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 Unpublished letters cannot be returned. The Nicotine Transdermal Patch: A Cautionary Note To the Editors: The nicotine transdermal patch, the newest pharmacologic adjunct for smoking cessation, has recently been introduced in the United States. Two recent reviews of this product concluded that it is effective (1, 2). The reviewers raised concerns about its long-term effectiveness and the generalizability of results (1), and they pointed out the importance of concomitant behavioral modification (2). Based on our experience with nicotine gum, we would add an additional concern: its potential for misuse. The results of early nicotine gum trials raised unrealistic expectations (3, 4). Nicotine replacement was often overprescribed or used without behavioral modification. Disappointing results followed, and perceptions of the product appeared to swing in the opposite direction, leading to underestimation of its efficacy. Fueled by promising research and aggressive marketing by three competing pharmaceutical companies, media and public attention about the patch has already surpassed that accompanying the release of nicotine gum. This initial enthusiasm for the patch, however, may presage difficulties similar to those encountered with the gum. The patch is simpler to use than the gum, which should enhance adherence. Nevertheless, patient expectations, motivation, and compliance will still influence its utility. Many patients look toward using the patch to break the habit; they must be informed that nicotine replacement alone is ineffective for smoking cessation. Practitioners are urged to advise all smokers to quit, to select patients carefully, to combine pharmacotherapy with behavioral interventions, and to monitor patients' progress after smoking cessation. Patients should be encouraged to set a quit date, to plan strategies for coping with urges, and to anticipate and prepare for relapse situations. The time constraints of a busy practice necessitate selecting patients for smoking interventions carefully. Good candidates are those who have shown their motivation by previously trying to quit, who commit to a quit date, and who agree to a follow-up appointment. Finally, nicotine replacement should be used only for those whose smoking reflects addiction according to the Fagerstrom Tolerance Scale or similar instruments (5). If transdermal nicotine is used in conjunction with these timehonored smoking cessation strategies, the product will enhance quit rates and past errors with nicotine replacement will not be repeated.
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References 1. Prochazka A. Commentary on "Transdermal nicotine patch for smoking cessation." ACP J Club. 1991;Nov-Dec:85. (Ann Intern Med. vol 115, suppl 1). Comment on: Tonnesen P, Norregaard J, Simonsen K, Sawe U. A double-blind trial of a 16-hour transdermal nicotine patch in smoking cessation. N Engl J Med. 1991;325:311-5. 2. Schorling JB. Commentary on "Transdermal nicotine delivery for smoking cessation." ACP J Club. 1991;Sep-Oct:51. (Ann Intern Med. vol 115, suppl 2). Comment on: Daughton DM, Heatly SA, Prendergast JJ, et al. Effect of transdermal nicotine delivery as an adjunct to low-intervention smoking cessation therapy: a randomized, placebo-controlled, double-blind study. Arch Intern Med. 1991; 151:749-52. 3. Lam W, Sze P, Sachs HS, Chalmers TC. Meta-analysis of randomized controlled trials of nicotine chewing-gum. Lancet. 1987;2:27-9. 4. Hughes JR, Gust SW, Keenan RM, Fenwick JW, Healey ML. Nicotine vs placebo gum in general medical practice. JAMA. 1989;261: 1300-5. 5. Fagerstrom KO, Schneider NG. Measuring nicotine dependence: a review of the Fagerstrom tolerance questionnaire. J Behav Med. 1989;12:159-82.
Wilson Disease—Penicillamine Therapy and Late Presentation To the Editors: The review by Stremmel and colleagues (1) is informative and provides a significant analysis of the presentation, evaluation, and long-term course of Wilson disease using current therapies. Their conclusion that the calculated serum free-copper concentration is the most reliable finding for the initial diagnosis and is the best indicator of the effectiveness of copper-reducing therapy is noteworthy. Of specific interest is the significantly reduced incidence of severe side effects of D-penicillamine compared with the incidence reported in previous studies of its use in rheumatoid arthritis, systemic sclerosis, and primary biliary cirrhosis. Current package labeling states "Because of the potential for serious hematological and renal adverse reactions to occur at any time, routine urinalysis, white and differential blood cell count, hemoglobin determination, and direct platelet count must be done every two weeks for at least the first six months of penicillamine therapy and monthly thereafter." These recommendations appear to be based on experience with penicillamine therapy for treatment of rheumatologic disorders. I have questioned the necessity of monthly monitoring in stable patients with Wilson disease after years of uncomplicated therapy. Current recommendations about monitoring of penicillamine therapy in patients with Wilson disease are difficult to find in the literature, and I would appreciate the recommendations of those with more experience with the use of long-term penicillamine therapy in patients with Wilson disease. Mark B. Skeen, MD Duke University Medical Center Durham, NC 27710 Reference 1. Stremmel W, Meyerrose K, Niederau C, Hefter H, Kreuzpaintner G, Strohmeyer G. Wilson disease: clinical presentation, treatment, and survival. Ann Intern Med. 1991;115:720-6.
