenteral nutrition in patients receiving cancer chemotherapy. Ann Intern Med. 1989;110:734-6.
Ethical Questions about Pay for Research In response: As outlined in our statement ( 1 ) , the investigators who did the randomized trials of parenteral nutritional support for patients undergoing intensive chemotherapy did so with the following rationale composed of three components: there was a known association between malnutrition and poor prognosis in cancer patients; patients undergoing intensive chemotherapy have a decreased tolerance for oral feeding; and, finally, parenteral nutritional support may maintain or improve the patients' nutritional status. It was hoped that maintenance or improvement in nutritional status might permit improved response to chemotherapy and protection from complications associated with malnutrition. As correctly pointed out by Dr. Kaminski and Ms. Haase, we do not believe that any of the trials were undertaken under the premise that nutritional support treats cancer. Unfortunately, the routine use of parenteral nutritional support for patients undergoing intensive chemotherapy was not associated with improved clinical outcomes in these trials and was associated with an increased risk of complications during the period of nutritional support. We believe that our analysis of these trials clearly shows this. The background paper that reviews the evidence in detail will be published shortly in the journal Nutrition. Dr. Kaminski and Ms. Haase note that "nutritional support is used to treat life-threatening degrees of malnutrition in patients with cancer at our institution." They correctly point out that our paper notes that most patients in studies reviewed were not severely malnourished. We did note that for these randomized trials the detrimental effects of parenteral nutritional support (that is, increased infections) seemed to be less in malnourished patients, and recommended that "in deciding to use such therapy in individual patients whose malnutrition is judged to be life-threatening, physicians should take into account possible exposure to increased risk." Thus, the recommendations do not preclude the use of parenteral nutritional support for patients who are malnourished before chemotherapy; unfortunately, we lack the data necessary to assess the overall effect of parenteral nutritional support during intensive chemotherapy in such patients. In addition, the recommendations do not preclude the use of nutritional support to treat life-threatening degrees of malnutrition for patients with cancer if the purpose of such support is to keep the patient alive while treating the patient with some other modality such as surgery for possible cure or palliation. Allison J. McGeer, MD Keith O'Rourke, MBA 472
To the Editor: Part 2 of The American College of Physicians' Ethics Manual (1) is first-rate throughout. Even I cannot find fault with it. I come from the school where a researcher was largely a "hired hand." I fear that not enough researchers will see the report; it needs wider distribution in purely scientifically oriented journals. One problem not discussed that needs guidelines is the question of pay for the scientific investigator. This problem is becoming bigger and bigger as more research is being financed by industry as well as through the usual sources. For example, should some investigators receive large stock options while others receive nothing? Must researchers patent their discoveries in order to receive some financial benefit instead of it all going to the company that manufactures a drug or apparatus? Is it sometimes ethical or acceptable to receive salaries from universities, government, and industry concurrently? These are all sticky subjects and I cannot blame the committee for keeping their distance. Someone must address these questions, however, and I hope it will be your very competent committee. Irvine H. Page, MD 100 Longwood Avenue Hyannis Port, M A 02647 Reference 1. American College of Physicians. American College of Physicians ethics manual. Part 2: The physician and society; research; lifesustaining treatment; other issues. Ann Intern Med. 1989;111:327-35.
