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 with the letter 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 only if their letter is accepted. Unpublished letters cannot be returned. Diagnosing Lyme Disease To the Editors: Uncritical clinical application of the T-cell proliferative assay described by Dressier and colleagues (1) may further confuse the evaluation of patients for Lyme disease. The investigators proposed that the test may be helpful in evaluating patients who have clinically apparent late-stage Lyme disease and whose humoral immune response has waned or has been aborted by early (subcurative) antibiotic therapy (1). Such circumstances are rarely encountered. Furthermore, the need for a confirmatory diagnostic test is arguable; few physicians would withhold antimicrobial therapy for Lyme disease on the basis of seronegativity when the patient's history and physical findings are as characteristic of Lyme disease as were those of the patients described (1). A far more common clinical dilemma is presented by patients who lack evidence of Lyme disease by history, physical examination, and serologic testing, but who are nonetheless convinced that they have Lyme disease and might benefit from intravenous antimicrobial therapy (2). Such patients, who often are conversant with the latest developments in Lyme disease research, will likely now request a T-cell proliferative assay to confirm borrellial infection. Alternatively, physicians who are frustrated by this dilemma may turn to the T-cell proliferative assay in hopes of an easy solution. The data presented by Dressier and coworkers (1) suggest that 5% of these patients will have a positive T-cell proliferative assay result despite the absence of borrellial infection. The (probable) extremely low prevalence of true Lyme disease among such patients (that is, the low pretest probability), together with the proliferative assay's estimated false-positive rate of 5% (1), give the test a very low positive predictive power in this population. Most positive results will be falsely so, likely leading to needless treatment of numerous patients with single or multiple courses of expensive and sometimes harmful intravenous antibiotics. Furthermore, the erroneous "confirmation" of a diagnosis of Lyme disease in such patients will reinforce the notion that their symptoms are due to infection and should be treated with antibiotics, thereby diverting attention from more appropriate diagnostic considerations and interventions. In short, the T-cell proliferative assay may broaden our understanding of the immunology of Lyme disease, but its clinical application is fraught with hazard. James R. Johnson, MD University of Minnesota Medical School Minneapolis, MN 55455
References 1. Dressier F, Yoshinari NH, Steere AC. The T-cell proliferative assay in the diagnosis of Lyme disease. Ann Intern Med. 1991;115:533-9. 2. Lettau LA. From the Centers for Fatigue Control (CFC) Weekly Report. Ann Intern Med. 1991; 114:602. In response: We agree with Dr. Johnson that uncritical application of the T-cell proliferative assay—or of any other diagnostic test—creates the potential for misuse. As we stated in our article, the T-cell proliferative assay has the same limitations as serologic testing in evaluating Lyme disease. It demonstrates exposure to Borrellia burgdorferi but does not prove the presence of active infection, and it may have falsenegative or false-positive results. Despite these limitations, we and others (1) have found that the T-cell proliferative assay often has a positive result in the small subset of patients who have Lyme disease, who are incompletely treated with antibiotics during the first several weeks of infection, and who are seronegative later in the illness. It should be emphasized that these patients also have an attenuated clinical presentation with only subtle joint or neurologic abnormalities. Why is the diagnosis of Lyme disease so controversial (2)? We believe that it is because "chronic Lyme disease" has become a common diagnosis for patients with the chronic fatigue syndrome, fibromyalgia, or other illnesses with prominent subjective symptoms, much as "chronic Epstein-Barr virus infection" (3) and "chronic brucellosis" (4) once were. Although B. burgdorferi may trigger chronic fatigue or fibromyalgia in a small percentage of patients, this infection rarely causes these syndromes, even in areas where Lyme disease is endemic. Furthermore, the association between Lyme disease and chronic fatigue has been reinforced inappropriately by the lack of standardization of diagnostic tests, producing variable rates of false-positive results. Lyme disease can usually be treated successfully with 10- to 30-day courses of oral or intravenous antibiotic therapy, depending on the stage and manifestation of the illness (5). No evidence indicates that prolonged courses of antibiotic therapy (lasting months or years) have a role in the treatment of Lyme disease or chronic fatigue. Frank Dressier, MD Allen C. Steere, MD New England Medical Center Tufts University School of Medicine Boston, MA 02111 References 1. Datrwyler RJ, Volkman DJ, Luft BJ, Halperin JJ, Thomas J, Golightly MG. Seronegative Lyme disease: dissociation of the specific T- and B-lymphocyte responses to Borrelia burgdorferi. N Engl J Med. 1988;319:1441-6. 2. Tosiello L, LeHau LA, Madhaven T, Berman DJ, Wenglin BD. Lime versus Lyme disease [letters]. Ann Intern Med. 1991;115:157-8. 3. Gold D, Bovvden R, Sixbey J, et al. Chronic fatigue: a prospective clinical and virologic study. JAMA. 1990;264:48-53. 4. Imboden JB, Canter A, Cluff LE, Trever RW. Brucellosis. III. Psychological aspects of delayed convalescence. Arch Intern Med. 1959; 103:406-14. 5. Steere AC. Lyme disease. N Engl J Med. 1989;321:586-96. Echovirus Meningitis and False-Positive Lyme Test Results To the Editors: Conditions reported to give false-positive results in enzyme immunoassays for Lyme disease include other
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spirochetal infections, viral infections (for example, EpsteinBarr virus), and autoimmune diseases (1). Most questions are resolved by appropriate clinical and laboratory evaluation (2). Enteroviral infections cause several characteristic syndromes, but are most often nonspecific or asymptomatic. Definitive diagnosis requires culture or serologic tests, or both. We report a case of aseptic meningitis that was caused by echovirus type 30 and that resulted in a transient false-positive result on an enzyme immunoassay for Lyme disease. A 39-year-old man was admitted with a history of diffuse myalgias, fever, malaise, flank pain, and a progressive headache for 5 days. Physical examination findings were otherwise unremarkable. Laboratory evaluation revealed a creatinine kinase level of 52.94 /Ltkat/L, an alanine aminotransferase level of 1.27 /ikat/L, and a lactate dehydrogenase level of 3.97 /ikat/L. A complete blood count and urinalysis were normal; blood culture results were negative. A computed tomographic scan of the head and a routine chest film were normal. Cerebrospinal fluid analysis revealed 66 leukocytes/mm 3 , with a mononuclear predominance of 0.98, a glucose level of 2.99 mmol/L, and a protein level of 0.35 g/L; no oligoclonal bands were seen. Because the patient had frequent exposure to farms, leptospiral cultures and serologic testing were done and the patient was treated with penicillin for 7 days. Antinuclear antibodies were not detected, and a VDRL had negative results. Stool, pharyngeal, and cerebrospinal cultures grew echovirus type 30, and serum antibody titers to this virus were increased fourfold at 4 weeks. Leptospiral study results were subsequently negative. The patient was well at all subsequent evaluations. This rather straightforward case was complicated by a Lyme disease IgG enzyme immunoassay performed by the Michigan Department of Public Health. The initial result was positive (optical density, 1.24; > 1 is considered positive). Within 3 months, the enzyme immunoassay result was 1.0. This patient's illness developed at the beginning of a wave of echovirus-associated disease in our community where hundreds of patients are being treated for Lyme disease with long-term intravenous and oral antibiotics, most often without any serologic or epidemiologic support. Most enteroviral syndromes are diagnosed clinically, and the nonspecific symptoms may suggest Lyme disease. This may lead to obtaining a falsepositive enzyme immunoassay result. This case highlights the need for clear pretest assessment of risk, better diagnostic tests, and broad awareness that common nonspecific viral illnesses may falsely elevate current Lyme disease enzyme immunoassay tests. Del J. DeHart, MD Ramesh Avula, MD Sivakumar R. Munnangi, MD Michigan State University College of Human Medicine Saginaw Cooperative Hospitals, Inc. Saginaw, MI 48602 References 1. Craft J, Grodzicki R, Steere AC. Antibody response in Lyme disease: evaluation of diagnostic tests. J Infect Dis. 1984;149:789-95. 2. Weiss NL, Philips MR, Sadock VA, et al. False positive seroreactivity to B. burgorferi in rheumatic disease: the value of immunoblotting [abstract]. IV International Conference on Lyme Borreliosis. 1990; 122.
