Letters
The Editors welcome submissions for possible publication in the Letters section. Authors of letters should: • Include no more than 400 words of text, three authors, and five references • Type with double-spacing • Send three copies of the letter and a transfer-of-copyright form (see Table of Contents for location) signed by all authors • Provide a self-addressed envelope if they want to be notified that the letter was received Letters commenting on an Annals article will be considered if they are received within 6 weeks of the time the article was published. Only some of the letters received can be published. Published letters are edited and may be shortened; tables and figures are included only selectively. Authors will be notified that the letter has been received. If the letter is selected for publication, the author will be notified about 3 weeks before the publication date. Unpublished letters cannot be returned. MRFIT, " M S F I T , " and Alcohol Use To the Editors: Suh and colleagues (1) report results from the Multiple Risk Factor Intervention Trial (MRFIT) suggesting that for light- to moderate-drinking middle-aged men, the inverse association between alcohol consumption and coronary heart disease mortality can be explained largely by increased high-density lipoprotein (HDL) levels. What is not stated explicitly is that these results should not be generalized from middle-aged men to women. Women differ from men, particularly concerning alcohol. What is considered light to moderate drinking for men is potentially hazardous for women. More specifically, the risk for alcoholrelated morbidity begins to increase significantly at alcohol consumption above two drinks per day (2). This difference cannot be explained solely by differences in body weight or total body water. Women achieve higher blood alcohol levels than do men for an equal amount of alcohol consumed and an equal volume of distribution. The biochemical basis for this observation was elucidated by Frezza and colleagues (3) who showed that lower levels of gastric alcohol dehydrogenase cause decreased local metabolism and increased absorption of alcohol in women. Women also experience specific alcohol-related morbidities. The association between alcohol and breast cancer has been established in several large studies. The level of alcohol consumption conferring the increased risk is approximately three drinks per week (4), an amount significantly below what is considered heavy drinking even for women. The association between osteoporosis, hip fractures, and alcohol use is extremely pertinent to women (5). Similarly, the obstetric and gynecologic complications of alcohol use, including fetal alcohol syndrome, highlight the need for concern (2). Although we applaud the authors for cautioning that "alcohol consumption cannot be recommended because of the known adverse effects of excess alcohol u s e , " a specific warning should be added for women. The basic danger of generalizing results from the MRFIT trial of men to women patients is compounded by the known gender differences in alcohol metabolism and morbidity. We need to study "MS F I T " before jumping to any hasty and potentially dangerous conclusions. Michele G. Cyr, MD Anne W. Moulton, MD Michael D. Stein, MD Rhode Island Hospital Brown University School of Medicine Providence, RI 02903 874
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References 1. Suh I, Shaten J, Cutler J, Kuller LH. Alcohol use and mortality from coronary heart disease: the role of high-density lipoprotein cholesterol. Ann Intern Med. 1992;116:881-7. 2. Cyr MG, Moulton AW. Substance abuse in women. Obstet Gynecol Clin North Am. 1990;17:905-25. 3. Frezza M, DiPadova C, Pozzato G, Terpin M, Baraona E, Lieber CS. High blood alcohol levels in women: the role of decreased gastric alcohol dehydrogenase activity in first-pass metabolism. N Engl J Med. 1990;22:95-9. 4. Schatzin A, Jones Y, Hoover RN, Taylor PR, Brinton LA, Ziegler RG, et al. Alcohol consumption and breast cancer in the epidemiologic follow-up study of the First National Health and Nutrition Examination Survey. N Engl J Med. 1987;316:1169-80. 5. Felson DT, Kiel DP, Anderson JJ, Kannel WB. Alcohol consumption and hip fractures: the Framingham Study. Am J Epidemiol. 1988; 128:1102-10. To the Editors: I read with interest the recent article by Suh and colleagues (1). The authors confirm what has already been noted previously: that the moderate use of alcohol reduces mortality from coronary heart disease and that the mechanism may involve HDL cholesterol, which is increased by the ingestion of alcohol. Strangely, they conclude by saying that despite these observations, "alcohol consumption cannot be recommended because of the known adverse effects of excess alcohol u s e " (the underline is mine). By similar reasoning, then, one could not take an aspirin tablet daily prophylactically, because of the adverse effects of excessive ingestion of aspirin. Michael M. Karl, MD Washington University School of Medicine St. Louis, MO 63110 Reference 1. Suh I, Shaten J, Cutler J, Kuller LH. Alcohol use and mortality from coronary heart disease: the role of high-density lipoprotein cholesterol. Ann Intern Med. 1992;116:881-7. In response: We welcome the opportunity to respond to letters regarding our report on the association between alcohol consumption and coronary heart disease in the MRFIT study
a)We reported an epidemiologic finding that, in a cohort study, alcohol consumption appears to protect against coronary heart disease and that the protective mechanism is likely to be, in part, mediated through the elevated level of plasma HDL cholesterol. These findings were consistent with those of other investigators, including those who examined data from the Lipid Research Clinics (LRC) Follow-Up Study (which included both men and women) (2). However, we agree with the general concerns raised by Dr. Cyr and colleagues. In accordance with their position, the LRC Study found the minimum rate of age-adjusted, all-cause mortality at somewhat lower levels of alcohol consumption for women than for men (3). In response to Dr. Karl: Although an increase in alcohol consumption may raise levels of HDL cholesterol and reduce heart disease risk, it may also result in an increased risk of death or illness from other causes, including injuries. We do not know whether an increase of even one or two drinks per day is a risk factor for alcoholism and its known complications. Such an adverse effect could occur in relatively few persons. Increased alcohol consumption has also been associated with higher blood pressure levels and greater risk for stroke. Increased alcohol consumption could also result in
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higher rates of motor vehicle and other types of accidents. Thus, unlike aspirin, alcohol intake has the potential to harm not only the consumer but others as well. For these reasons, we reaffirm our conclusion. B. Jessica Shaten, MS, for the authors University of Minnesota Minneapolis, MN 55414 References 1. Suh I, Shaten BJ, Cutler JA, Kuller LH. Alcohol use and mortality from coronary heart disease: the role of high-density lipoprotein cholesterol. Ann Intern Med. 1992;116:881-7. 2. Criqui MH, Cowan LD, Tyroler HA, Bangdiwala S, Heiss G, Wallace RB, et al. Lipoproteins as mediators for the effects of alcohol consumption and cigarette smoking on cardiovascular mortality: results from the Lipid Research Clinics Follow-Up Study. Am J Epidemiol. 1987;126:629-37. 3. Criqui MH. The roles of alcohol in the epidemiology of cardiovascular disease. Acta Med Scand (Suppl). 1987;717:73-85.