Diclofenac Sodium and Bruising To the Editor: N o reports to date have described prolonged bleeding time and spontaneous bruising with the use of diclofenac sodium. A literature search {Index Medicus and Excerpta Medica) revealed a single study that described reversible inhibition of platelet aggregation without prolongation of bleeding time with the use of diclofenac sodium ( 1 ) . Moreover, the manufacturer (Geigy) reports no effect on bleeding time with its use ( 2 ) . We report a case of spontaneous bruising and prolongation of bleeding time temporally associated with the use of diclofenac sodium. An otherwise healthy 45-year-old woman complained of spontaneous bruising for 1 week. She denied any history of trauma or blood dyscrasias, but admitted to easy bruising in the past. The patient had been placed on diclofenac sodium (75 mg orally, twice a day) 5 months earlier for plantar fasciitis, which responded well to this therapy. She was on no other
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medication. She had extensive bruises over her abdomen and extremities. No petechiae or purpura was noted. Laboratory tests included a complete blood count, platelet count, prothrombin time, partial thromboplastin time, fibrinogen, fibrin split products, and bleeding time. The bleeding time was prolonged at 18.5 minutes (normal range, 2.3 to 9.5 min). The other laboratory values were within normal limits. A repeat bleeding time returned to normal (7.0 min) 36 hours after her last dose of diclofenac sodium. Diclofenac sodium was withdrawn with resolution of spontaneous bruising. Prolonged bleeding time and bruising have been demonstrated with other nonsteroidal antiinflammatory agents ( 3 ) . This case shows that these effects can also occur with diclofenac sodium. UriKhazan,MD Mary Toth, MD Anand Mutgi, MD Medical College of Ohio Toledo, O H 43699 References 1. Francis J L , Daws RF, Roath O S . The effect of diclofenac on platelet aggregation and post-operative bleeding. Hematol Rev Commun. 1988;2/3:283-91. 2. Physicians' Desk Reference. 43d ed. Oradel, New Jersey: Medical Economics Company; 1989:984-5. 3. Nadel J, Bruno J, Varady E J . Effect of naproxen and of aspirin on bleeding time and platelet aggregation. / Clin Pharmacol 1974;14:1975-82.
Heparin-Associated Thrombocytopenia and Immunoglobulin Therapy To the Editor: The report by Frame and associates (1) claims to "report the first case of severe heparinassociated thrombocytopenia complicated by intestinal bleeding and progressive thrombocytopenia that had intestinal bleeding stopped and normal platelet counts restored shortly after the administration of intravenous immunoglobulin." The patient, a 62-yearold woman who presented with deep venous thrombosis and pulmonary emboli, was subsequently found to have carcinoma of the colon. Her platelets were positive for P L A 1 antigen. Platelet and fibrinogen levels were low but fibrin split products were elevated. There were no data to rule in or out the diagnoses of heparinassociated thrombocytopenia or immune thrombocytopenia. Gastrointestinal bleeding (in this patient with colon carcinoma) occurred when she was on heparin, had been given warfarin, and while her platelet count was low. Recovery of the platelet count coincided with return of the fibrinogen level to normal. It is hard to reconcile the claims of the title and the first paragraph of this report with the data provided. It is impossible to define the role of the malignancy, parameters of disseminated intravascular coagulation, P L A 1 antigen, and heparin in this case. In addition, heparin-associated platelet aggregation remains positive for " m o n t h s " even after stopping heparin (2, 3) and could have been checked later in the course of this patient.
Finally, was informed consent obtained from this patient as she was given a previously untried therapy for her "heparin-associated thrombocytopenia"? Sucha Nand, MD Loyola University Stritch School of Medicine Maywood, IL 60153 Edward Hines Jr., Hospital Veterans Affairs Hines, IL 60141 References 1. Frame J N , Mulvey KP, Phares J C , Anderson M J . Correction of severe heparin-associated thrombocytopenia with intravenous immunoglobulin. Ann Intern Med. 1989;111:946-7. 2. King DJ, Kelton J G . Heparin-associated thrombocytopenia. Ann Intern Med. 1984;100:535-40. 3. Gall us AS, Goodall KT, Beswick W, Chesterman CN. Heparinassociated thrombocytopenia. Case report and prospective study. AustNZJMed. 1980;10:25-31.