Why Was Treatment of Cytomegalovirus Retinitis Randomized? To the Editors: Palestine and colleagues (1) examined the role of foscarnet in the treatment of cytomegalovirus retinitis in the acquired immunodeficiency syndrome (AIDS). They conducted a randomized, controlled trial in which the patients in one study arm initially received no treatment. What was the rational for having such a control group? Cytomegalovirus retinitis is the most common intraocular infection and the most common cause of blindness in patients with AIDS. Both ganciclovir and foscarnet have been shown to be approximately 90% effective in arresting retinitis, at least during the induction 604
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phase (2-4). It is also well known that, despite daily maintenance therapy, cytomegalovirus retinitis eventually progresses (1, 3, 4). Why then would disease progression in the control group (which received no treatment) be surprising? The investigators acknowledged that a placebo-controlled trial design "is not appropriate for the evaluation of a disease process that permanently destroys vision" when an available agent is known to be effective. The investigators therefore used subjects whose retinal disease did not threaten immediate, significant visual loss. However, the subjects probably had some visual symptoms (which brought them to medical attention). Furthermore, the time between diagnosis and study entry (3.9 months for the "immediate treatment" group and 3.3 months for the "delayed-treatment" group) was inordinately long. The AIDS epidemic has stimulated reassessment of the randomized controlled trial. Palestine and coworkers (1) implied that known effective therapy was not used for the controls because, at the time, ganciclovir was not licensed for use in cytomegalovirus retinitis. This should not be a reason to delay treatment in cytomegalovirus retinitis. A placebo or no-treatment arm should not be used when disease progression is highly predictable or when acceptable and effective therapy is available. Irving E. Salit, MD, CM The Toronto Hospital University of Toronto Toronto, Ontario M5G 2C4, Canada References 1. Palestine AG, Polis MA, De Smet MD, et al. A randomized, controlled trial of foscarnet in the treatment of cytomegalovirus retinitis in patients with AIDS. Ann Intern Med. 1991;115:665-73. 2. Felsenstein D, D'Amico DJ, Hirsch MS, et al. Treatment of cytomegalovirus retinitis with 9-[2-hydroxyl-l-(hydroxymethyl)ethoxymethyl] guanine. Ann Intern Med. 1985;103:381-2. 3. Walmsley SL, Chew E, Read SE, et al. Treatment of cytomegalovirus retinitis with trisodium phosphonoformate hexahydrate (foscarnet). J Infect Dis. 1988;157:569-72. 4. Fanning MM, Read SE, Benson M, et al. Foscarnet therapy of cytomegalovirus retinitis in AIDS. J Acquir Immune Defic Synd. 1990; 3:472-9.
In response: Although cytomegalovirus retinitis is known to be progressive, its progression is not sufficiently predictable to demonstrate activity of a putative therapeutic agent in the absence of a control group. Our study was the first to show that, using an unbiased, masked ophthalmologic reading center, untreated retinal lesions due to cytomegalovirus progressed by at least 750 /urn over a 750 /xm front in a mean of 3.2 weeks, with progression ranging from 1 week to 6 weeks. An error in Table 2 inaccurately presented the time from diagnosis of cytomegalovirus retinitis to study entry (1); it should read 3.9 weeks and 3.3 weeks (not months) for the immediate treatment and control groups, respectively. The subjects presented with retinal lesions that did not immediately threaten sight and had no significant visual symptoms other than floaters. Two medications are now licensed for the treatment of cytomegalovirus retinitis; however, when the study was initiated, none were. We tried to show, without putting our subjects at risk and in a manner conclusive enough to allow licensure of the drug, that foscarnet was effective in treating cytomegalovirus retinitis. The most efficient vehicle was a randomized controlled trial. The use of ganciclovir for the treatment of non-sight-threatening cytomegalovirus retinitis was both controversial and not routinely acceptable. Zidovudine was the only antiretroviral agent available for treatment of human immunodeficiency virus (HIV) infection, and the difficulty in administering it with ganciclovir was well documented (2). Many persons found themselves having to choose between treatment with an investigational agent with anecdotal evidence of efficacy against cytomegalovirus retinitis and treatment of their underlying HIV infection. Many whose retinal lesions did not immediately threaten their vision chose to receive zidovudine
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until the lesions progressed. Thus, there was no ethical dilemma in designing a study with a short, no-treatment control arm. All patients were made aware of alternative treatment options and of their participation in research. The success of our approach was borne out by the rapid licensure of foscarnet following the completion of the study and the lack of significant deterioration in the visual acuity of subjects on the control arm compared with those on the immediate treatment arm. The randomized controlled trial remains the most efficient mechanism for showing a treatment's efficacy (or lack thereof), and we encourage its use to assist in the rapid evaluation of new therapeutic options. Michael A. Polis, MD, MPH Warren Grant Magnuson Clinical Center Robert B. Nussenblatt, MD National Eye Institute H. Clifford Lane, MD National Institute of Allergy and Infectious Diseases Bethesda, MD 20892 References 1. Palestine AG, Polis MA, de Smet MD, et al. A randomized, controlled trial of foscarnet in the treatment of cytomegalovirus in patients with AIDS. Ann Intern Med. 1991;115:665-73. 2. Hochster H, Dieterich D, Bozzette S, et al. Toxicity of combined ganciclovir and zidovudine for cytomegalovirus disease associated with AIDS. Ann Intern Med. 1990;113:111-7.