Glen D. Morgan, PhD Wyoming Valley Family Practice Kingston, PA 424
Victor G. Villagra, MD Geisinger Medical Center Danville, PA
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To the Editors: We read with great interest the article by Stremmel and colleagues (1) about patients with Wilson Disease. Of note, the median age of these patients at symptom onset was 15.5 years. Although Wilson disease presents more often in adolescence, patients with primarily neurologic disease may present much later in life. We report the case of a man who presented in the fifth decade. This 41-year-old petrochemical worker reported to his company medical department with complaints of right-handed tremor and metallic taste on the tongue for 9 months. He had been diagnosed as having benign essential tremor by a movement disorder clinic. The patient was subsequently hospitalized for evaluation of progressive manic symptoms and disabling tremor. His serum copper level was 63 /ig/dL (normal range, 70 to 155 /xg/dL), and his ceruloplasmin level was 110 mg/L (normal range, 210 to 530 mg/L). Further examination confirmed Kayser-Fleischer rings, and a liver biopsy revealed a copper content of 961 /xg/g of dry weight. Treatment with D-penicillamine was initiated, and the mania improved, although the tremor initially worsened. The patient returned to work 5 months after the initiation of therapy and now has normal neuropsychologic examination results.
Bruce W. Brown, MD James A. Palmier, MD 2955 Harrison #300 Beaumont, TX 77702
Reference 1. Stremmel W, Meyerrose K, Niederau C, Hefter H, Kreuzpaintner G, Strohmeyer G. Wilson disease: clinical presentation, treatment, and survival. Ann Intern Med. 1991;115:720-6.
In response: In our experience, side effects of D-penicillamine are less frequent in patients with Wilson disease (10% to 20%) than in other patients, such as those with rheumatoid arthritis (20% to 30%), possibly because of its copper-binding capacity in these patients. Some serious and frequently observed side effects are a slowly emerging sensory polyneuropathy, autoimmune disease, nephropathy, thrombocytopenia, and bone marrow aplasia. In stable patients with Wilson disease after years of uncomplicated therapy, we monitor renal status, the presence of autoimmune antibodies in plasma, blood cell count, and we conduct a neurologic examination every third month. In our series, we did not observe any patient with Wilson disease whose onset of symptoms occurred after the age of 40 years. We nevertheless strongly recommend that Wilson disease be excluded in patients with classical clinical symptoms even with onset after 40 years of age; exceptional cases can occur.
Wolfgang Stremmel, MD University of Diisseldorf 4000 Diisseldorf, Germany
Serum Cholesterol as a Prognostic Factor after Myocardial Infarction To the Editors: In men with baseline cardiovascular disease, there appears to be a direct relation between increasing cholesterol levels and subsequently increasing cardiovascular and all-cause mortality (1). In contrast, according to the Framingham data presented by Wong and colleagues (2), the relative risk for both coronary death and all-cause death in women who recovered from myocardial infarction was lower in those with cholesterol levels between 5.17 and 7.11 mmol/L (200 and 274 mg/dL) than in those with levels of less than 5.17 mmol/L (200 mg/dL) (P > 0.05). In a large population study conducted in Scotland (3), which did not show a relation between all-cause mortality and cho-
lesterol levels in women, there was a trend for lower all-cause mortality in those with cholesterol levels between 6.1 and 7.2 mmol/L. A study of elderly female nursing home residents showed that the relation between cholesterol levels and subsequent all-cause death was J-shaped; the lowest relative risk was associated with cholesterol levels of 7 mmol/L (4). Women with cholesterol levels between 5.17 and 7.11 mmol/L comprise a significant segment of our population. Additionally, elderly women may be more susceptible to the adverse effects of hypolipidemic agents (5). Well-designed clinical trials are needed to advance the primary and secondary prevention of coronary disease in women. Mark R. Goldstein, MD Crozer-Chester Medical Center Upland, PA 19013
References 1. Pekkanen J. Relation of cholesterol level to cardiovascular mortality among men with and without preexisting cardiovascular disease. N Engl J Med. 1991;324:61. 2. Wong ND, Wilson PW, Kannel WB. Serum cholesterol as a prognostic factor after myocardial infarction: the Framingham Study. Ann Intern Med. 1991;115:687-93. 3. Isles CG, Hole DJ, Gillis CR, Hawthorne VM, Lever AF. Plasma cholesterol, coronary heart disease, and cancer in the Renfrew and Paisley survey. BMJ. 1989;298:920-4. 4. Forette B, Tortrat D, Wolmark Y. Cholesterol as a risk factor for mortality in elderly women. Lancet. 1989;1:868-70. 5. Goldstein MR. Myopathy and rhabdomyolysis with lovastatin taken with gemfibrozil. JAMA. 1990;264:2991.