In response: We welcome the opportunity to respond to Dr. Nand's comments about our recent report ( 1 ) . We believe there is reasonable clinical evidence to support a diagnosis of heparin-associated thrombocytopenia as we outlined and referenced ( 1 ) . Further evidence to support this diagnosis arises from the development of thrombocytopenia on heparin rechallenge for recurrent thrombotic episodes later in the patient's clinical course ( 2 ) . We agree with Dr. Nand that platelet aggregation testing may remain positive after withdrawal of heparin in this disorder. This test has been reported (3) to be negative, however, in a significant number of patients, thus limiting its clinical usefulness as a diagnostic tool. Because heparinassociated thrombocytopenia remains a clinical diagnosis of exclusion, we are not aware of data that absolutely require in-vitro demonstration of an underlying immune mechanism for the thrombocytopenia or tests for platelet aggregation to establish this diagnosis. Although the mechanism of this disorder is under investigation, there is growing evidence, as referenced in our report, of an immune-mediated mechanism for heparin-associated thrombocytopenia. We believe such data warranted the consideration of this possibility in our patient. Dr. Nand addresses a broader issue for defining the role of the malignancy, parameters of disseminated intravascular coagulation, P L A 1 antigen, and heparin. Gastrointestinal bleeding during anticoagulant therapy may be a harbinger of an underlying lesion in the gastrointestinal tract ( 4 ) . This proved to be the case in our patient. The patient's underlying colon carcinoma, however, may have been unmasked by the complicating thrombocytopenia. As we cited in our report ( 1 ) , hypofibrinogenemia and increased fibrin degradation products have been reported in some patients with heparin-associated thrombocytopenia. Although the mechanism of these abnormalities is open to speculation ( 5 ) , we do not believe this sufficiently detracts from a diagnosis of heparin-associated thrombocytopenia. The presence of the P L A 1 antigen excludes the diagnosis of " P L A 1 antigen-negative" post-transfusion
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purpura. The role of heparin in this patient has been previously discussed. We do not share Dr. Nand's difficulty in reconciling our findings. That a platelet transfusion was administered after the initial dose of immunoglobulin and subsequent doses of immunoglobulin alone were given does not exclude a causal role for intravenous immunoglobulin given the temporal relationship of the reported observations. We are cautious in interpreting the results from a single patient and support further study into the nature of these clinical findings. Informed consent was obtained. The views expressed in this letter are those of the authors and do not reflect the official policy or position of the Department of the Navy, the Department of Defense, or the U.S. Government. James N. Frame, MD Kevin P. Mulvey, MD John C. Phares, MD Michael J. Anderson, MD National Naval Medical Center Bethesda, M D 20814-5000 References 1. Frame JN, Mulvey KP, Phares JC, Anderson MJ. Correction of severe heparin-associated thrombocytopenia with intravenous immunoglobulin. Ann Intern Med. 1989;111:946-7. 2. Sheridan D, Carter C, Kelton JG. A diagnostic test for heparininduced thrombocytopenia. Blood. 1986;67:27-30. 3. King DJ, Kelton JG. Heparin-associated thrombocytopenia. Ann Intern Med. 1984;100:535-40. 4. Mosley DH, Schatz IJ, Breneman GH, Keyes JW. Long-term anticoagulant therapy: complications and control in a review of 978 cases. JAMA. 1963;186:914-6. 5. Bell WR, Tamasulo PA, Alving BA, Duffy TP. Thrombocytopenia occurring during the administration of heparin. Ann Intern Med. 1976;85:155-60.