HLA-B38 and Clozapine-induced Agranulocytosis To the Editors: Clozapine (Clozaril), a dibenzodiazepine neuroleptic, is associated with a 1% to 2% incidence of druginduced agranulocytosis. Its use, therefore, has been largely limited to select patients with refractory schizophrenia. Very close monitoring of patients receiving this drug has significantly increased the cost of therapy. Lieberman and coworkers (1) noted a 20% incidence of agranulocytosis in a predominantly Jewish group of patients receiving the drug strongly correlating with the presence of the haplotype HLA-B38, DR4, DQw3. We report the occurrence of clozapine-induced agranulocytosis in two non-Jewish patients, both of whom expressed HLA-B38 but did not express DR4 or DQw3. A 32-year-old man who had been receiving clozapine for 58 days was admitted to the University Hospital with a leukocyte count of 2100/mm3 and a granulocyte count of 504/mm3. The granulocyte count subsequently dropped to 0/mm3. Granulopoiesis recovered 12 days after withdrawal of Clozapine. Human leukocyte antigen typing revealed HLA-A1, A3, B38, B63, DR2, DR10, Dql. The second patient was a 41-year-old man admitted to the Veterans Hospital after receiving clozapine for 76 days. His leukocyte count was 1800/mm3, and his granulocyte count was 0/mm3. His leukocyte count normalized 15 days after withdrawal of clozapine. Human leukocyte antigen typing showed HLA-A3, A32, B38, Bw62, DR3, DR6, and Dql,2. Lieberman and colleagues (1) report five of the six cases of clozapine-induced agranulocytosis were in Jewish persons who expressed haplotype HLA B38, DR4, DQ3. Of 17 Jewish controls who did not develop agranulocytosis, only 2 expressed this haplotype. Their study sample was too small to draw firm conclusions about the role of HLA B38 as a predictor, independent of the reported haplotype. Here we report the cases of two non-Jewish patients who developed clozapine-induced agranulocytosis and who expressed HLA B38 but not DR4 or DQw3. HLA B38 has not been associated with schizophrenia per se (2, 3). Our findings support those of Lieberman and coworkers (1) and suggest that HLA B38 may be a predictor of clozapine-induced agranulocytosis. The incidence of agranulocytosis in patients treated with clozapine is 1% to 2%, and the incidence of HLA B38 in white North Americans is 6% (4). Further studies of HLA typing as
a screening test for clozapine-induced agranulocytosis may be indicated. Geetha Joseph, MD Vu Nguyen, MD Jeffrey D. Smith, MD University of Louisville Louisville, KY 40292 References 1. Lieberman JA, Yunis J, Egea E, Canoso RT, Kane JM, Yunis EJ. HLA-B38,DR4,DQw3 and Clozapine-induced agranulocytosis in Jewish patients with schizophrenia. Arch Gen Psych. 1990;47:945. 2. Alexander RC, Coggiano M, Daniel DG, Wyatt RJ. HLA antigens in schizophrenia. Psych Res. 1990;31:221. 3. McGuffin P, Farmer AE, Yonace AH. HLA antigens and subtypes of schizophrenia. Psych Res. 1981;5:115. 4. Histocompatibility Testing 1980: Report of the Eighth International Histocompatibility Workshop. Los Angeles: UCLA Tissue Typing Laboratory; 1980:962.
Polyarteritis Nodosa and Hepatitis C Virus Infection To the Editors: Markers of hepatitis B virus (HBV) infection have been reported in 20% to 40% of patients with polyarteritis nodosa, suggesting that HBV could be an etiologic factor (1-3). Infection with hepatitis C virus (HCV), a recently characterized RNA virus, is responsible for chronic hepatitis and liver cirrhosis and is frequently associated with HBV infection (4). Our aim was to assess the prevalence of HCV markers in patients with polyarteritis nodosa. To avoid bias due to false-positive reactions with a secondgeneration enzyme-linked immunosorbent assay (ELISA 2) (Ortho HCV ELISA Test System 2nd Generation, Ortho Diagnostic Systems, Raritan, New Jersey), patients who had systemic lupus erythematosus or Wegener granulomatosis, who had similar risk factors for HCV infection, and who were hospitalized during the same period, were also studied. Fifty patients had polyarteritis nodosa according to American College of Rheumatology criteria (5): 31 men and 19 women, ranging in age from 24 to 77 years (mean ± SD, 46 ± 17 years). Sixty-two patients had systemic lupus erythematosis: 9 men and 53 women, ranging in age from 16 to 76 years (mean, 34 ± 13 years). Eleven patients had Wegener granulomatosis: 8 men and 3 women, ranging in age from 28 to 70 years (mean, 54 ± 12 years). Anti-HCV antibodies were detected in serum samples that had been frozen at - 80 °C using a ELISA 2, which allows detection of antibodies directed against HCV antigens (C 100-3, C 200, C 22-3). The presence of anti-HCV antibodies was confirmed by a 4-antigen (C 100-3, C 5-1-1, C 33c, C 22-3), recombinant, immunoblot assay (Chiron RIBA HCV Test System 2nd Generation, Abbott Laboratories, Emeryville, California). Serum samples were also tested for HBs antigen and anti-HBc antibodies. Using ELISA 2, anti-HCV antibodies were found in 7 of 50 patients with polyarteritis nodosa (14%) and in 7 of 62 patients with systemic lupus erythematous (11%) but in none of the patients with Wegener granulomatosis. The RIBA 2 assay confirmed the presence of anti-HCV antibodies in 6 of 50 patients with polyarteritis nodosa (12%) and in only 1 patient with systemic lupus erythematosis (2%) (P = 0.03, Fisher exact test, one tail). HBs antigen was detected in 4 of 50 patients with polyarteritis nodosa (8%) and in no patient with systemic lupus erythmatosis or Wegener granulomatosis. Anti-HBc antibodies were found in 10 of 50 (20%), 9 of 62 (15%), and 0 of 11 (0%) of these patients, respectively. Only 1 of the 6 patients with polyarteritis nodosa and anti-HCV antibodies confirmed by the RIBA 2 test had a serum HBV marker (anti-HBc antibodies), and none had liver abnormalities. These results suggest that HCV may play a role in causing polyarteritis nodosa. Patrice Cacoub, MD Franqoise Lunel-Fabiani, MD, PhD Le Thi Huong Du, MD CHU Pitie-Salpetriere 75013 Paris, France
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References 1. Guillevin L, Fechner J, Godeau P, et al. Periarterite noueuse. Etude clinique et therapeutique. 126 malades etudies en 23 ans. Ann Med Intern. 1985;136:6-12. 2. Gocke DJ, Hsu K, Morgan C, Bombardini S, Locksin M, Christian CL. Association between polyarteritis nodosa and Australia antigen. Lancet. 1970;2:1149-53. 3. Michalak T. Immune complexes of hepatitis B surface antigen in the pathogenesis of periarteritis nodosa. A study of seven necropsy cases. Am J Pathol. 1978;90:619-32. 4. Alter HJ, Purcell RH, Shih JW, et al. Detection of antibody to hepatitis C virus in prospectively followed transfusion recipients with acute and chronic non-A non B hepatitis. N Engl J Med. 1989;321: 1494-500. 5. Lightfoot RW Jr, Michel BA, B!och DA, et al. The American College of Rheumatology 1990 criteria for the classification of polyarteritis nodosa. Arthritis Rheum. 1990;33:1088-93.