In response: The findings that Dr. Goldstein refers to in our report—those showing lower relative risks for coronary death and all-cause death among women with moderately elevated levels of total cholesterol (5.17 to 7.11 mmol/L [200 to 274 mg/dL]) than among women with lower levels (less than 5.17 mmol/L [200 mg/dL])—must be interpreted with caution (1). They are based on a small number of events and do not reach statistical significance. A possible explanation is that high-density-lipoprotein (HDL) cholesterol, which is generally higher in women, could offer protection even in conjunction with total cholesterol levels of up to 7.11 mmol/L (275 mg/dL). Conversely, those in the reference group may have had particularly low levels of HDL cholesterol, thus placing this group at a risk similar to that of those in the middle two total cholesterol level categories. Unfortunately, lipoprotein levels were not available for the majority of participants in our study, so this possibility cannot be confirmed. The fact that these moderate cholesterol levels were associated with an increased risk for reinfarction, on the other hand, suggests that in women who have had a myocardial infarction, such levels of cholesterol might influence the risk for a cardiac event but not necessarily the risk for death. These inconsistent findings, nevertheless, suggest the need for clinical trials among persons with only moderate elevations of total and low-density-lipoprotein cholesterol. Such persons account for a much greater segment of the population than do those with very high levels, as has been noted in previously reported trials. We agree with Dr. Goldstein about the need for clinical trials of lipid intervention in women and the elderly. These groups, already sizable, will only become greater in future years as a result of the aging of the baby boomers and better health care. In addition to new federal initiatives, pharmaceutical companies have an important obligation to justify claims about hypolipidemic agents' effects in reducing cardiovascular events. They have thus far reported only the results of studies in men. Although a recently reported regression trial showed beneficial results of lipid-lowering in reversing atherosclerosis, relatively few women were included (2). An important National Heart, Lung and Blood Institute-funded trial conducted in the elderly is currently in a pilot phase. If expanded to a full-scale trial, it will examine the lipid hypothesis with respect to primary prevention of cardiovascular disease.
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of amyloid suppression and may reverse even the nephrotic syndrome.
Nathan D. Wong, PhD University of California Irvine, CA 92717
Deborah Zemer, MD Avi Livneh, MD Pnina Langevitz, MD The Heller Institute of Medical Research Tel Aviv, Israel
Peter W. F. Wilson, MD William B. Kannel, MD The Framingham Heart Study Framingham, MA 01701
References 1. Wong ND, Wilson PW, Kannel WB. Serum cholesterol as a prognostic factor after myocardial infarction: the Framingham Study. Ann Intern Med. 1991;115:687-93. 2. Kane JP, Malloy MJ, Ports TA, Phillips NR, Diehl JC, Havel RJ. Regression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens. JAMA. 1990; 264:3007-12.
References 1. Zemer D, Pras M, Sohar E, Modan M, Cabili S, Gafni J. Colchicine in the prevention and treatment of the amyloidosis of familial mediterranean fever. N Engl J Med. 1986;314:1001-5. 2. Livneh A, Zemer D, Siegal B, Laor A, Sohar E, Pras M. Colchicine prevents kidney-transplant amyloidosis in familial mediterranean fever. Nephron. [In press].