Thrombosis in Antithrombin-III Deficiency To the Editors: Demers and colleagues (1) reported on the prevalence of thrombosis in antithrombin-III-deficient patients. They analyzed 31 patients from a large kindred and another 449 patients from 62 kindreds described in the literature. All had antithrombin-III quantitative deficiency or impairment in serine protease inactivation; families with isolated disturbance in heparin binding were not included. The pooled prevalence of venous thrombosis was found to be 51%. We analyzed 552 patients affected with (n = 344) or at high risk (0.5) for antithrombin-III deficiency (n = 208) and belonging to 40 different kindreds. Of 120 recorded deaths, 44 (36.7%) were attributed to venous thromboembolism; the median age at death was 36 years. The fatal episode was a thromboembolic recurrence in 22 cases. In 11 patients (25%) exposure to a risk factor (pregnancy and puerperium, surgery, bed immobilization) preceded thrombosis; this figure substantially supports their finding that 32% of thrombotic episodes were associated with risk factors (1). As Demers and colleagues pointed out, the reliability of the information obtained from the literature is limited, and a bias could result from a diagnostic suspicion related to the knowledge of patients' antithrombin-III-deficiency status. A postmortem examination was reported in 16 cases; in all of these, pulmonary embolism and mesenteric vein thrombosis were thought to be the cause of death. This yields a prevalence of 13% in the 120 patients who died. Because only a minority of patients had necropsy, this prevalence could have been underestimated. Nonetheless, it is definitely higher than the primary-cause mortality from venous thromboembolism seen in the general population, which was estimated to be between 0.3% (death certificates) and 2.4% (necropsy studies) (2). These findings do not necessarily conflict with a recent report showing no increased mortality in 10 Dutch antithrombin-III-deficient families (3), because in this study the cause of death was not investigated. The policy of prophylaxis in high-risk situations, recommended by Demers and colleagues, is further supported by the possibility of preventing 25% of the fatalities due to thrombosis in the antithrombin-III-deficient kindreds. The bleeding risk associated with oral anticoagulant prophylaxis in patients with inherited thrombophilia has been estimated to be 0.62 major episodes per 100 patient-years (4), so that treatment lasting 30 to 40 years could lead to a cumulative risk of about 20% to 25% in each patient. Nevertheless, we believe that in these patients the bleeding risk should be carefully weighed against their risk for a fatal thromboembolic episode. Further retrospective, multicenter surveys are needed to provide more information on this issue. Valerio De Stefano, MD Giuseppe Leone, MD Istituto di Semeiotica Medica Universita Cattolica 00168 Rome, Italy
References 1. Demers C, Ginsberg JS, Hirsh J, Henderson P, Blajchman MA. Thrombosis in antithrombin-III-deficient persons. Report of a large kindred and literature review. Ann Intern Med. 1992;116:754-61. 2. De Stefano V, Leone G. Mortality related to thrombosis in congenital antithrombin-III deficiency. Lancet. 1991;1:847-8. 3. Rosendaal FR, Heijboer H, Briet E, et al. Mortality in hereditary antithrombin-III deficiency—1830 to 1989. Lancet. 1991;1:260-2. 4. Finazzi G, Barbui T and the ad hoc Study Group. A retrospective study on oral anticoagulant prophylaxis in 103 Italian patients with hereditary thrombophilia and thrombosis. Res Clin Lab. 1990;20:24552. In response: We agree with De Stefano and Leone that the risk-benefit ratio should always be estimated when considering anticoagulant therapy in asymptomatic antithrombin-III-deficient patients. Management can include either prophylaxis in high-risk situations or lifelong anticoagulant prophylaxis. The former is more convenient and preferable, if safe. Implicit in these approaches is that after antithrombin-III-deficient patients experience an episode of venous thrombosis, lifelong anticoagulant therapy should be administered. Therefore, in asymptomatic carriers, lifelong anticoagulant therapy would be indicated if the incidence of unheralded spontaneous venous thrombosis were high and the first episode of venous thrombosis were often fatal. On the other hand, prophylaxis could be limited to high-risk situations if most episodes occurred then. De Stefano and colleagues reported 44 deaths attributed to venous thrombosis, 16 of which were confirmed by autopsy. Of these 44 deaths, 22 were due to episodes of recurrent venous thrombosis for which no information was provided about the use of oral anticoagulant therapy. If these patients had been receiving oral anticoagulant therapy, it is likely that most (or all) of the episodes would have been prevented. Of the remaining 22 patients who died with suspected thrombosis, we were not told the proportion of patients whose cause of death was confirmed by autopsy, nor whether the episodes of thrombosis were idiopathic or secondary. Only 11 of these 44 patients had risk factors, but reporting of risk factors is frequently inaccurate. Estimates of the incidence of fatal venous thrombosis are subject to reporting bias; an antithrombin-III-deficient family whose members had fatal episodes of thrombosis may be more likely to be reported than a family with no episodes of thrombosis. Still, certain families with antithrombin III deficiency may be more prone than others to fatal and nonfatal episodes of venous thrombosis. In summary, both the study by De Stefano and colleagues and ours suffer from being retrospective, and the estimates of the incidence of fatal and nonfatal venous thrombosis in antithrombin-III-deficient patients are probably unreliable. Rather than more retrospective studies, we believe multicenter, prospective cohort studies are needed. Christine Demers, MD Department D'Hematologie Hopital du Saint Sacrement Quebec G1S 4L8, Canada Jeffrey Ginsberg, MD McMaster University Medical Centre Hamilton, Ontario L8N 3Z5, Canada Jack Hirsh, MD Hamilton Civic Hospitals Research Centre Hamilton, Ontario L8V 1C3, Canada The Sweet Syndrome or G-CSF Reaction? To the Editors: Park and colleagues (1) describe the development of the Sweet syndrome in a woman receiving chemotherapy for breast cancer during treatment with subcutaneous granulocyte colony-stimulating factor (G-CSF). The authors largely base their diagnosis on a skin biopsy that showed a dermal neutrophilic infiltrate. They attribute the Sweet syndrome to treatment with G-CSF because the patient did not require corticosteroids and because the eruption resolved with termination of the G-CSF treatment. The Sweet syndrome is characterized histologically by a
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dense dermal and perivascular infiltrate composed largely of neutrophils without evidence of vasculitis (2). Granulocyte colony-stimulating factor, a hematopoietic growth factor, promotes the proliferation and differentiation of polymorphonuclear leukocytes and might create a predominantly neutrophilic infiltrate in the skin. Horn and associates (3) reported three patients (two with acute myelocytic leukemia and one with chronic myelogenous leukemia) who received granulocyte-macrophage colony-stimulating factor (GM-CSF) and who developed erythematous macules and papules paralleling the time of GM-CSF infusion and resolving with completion of the treatment. Histologic features of these lesions showed an upper dermal inflammatory cell infiltrate composed of neutrophils and mononuclear cells with an increased number and size of macrophages. The cutaneous eruption observed by Park and coworkers may represent this entity and not the Sweet syndrome. Debra Lynn Karp, MD Johns Hopkins Hospital Baltimore, MD 21205 References 1. Park JW, Mehrotra B, Barnett BO, Baron AD, Venook AP. The Sweet syndrome during therapy with granulocyte colony-stimulating factor. Ann Intern Med. 1992;116:996-8. 2. Lever WF, Schaumburg-Lever G. Histopathology of the Skin. Philadelphia: J.B. Lippincott Company; 1990:196. 3. Horn TD, Burke PJ, Karp JE, Hood AF. Intravenous administration of recombinant human granulocyte-macrophage colony-stimulating factor causes a cutaneous eruption. Arch Dermatol. 1991;127:49-52. In response: As Dr. Karp notes, Horn and colleagues described three patients in whom a generalized maculopapular eruption developed during intravenous granulocyte-macrophage colony-stimulating factor (GM-CSF) administration with subsequent desquamation (1). These lesions were not described as tender or painful and in one case were pruritic. These cases display very different clinical and histopathologic features than those found in our patient (2), and do not appear to represent the Sweet syndrome (3, 4). Our patient developed a plaque, pustules, and nodules that were not generalized and never showed desquamation. The lesions were intensely tender and painful, without pruritus. The eruptions described by Horn and associates occurred within 24 to 48 hours after starting GM-CSF at a time when the leukocyte count remained depressed; and none of their patients were described as ever demonstrating leukocytosis. In the Sweet syndrome, as in our patient, leukocytosis is a salient feature. The histopathologic findings reported by Horn and colleagues also do not suggest the Sweet syndrome. These patients showed dermal infiltration by mononuclear cells as well as neutrophils. The most striking finding was a great increase in size and number of macrophages (1). In our patient, on the other hand, skin biopsy showed much denser dermal infiltration by sheets of neutrophils, without any significant lymphocyte or macrophage infiltration. Although the cases reported by Horn and colleagues clearly represent a different clinical and histopathologic entity than our case, there may indeed be that some common pathogenetic mechanisms are involved. As we discuss in our report, both granulocyte colony-stimulating factor (G-CSF) and GM-CSF can exacerbate pre-existing inflammatory cutaneous disorders. The interesting observations of Horn and coworkers further support the idea that hematopoietic growth factor therapy can lead to inflammatory manifestations in the skin. John W. Park, MD Bryan O. Barnett, MD Alan P. Venook, MD University of California, San Francisco San Francisco, CA 94143
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SI Units and the Friedewald Formula To the Editors: Bagatell and colleagues (1) studied the effects of experimentally induced androgen deficiency on levels of serum lipoproteins. To estimate the low-density lipoprotein (LDL) cholesterol, they used the Friedewald formula (2), which they expressed as: LDL cholesterol = total cholesterol - (high-density lipoprotein cholesterol + [triglycerides -*• 5]). This formula works when conventional units (mg/dL) are used but is inadequate with Systeme International (SI) units (3). To be used with the latter, the triglycerides must be divided by 2.18 instead of by 5. Because the LDL cholesterol levels reported by the authors in their Table 1 are correct, I presume that they made the calculations using the conventional units before converting all their results to SI units. Because this is not mentioned in the Methods, the readers can be misled to think that the nonadapted equation is also applicable with SI units. In fact I have been guilty of the same misconception (4, 5). If authors of manuscripts wish to write down the Friedewald equation, they should use the adapted version or specify that it was applied before the conversion of results to SI units. Jacques Masse, MD, MSc Hopital du Saint Sacrement Quebec G1S 4L8, Canada References 1. Bagatell CJ, Knopp RH, Vale WW, Rivier JE, Bremmer WJ. Physiologic testosterone levels in normal men suppress high-density lipoprotein cholesterol levels. Ann Intern Med. 1992;116:967-73. 2. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma without the use of the preparative ultracentrifuge. Clin Chem. 1972;18:499-501. 3. Masse J. Changes in lipoproteins during weight loss [Letter]. N Engl J Med. 1989;320:668. 4. Masse J. Effects of fish-oil ingestion on cardiovascular risk factors [Letter]. Am J Clin Nutr. 1991;54:610-1. 5. Masse J. Lipoprotein(a) levels in black and white children and adolescents with IDDM [Letter]. Diabetes Care. 1991;14:1108-9. In response: In our study (1) we calculated LDL cholesterol in conventional units using the Friedewald formula (2). We then converted all the lipid data, including LDL cholesterol, to SI units. We thank Dr. Masse for pointing out that the Friedewald equation cannot be applied directly to data in SI units. Carrie J. Bagatell, MD Robert H. Knopp, MD William J. Bremner, MD, PhD Veterans Affairs Medical Center and Lipid Research Clinics University of Washington Seattle, WA 98108 References 1. Bagatell CJ, Knopp RH, Vale WW, Rivier JE, Bremmer WJ. Physiologic testosterone levels in normal men suppress high-density lipoprotein cholesterol levels. Ann Intern Med. 1992;116:967-73. 2. Friedewald WT, Levy RI, Frerickson DS. Estimation of the concentration of low density lipoprotein cholesterol in the plasma without the use of the preparative ultracentrifuge. Clin Chem. 1972; 18:499501. Watchful Waiting and Craniopharyngioma
References 1. Park JW, Mehrotra B, Barnett BO, Baron AD, Venook AP. The Sweet syndrome during therapy with granulocyte colony-stimulating factor. Ann Intern Med. 1992;116:996-8. 876
2. Horn TD, Burke PJ, Karp JE, Hood AF. Intravenous administration of recombinant human granulocyte-macrophage colony-stimulating factor causes a cutaneous eruption. Arch Dermatol. 1991;127:49-52. 3. Sweet RD. An acute febrile neutrophilic dermatosis. Br J Dermatol. 1864;76:349-56. 4. Kemmett D, Hunter JA. Sweet's syndrome: a clinicopathologic review of twenty-nine cases. J Am Acad Dermaol. 1990;12:503-7.