The General Internist—Another Dinosaur? To the Editors: Your editorial (1) spurred me to write. I am very pleased to see someone support continued general medical care. I agree with you that the subspecialization of medicine has resulted in a fractionation of care. General internists must continue to provide comprehensive care for common diseases, such as hypertension, rheumatoid arthritis, and diabetes. Many of our peers are now referring cases to subspecialists because of fear of medical-legal repercussions and because of a general loss in their knowledge, because of their practice of frequent referral. Further reward for providing comprehensive care is necessary; nowadays, it is difficult to have a profitable medical practice. The number of nonreimbursed services provided by primary care physicians increases daily. I hope that lobbying by the American College of Physicians and the American Society for Internal Medicine may yield continued changes in reimbursement. Norman J. Dreher, MD 405-C Black Hills Lane, SW Olympia, WA 98502 Reference 1. Fletcher SW, Fletcher RH. Internal medicine: Whole or in pieces? [Editoriall. Ann Intern Med. 1991;115:978-9.
To the Editors: I agree with all you said in your editorial (1) except for "There is still time to consider . . . to make adjustments." I doubt there is much time—or even will within the medical establishment—to produce change. The approaching collision between subspecialists' dreams of instant wealth and the Federal Governments' increasing control of the delivery system will forcibly make the necessary "adjustments." What we doctors say has become almost irrelevant. Our image is dominated by medical entrepreneurialism. This entrepreneurialism (defined as getting excessive fees from an almost
Corrections Surviving Sudden Death: Whatever Happened to Webster? References 2-5 w e r e omitted from a letter (1). A l s o , T h e Ohio State U n i v e r s i t y is in Columbus, Ohio. References 1. Bell BM, Murden R. Surviving sudden death: Whatever happened to Webster? Ann Intern Med. 1992;116:172. 2. Webster's Seventh New Collegiate Dictionary, Springfield, Massachusetts; G. & C. Merriam Company; 1972:484. 3. Reid PR, Mirowski M, Mower MM, Platia EV, Griffith LSC, Watkins L, et. al. Clinical evaluation of the internal automatic cardioverterdefibrillator in survivors of sudden cardiac death. Am J Cardiol. 1983;51:1608-13. 4. Echt DS, Armstrong K, Schmidt P, Oyer PE, Stinson EB, Winkle RA.
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bankrupt government medical program under siege) makes us a proper target for bureaucratic manipulation. Everybody loved the corner grocer, the general store, and the full-service gasoline-filling station, but where are they today? Everyone loved the one-room school, and it, too, is gone. Everyone loved the family general practitioner and the general internist who gave personal service, made house calls when needed, saw patients in the emergency room, and followed them to surgery and even to the nursing home. The system, however, is making such medical practice either impossible or financially naive. Philip Ball, MD 4915 North Nebro Road Muncie, IN 47304 Reference 1. Fletcher SW, Fletcher RH. Internal medicine: Whole or in pieces? [Editorial]. Ann Intern Med. 1991;115:978-9.
We Thank Our Computer for Performing the Research To the Editors: Microcomputers are now ubiquitous tools in biomedical research, but one would hardly know it from reading most medical journals. In scientific papers, data are usually conceived in the "Introduction," born in the "Methods," and presented in their mature adult form as "Results." What is missing is a sense of the turbulent adolescent development of the data, which nowadays takes place almost entirely in a microcomputer: storage and recovery (in a database management program), editing and manipulation (in a spreadsheet program), mathematical analysis (in a statistical program), and visual display (in a graphics program). Developing the data requires selectivity and skill; the investigator attempts to extract and emphasize the most important findings. This intensely subjective process runs the risk that significant findings may be selectively suppressed. Most scientific papers could be improved if the process of data management was made explicit in the "Methods." What software was used and how it was used to massage the data into their final form should be stated. Which results were and which were not included in the "Results" also should be stated. This information would serve several valuable purposes. It could aid in the evaluation and replication of the research, provide insights into the investigators' thinking, and draw attention to data that may have been misinterpreted or selectively withheld. In addition, it could aid readers in selecting the best software for their own use. Michael Phillips, MD New York Medical College St. Vincent's Medical Center of Richmond Staten Island, NY 10310-1699
Clinical experience, complications, and survival in 70 patients with the automatic implantable cardioverter/defibrillator. Circulation. 1985;71:289-96. 5. Webster's Seventh New Collegiate Dictionary, Springfield, Massachusetts; G. & C. Merriam Company; 1972:212.
Cholesterol Screening D r . K r a h n w a s listed as the sole author of a letter (1). T h r e e other a u t h o r s (2) also contributed to the letter. References 1. Krahn M. Cholesterol screening. Ann Intern Med. 1991;115:983. 2. Krahn M, Naylor D, Basinski AS, Detsky AS. Comparison of an aggressive (U.S.) and a less aggressive (Canadian) policy for cholesterol screening and treatment. Ann Intern Med. 1991;115:248-55.