Angioedema after Substituting Lisinopril for Captopril Reversal of the Nephrotic Syndrome by Colchicine in Amyloidosis of Familial Mediterranean Fever To the Editors: Preventive long-term treatment with colchicine (using an appropriate daily dosage) may reduce kidney damage to minimal proteinuria in patients with familial mediterranean fever, even when it is introduced in the nephrotic stage of this amyloidotic renal disease. We are writing to correct our previous statement that colchicine does not affect amyloidotic kidney disease once it has reached the nephrotic stage (1). We report three cases in which colchicine treatment reduced such kidney damage. We treated a 40-year-old man of Jewish Sephardi origin who has had febrile attacks since the age of 6 months. In 1981, colchicine treatment, 1 mg/d, was recommended, but the patient took only 0.5 mg/d. Three years later, he developed peripheral edema, and his 24-hour urinary protein excretion was 13.5 g. Biopsy confirmation was not sought because, in all our young patients with familial mediterranean fever, persistent proteinuria has resulted from renal amyloidosis (1). The dose of colchicine was increased to 2 mg/d. In the following year, the patient's edema gradually disappeared, and his 24hour urinary protein excretion decreased to 3 g. Since 1987, he has been in stable condition with a 24-hour urinary protein excretion of 0.4 to 0.7 g and normal kidney function. We treated a 30-year-old man of Jewish Sephardi origin who has had febrile attacks since the age of 9 years. In 1981, the patient's parents refused colchicine treatment. In 1983, the nephrotic syndrome was evidenced by peripheral edema, hypoalbuminemia (2.2 g%), and proteinuria (24-hour urinary protein excretion, 4.2 g). Colchicine treatment, 2 mg/d, was started. In 1985, the patient's 24-hour urinary protein excretion decreased to 2.2 g, and his albumin blood level was 3.3 g%. At present, his albumin blood level and kidney function are normal, and his 24-hour urinary protein excretion is 0.750 g. We also treated a 62-year-old man of Jewish Ashkenazi origin who has had recurrent febrile attacks of abdominal and chest pains since childhood. In 1953, the patient was found to have proteinuria, but familial mediterranean fever was excluded because of his Ashkenazi origin. In 1984, the full-blown nephrotic syndrome developed: The patient had peripheral edema, proteinuria (24-hour urinary protein excretion, 6 g), and hypoalbuminemia (2 g%). A rectal biopsy specimen indicated amyloidosis. He was diagnosed as having familial mediterranean fever with amyloidotic kidney disease, and colchicine treatment, 1 g/d, was instituted. In 1986, the patient's nephrotic syndrome started to regress, and, since 1988, his 24-hour urinary protein excretion is approximately 0.540 g. His blood albumin level and renal function are normal. The minimal daily dose of colchicine for prevention of amyloidosis in patients with familial mediterranean fever is 1 mg/d, even if attacks are suppressed with a smaller dose. Patients with clinical evidence of amyloidotic kidney disease and kidney transplant recipients should receive daily doses of between 1.5 and 2 mg/d, regardless of the intensity or frequency of attacks, age, or weight. Such treatment improves the chances 426
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To the Editors: Angiotensin-converting enzyme inhibitors are now among the ten most frequently prescribed drugs in the United States (1). Increased prescription of these inhibitors has exposed more persons to the possibly life-threatening side effect of angioedema (2). The risk for angioedema is estimated to be between 0.1% and 0.2% in patients receiving an angiotensin-converting enzyme inhibitor (3). Angioedema commonly involves the face and oropharyngeal tissues and can result in acute airway obstruction that necessitates emergency intervention. Such obstruction has been reported with the three most commonly prescribed of these inhibitors: captopril, enalapril, and lisinopril (2, 3). Other investigators have reported this effect with a first dose as well as after prolonged exposure (4, 5). To our knowledge, our patient's case is the first angioedema with lisinopril treatment documented in a patient who previously received captopril treatment without side effects. A 20-year-old man with a recent history of progressively worsening congestive heart failure consistent with idiopathic cardiomyopathy was being evaluated for heart transplantation. He had been taking captopril, 50 mg every 8 hours, for the past 4.5 weeks for severe congestive heart failure and pulmonary hypertension. The patient developed a nonproductive cough while taking captopril, and his therapy was modified to lisinopril, 10 mg twice a day. Two hours after administration of the first dose of lisinopril, the patient noticed that his throat felt dry and that his tongue was swelling. When his tongue became too edematous to retract into