To the Editors: Craniopharyngiomas constitute 3% to 5% of all intracranial tumors in adults and about 15% in children. These tumors usually consist of solid cellular components and cystic areas containing oily mixtures of degenerated blood and desquamated epithelium or necrotic tissue with cholesterol
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crystals. Calcifications may be present in as many as 85% of cases and are detected by computed tomographic (CT) scan but not by magnetic resonance imaging (MRI) (1). Though usually slow-growing and almost always benign, they can invade various sellar and suprasellar tissues and cause significant pathology. Management has been primarily surgical, with radiation therapy as an adjunct. To our knowledge, the role of expectant management in the absence of major optic nerve compression and endocrine dysfunction has not been evaluated. We present a case report of such a management with a 6-year follow-up. A 35-year-old, white woman started having mild, frontal headaches and sinus complaints in 1985. Radiographs of the skull showed a markedly enlarged sella turcica. On referral to the National Institutes of Health Clinical Center, MRI of the head showed an intra- and suprasellar mass compressing the optic chiasm and the hypothalamus. A CT scan showed a 2.7 x 2-cm heterogeneous, partially calcified solid mass with a cystic component containing fluid. The imaging characteristics were consistent with craniopharyngioma. Anterior pituitary testing showed normal plasma concentrations of follicle-stimulating hormone, leutinizing hormone, estradiol, and prolactin; results of a 1-hour adrenocorticotropic hormone stimulation test were normal. Visual field examination showed a mild inferior nasal quadrant defect in the right eye and a relative superior small temporal quadrant defect with some minor involvement of the inferior temporal quadrant on the left side. The patient had regular cyclic menses and an uncomplicated pregnancy 1 year before presentation. The patient made the decision not to have neurologic surgery or radiotherapy and was followed regularly at frequent intervals for 2 years, despite strong reservations from the neurosurgery and radiotherapy services. She has been seen every 6 to 12 months with no change in symptoms, hormonal or visual test results, or imaging findings for over 6 years. Both surgery and radiotherapy of craniopharyngiomas have been associated with major complications and significant mortality. Intracerebral or epidural hemorrhages, cerebral infarction, blindness, hemiparesis, or Addisonian crises were noted in 43% of patients who had radical surgery alone and in 25% of patients who had limited surgery and postoperative radiotherapy (2). Thirty-eight percent to 42% of patients treated with radiotherapy alone, however, developed delayed side effects including optic atrophy, hypothalamic-pituitary dysfunction, brain necrosis, and induction of new tumors (3-5). Use of hormonal replacement has ranged from 87% to 100% with all forms of therapy (2). Perioperative mortality rates from 3% to 41% have been reported. Five-year survival rates are 71% with radical surgery, 100% with limited surgery and postoperative radiotherapy (2), and 89% with radiotherapy alone (3). Due to the high incidence of progressive and major morbidity as well as the significant mortality associated with currently recommended approaches, the role of frequent monitoring in the absence of major optic nerve compression and endocrine dysfunction needs to be evaluated. This patient represents a fine example of primum non nocere (first do no harm).
Cytomegalovirus-associated Gastric Ulcer To the Editors: Gastric ulceration in association with cytomegalovirus (CMV) most commonly occurs in immunocompromised patients (1, 2). We report a case of CMV-associated gastric ulceration in an immunosuppressed patient in whom healing of ulceration and rapid resolution of fever and constitutional symptoms occurred twice after treatment with ganciclovir. A 74-year-old woman presented with a 3-week history of fever, weight loss, and epigastric pain after meals. She had a history of autoimmune haemolytic anaemia (treated with azathioprine, 100 mg daily, and danazol), pernicious anaemia, renal impairment, and IgA deficiency. Gastroscopy showed shallow ulcers in the stomach, and histologic examination showed inflammatory cells containing inclusions typical of CMV. Neither malignant cells nor helicobacter were seen. Cytomegalovirus was cultured in gastric biopsies. Results of serologic tests for human immunodeficiency virus (HIV) were negative. Epigastric pain, fever, and constitutional symptoms rapidly resolved after treatment with ranitidine, 150 mg twice daily, and 3 weeks of intravenous ganciclovir, 2.5 mg/kg body weight twice daily (creatinine clearance, 40 mL/[min.l.73 m 2 ]). Gastroscopy showed healing of ulceration, and CMV could not be identified from biopsy samples. Two months later, identical symptoms recurred despite treatment with ranitidine. Recurrent ulceration was seen at gastroscopy, with positive CMV inclusions and culture. Ganciclovir was given as before with good symptomatic response, and follow-up gastroscopy showed healing and absence of CMV on biopsy samples. Ranitidine and maintenance ganciclovir, 10 mg/kg intravenously three times a week, were continued. Two months later, when epigastric pain developed, gastroscopy showed a nodular gastritis with histologically confirmed chronic inflammation. Neither CMV, helicobacter, nor malignant cells were identified. Ganciclovir was stopped. Three months later, epigastric pain, fever, diarrhea, and paranoid ideation occurred. Gastroscopy and sigmoidoscopy showed inflamed mucosa with positive staining and culture for CMV. Cytomegalovirus was also isolated from blood. Further investigation or therapy was refused, and the patient died. Resolution of epigastric pain, fever, and constitutional symptoms occurred on both occasions soon after commencement of ganciclovir, and follow-up gastroscopies showed complete healing and loss of CMV. Subsequent maintenance ganciclovir appeared effective initially but was stopped after a relapse of gastritis. The inability to identify CMV in association with nodular gastritis suggests that it may have had another etiology. The subsequent course argued for continuing maintenance gancyclovir, probably in higher doses (3). Wendy J. Munckhof, MBBS Michael J. Richards, MBBS Austin Hospital Heidelberg, Victoria, Australia References 1. Shuster L, Cox G, Bhatia P, Miner P. Gastric mucosal nodules due to cytomegalovirus infection. Dig Dis Sci. 1989;34:103-7. 2. Buhles WC Jr, Mastre BJ, Tinker AJ and the Syntex Collaborative Ganciclovir Treatment Study Group. Ganciclovir treatment of life- or sight-threatening cytomegalovirus infection: experience in 314 immunocompromised patients. Rev Infect Dis. 1988;10(Suppl 3):S495-506. 3. Balfour HH. Management of cytomegalovirus disease with antiviral drugs. Rev Infect Dis. 1990;12(Suppl 7):S849-60.
Fady I. Sharara, MD George P. Chrousos, MD Nicholas J. Patronas, MD National Institutes of Health Bethesda, MD 20892 References 1. Kaufman B. Perisellar lesions. In: Tavaras JM, Ferruci JT; eds. Radiology, v. 3. Philadelphia: J.B. Lippincott Co.; 1987:1-12. 2. Chen Wen B, et al. A comparison of the roles of surgery and radiation therapy in the management of craniopharyngiomas. Int J Radiation Oncology Biol Phys. 1989;15:17-24. 3. Flickinger J, et al. Megavoltage external beam irradiation of craniopharyngiomas: analysis of tumor control and morbidity. Int J Radiation Oncology Biol Phys. 1990;19:117-22. 4. Shillito J J r . Treatment of craniopharyngioma. Clin Neurosurg. 1985; 33:533-46. 5. Manaka S, Teramoto A, Takakura K. The efficacy of radiotherapy for craniopharyngioma. J Neurosurg. 1985;62:648-56.
Pancytopenia from Using Trimethoprim and Methotrexate To the Editors: Methotrexate is currently used for the treatment of psoriasis, asthma, rheumatoid arthritis, and cancer. Hazardous interactions may occur when combined with other drugs whose mechanism of action involves the same biochemical pathway. One such rarely described interaction is between low-dose, oral methotrexate and the antibiotic trimethoprim-
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sulfamethoxazole (TMP-SMX) resulting in marrow hypoplasia (1-3). A 58-year-old, white man with a long history of rheumatoid arthritis presented with symptoms and signs of prostatitis. His arthritis had been successfully managed with oral methotrexate, 7.5 mg weekly since 1988. A complete blood count showed a hemoglobin of 133 g/L, a hematocrit of 0.40, a leukocyte count of 8.7 x 10 6 /L, and a platelet count of 197 x 109/L. The patient's urine grew Escherichia coli, and the patient was started on a 6-week regimen of TMP-SMX. Results of further tests with intravenous pyelography and cystoscopy were normal. Four weeks after initiation of TMP-SMX therapy, symptoms of prostatitis had resolved, but the patient had hematuria, fatigue, decreased appetite, and orthostatic dizziness. A complete blood count showed a hemoglobin of 72 g/L, a hematocrit of 0.21, a leukocyte count of 2.0 x 10 6 /L, and a platelet count of 5 x 109/L with macrocytic red cells, absence of reticulocytes, and markedly hypersegmented neutrophils on the peripheral smear. The patient was hospitalized for transfusion of platelets and packed red blood cells, and all drugs were stopped. Examination of bone marrow showed hypocellularity with megaloblastic red-cell precursors and hypersegmented polys. Serum folate and vitamin B12 levels were normal. The patient was diagnosed with megaloblastic pancytopenia, secondary to methotrexate and TMP-SMX. Administration of oral leucovorin, 25 mg every 6 hours, was begun. Within 48 hours, early recovery of all hematopoietic cell lines was noted, and by discharge, 96 hours after leucovorin administration, the patient's complete blood count showed a hemoglobin of 106 g/L, a hematocrit of 0.32, a leukocyte count of 7.1 x 106/L, and a platelet count of 218 x 109/L.