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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 with the letter 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 only if their letter is accepted. Unpublished letters cannot be returned. Diagnosing Lyme Disease To the Editors: Uncritical clinical application of the T-cell proliferative assay described by Dressier and colleagues (1) may further confuse the evaluation of patients for Lyme disease. The investigators proposed that the test may be helpful in evaluating patients who have clinically apparent late-stage Lyme disease and whose humoral immune response has waned or has been aborted by early (subcurative) antibiotic therapy (1). Such circumstances are rarely encountered. Furthermore, the need for a confirmatory diagnostic test is arguable; few physicians would withhold antimicrobial therapy for Lyme disease on the basis of seronegativity when the patient's history and physical findings are as characteristic of Lyme disease as were those of the patients described (1). A far more common clinical dilemma is presented by patients who lack evidence of Lyme disease by history, physical examination, and serologic testing, but who are nonetheless convinced that they have Lyme disease and might benefit from intravenous antimicrobial therapy (2). Such patients, who often are conversant with the latest developments in Lyme disease research, will likely now request a T-cell proliferative assay to confirm borrellial infection. Alternatively, physicians who are frustrated by this dilemma may turn to the T-cell proliferative assay in hopes of an easy solution. The data presented by Dressier and coworkers (1) suggest that 5% of these patients will have a positive T-cell proliferative assay result despite the absence of borrellial infection. The (probable) extremely low prevalence of true Lyme disease among such patients (that is, the low pretest probability), together with the proliferative assay's estimated false-positive rate of 5% (1), give the test a very low positive predictive power in this population. Most positive results will be falsely so, likely leading to needless treatment of numerous patients with single or multiple courses of expensive and sometimes harmful intravenous antibiotics. Furthermore, the erroneous "confirmation" of a diagnosis of Lyme disease in such patients will reinforce the notion that their symptoms are due to infection and should be treated with antibiotics, thereby diverting attention from more appropriate diagnostic considerations and interventions. In short, the T-cell proliferative assay may broaden our understanding of the immunology of Lyme disease, but its clinical application is fraught with hazard. James R. Johnson, MD University of Minnesota Medical School Minneapolis, MN 55455
References 1. Dressier F, Yoshinari NH, Steere AC. The T-cell proliferative assay in the diagnosis of Lyme disease. Ann Intern Med. 1991;115:533-9. 2. Lettau LA. From the Centers for Fatigue Control (CFC) Weekly Report. Ann Intern Med. 1991; 114:602. In response: We agree with Dr. Johnson that uncritical application of the T-cell proliferative assay—or of any other diagnostic test—creates the potential for misuse. As we stated in our article, the T-cell proliferative assay has the same limitations as serologic testing in evaluating Lyme disease. It demonstrates exposure to Borrellia burgdorferi but does not prove the presence of active infection, and it may have falsenegative or false-positive results. Despite these limitations, we and others (1) have found that the T-cell proliferative assay often has a positive result in the small subset of patients who have Lyme disease, who are incompletely treated with antibiotics during the first several weeks of infection, and who are seronegative later in the illness. It should be emphasized that these patients also have an attenuated clinical presentation with only subtle joint or neurologic abnormalities. Why is the diagnosis of Lyme disease so controversial (2)? We believe that it is because "chronic Lyme disease" has become a common diagnosis for patients with the chronic fatigue syndrome, fibromyalgia, or other illnesses with prominent subjective symptoms, much as "chronic Epstein-Barr virus infection" (3) and "chronic brucellosis" (4) once were. Although B. burgdorferi may trigger chronic fatigue or fibromyalgia in a small percentage of patients, this infection rarely causes these syndromes, even in areas where Lyme disease is endemic. Furthermore, the association between Lyme disease and chronic fatigue has been reinforced inappropriately by the lack of standardization of diagnostic tests, producing variable rates of false-positive results. Lyme disease can usually be treated successfully with 10- to 30-day courses of oral or intravenous antibiotic therapy, depending on the stage and manifestation of the illness (5). No evidence indicates that prolonged courses of antibiotic therapy (lasting months or years) have a role in the treatment of Lyme disease or chronic fatigue. Frank Dressier, MD Allen C. Steere, MD New England Medical Center Tufts University School of Medicine Boston, MA 02111 References 1. Datrwyler RJ, Volkman DJ, Luft BJ, Halperin JJ, Thomas J, Golightly MG. Seronegative Lyme disease: dissociation of the specific T- and B-lymphocyte responses to Borrelia burgdorferi. N Engl J Med. 1988;319:1441-6. 2. Tosiello L, LeHau LA, Madhaven T, Berman DJ, Wenglin BD. Lime versus Lyme disease [letters]. Ann Intern Med. 1991;115:157-8. 3. Gold D, Bovvden R, Sixbey J, et al. Chronic fatigue: a prospective clinical and virologic study. JAMA. 1990;264:48-53. 4. Imboden JB, Canter A, Cluff LE, Trever RW. Brucellosis. III. Psychological aspects of delayed convalescence. Arch Intern Med. 1959; 103:406-14. 5. Steere AC. Lyme disease. N Engl J Med. 1989;321:586-96. Echovirus Meningitis and False-Positive Lyme Test Results To the Editors: Conditions reported to give false-positive results in enzyme immunoassays for Lyme disease include other
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spirochetal infections, viral infections (for example, EpsteinBarr virus), and autoimmune diseases (1). Most questions are resolved by appropriate clinical and laboratory evaluation (2). Enteroviral infections cause several characteristic syndromes, but are most often nonspecific or asymptomatic. Definitive diagnosis requires culture or serologic tests, or both. We report a case of aseptic meningitis that was caused by echovirus type 30 and that resulted in a transient false-positive result on an enzyme immunoassay for Lyme disease. A 39-year-old man was admitted with a history of diffuse myalgias, fever, malaise, flank pain, and a progressive headache for 5 days. Physical examination findings were otherwise unremarkable. Laboratory evaluation revealed a creatinine kinase level of 52.94 /Ltkat/L, an alanine aminotransferase level of 1.27 /ikat/L, and a lactate dehydrogenase level of 3.97 /ikat/L. A complete blood count and urinalysis were normal; blood culture results were negative. A computed tomographic scan of the head and a routine chest film were normal. Cerebrospinal fluid analysis revealed 66 leukocytes/mm 3 , with a mononuclear predominance of 0.98, a glucose level of 2.99 mmol/L, and a protein level of 0.35 g/L; no oligoclonal bands were seen. Because the patient had frequent exposure to farms, leptospiral cultures and serologic testing were done and the patient was treated with penicillin for 7 days. Antinuclear antibodies were not detected, and a VDRL had negative results. Stool, pharyngeal, and cerebrospinal cultures grew echovirus type 30, and serum antibody titers to this virus were increased fourfold at 4 weeks. Leptospiral study results were subsequently negative. The patient was well at all subsequent evaluations. This rather straightforward case was complicated by a Lyme disease IgG enzyme immunoassay performed by the Michigan Department of Public Health. The initial result was positive (optical density, 1.24; > 1 is considered positive). Within 3 months, the enzyme immunoassay result was 1.0. This patient's illness developed at the beginning of a wave of echovirus-associated disease in our community where hundreds of patients are being treated for Lyme disease with long-term intravenous and oral antibiotics, most often without any serologic or epidemiologic support. Most enteroviral syndromes are diagnosed clinically, and the nonspecific symptoms may suggest Lyme disease. This may lead to obtaining a falsepositive enzyme immunoassay result. This case highlights the need for clear pretest assessment of risk, better diagnostic tests, and broad awareness that common nonspecific viral illnesses may falsely elevate current Lyme disease enzyme immunoassay tests. Del J. DeHart, MD Ramesh Avula, MD Sivakumar R. Munnangi, MD Michigan State University College of Human Medicine Saginaw Cooperative Hospitals, Inc. Saginaw, MI 48602 References 1. Craft J, Grodzicki R, Steere AC. Antibody response in Lyme disease: evaluation of diagnostic tests. J Infect Dis. 1984;149:789-95. 2. Weiss NL, Philips MR, Sadock VA, et al. False positive seroreactivity to B. burgorferi in rheumatic disease: the value of immunoblotting [abstract]. IV International Conference on Lyme Borreliosis. 1990; 122.