his mouth, he called for his nurse. During this event, he had no pain or shortness of breath. His past history was remarkable only for penicillin allergy. He had no known food allergies. On physical examination, the patient had good breath sounds without wheezes and a swollen tongue, but no swollen nodes. He was treated with diphenhydramine, 25 mg intravenously, and dexamethasone, 8 mg intravenously. Within 1 hour, the swelling subsided. Steroid treatment was continued and tapered over 48 hours because of the long-acting nature of lisinopril. The next day, captopril treatment was reinstituted without event. A biologic assay of Q esterase inhibitor activity and C 4 levels, which may reflect a hereditary propensity toward angioedema, had normal results. Presently, seven angiotensin-converting enzyme inhibitors are on the market in the United States. As a group, they are ordinarily well tolerated for the treatment of hypertension and heart failure. However, with so many agents now available to prescribing physicians, the likelihood of changing from one such inhibitor to another has increased substantially in the past year. This case demonstrates that previous tolerance does not exclude the risk for angioedema when one angiotensin-converting enzyme inhibitor is substituted for another. Sean McElligott, PharmD Mark Perlroth, MD Linda Raish, PharmD Stanford University Hospital Stanford, CA 94305
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References 1. Simonsen LL. What are pharmacists dispensing most often? Pharmacy Times. 1991;57-71. 2. Barna JS, Frable MS. Life-threatening angioedema. Otolaryngol Head Neck Surg. 1990;103:795-8. 3. Orfan N, Patterson R, Dykewicz MS. Severe angioedema related to ACE inhibitors in patients with a history of idiopathic angioedema. JAMA. 1990;264:1287-9. 4. Gannon TH, Eby TL. Angioedema from angiotensin converting enzyme inhibitors: a cause of upper airway obstruction. Laryngoscope. 1990;100:1156-60. 5. Chin HL, Buchan DA. Severe angioedema after long-term use of an angiotensin-converting enzyme inhibitor [Letter]. Ann Intern Med. 1990;112:312-3.
Rheumatoid Arthritis-like Disease after Alpha-Interferon Therapy To the Editors: We read with great interest the article by Ronnblom and colleagues (1) describing the development of autoimmune diseases after alpha-interferon therapy for malignant carcinoid tumors. We extend the scope of alpha-interferon-induced autoimmune diseases by reporting the cases of three patients with rheumatoid arthritis-like disease. Two men and one woman (64, 52, and 42 years of age, respectively) with chronic myeloproliferative disorders (two patients) and chronic active autoimmune hepatitis (one patient) developed symptoms and signs consistent with acute (one patient) or chronic (two patients) polyarthritis during treatment with recombinant alpha-interferon (alpha-2a, Roferon, Roche, Nutley, New Jersey; or alpha-2b, Intron-A, Schering, Kenilworth, New Jersey). Symmetrical polyarthritis affected the wrists, metacarpal phalanges, proximal intraphalangial joints, knees, and ankles with inflammatory synovial fluid in two patients. Rheumatoid factor (latex to rheumatoid factor titer, 1:640) was present in one patient during therapy. Antinuclear antibodies (IIF titer, 1:500) were detected in another patient before therapy and increased to 1:1000 after a 6-week course of alpha-interferon therapy (3 x 106 units three times per week). Wrist radiographs were consistent with early erosive rheumatoid arthritis in one patient with a positive test result for rheumatoid factor. Symptoms improved in two patients after discontinuation of interferon therapy and administration of corticosteroids. Polyarthritis remained active in the third patient despite oral therapy with prednisone (20 mg/d) and azathioprin (100 mg/d). The causative role of recombinant alpha-interferon is likely, even if autoantibodies and rheumatic disorders have been associated with either chronic active hepatitis or myeloproliferative disorders (2). These case reports extend the spectrum of autoimmune disorders induced by alpha-interferon therapy (3). We recommend the testing of sera for autoantibodies before the start of alpha-interferon therapy and the reconsideration of this treatment for malignant as well as nonmalignant disorders in patients with serologic abnormalities at baseline. Pascal Chazerain, MD Olivier Meyer, MD Marcel-Francis Kahn, MD Xavier Bichet Medical School 75018 Paris, France References 1. Ronnblom LE, Aim GV, Oberg KE. Autoimmunity after alpha-interferon therapy for malignant carcinoid tumors. Ann Intern Med. 1991; 115:178-83. 2. Rondeau E, Solal-Celigny P, Dherm Y, Boivin P. Immune disorders in a gnogenic myeloid metaplasia: relations to myelofibrosis. Br J Haematol. 1983;53:467-75. 3. Conlon KC, Urba WJ, Smith JW, Steis RG, Longo DL, Clark JW. Exacerbation of symptoms of autoimmune disease in patients receiving alpha-interferon therapy. Cancer. 1990;65:2237-42.