Figure 1. Sites of major inhibition for methotrexate (MTX) and trimethoprim (TMP) and rescue by leucovorin of de novo purine synthesis and thymidylate (dTMP) production. CH 2 FH 4 = 5, 10-methylenetetrahydrofolate; 10-CHO-FH 4 = 10-formyltetrahydrofolate; DHFR = dihydrofolate reductase; dTMP = deoxythymidine monophosphate; dUMP = deoxyuridine monophosphate; FH 2 = dihydrofolate; FH 4 = tetrahydrofolate; T.S. = thymidylate synthase. Methotrexate is a dihydrofolate antagonist that binds to the catalytic site of dihydrofolate reductase (DHFR), interfering with the synthesis of de-novo purine nucleosides, conversion of uridylate to thymidylate, and synthesis of the amino acids serine and methionine (4) (Figure 1). The trimethoprim component of TMP-SMX also inhibits mammalian DHFR, although 10 000 times less efficiently than it inhibits bacterial DHFR (see Figure 1). The combination of low-dose methotrexate and TMP-SMX acted additively or synergistically to inhibit dihydrofolate reductase, producing a severe megaloblastic pancytopenia. Leucovorin or 5-folinic acid, a reduced folate analog, is frequently used to " r e s c u e " normal hematopoietic cells by substituting for folate later in the purine pathway, whereas DHFR remains inhibited by methotrexate (see Figure 1). 878
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Given the increasing use of low-dose methotrexate in patients with rheumatoid arthritis, asthma, and psoriasis as well as the routine use of TMP-SMX, internists should be aware of the possibility of life-threatening pancytopenia. Joseph A. Govert, MD Suzanne Patton, MD, PhD Robert L. Fine, MD Duke University Medical Center Durham Veterans Affairs Medical Center Durham, NC 27705 References 1. Maricic M, Davis M, Gall E. Megaloblastic pancytopenia in a patient receiving concurrent methotrexate and trimethoprim-sulfamethoxazole treatment. Arthritis Rheum. 1986;29:133-5. 2. Thomas M, Gutterman L. Methotrexate toxicity in a patient receiving trimethoprim-sulfamethoxazole. J Rheum. 1986;13:440-1. 3. Groenendal H, Ram pen FH. Methotrexate and trimethoprim-sulfamethoxazole—a potentially hazardous combination. Clin Ex Derm. 1990;15:358-60. 4. Joviet J, Cowan K, Curt G, Glendeninn N, Chabner B. The pharmacology and clinical use of methotrexate. N Engl J Med. 1983;309: 1094-104.
Aging and Warfarin T h e r a p y To the Editors: Gurwitz and coworkers (1) purport to show that the anticoagulant response to warfarin increases with age due to an "increased sensitivity" to warfarin; however, the ratio of warfarin dose to prothrombin time response used by the authors as the principal measure of sensitivity does not allow the differentiation of pharmacokinetic variability from pharmacologic sensitivity. In a prospective study of 88 chronically treated outpatients, we snowed that age does not alter the pharmacodynamic response to warfarin (2). The study by Shepard and coworkers (3), cited in dismissing a change in warfarin pharmacokinetics with age, was limited by a small sample size and failure to use the most accurate warfarin assay (4). Our prospective study of 163 patients on chronic warfarin therapy showed that warfarin clearance, assayed by high-pressure liquid chromatography, decreased approximately 1% a year from 18 to 70 years of age (5). These data were used to generate initial estimates of warfarin pharmacokinetic and pharmacodynamic variables using the software program, Drugcalc (Medifore, Lansing, Michigan), which predicts the anticoagulant warfarin response to using the most widely accepted mathematic models of warfarin pharmacokinetics and dynamics. Entering hypothetical demographic data and steady-state warfarin doses into this program, we found that 25% to 70% of the rise in the dose-adjusted prothrombin ratio observed by Gurwitz and colleagues could be explained by age-related decreased clearance changes alone. Finally, the authors provide no data to support their suggestion that older patients need "scrupulous monitoring" of warfarin therapy. The important point for clinicians is that older patients require lower doses of warfarin, particularly during the initiation of warfarin therapy. Dennis Mungall, PharmD Ferris State University Big Rapids, MI Richard White, MD UC Davis Medical Center Sacramento, CA References 1. Gurwitz JH, Avorn J, Ross-Degnan D, Choodnovskiy I, Ansell J. Aging and the anticoagulant response to warfarin therapy. Ann Intern Med. 1992;116:901-4. 2. Murray B, Coleman R, McWarters D, Ludden T, Mungall D. Pharmacodynamics of warfarin at steady state. Therapeutic Drug Monit. 1987;9:1-5. 3. Sheparid AM, Hewick DS, Moreland TA, Stevenson IH. Age as a determinant of sensitivity to warfarin. Br J Clin Pharmacol. 1977;4: 315-20.
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4. Robinson CA, Mungall D, Poon MC. Quantitation of plasma warfarin concentrations by high performance liquid chromatography. Therapeutic Drug Monit. 1981;3:287-90. 5. Mungall DR, Ludden TM, Marshall J, Hawkins DW, Talbert RL, Crawford MH. Population pharmacokinetics of racemic warfarin in adult patients. J Pharmacok and Biopharm. 1985;13:213-26.
In response: Drs. Mungall and White do not appear to dispute our core finding that the anticoagulant response to warfarin is exaggerated with advancing age (1). The underlying mechanism is less clear. Although Shepherd and colleagues reported that warfarin pharmacokinetics do not change substantially with advancing age (2), Mungall and associates have reported an age-related reduction in warfarin clearance (3). Thus, it is plausible that the increased warfarin effect in older patients is at least partly the result of pharmacokinetic changes. We do not feel, however, that the findings of Murray and colleagues are sufficient to exclude the possibility of an important alteration in warfarin pharmacodynamics with aging (4). From a population standpoint, we agree that older patients require lower doses of warfarin than younger patients to achieve the same anticoagulant response. In clinical practice, dosing and monitoring of warfarin therapy go hand in hand. In managing individual patients, we believe that increased care in monitoring elderly patients on anticoagulant therapy is indicated. Jerry H. Gurwitz, MD Jerry Avorn, MD Harvard Medical School Boston, MA 02115
3. Mungall DR, Ludden TM, Marshall J, Hawkins DW, Talbert RL, Crawford MH. Population pharmacokinetics of racemic warfarin in adult patients. J Pharmacok Biopharm. 1985;13:213-27. 4. Murray B, Coleman R, McWaters D, Ludden T, Mungall D. Pharmacodynamics of warfarin at steady state. Ther Drug Monit. 1987;9:1-5.
Bearing Bad News To the Editors: I was very moved by Dr. Litwin's "Ode to J o y " (1) and at the same time was saddened by the failure of the attending physician to adequately prepare the intern to meet with the family. Thank God for the supportive nursing supervisor, Joy, who picked up the emotional pieces and taught the fledging intern how to communicate his caring to the patient's family. This failure is too often repeated in teaching hospitals. Housestaff and students are frequently asked to break bad news to patients and families without ever having this difficult role discussed or modeled for them by an expert clinician. We teachers have a lot of work to do to correct this situation. Richard H. Fine, MD University of California, San Francisco San Francisco General Hospital San Francisco, CA 94110 Reference 1. Litwin J. Ode to joy. Ann Intern Med. 1992; 117:337.
Correction
Jack Anselly MD University of Massachusetts Medical School Worcester, MA 01655 References 1. Gurwitz JH, Avorn J, Ross-Degnan D, Choodnovskiy I, Ansell J. Aging and the anticoagulant response to warfarin therapy. Ann Intern Med. 1992;116:901-4. 2. Shepherd AM, Hewick DS, Moreland TA, Stevenson IH. Age as a determinant of sensitivity to warfarin. Br J Clin Pharmacol. 1977;4: 315-20.
Resistance to Zidovudine and Alpha-Interferon An article (1) incorrectly noted the date of the symposium at which the paper was initially presented. The correct date is 20-24 June 1990. Reference 1. Edlin BR, St. Clair MH, Pitha PM, Whaling SM, King DM, Bitran JD, et al. In-vitro resistance to zidovudine and alpha-interferon in HIV-1 isolates from patients: correlations with treatment duration and response. Ann Intern Med. 1992;117:457-60.