Danazol and Idiopathic Thrombocytopenic Purpura To the Editor: Does long-term treatment with danazol really benefit patients with autoimmune thrombocytopenia? Unfortunately, Dr. Ahn and colleagues (1) have not answered this question convincingly because their study did not incorporate controls who were not treated with danazol. The improved platelet counts observed in this uncontrolled "before and after" experiment could possibly have been due to factors other than danazol alone, for example, spontaneous improvement, placebo response, potentiation of the effects of glucocorticoids, or a combination of these effects. A study incorporating a placebo control group would answer these objections and would also be completely ethical because all subjects could receive therapy of proven value for the disease (glucocorticoids or splenectomy, or b o t h ) . In the absence of a long-term prospective randomized double-blind placebo-controlled study, the authors have yet to show that danazol is superior to placebo in the treatment of autoimmune thrombocytopenia. Because treatment with danazol may be accompanied by severe adverse effects, including amenorrhea 474
and masculinization in females and cholestatic jaundice (2), the authors' recommendations regarding the use of this experimental drug in autoimmune thrombocytopenia should be received with caution. Michael Phillips, MD St. Vincent's Medical Center of Richmond Staten Island, N Y 10310-1699 References 1. Ahn YS, Rocha R, Mylvaganam R, Garcia R, Duncan R, Harrington WJ. Long-term danazol therapy in autoimmune thrombocytopenia: unmaintained remission and age-dependent response in women. Ann Intern Med. 1989;111:723-9. 2. Androgens. In: McEvoy GK, ed. American Hospital Formulary Service Drug Information 89. Bethesda, Maryland: American Society of Hospital Pharmacists. 1989:1685-7.
In response: We have cared for approximately 2000 patients with idiopathic thrombocytopenic purpura. In our clinic, we do not include under the designation "idiopathic" the postviral syndrome of childhood or thrombocytopenia seen in such diverse settings as collagen vascular diseases, lymphomas, or drug sensitivities. Idiopathic thrombocytopenic purpura is usually a lifelong disorder with a generally predictable clinical course. It usually improves with therapy and relapses on its withdrawal. Spontaneous remissions in adults with chronic idiopathic thrombocytopenic purpura are rare. In the series we described ( 1 ) , because glucocorticoids were tapered off completely in 8 0 % of the patients, potentiation of glucocorticoid effect does not apply. The time for responses to danazol also assumed a definite pattern: in early responders ( 7 1 % ) it took 0.5 to 2 months whereas in late responders ( 2 7 % ) it took 4 to 10 months ( 1 ) . Late responses are also seen in paroxysmal nocturnal hemoglobinuria and cyclic thrombocytopenia (2) where complete cessation of transfusion requirement and amelioration of cycling of thrombocytopenia followed about 10 months of therapy. Could a tripling of platelet counts in a predictable time after treatment in 58 of 96 patients, most of whom were entirely weaned away from glucocorticoids and who had had idiopathic thrombocytopenic purpura for decades be due to "placebo effect" or "spontaneous" remission? A carefully controlled study is required for treatments with marginal therapies but is not a prerequisite for treatments with obvious clinical efficacy. Digitalis in heart failure was not proved by a controlled study nor glucocorticoids in idiopathic thrombocytopenic purpura or rheumatoid arthritis. For a controlled study, prognostic factors must be controlled in the design or in the analysis. Prognostic factors for this disorder have not been systematically investigated, although our study showed that age, sex, and status of splenectomy are determining factors. There must be other unknown factors (for example, immunologic variables, target antigens, H L A type). Without knowing such prognostic factors in the con-