Why Was Treatment of Cytomegalovirus Retinitis Randomized? To the Editors: Palestine and colleagues (1) examined the role of foscarnet in the treatment of cytomegalovirus retinitis in the acquired immunodeficiency syndrome (AIDS). They conducted a randomized, controlled trial in which the patients in one study arm initially received no treatment. What was the rational for having such a control group? Cytomegalovirus retinitis is the most common intraocular infection and the most common cause of blindness in patients with AIDS. Both ganciclovir and foscarnet have been shown to be approximately 90% effective in arresting retinitis, at least during the induction 604
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phase (2-4). It is also well known that, despite daily maintenance therapy, cytomegalovirus retinitis eventually progresses (1, 3, 4). Why then would disease progression in the control group (which received no treatment) be surprising? The investigators acknowledged that a placebo-controlled trial design "is not appropriate for the evaluation of a disease process that permanently destroys vision" when an available agent is known to be effective. The investigators therefore used subjects whose retinal disease did not threaten immediate, significant visual loss. However, the subjects probably had some visual symptoms (which brought them to medical attention). Furthermore, the time between diagnosis and study entry (3.9 months for the "immediate treatment" group and 3.3 months for the "delayed-treatment" group) was inordinately long. The AIDS epidemic has stimulated reassessment of the randomized controlled trial. Palestine and coworkers (1) implied that known effective therapy was not used for the controls because, at the time, ganciclovir was not licensed for use in cytomegalovirus retinitis. This should not be a reason to delay treatment in cytomegalovirus retinitis. A placebo or no-treatment arm should not be used when disease progression is highly predictable or when acceptable and effective therapy is available. Irving E. Salit, MD, CM The Toronto Hospital University of Toronto Toronto, Ontario M5G 2C4, Canada References 1. Palestine AG, Polis MA, De Smet MD, et al. A randomized, controlled trial of foscarnet in the treatment of cytomegalovirus retinitis in patients with AIDS. Ann Intern Med. 1991;115:665-73. 2. Felsenstein D, D'Amico DJ, Hirsch MS, et al. Treatment of cytomegalovirus retinitis with 9-[2-hydroxyl-l-(hydroxymethyl)ethoxymethyl] guanine. Ann Intern Med. 1985;103:381-2. 3. Walmsley SL, Chew E, Read SE, et al. Treatment of cytomegalovirus retinitis with trisodium phosphonoformate hexahydrate (foscarnet). J Infect Dis. 1988;157:569-72. 4. Fanning MM, Read SE, Benson M, et al. Foscarnet therapy of cytomegalovirus retinitis in AIDS. J Acquir Immune Defic Synd. 1990; 3:472-9.
In response: Although cytomegalovirus retinitis is known to be progressive, its progression is not sufficiently predictable to demonstrate activity of a putative therapeutic agent in the absence of a control group. Our study was the first to show that, using an unbiased, masked ophthalmologic reading center, untreated retinal lesions due to cytomegalovirus progressed by at least 750 /urn over a 750 /xm front in a mean of 3.2 weeks, with progression ranging from 1 week to 6 weeks. An error in Table 2 inaccurately presented the time from diagnosis of cytomegalovirus retinitis to study entry (1); it should read 3.9 weeks and 3.3 weeks (not months) for the immediate treatment and control groups, respectively. The subjects presented with retinal lesions that did not immediately threaten sight and had no significant visual symptoms other than floaters. Two medications are now licensed for the treatment of cytomegalovirus retinitis; however, when the study was initiated, none were. We tried to show, without putting our subjects at risk and in a manner conclusive enough to allow licensure of the drug, that foscarnet was effective in treating cytomegalovirus retinitis. The most efficient vehicle was a randomized controlled trial. The use of ganciclovir for the treatment of non-sight-threatening cytomegalovirus retinitis was both controversial and not routinely acceptable. Zidovudine was the only antiretroviral agent available for treatment of human immunodeficiency virus (HIV) infection, and the difficulty in administering it with ganciclovir was well documented (2). Many persons found themselves having to choose between treatment with an investigational agent with anecdotal evidence of efficacy against cytomegalovirus retinitis and treatment of their underlying HIV infection. Many whose retinal lesions did not immediately threaten their vision chose to receive zidovudine
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until the lesions progressed. Thus, there was no ethical dilemma in designing a study with a short, no-treatment control arm. All patients were made aware of alternative treatment options and of their participation in research. The success of our approach was borne out by the rapid licensure of foscarnet following the completion of the study and the lack of significant deterioration in the visual acuity of subjects on the control arm compared with those on the immediate treatment arm. The randomized controlled trial remains the most efficient mechanism for showing a treatment's efficacy (or lack thereof), and we encourage its use to assist in the rapid evaluation of new therapeutic options. Michael A. Polis, MD, MPH Warren Grant Magnuson Clinical Center Robert B. Nussenblatt, MD National Eye Institute H. Clifford Lane, MD National Institute of Allergy and Infectious Diseases Bethesda, MD 20892 References 1. Palestine AG, Polis MA, de Smet MD, et al. A randomized, controlled trial of foscarnet in the treatment of cytomegalovirus in patients with AIDS. Ann Intern Med. 1991;115:665-73. 2. Hochster H, Dieterich D, Bozzette S, et al. Toxicity of combined ganciclovir and zidovudine for cytomegalovirus disease associated with AIDS. Ann Intern Med. 1990;113:111-7.