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The Editors welcome submissions for possible publication in the Letters section. Authors of letters should: • Include no more than 400 words of text, three authors, and five references • Type with double-spacing • Send three copies of the letter and a transfer-of-copyright form (see Table of Contents for location) signed by all authors • Provide a self-addressed envelope if they want to be notified that the letter was received Letters commenting on an Annals article will be considered if they are received within 6 weeks of the time the article was published. Only some of the letters received can be published. Published letters are edited and may be shortened; tables and figures are included only selectively. Authors will be notified that the letter has been received. If the letter is selected for publication, the author will be notified about 3 weeks before the publication date. Unpublished letters cannot be returned. MRFIT, " M S F I T , " and Alcohol Use To the Editors: Suh and colleagues (1) report results from the Multiple Risk Factor Intervention Trial (MRFIT) suggesting that for light- to moderate-drinking middle-aged men, the inverse association between alcohol consumption and coronary heart disease mortality can be explained largely by increased high-density lipoprotein (HDL) levels. What is not stated explicitly is that these results should not be generalized from middle-aged men to women. Women differ from men, particularly concerning alcohol. What is considered light to moderate drinking for men is potentially hazardous for women. More specifically, the risk for alcoholrelated morbidity begins to increase significantly at alcohol consumption above two drinks per day (2). This difference cannot be explained solely by differences in body weight or total body water. Women achieve higher blood alcohol levels than do men for an equal amount of alcohol consumed and an equal volume of distribution. The biochemical basis for this observation was elucidated by Frezza and colleagues (3) who showed that lower levels of gastric alcohol dehydrogenase cause decreased local metabolism and increased absorption of alcohol in women. Women also experience specific alcohol-related morbidities. The association between alcohol and breast cancer has been established in several large studies. The level of alcohol consumption conferring the increased risk is approximately three drinks per week (4), an amount significantly below what is considered heavy drinking even for women. The association between osteoporosis, hip fractures, and alcohol use is extremely pertinent to women (5). Similarly, the obstetric and gynecologic complications of alcohol use, including fetal alcohol syndrome, highlight the need for concern (2). Although we applaud the authors for cautioning that "alcohol consumption cannot be recommended because of the known adverse effects of excess alcohol u s e , " a specific warning should be added for women. The basic danger of generalizing results from the MRFIT trial of men to women patients is compounded by the known gender differences in alcohol metabolism and morbidity. We need to study "MS F I T " before jumping to any hasty and potentially dangerous conclusions. Michele G. Cyr, MD Anne W. Moulton, MD Michael D. Stein, MD Rhode Island Hospital Brown University School of Medicine Providence, RI 02903 874
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References 1. Suh I, Shaten J, Cutler J, Kuller LH. Alcohol use and mortality from coronary heart disease: the role of high-density lipoprotein cholesterol. Ann Intern Med. 1992;116:881-7. 2. Cyr MG, Moulton AW. Substance abuse in women. Obstet Gynecol Clin North Am. 1990;17:905-25. 3. Frezza M, DiPadova C, Pozzato G, Terpin M, Baraona E, Lieber CS. High blood alcohol levels in women: the role of decreased gastric alcohol dehydrogenase activity in first-pass metabolism. N Engl J Med. 1990;22:95-9. 4. Schatzin A, Jones Y, Hoover RN, Taylor PR, Brinton LA, Ziegler RG, et al. Alcohol consumption and breast cancer in the epidemiologic follow-up study of the First National Health and Nutrition Examination Survey. N Engl J Med. 1987;316:1169-80. 5. Felson DT, Kiel DP, Anderson JJ, Kannel WB. Alcohol consumption and hip fractures: the Framingham Study. Am J Epidemiol. 1988; 128:1102-10. To the Editors: I read with interest the recent article by Suh and colleagues (1). The authors confirm what has already been noted previously: that the moderate use of alcohol reduces mortality from coronary heart disease and that the mechanism may involve HDL cholesterol, which is increased by the ingestion of alcohol. Strangely, they conclude by saying that despite these observations, "alcohol consumption cannot be recommended because of the known adverse effects of excess alcohol u s e " (the underline is mine). By similar reasoning, then, one could not take an aspirin tablet daily prophylactically, because of the adverse effects of excessive ingestion of aspirin. Michael M. Karl, MD Washington University School of Medicine St. Louis, MO 63110 Reference 1. Suh I, Shaten J, Cutler J, Kuller LH. Alcohol use and mortality from coronary heart disease: the role of high-density lipoprotein cholesterol. Ann Intern Med. 1992;116:881-7. In response: We welcome the opportunity to respond to letters regarding our report on the association between alcohol consumption and coronary heart disease in the MRFIT study
a)We reported an epidemiologic finding that, in a cohort study, alcohol consumption appears to protect against coronary heart disease and that the protective mechanism is likely to be, in part, mediated through the elevated level of plasma HDL cholesterol. These findings were consistent with those of other investigators, including those who examined data from the Lipid Research Clinics (LRC) Follow-Up Study (which included both men and women) (2). However, we agree with the general concerns raised by Dr. Cyr and colleagues. In accordance with their position, the LRC Study found the minimum rate of age-adjusted, all-cause mortality at somewhat lower levels of alcohol consumption for women than for men (3). In response to Dr. Karl: Although an increase in alcohol consumption may raise levels of HDL cholesterol and reduce heart disease risk, it may also result in an increased risk of death or illness from other causes, including injuries. We do not know whether an increase of even one or two drinks per day is a risk factor for alcoholism and its known complications. Such an adverse effect could occur in relatively few persons. Increased alcohol consumption has also been associated with higher blood pressure levels and greater risk for stroke. Increased alcohol consumption could also result in
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higher rates of motor vehicle and other types of accidents. Thus, unlike aspirin, alcohol intake has the potential to harm not only the consumer but others as well. For these reasons, we reaffirm our conclusion. B. Jessica Shaten, MS, for the authors University of Minnesota Minneapolis, MN 55414 References 1. Suh I, Shaten BJ, Cutler JA, Kuller LH. Alcohol use and mortality from coronary heart disease: the role of high-density lipoprotein cholesterol. Ann Intern Med. 1992;116:881-7. 2. Criqui MH, Cowan LD, Tyroler HA, Bangdiwala S, Heiss G, Wallace RB, et al. Lipoproteins as mediators for the effects of alcohol consumption and cigarette smoking on cardiovascular mortality: results from the Lipid Research Clinics Follow-Up Study. Am J Epidemiol. 1987;126:629-37. 3. Criqui MH. The roles of alcohol in the epidemiology of cardiovascular disease. Acta Med Scand (Suppl). 1987;717:73-85.