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trol population, a "controlled study" is not really controlled. We cited (1) nine other papers that independently confirmed our positive results with danazol in this disorder. We observed no "severe adverse effects"; if they were incipient, they were reversible ( 1 ) . Our observations were consistent with an earlier study on longterm danazol therapy in patients with angioneurotic edema ( 3 ) ; abnormal liver function associated with danazol therapy is dose-related and reversible. Benefits included freedom from the inevitable side effects of glucocorticoids and life-threatening hemorrhage. Further, many patients now have been in complete remission for up to 5 years (that is, without further treatment). Indeed, perhaps the most remarkable result of our study is the finding of unmaintained lasting remission in autoimmune disease after prolonged danazol therapy. Similar observations have been made in patients with endometriosis (4) and autoimmune hemolytic anemia ( 5 ) . Elucidation of the mechanism of action of danazol and further refinements in its use would be of great value in the management of idiopathic thrombocytopenic purpura and other autoimmune diseases. Yeon S. Ahn, MD William J. Harrington, MD Robert C. Duncan, PhD University of Miami School of Medicine Miami, F L 33136 References 1. Ahn YS, Mylvaganam R, Rocha R, Garcia R, Duncan R, Harrington WJ. Long-term danazol therapy in autoimmune thrombocytopenia: unmaintained remission and age-dependent response in women. Ann Intern Med. 1989;111:723-9. 2. Rocha R, Ahn YS, Mylvaganam R, Harrington WJ. Danazol therapy for cyclic thrombocytopenia [Abstract]. Blood. 1988;72:1254a. 3. Hosea SW, Santaella ML, Brown EJ, Berger M, Katusha K, Frank MM. Long-term therapy of hereditary angioneurotic edema with danazol. Ann Intern Med. 1980;93:809-12. 4. Madanes AE, Farber M. Danazol. Ann Intern Med. 1982;96:625-30. 5. Ahn YS, Rocha R, Antunez J, Garcia R, Mylvaganam R, Harrington WJ. Long term danazol therapy for idiopathic secondary autoimmune hemolytic anemias [Abstract 700]. Blood. 1989;74:187a.
Measles Vaccine and Travelers To the Editor: The need for adequate immunity to measles in international travelers, outlined by Hill and Pearson (1) and von Reyn and Saviteer ( 2 ) , is clear cut. These authors have not adequately emphasized, however, the logistic or financial impact that the administration of a live-virus vaccine such as the measles vaccine will have on the pretravel immunization protocols used by travel clinics. Well-defined administration guidelines for the spacing of live-antigen preparations with other live-virus preparations or with immune globulin (a biological given to virtually all travelers to the developing world) will-with the addition of measles vaccine-ultimately lead to the inconvenience and expense of additional pretravel clinic visits for many persons. Unlike killed vaccines that can be administered at any time, live-virus vaccines like measles must gener-
ally be administered at least 2 weeks before or 3 months after immune globulin ( 3 ) . Two of the most commonly used live-virus "travel" vaccines-yellow fever and oral polio vaccines-are exceptions and can be administered at the same time as immune globulin. Therefore, many persons have up until now required only a single clinic visit before travel. The expense and inconvenience caused by the extra clinic visit required to administer measles vaccine must be added to the $18 cost Drs. Hill and Pearson (1) quoted for each dose. Our experience is that a large proportion of persons come to travel clinics a week or two before departure requesting an immune globulin shot and a prescription for malaria prophylaxis. Logistic and compliance issues will arise after these persons are informed that they must incur the cost and inconvenience of an extra clinic visit along with the cost of the actual measles vaccine and will have to wait 2 weeks to receive the immune globulin they originally came for. Alternatively, for travelers who come in less than 2 weeks before travel or who refuse a second visit, the measles vaccine can be administered at the same time as the immune globulin, realizing that a suboptimal response to measles will occur and they will have to be revaccinated against measles later. This approach not only entails an additional clinic visit but also the cost of a second dose of vaccine. Clearly, measles prophylaxis for international travel is indicated. Integrating this vaccine into the clinical practice of travel medicine, however, will not be as trivial as intimated in the editorial by Drs. Hill and Pearson. David O. Freedman, MD University of Alabama at Birmingham Travelers Health Clinic Birmingham, A L 35294 References 1. Hill DR, Pearson RD. Measles prophylaxis for international travel [Editorial]. Ann Intern Med. 1989;111:699-700. 2. von Reyn CF, Saviteer SM. Measles immunization for international travelers [Letter]. Ann In tern Med. 1989;111:766-7. 3. General recommendations on immunization. MMWR. 1989;38:20514, 219-27.