HLA-B38 and Clozapine-induced Agranulocytosis To the Editors: Clozapine (Clozaril), a dibenzodiazepine neuroleptic, is associated with a 1% to 2% incidence of druginduced agranulocytosis. Its use, therefore, has been largely limited to select patients with refractory schizophrenia. Very close monitoring of patients receiving this drug has significantly increased the cost of therapy. Lieberman and coworkers (1) noted a 20% incidence of agranulocytosis in a predominantly Jewish group of patients receiving the drug strongly correlating with the presence of the haplotype HLA-B38, DR4, DQw3. We report the occurrence of clozapine-induced agranulocytosis in two non-Jewish patients, both of whom expressed HLA-B38 but did not express DR4 or DQw3. A 32-year-old man who had been receiving clozapine for 58 days was admitted to the University Hospital with a leukocyte count of 2100/mm3 and a granulocyte count of 504/mm3. The granulocyte count subsequently dropped to 0/mm3. Granulopoiesis recovered 12 days after withdrawal of Clozapine. Human leukocyte antigen typing revealed HLA-A1, A3, B38, B63, DR2, DR10, Dql. The second patient was a 41-year-old man admitted to the Veterans Hospital after receiving clozapine for 76 days. His leukocyte count was 1800/mm3, and his granulocyte count was 0/mm3. His leukocyte count normalized 15 days after withdrawal of clozapine. Human leukocyte antigen typing showed HLA-A3, A32, B38, Bw62, DR3, DR6, and Dql,2. Lieberman and colleagues (1) report five of the six cases of clozapine-induced agranulocytosis were in Jewish persons who expressed haplotype HLA B38, DR4, DQ3. Of 17 Jewish controls who did not develop agranulocytosis, only 2 expressed this haplotype. Their study sample was too small to draw firm conclusions about the role of HLA B38 as a predictor, independent of the reported haplotype. Here we report the cases of two non-Jewish patients who developed clozapine-induced agranulocytosis and who expressed HLA B38 but not DR4 or DQw3. HLA B38 has not been associated with schizophrenia per se (2, 3). Our findings support those of Lieberman and coworkers (1) and suggest that HLA B38 may be a predictor of clozapine-induced agranulocytosis. The incidence of agranulocytosis in patients treated with clozapine is 1% to 2%, and the incidence of HLA B38 in white North Americans is 6% (4). Further studies of HLA typing as
a screening test for clozapine-induced agranulocytosis may be indicated. Geetha Joseph, MD Vu Nguyen, MD Jeffrey D. Smith, MD University of Louisville Louisville, KY 40292 References 1. Lieberman JA, Yunis J, Egea E, Canoso RT, Kane JM, Yunis EJ. HLA-B38,DR4,DQw3 and Clozapine-induced agranulocytosis in Jewish patients with schizophrenia. Arch Gen Psych. 1990;47:945. 2. Alexander RC, Coggiano M, Daniel DG, Wyatt RJ. HLA antigens in schizophrenia. Psych Res. 1990;31:221. 3. McGuffin P, Farmer AE, Yonace AH. HLA antigens and subtypes of schizophrenia. Psych Res. 1981;5:115. 4. Histocompatibility Testing 1980: Report of the Eighth International Histocompatibility Workshop. Los Angeles: UCLA Tissue Typing Laboratory; 1980:962.
Polyarteritis Nodosa and Hepatitis C Virus Infection To the Editors: Markers of hepatitis B virus (HBV) infection have been reported in 20% to 40% of patients with polyarteritis nodosa, suggesting that HBV could be an etiologic factor (1-3). Infection with hepatitis C virus (HCV), a recently characterized RNA virus, is responsible for chronic hepatitis and liver cirrhosis and is frequently associated with HBV infection (4). Our aim was to assess the prevalence of HCV markers in patients with polyarteritis nodosa. To avoid bias due to false-positive reactions with a secondgeneration enzyme-linked immunosorbent assay (ELISA 2) (Ortho HCV ELISA Test System 2nd Generation, Ortho Diagnostic Systems, Raritan, New Jersey), patients who had systemic lupus erythematosus or Wegener granulomatosis, who had similar risk factors for HCV infection, and who were hospitalized during the same period, were also studied. Fifty patients had polyarteritis nodosa according to American College of Rheumatology criteria (5): 31 men and 19 women, ranging in age from 24 to 77 years (mean ± SD, 46 ± 17 years). Sixty-two patients had systemic lupus erythematosis: 9 men and 53 women, ranging in age from 16 to 76 years (mean, 34 ± 13 years). Eleven patients had Wegener granulomatosis: 8 men and 3 women, ranging in age from 28 to 70 years (mean, 54 ± 12 years). Anti-HCV antibodies were detected in serum samples that had been frozen at - 80 °C using a ELISA 2, which allows detection of antibodies directed against HCV antigens (C 100-3, C 200, C 22-3). The presence of anti-HCV antibodies was confirmed by a 4-antigen (C 100-3, C 5-1-1, C 33c, C 22-3), recombinant, immunoblot assay (Chiron RIBA HCV Test System 2nd Generation, Abbott Laboratories, Emeryville, California). Serum samples were also tested for HBs antigen and anti-HBc antibodies. Using ELISA 2, anti-HCV antibodies were found in 7 of 50 patients with polyarteritis nodosa (14%) and in 7 of 62 patients with systemic lupus erythematous (11%) but in none of the patients with Wegener granulomatosis. The RIBA 2 assay confirmed the presence of anti-HCV antibodies in 6 of 50 patients with polyarteritis nodosa (12%) and in only 1 patient with systemic lupus erythematosis (2%) (P = 0.03, Fisher exact test, one tail). HBs antigen was detected in 4 of 50 patients with polyarteritis nodosa (8%) and in no patient with systemic lupus erythmatosis or Wegener granulomatosis. Anti-HBc antibodies were found in 10 of 50 (20%), 9 of 62 (15%), and 0 of 11 (0%) of these patients, respectively. Only 1 of the 6 patients with polyarteritis nodosa and anti-HCV antibodies confirmed by the RIBA 2 test had a serum HBV marker (anti-HBc antibodies), and none had liver abnormalities. These results suggest that HCV may play a role in causing polyarteritis nodosa. Patrice Cacoub, MD Franqoise Lunel-Fabiani, MD, PhD Le Thi Huong Du, MD CHU Pitie-Salpetriere 75013 Paris, France
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References 1. Guillevin L, Fechner J, Godeau P, et al. Periarterite noueuse. Etude clinique et therapeutique. 126 malades etudies en 23 ans. Ann Med Intern. 1985;136:6-12. 2. Gocke DJ, Hsu K, Morgan C, Bombardini S, Locksin M, Christian CL. Association between polyarteritis nodosa and Australia antigen. Lancet. 1970;2:1149-53. 3. Michalak T. Immune complexes of hepatitis B surface antigen in the pathogenesis of periarteritis nodosa. A study of seven necropsy cases. Am J Pathol. 1978;90:619-32. 4. Alter HJ, Purcell RH, Shih JW, et al. Detection of antibody to hepatitis C virus in prospectively followed transfusion recipients with acute and chronic non-A non B hepatitis. N Engl J Med. 1989;321: 1494-500. 5. Lightfoot RW Jr, Michel BA, B!och DA, et al. The American College of Rheumatology 1990 criteria for the classification of polyarteritis nodosa. Arthritis Rheum. 1990;33:1088-93.