Thrombosis in Antithrombin-III Deficiency To the Editors: Demers and colleagues (1) reported on the prevalence of thrombosis in antithrombin-III-deficient patients. They analyzed 31 patients from a large kindred and another 449 patients from 62 kindreds described in the literature. All had antithrombin-III quantitative deficiency or impairment in serine protease inactivation; families with isolated disturbance in heparin binding were not included. The pooled prevalence of venous thrombosis was found to be 51%. We analyzed 552 patients affected with (n = 344) or at high risk (0.5) for antithrombin-III deficiency (n = 208) and belonging to 40 different kindreds. Of 120 recorded deaths, 44 (36.7%) were attributed to venous thromboembolism; the median age at death was 36 years. The fatal episode was a thromboembolic recurrence in 22 cases. In 11 patients (25%) exposure to a risk factor (pregnancy and puerperium, surgery, bed immobilization) preceded thrombosis; this figure substantially supports their finding that 32% of thrombotic episodes were associated with risk factors (1). As Demers and colleagues pointed out, the reliability of the information obtained from the literature is limited, and a bias could result from a diagnostic suspicion related to the knowledge of patients' antithrombin-III-deficiency status. A postmortem examination was reported in 16 cases; in all of these, pulmonary embolism and mesenteric vein thrombosis were thought to be the cause of death. This yields a prevalence of 13% in the 120 patients who died. Because only a minority of patients had necropsy, this prevalence could have been underestimated. Nonetheless, it is definitely higher than the primary-cause mortality from venous thromboembolism seen in the general population, which was estimated to be between 0.3% (death certificates) and 2.4% (necropsy studies) (2). These findings do not necessarily conflict with a recent report showing no increased mortality in 10 Dutch antithrombin-III-deficient families (3), because in this study the cause of death was not investigated. The policy of prophylaxis in high-risk situations, recommended by Demers and colleagues, is further supported by the possibility of preventing 25% of the fatalities due to thrombosis in the antithrombin-III-deficient kindreds. The bleeding risk associated with oral anticoagulant prophylaxis in patients with inherited thrombophilia has been estimated to be 0.62 major episodes per 100 patient-years (4), so that treatment lasting 30 to 40 years could lead to a cumulative risk of about 20% to 25% in each patient. Nevertheless, we believe that in these patients the bleeding risk should be carefully weighed against their risk for a fatal thromboembolic episode. Further retrospective, multicenter surveys are needed to provide more information on this issue. Valerio De Stefano, MD Giuseppe Leone, MD Istituto di Semeiotica Medica Universita Cattolica 00168 Rome, Italy
References 1. Demers C, Ginsberg JS, Hirsh J, Henderson P, Blajchman MA. Thrombosis in antithrombin-III-deficient persons. Report of a large kindred and literature review. Ann Intern Med. 1992;116:754-61. 2. De Stefano V, Leone G. Mortality related to thrombosis in congenital antithrombin-III deficiency. Lancet. 1991;1:847-8. 3. Rosendaal FR, Heijboer H, Briet E, et al. Mortality in hereditary antithrombin-III deficiency—1830 to 1989. Lancet. 1991;1:260-2. 4. Finazzi G, Barbui T and the ad hoc Study Group. A retrospective study on oral anticoagulant prophylaxis in 103 Italian patients with hereditary thrombophilia and thrombosis. Res Clin Lab. 1990;20:24552. In response: We agree with De Stefano and Leone that the risk-benefit ratio should always be estimated when considering anticoagulant therapy in asymptomatic antithrombin-III-deficient patients. Management can include either prophylaxis in high-risk situations or lifelong anticoagulant prophylaxis. The former is more convenient and preferable, if safe. Implicit in these approaches is that after antithrombin-III-deficient patients experience an episode of venous thrombosis, lifelong anticoagulant therapy should be administered. Therefore, in asymptomatic carriers, lifelong anticoagulant therapy would be indicated if the incidence of unheralded spontaneous venous thrombosis were high and the first episode of venous thrombosis were often fatal. On the other hand, prophylaxis could be limited to high-risk situations if most episodes occurred then. De Stefano and colleagues reported 44 deaths attributed to venous thrombosis, 16 of which were confirmed by autopsy. Of these 44 deaths, 22 were due to episodes of recurrent venous thrombosis for which no information was provided about the use of oral anticoagulant therapy. If these patients had been receiving oral anticoagulant therapy, it is likely that most (or all) of the episodes would have been prevented. Of the remaining 22 patients who died with suspected thrombosis, we were not told the proportion of patients whose cause of death was confirmed by autopsy, nor whether the episodes of thrombosis were idiopathic or secondary. Only 11 of these 44 patients had risk factors, but reporting of risk factors is frequently inaccurate. Estimates of the incidence of fatal venous thrombosis are subject to reporting bias; an antithrombin-III-deficient family whose members had fatal episodes of thrombosis may be more likely to be reported than a family with no episodes of thrombosis. Still, certain families with antithrombin III deficiency may be more prone than others to fatal and nonfatal episodes of venous thrombosis. In summary, both the study by De Stefano and colleagues and ours suffer from being retrospective, and the estimates of the incidence of fatal and nonfatal venous thrombosis in antithrombin-III-deficient patients are probably unreliable. Rather than more retrospective studies, we believe multicenter, prospective cohort studies are needed. Christine Demers, MD Department D'Hematologie Hopital du Saint Sacrement Quebec G1S 4L8, Canada Jeffrey Ginsberg, MD McMaster University Medical Centre Hamilton, Ontario L8N 3Z5, Canada Jack Hirsh, MD Hamilton Civic Hospitals Research Centre Hamilton, Ontario L8V 1C3, Canada The Sweet Syndrome or G-CSF Reaction? To the Editors: Park and colleagues (1) describe the development of the Sweet syndrome in a woman receiving chemotherapy for breast cancer during treatment with subcutaneous granulocyte colony-stimulating factor (G-CSF). The authors largely base their diagnosis on a skin biopsy that showed a dermal neutrophilic infiltrate. They attribute the Sweet syndrome to treatment with G-CSF because the patient did not require corticosteroids and because the eruption resolved with termination of the G-CSF treatment. The Sweet syndrome is characterized histologically by a
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dense dermal and perivascular infiltrate composed largely of neutrophils without evidence of vasculitis (2). Granulocyte colony-stimulating factor, a hematopoietic growth factor, promotes the proliferation and differentiation of polymorphonuclear leukocytes and might create a predominantly neutrophilic infiltrate in the skin. Horn and associates (3) reported three patients (two with acute myelocytic leukemia and one with chronic myelogenous leukemia) who received granulocyte-macrophage colony-stimulating factor (GM-CSF) and who developed erythematous macules and papules paralleling the time of GM-CSF infusion and resolving with completion of the treatment. Histologic features of these lesions showed an upper dermal inflammatory cell infiltrate composed of neutrophils and mononuclear cells with an increased number and size of macrophages. The cutaneous eruption observed by Park and coworkers may represent this entity and not the Sweet syndrome. Debra Lynn Karp, MD Johns Hopkins Hospital Baltimore, MD 21205 References 1. Park JW, Mehrotra B, Barnett BO, Baron AD, Venook AP. The Sweet syndrome during therapy with granulocyte colony-stimulating factor. Ann Intern Med. 1992;116:996-8. 2. Lever WF, Schaumburg-Lever G. Histopathology of the Skin. Philadelphia: J.B. Lippincott Company; 1990:196. 3. Horn TD, Burke PJ, Karp JE, Hood AF. Intravenous administration of recombinant human granulocyte-macrophage colony-stimulating factor causes a cutaneous eruption. Arch Dermatol. 1991;127:49-52. In response: As Dr. Karp notes, Horn and colleagues described three patients in whom a generalized maculopapular eruption developed during intravenous granulocyte-macrophage colony-stimulating factor (GM-CSF) administration with subsequent desquamation (1). These lesions were not described as tender or painful and in one case were pruritic. These cases display very different clinical and histopathologic features than those found in our patient (2), and do not appear to represent the Sweet syndrome (3, 4). Our patient developed a plaque, pustules, and nodules that were not generalized and never showed desquamation. The lesions were intensely tender and painful, without pruritus. The eruptions described by Horn and associates occurred within 24 to 48 hours after starting GM-CSF at a time when the leukocyte count remained depressed; and none of their patients were described as ever demonstrating leukocytosis. In the Sweet syndrome, as in our patient, leukocytosis is a salient feature. The histopathologic findings reported by Horn and colleagues also do not suggest the Sweet syndrome. These patients showed dermal infiltration by mononuclear cells as well as neutrophils. The most striking finding was a great increase in size and number of macrophages (1). In our patient, on the other hand, skin biopsy showed much denser dermal infiltration by sheets of neutrophils, without any significant lymphocyte or macrophage infiltration. Although the cases reported by Horn and colleagues clearly represent a different clinical and histopathologic entity than our case, there may indeed be that some common pathogenetic mechanisms are involved. As we discuss in our report, both granulocyte colony-stimulating factor (G-CSF) and GM-CSF can exacerbate pre-existing inflammatory cutaneous disorders. The interesting observations of Horn and coworkers further support the idea that hematopoietic growth factor therapy can lead to inflammatory manifestations in the skin. John W. Park, MD Bryan O. Barnett, MD Alan P. Venook, MD University of California, San Francisco San Francisco, CA 94143
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SI Units and the Friedewald Formula To the Editors: Bagatell and colleagues (1) studied the effects of experimentally induced androgen deficiency on levels of serum lipoproteins. To estimate the low-density lipoprotein (LDL) cholesterol, they used the Friedewald formula (2), which they expressed as: LDL cholesterol = total cholesterol - (high-density lipoprotein cholesterol + [triglycerides -*• 5]). This formula works when conventional units (mg/dL) are used but is inadequate with Systeme International (SI) units (3). To be used with the latter, the triglycerides must be divided by 2.18 instead of by 5. Because the LDL cholesterol levels reported by the authors in their Table 1 are correct, I presume that they made the calculations using the conventional units before converting all their results to SI units. Because this is not mentioned in the Methods, the readers can be misled to think that the nonadapted equation is also applicable with SI units. In fact I have been guilty of the same misconception (4, 5). If authors of manuscripts wish to write down the Friedewald equation, they should use the adapted version or specify that it was applied before the conversion of results to SI units. Jacques Masse, MD, MSc Hopital du Saint Sacrement Quebec G1S 4L8, Canada References 1. Bagatell CJ, Knopp RH, Vale WW, Rivier JE, Bremmer WJ. Physiologic testosterone levels in normal men suppress high-density lipoprotein cholesterol levels. Ann Intern Med. 1992;116:967-73. 2. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma without the use of the preparative ultracentrifuge. Clin Chem. 1972;18:499-501. 3. Masse J. Changes in lipoproteins during weight loss [Letter]. N Engl J Med. 1989;320:668. 4. Masse J. Effects of fish-oil ingestion on cardiovascular risk factors [Letter]. Am J Clin Nutr. 1991;54:610-1. 5. Masse J. Lipoprotein(a) levels in black and white children and adolescents with IDDM [Letter]. Diabetes Care. 1991;14:1108-9. In response: In our study (1) we calculated LDL cholesterol in conventional units using the Friedewald formula (2). We then converted all the lipid data, including LDL cholesterol, to SI units. We thank Dr. Masse for pointing out that the Friedewald equation cannot be applied directly to data in SI units. Carrie J. Bagatell, MD Robert H. Knopp, MD William J. Bremner, MD, PhD Veterans Affairs Medical Center and Lipid Research Clinics University of Washington Seattle, WA 98108 References 1. Bagatell CJ, Knopp RH, Vale WW, Rivier JE, Bremmer WJ. Physiologic testosterone levels in normal men suppress high-density lipoprotein cholesterol levels. Ann Intern Med. 1992;116:967-73. 2. Friedewald WT, Levy RI, Frerickson DS. Estimation of the concentration of low density lipoprotein cholesterol in the plasma without the use of the preparative ultracentrifuge. Clin Chem. 1972; 18:499501. Watchful Waiting and Craniopharyngioma
References 1. Park JW, Mehrotra B, Barnett BO, Baron AD, Venook AP. The Sweet syndrome during therapy with granulocyte colony-stimulating factor. Ann Intern Med. 1992;116:996-8. 876
2. Horn TD, Burke PJ, Karp JE, Hood AF. Intravenous administration of recombinant human granulocyte-macrophage colony-stimulating factor causes a cutaneous eruption. Arch Dermatol. 1991;127:49-52. 3. Sweet RD. An acute febrile neutrophilic dermatosis. Br J Dermatol. 1864;76:349-56. 4. Kemmett D, Hunter JA. Sweet's syndrome: a clinicopathologic review of twenty-nine cases. J Am Acad Dermaol. 1990;12:503-7.