Hepatitis C Virus Testing in African Sera To the Editors: Esteban and colleagues (1) reported that in Spain a large proportion (about 70%) of blood donors who are
found to be reactive for antibodies to hepatitis C virus (HCV) by enzyme-linked immunosorbent assay (ELISA) are confirmed to be positive by a second-generation recombinant immunoblot assay (RIBA-2). We recently evaluated the ELISA's specificity in normal donors living in tropical communities. For this purpose, sera specimens from 90 African donors (33 from Mogadishu, Somalia; 25 from Mbalmayo, Cameroon; and 22 from Mbabane, Swaziland) that were found by ELISA (Ortho HCV ELISA Test System 2nd Generation, Raritan, New Jersey) to be repeatedly reactive for anti-HCV were selected for confirmatory testing with RIBA-2 (Chiron RIBA HCV Test System 2nd Generation, Emeryville, California). None had a history of parenteral exposure to blood or blood products, a clinical or pathologic picture compatible with viral hepatitis, or another apparent cause of liver disease. Of the ELISA-positive serum specimens, 30 had an absorbance value of more than 2.4 and were scored as strongly reactive; 30 had a value between 2.4 and 1.1 and were scored as intermediately reactive; and 30 had a value of less than 1.1 and were scored as weakly reactive. According to RIBA-2 testing, 23 (25.6%) sera specimens were positive (reacting with two or more viral antigens), 4 (4.4%) were indeterminate (reacting with only one band), and 63 (70%) were negative (reacting with no bands). The RIBA-2 results correlated with ELISA values. The RIBA-2 positivity rate was 67% in ELISA strongly reactive sera, 10% in ELISA intermediately reactive sera, and 0% in ELISA weakly reactive sera (P < 0.000001, chi-square analysis). No difference was found among donors from different countries. Because RIBA is a very reliable confirmatory test (1), the data are consistent with a high rate of anti-HCV false positivity in African sera with an intermediately or weakly positive ELISA result. Reliance on a single screening ELISA to estimate the prevalence of anti-HCV in sera from tropical communities may lead to gross over-estimation of prevalence. Epidemiologic analysis of HCV prevalence in developing countries will have to await the development of low-cost, more specific assays. Antonio Aceti, MD Gloria Taliani, MD Institute for Tropical and Infectious Diseases La Sapienza University 00161 Rome, Italy Reference 1. Esteban JI, Lopez-Talavera JC, Genesca J, et al. High rate of infectivity and liver disease in blood donors with antibodies to hepatitis C virus. Ann Intern Med. 1991;115:443-9.
Mortality Rate of Community-acquired Pneumonia: 1944 and Today To the Editors: Some old data seem to have been overlooked in the literature. In their article, Farr and colleagues (1) discussed pneumonia mortality, quoting the usual rates of 6% to 24%. In 1946, we reported a mortality rate of 2.6% among 543 cases of acute pneumonia, all of which were presumed to be pneumococcal, with positive roentgenographic findings (2). This finding was of the same order of magnitude as the 1.5% reported by Collen and colleagues (3). The U.S. Army reported case fatality rates of 1.8% among officers and of 0.6% among enlisted men (4). Now many cases are treated without hospitalization. Only more seriously ill patients, many of whom are elderly, are admitted. Perhaps the prepaid insurance of the "shipyard" days, and the approach to medical care in the Army led to earlier hospitalization and treatment. Charles Grossman, MD 622 Oregon National Building Portland, OR 97205 References 1. Farr BM, Sloman AJ, Fisch MJ. Predicting death in patients hospitalized for community-acquired pneumonia. Ann Intern Med. 1991; 115:428-36.