The General Internist—Another Dinosaur? To the Editors: Your editorial (1) spurred me to write. I am very pleased to see someone support continued general medical care. I agree with you that the subspecialization of medicine has resulted in a fractionation of care. General internists must continue to provide comprehensive care for common diseases, such as hypertension, rheumatoid arthritis, and diabetes. Many of our peers are now referring cases to subspecialists because of fear of medical-legal repercussions and because of a general loss in their knowledge, because of their practice of frequent referral. Further reward for providing comprehensive care is necessary; nowadays, it is difficult to have a profitable medical practice. The number of nonreimbursed services provided by primary care physicians increases daily. I hope that lobbying by the American College of Physicians and the American Society for Internal Medicine may yield continued changes in reimbursement. Norman J. Dreher, MD 405-C Black Hills Lane, SW Olympia, WA 98502 Reference 1. Fletcher SW, Fletcher RH. Internal medicine: Whole or in pieces? [Editoriall. Ann Intern Med. 1991;115:978-9.
To the Editors: I agree with all you said in your editorial (1) except for "There is still time to consider . . . to make adjustments." I doubt there is much time—or even will within the medical establishment—to produce change. The approaching collision between subspecialists' dreams of instant wealth and the Federal Governments' increasing control of the delivery system will forcibly make the necessary "adjustments." What we doctors say has become almost irrelevant. Our image is dominated by medical entrepreneurialism. This entrepreneurialism (defined as getting excessive fees from an almost
Corrections Surviving Sudden Death: Whatever Happened to Webster? References 2-5 w e r e omitted from a letter (1). A l s o , T h e Ohio State U n i v e r s i t y is in Columbus, Ohio. References 1. Bell BM, Murden R. Surviving sudden death: Whatever happened to Webster? Ann Intern Med. 1992;116:172. 2. Webster's Seventh New Collegiate Dictionary, Springfield, Massachusetts; G. & C. Merriam Company; 1972:484. 3. Reid PR, Mirowski M, Mower MM, Platia EV, Griffith LSC, Watkins L, et. al. Clinical evaluation of the internal automatic cardioverterdefibrillator in survivors of sudden cardiac death. Am J Cardiol. 1983;51:1608-13. 4. Echt DS, Armstrong K, Schmidt P, Oyer PE, Stinson EB, Winkle RA.
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bankrupt government medical program under siege) makes us a proper target for bureaucratic manipulation. Everybody loved the corner grocer, the general store, and the full-service gasoline-filling station, but where are they today? Everyone loved the one-room school, and it, too, is gone. Everyone loved the family general practitioner and the general internist who gave personal service, made house calls when needed, saw patients in the emergency room, and followed them to surgery and even to the nursing home. The system, however, is making such medical practice either impossible or financially naive. Philip Ball, MD 4915 North Nebro Road Muncie, IN 47304 Reference 1. Fletcher SW, Fletcher RH. Internal medicine: Whole or in pieces? [Editorial]. Ann Intern Med. 1991;115:978-9.
We Thank Our Computer for Performing the Research To the Editors: Microcomputers are now ubiquitous tools in biomedical research, but one would hardly know it from reading most medical journals. In scientific papers, data are usually conceived in the "Introduction," born in the "Methods," and presented in their mature adult form as "Results." What is missing is a sense of the turbulent adolescent development of the data, which nowadays takes place almost entirely in a microcomputer: storage and recovery (in a database management program), editing and manipulation (in a spreadsheet program), mathematical analysis (in a statistical program), and visual display (in a graphics program). Developing the data requires selectivity and skill; the investigator attempts to extract and emphasize the most important findings. This intensely subjective process runs the risk that significant findings may be selectively suppressed. Most scientific papers could be improved if the process of data management was made explicit in the "Methods." What software was used and how it was used to massage the data into their final form should be stated. Which results were and which were not included in the "Results" also should be stated. This information would serve several valuable purposes. It could aid in the evaluation and replication of the research, provide insights into the investigators' thinking, and draw attention to data that may have been misinterpreted or selectively withheld. In addition, it could aid readers in selecting the best software for their own use. Michael Phillips, MD New York Medical College St. Vincent's Medical Center of Richmond Staten Island, NY 10310-1699
Clinical experience, complications, and survival in 70 patients with the automatic implantable cardioverter/defibrillator. Circulation. 1985;71:289-96. 5. Webster's Seventh New Collegiate Dictionary, Springfield, Massachusetts; G. & C. Merriam Company; 1972:212.
Cholesterol Screening D r . K r a h n w a s listed as the sole author of a letter (1). T h r e e other a u t h o r s (2) also contributed to the letter. References 1. Krahn M. Cholesterol screening. Ann Intern Med. 1991;115:983. 2. Krahn M, Naylor D, Basinski AS, Detsky AS. Comparison of an aggressive (U.S.) and a less aggressive (Canadian) policy for cholesterol screening and treatment. Ann Intern Med. 1991;115:248-55.
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