To the Editors: Craniopharyngiomas constitute 3% to 5% of all intracranial tumors in adults and about 15% in children. These tumors usually consist of solid cellular components and cystic areas containing oily mixtures of degenerated blood and desquamated epithelium or necrotic tissue with cholesterol
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crystals. Calcifications may be present in as many as 85% of cases and are detected by computed tomographic (CT) scan but not by magnetic resonance imaging (MRI) (1). Though usually slow-growing and almost always benign, they can invade various sellar and suprasellar tissues and cause significant pathology. Management has been primarily surgical, with radiation therapy as an adjunct. To our knowledge, the role of expectant management in the absence of major optic nerve compression and endocrine dysfunction has not been evaluated. We present a case report of such a management with a 6-year follow-up. A 35-year-old, white woman started having mild, frontal headaches and sinus complaints in 1985. Radiographs of the skull showed a markedly enlarged sella turcica. On referral to the National Institutes of Health Clinical Center, MRI of the head showed an intra- and suprasellar mass compressing the optic chiasm and the hypothalamus. A CT scan showed a 2.7 x 2-cm heterogeneous, partially calcified solid mass with a cystic component containing fluid. The imaging characteristics were consistent with craniopharyngioma. Anterior pituitary testing showed normal plasma concentrations of follicle-stimulating hormone, leutinizing hormone, estradiol, and prolactin; results of a 1-hour adrenocorticotropic hormone stimulation test were normal. Visual field examination showed a mild inferior nasal quadrant defect in the right eye and a relative superior small temporal quadrant defect with some minor involvement of the inferior temporal quadrant on the left side. The patient had regular cyclic menses and an uncomplicated pregnancy 1 year before presentation. The patient made the decision not to have neurologic surgery or radiotherapy and was followed regularly at frequent intervals for 2 years, despite strong reservations from the neurosurgery and radiotherapy services. She has been seen every 6 to 12 months with no change in symptoms, hormonal or visual test results, or imaging findings for over 6 years. Both surgery and radiotherapy of craniopharyngiomas have been associated with major complications and significant mortality. Intracerebral or epidural hemorrhages, cerebral infarction, blindness, hemiparesis, or Addisonian crises were noted in 43% of patients who had radical surgery alone and in 25% of patients who had limited surgery and postoperative radiotherapy (2). Thirty-eight percent to 42% of patients treated with radiotherapy alone, however, developed delayed side effects including optic atrophy, hypothalamic-pituitary dysfunction, brain necrosis, and induction of new tumors (3-5). Use of hormonal replacement has ranged from 87% to 100% with all forms of therapy (2). Perioperative mortality rates from 3% to 41% have been reported. Five-year survival rates are 71% with radical surgery, 100% with limited surgery and postoperative radiotherapy (2), and 89% with radiotherapy alone (3). Due to the high incidence of progressive and major morbidity as well as the significant mortality associated with currently recommended approaches, the role of frequent monitoring in the absence of major optic nerve compression and endocrine dysfunction needs to be evaluated. This patient represents a fine example of primum non nocere (first do no harm).
Cytomegalovirus-associated Gastric Ulcer To the Editors: Gastric ulceration in association with cytomegalovirus (CMV) most commonly occurs in immunocompromised patients (1, 2). We report a case of CMV-associated gastric ulceration in an immunosuppressed patient in whom healing of ulceration and rapid resolution of fever and constitutional symptoms occurred twice after treatment with ganciclovir. A 74-year-old woman presented with a 3-week history of fever, weight loss, and epigastric pain after meals. She had a history of autoimmune haemolytic anaemia (treated with azathioprine, 100 mg daily, and danazol), pernicious anaemia, renal impairment, and IgA deficiency. Gastroscopy showed shallow ulcers in the stomach, and histologic examination showed inflammatory cells containing inclusions typical of CMV. Neither malignant cells nor helicobacter were seen. Cytomegalovirus was cultured in gastric biopsies. Results of serologic tests for human immunodeficiency virus (HIV) were negative. Epigastric pain, fever, and constitutional symptoms rapidly resolved after treatment with ranitidine, 150 mg twice daily, and 3 weeks of intravenous ganciclovir, 2.5 mg/kg body weight twice daily (creatinine clearance, 40 mL/[min.l.73 m 2 ]). Gastroscopy showed healing of ulceration, and CMV could not be identified from biopsy samples. Two months later, identical symptoms recurred despite treatment with ranitidine. Recurrent ulceration was seen at gastroscopy, with positive CMV inclusions and culture. Ganciclovir was given as before with good symptomatic response, and follow-up gastroscopy showed healing and absence of CMV on biopsy samples. Ranitidine and maintenance ganciclovir, 10 mg/kg intravenously three times a week, were continued. Two months later, when epigastric pain developed, gastroscopy showed a nodular gastritis with histologically confirmed chronic inflammation. Neither CMV, helicobacter, nor malignant cells were identified. Ganciclovir was stopped. Three months later, epigastric pain, fever, diarrhea, and paranoid ideation occurred. Gastroscopy and sigmoidoscopy showed inflamed mucosa with positive staining and culture for CMV. Cytomegalovirus was also isolated from blood. Further investigation or therapy was refused, and the patient died. Resolution of epigastric pain, fever, and constitutional symptoms occurred on both occasions soon after commencement of ganciclovir, and follow-up gastroscopies showed complete healing and loss of CMV. Subsequent maintenance ganciclovir appeared effective initially but was stopped after a relapse of gastritis. The inability to identify CMV in association with nodular gastritis suggests that it may have had another etiology. The subsequent course argued for continuing maintenance gancyclovir, probably in higher doses (3). Wendy J. Munckhof, MBBS Michael J. Richards, MBBS Austin Hospital Heidelberg, Victoria, Australia References 1. Shuster L, Cox G, Bhatia P, Miner P. Gastric mucosal nodules due to cytomegalovirus infection. Dig Dis Sci. 1989;34:103-7. 2. Buhles WC Jr, Mastre BJ, Tinker AJ and the Syntex Collaborative Ganciclovir Treatment Study Group. Ganciclovir treatment of life- or sight-threatening cytomegalovirus infection: experience in 314 immunocompromised patients. Rev Infect Dis. 1988;10(Suppl 3):S495-506. 3. Balfour HH. Management of cytomegalovirus disease with antiviral drugs. Rev Infect Dis. 1990;12(Suppl 7):S849-60.
Fady I. Sharara, MD George P. Chrousos, MD Nicholas J. Patronas, MD National Institutes of Health Bethesda, MD 20892 References 1. Kaufman B. Perisellar lesions. In: Tavaras JM, Ferruci JT; eds. Radiology, v. 3. Philadelphia: J.B. Lippincott Co.; 1987:1-12. 2. Chen Wen B, et al. A comparison of the roles of surgery and radiation therapy in the management of craniopharyngiomas. Int J Radiation Oncology Biol Phys. 1989;15:17-24. 3. Flickinger J, et al. Megavoltage external beam irradiation of craniopharyngiomas: analysis of tumor control and morbidity. Int J Radiation Oncology Biol Phys. 1990;19:117-22. 4. Shillito J J r . Treatment of craniopharyngioma. Clin Neurosurg. 1985; 33:533-46. 5. Manaka S, Teramoto A, Takakura K. The efficacy of radiotherapy for craniopharyngioma. J Neurosurg. 1985;62:648-56.
Pancytopenia from Using Trimethoprim and Methotrexate To the Editors: Methotrexate is currently used for the treatment of psoriasis, asthma, rheumatoid arthritis, and cancer. Hazardous interactions may occur when combined with other drugs whose mechanism of action involves the same biochemical pathway. One such rarely described interaction is between low-dose, oral methotrexate and the antibiotic trimethoprim-
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sulfamethoxazole (TMP-SMX) resulting in marrow hypoplasia (1-3). A 58-year-old, white man with a long history of rheumatoid arthritis presented with symptoms and signs of prostatitis. His arthritis had been successfully managed with oral methotrexate, 7.5 mg weekly since 1988. A complete blood count showed a hemoglobin of 133 g/L, a hematocrit of 0.40, a leukocyte count of 8.7 x 10 6 /L, and a platelet count of 197 x 109/L. The patient's urine grew Escherichia coli, and the patient was started on a 6-week regimen of TMP-SMX. Results of further tests with intravenous pyelography and cystoscopy were normal. Four weeks after initiation of TMP-SMX therapy, symptoms of prostatitis had resolved, but the patient had hematuria, fatigue, decreased appetite, and orthostatic dizziness. A complete blood count showed a hemoglobin of 72 g/L, a hematocrit of 0.21, a leukocyte count of 2.0 x 10 6 /L, and a platelet count of 5 x 109/L with macrocytic red cells, absence of reticulocytes, and markedly hypersegmented neutrophils on the peripheral smear. The patient was hospitalized for transfusion of platelets and packed red blood cells, and all drugs were stopped. Examination of bone marrow showed hypocellularity with megaloblastic red-cell precursors and hypersegmented polys. Serum folate and vitamin B12 levels were normal. The patient was diagnosed with megaloblastic pancytopenia, secondary to methotrexate and TMP-SMX. Administration of oral leucovorin, 25 mg every 6 hours, was begun. Within 48 hours, early recovery of all hematopoietic cell lines was noted, and by discharge, 96 hours after leucovorin administration, the patient's complete blood count showed a hemoglobin of 106 g/L, a hematocrit of 0.32, a leukocyte count of 7.1 x 106/L, and a platelet count of 218 x 109/L.