In response: We appreciate the letter from Dr. Freedman addressing our recommendations ( 1 ) . We obviously agree with Dr. Freedman's comment that "measles prophylaxis for international travel is indicated," but we strongly disagree that we have "trivialized" its integration into clinical practice. Indeed, in our editorial we carefully examined the data on measles in travelers in order to provide appropriate recommendations. These recommendations are in keeping with recent changes in measles immunization for all persons (2, 3 ) . Although the addition of the live, attenuated measles vaccine to pretravel immunizations requires careful planning on the part of both physician and traveler, we disagree that its administration will either be a major inconvenience or expense. Many, if not most,
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physicians in emporiatrics do not charge an additional consultation fee for travelers who need to return a second or third time to complete immunizations before a given trip. Dr. Freedman already agrees with us that the cost of the measles vaccine itself is justified as analyzed in our editorial. Therefore, only the potential inconvenience of a second visit for the proper spacing of vaccines is an issue. In our experience, nearly 5 0 % of travelers already return for a second visit because they need other immunobiologics or want to receive immune globulin close to their departure date. The importance of receiving optimal protection overrides this type of inconvenience for travelers. Dr. Freedman also questioned how best to handle travelers who wait until 2 weeks of departure before seeking advice. In the experience of the International Traveler's Medical Service at the University of Connecticut, where 2100 travelers have been seen, 2 9 % are first seen by the service within 2 weeks of travel. Of these, only 2 7 % , or 8% of all travelers, are candidates for measles vaccination by virtue of being born in 1957 or later. Some in this group are immune owing to natural measles whereas others have already received a second dose of the vaccine. Therefore, only a small percentage of travelers are faced with the dilemma of needing measles vaccination in close temporal proximity to immune globulin. In that situation, we explain to the patient the relative risks of measles (3 to 30 cases per 1 000 000 travelers) compared with hepatitis A (1 to 10 cases per 1000 travelers for a 3-week stay) ( 1 , 4 ) . In almost all instances, the traveler chooses to receive immune globulin. A traveler who waits until the last minute to seek pretravel medical advice cannot expect to always receive optimal prophylactic measures before his or her trip. The need for the spacing of immunobiologics applies to typhoid, rabies, hepatitis B, and other vaccines as well as measles. The scenario of a traveler presenting within 2 weeks of departure stresses the importance of primary care physicians, travel agents, and
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perhaps even airlines in informing patients of potential medical risks and encouraging them to plan ahead in order to obtain optimal pretravel preparation. DavidR. Hill, MD The University of Connecticut Health Center Farmington, CT 06032 Richard D. Pearson, MD University of Virginia Health Sciences Center Charlottesville, VA 22908 References 1. Hill DR, Pearson RD. Measles prophylaxis for international travel [Editorial]. Ann Intern Med. 1989;11:699-700. 2. Measles: reassessment of current immunization policy. American Academy of Pediatrics, Committee on Infectious Diseases. American Academy of Pediatrics News. 1989;5:6. 3. Measles prevention: recommendations of the Immunization Practices Advisory Committee ( A C I P ) . MMWR. 1989;38:(Suppl 9). 4. Steffen R, Rickenbach M, Wilhelm U, Helminger A, Schar M. Health problems after travel to developing countries. / Infect Dis. 1987;156:84-91.
Correction: Human Immunodeficiency Virus (HIV) Infection and the Kidney To the Editor: Please note the correct citation (1) for the work cited as unpublished observations (page 35, second paragraph) in our article (2) appearing in the 1 January 1990 issue. Richard J. Glassock, MD Harbor-UCLA Medical Center Torrance, C A 90509 References 1. Tang WW, Feinstein EI, Massry SG. Hyponatremia in patients with acquired immunodeficiency syndrome (AIDS) and the AIDS related complex ( A R C ) . Kidney Int. 1988;33:211. 2. Glassock RJ, Cohen AH, Danovitch G, Parsa KP. Human immunodeficiency virus (HIV) infection and the kidney. Ann Intern Med. 1990;112:35-49.
15 March 1990 • Annals ofInternal Medicine • Volume 112 • Number 6
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