Figure 1. Sites of major inhibition for methotrexate (MTX) and trimethoprim (TMP) and rescue by leucovorin of de novo purine synthesis and thymidylate (dTMP) production. CH 2 FH 4 = 5, 10-methylenetetrahydrofolate; 10-CHO-FH 4 = 10-formyltetrahydrofolate; DHFR = dihydrofolate reductase; dTMP = deoxythymidine monophosphate; dUMP = deoxyuridine monophosphate; FH 2 = dihydrofolate; FH 4 = tetrahydrofolate; T.S. = thymidylate synthase. Methotrexate is a dihydrofolate antagonist that binds to the catalytic site of dihydrofolate reductase (DHFR), interfering with the synthesis of de-novo purine nucleosides, conversion of uridylate to thymidylate, and synthesis of the amino acids serine and methionine (4) (Figure 1). The trimethoprim component of TMP-SMX also inhibits mammalian DHFR, although 10 000 times less efficiently than it inhibits bacterial DHFR (see Figure 1). The combination of low-dose methotrexate and TMP-SMX acted additively or synergistically to inhibit dihydrofolate reductase, producing a severe megaloblastic pancytopenia. Leucovorin or 5-folinic acid, a reduced folate analog, is frequently used to " r e s c u e " normal hematopoietic cells by substituting for folate later in the purine pathway, whereas DHFR remains inhibited by methotrexate (see Figure 1). 878
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Given the increasing use of low-dose methotrexate in patients with rheumatoid arthritis, asthma, and psoriasis as well as the routine use of TMP-SMX, internists should be aware of the possibility of life-threatening pancytopenia. Joseph A. Govert, MD Suzanne Patton, MD, PhD Robert L. Fine, MD Duke University Medical Center Durham Veterans Affairs Medical Center Durham, NC 27705 References 1. Maricic M, Davis M, Gall E. Megaloblastic pancytopenia in a patient receiving concurrent methotrexate and trimethoprim-sulfamethoxazole treatment. Arthritis Rheum. 1986;29:133-5. 2. Thomas M, Gutterman L. Methotrexate toxicity in a patient receiving trimethoprim-sulfamethoxazole. J Rheum. 1986;13:440-1. 3. Groenendal H, Ram pen FH. Methotrexate and trimethoprim-sulfamethoxazole—a potentially hazardous combination. Clin Ex Derm. 1990;15:358-60. 4. Joviet J, Cowan K, Curt G, Glendeninn N, Chabner B. The pharmacology and clinical use of methotrexate. N Engl J Med. 1983;309: 1094-104.
Aging and Warfarin T h e r a p y To the Editors: Gurwitz and coworkers (1) purport to show that the anticoagulant response to warfarin increases with age due to an "increased sensitivity" to warfarin; however, the ratio of warfarin dose to prothrombin time response used by the authors as the principal measure of sensitivity does not allow the differentiation of pharmacokinetic variability from pharmacologic sensitivity. In a prospective study of 88 chronically treated outpatients, we snowed that age does not alter the pharmacodynamic response to warfarin (2). The study by Shepard and coworkers (3), cited in dismissing a change in warfarin pharmacokinetics with age, was limited by a small sample size and failure to use the most accurate warfarin assay (4). Our prospective study of 163 patients on chronic warfarin therapy showed that warfarin clearance, assayed by high-pressure liquid chromatography, decreased approximately 1% a year from 18 to 70 years of age (5). These data were used to generate initial estimates of warfarin pharmacokinetic and pharmacodynamic variables using the software program, Drugcalc (Medifore, Lansing, Michigan), which predicts the anticoagulant warfarin response to using the most widely accepted mathematic models of warfarin pharmacokinetics and dynamics. Entering hypothetical demographic data and steady-state warfarin doses into this program, we found that 25% to 70% of the rise in the dose-adjusted prothrombin ratio observed by Gurwitz and colleagues could be explained by age-related decreased clearance changes alone. Finally, the authors provide no data to support their suggestion that older patients need "scrupulous monitoring" of warfarin therapy. The important point for clinicians is that older patients require lower doses of warfarin, particularly during the initiation of warfarin therapy. Dennis Mungall, PharmD Ferris State University Big Rapids, MI Richard White, MD UC Davis Medical Center Sacramento, CA References 1. Gurwitz JH, Avorn J, Ross-Degnan D, Choodnovskiy I, Ansell J. Aging and the anticoagulant response to warfarin therapy. Ann Intern Med. 1992;116:901-4. 2. Murray B, Coleman R, McWarters D, Ludden T, Mungall D. Pharmacodynamics of warfarin at steady state. Therapeutic Drug Monit. 1987;9:1-5. 3. Sheparid AM, Hewick DS, Moreland TA, Stevenson IH. Age as a determinant of sensitivity to warfarin. Br J Clin Pharmacol. 1977;4: 315-20.
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4. Robinson CA, Mungall D, Poon MC. Quantitation of plasma warfarin concentrations by high performance liquid chromatography. Therapeutic Drug Monit. 1981;3:287-90. 5. Mungall DR, Ludden TM, Marshall J, Hawkins DW, Talbert RL, Crawford MH. Population pharmacokinetics of racemic warfarin in adult patients. J Pharmacok and Biopharm. 1985;13:213-26.
In response: Drs. Mungall and White do not appear to dispute our core finding that the anticoagulant response to warfarin is exaggerated with advancing age (1). The underlying mechanism is less clear. Although Shepherd and colleagues reported that warfarin pharmacokinetics do not change substantially with advancing age (2), Mungall and associates have reported an age-related reduction in warfarin clearance (3). Thus, it is plausible that the increased warfarin effect in older patients is at least partly the result of pharmacokinetic changes. We do not feel, however, that the findings of Murray and colleagues are sufficient to exclude the possibility of an important alteration in warfarin pharmacodynamics with aging (4). From a population standpoint, we agree that older patients require lower doses of warfarin than younger patients to achieve the same anticoagulant response. In clinical practice, dosing and monitoring of warfarin therapy go hand in hand. In managing individual patients, we believe that increased care in monitoring elderly patients on anticoagulant therapy is indicated. Jerry H. Gurwitz, MD Jerry Avorn, MD Harvard Medical School Boston, MA 02115
3. Mungall DR, Ludden TM, Marshall J, Hawkins DW, Talbert RL, Crawford MH. Population pharmacokinetics of racemic warfarin in adult patients. J Pharmacok Biopharm. 1985;13:213-27. 4. Murray B, Coleman R, McWaters D, Ludden T, Mungall D. Pharmacodynamics of warfarin at steady state. Ther Drug Monit. 1987;9:1-5.
Bearing Bad News To the Editors: I was very moved by Dr. Litwin's "Ode to J o y " (1) and at the same time was saddened by the failure of the attending physician to adequately prepare the intern to meet with the family. Thank God for the supportive nursing supervisor, Joy, who picked up the emotional pieces and taught the fledging intern how to communicate his caring to the patient's family. This failure is too often repeated in teaching hospitals. Housestaff and students are frequently asked to break bad news to patients and families without ever having this difficult role discussed or modeled for them by an expert clinician. We teachers have a lot of work to do to correct this situation. Richard H. Fine, MD University of California, San Francisco San Francisco General Hospital San Francisco, CA 94110 Reference 1. Litwin J. Ode to joy. Ann Intern Med. 1992; 117:337.
Correction
Jack Anselly MD University of Massachusetts Medical School Worcester, MA 01655 References 1. Gurwitz JH, Avorn J, Ross-Degnan D, Choodnovskiy I, Ansell J. Aging and the anticoagulant response to warfarin therapy. Ann Intern Med. 1992;116:901-4. 2. Shepherd AM, Hewick DS, Moreland TA, Stevenson IH. Age as a determinant of sensitivity to warfarin. Br J Clin Pharmacol. 1977;4: 315-20.
Resistance to Zidovudine and Alpha-Interferon An article (1) incorrectly noted the date of the symposium at which the paper was initially presented. The correct date is 20-24 June 1990. Reference 1. Edlin BR, St. Clair MH, Pitha PM, Whaling SM, King DM, Bitran JD, et al. In-vitro resistance to zidovudine and alpha-interferon in HIV-1 isolates from patients: correlations with treatment duration and response. Ann Intern Med. 1992;117:457-60.
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