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2. Grossman CM. Lobar pneumonia in the shipbuilding industry. J Ind Hyg Tox. 1946;28:233-6. 3. Collen MF, Sellers AL, Cast EC. Combined penicillin and sulfadiazine therapy in pneumococcal pneumonia. Am J Med Sci. 1946;211: 299-306. 4. Review of Morbidity and Mortality from Respiratory Diseases; 1930 through June 1944. Army in the Continental United States. Washington, DC: Office of the Surgeon General; 15 December 1944: Report 2-MS.
In response: We enjoyed Dr. Grossman's letter and the cited articles by Collen and coworkers (1) and Grossman (2). That lower pneumonia case fatality rates were observed in these two studies than in more recent studies may relate, at least in part, to the healthy worker effect (that is, persons who work in a shipyard are probably younger and healthier, and therefore have a lower frequency of underlying disease or less severe underlying disease than do other persons who are hospitalized for pneumonia). The article by Collen and colleagues (1) demonstrates a younger age distribution and a lower frequency of underlying illness than have been demonstrated in recent studies, including our own (3), of patients hospitalized for pneumonia. Barry Farr, MD, MSc Michael Fisch, MD University of Virginia Health Sciences Center Charlottesville, VA 22908 References 1. Collen MF, Sellers AL, Kast EC. Combined penicillin and sulfadiazine therapy in pneumococcic pneumonia. Am J Med Sci. 1946;211: 299-306. 2. Grossman CM. Lobar pneumonia in the shipbuilding industry. J Ind Hyg Tox. 1946;28:233-6. 3. Farr BM, Sloman AJ, Fisch MJ. Predicting death in patients hospitalized for community-acquired pneumonia. Ann Intern Med. 1991; 115:428-36.
Hepatitis B—An Occupational Risk for Butchers? To the Editors: Hepatitis B virus (HBV) infection, for which preventive vaccination is still the best available therapy, has significant morbidity and mortality. We report the outbreak of hepatitis B in a butchery in which four of the five employees as well as their spouses snowed evidence of HBV infection. The means of transmission of HBV are discussed. A 57-year-old man was hospitalized for management of excessive hypertension that was resistant to metoprolol and diltiazem. Physical examination revealed no relevant findings except for high blood pressure (180 to 200/120). A complete blood count and the results of liver enzyme and kidney function tests were normal. On day 7 of hospitalization, he complained of arthralgia, nausea, and fever, and he developed jaundice. His aspartate aminotransferase level increased to 1610 IU/L (normal range, 5 to 40 IU/L), his alanine aminotransferase level increased to 3470 IU/L (normal range, 5 to 53 IU/L), his alkaline phosphatase level increased to 250 IU/L (normal range, 45 to 115 IU/L), his gamma-glutamyl transpeptidase level increased to 255 IU/L (normal range, 11 to 40 IU/L), and his total bilirubin level increased to 280 /tmol/L (normal range, 0 to 17 /xmol/L). HBeAg and HBsAg tests were positive; Anti-HBc (IgM) was detected at the initial examination, but not 6 weeks later, while the patient developed antibodies to HBe and HBsAg. No serologic evidence of acute delta or hepatitis A virus infection was found. The patient recovered uneventfully. Because the patient was heterosexual and denied abusing drugs, and had received no injections or blood transfusions, the source of his infection was fully investigated. He was a butcher working with four employees. His work involved cutting meat with sharp knives that were often exchanged among the butchers. Small hand cuts were a frequent occurrence. One employee in the butchery was an intravenous drug addict with asymptomatic hepatitis; his sera was positive for HBsAg and HBeAg. This employee had been hired approximately 5 months before the development of hepatitis in the index case. Another two butchers had serologic evidence of exposure to 428
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the virus: One had antibodies to HBs, HBe, and HBc (IgG), and the other had positive HBsAg, HBeAg, and anti-HBc antibodies. The sexual partners of the infected butchers had asymptomatic infection with HBV (they had anti-HBs and HBc IgG antibodies). Except for the drug abuser, none of the employees and none of their spouses had risk factors for HBV infection. At least four modes of transmission of HBV are known (1, 2): parenteral, perinatal, sexual, and "horizontal." Horizontal transmission includes all other modes of transmission and accounts for 50% of hepatitis B infection cases. Most such transmission is through open wounds and, perhaps, saliva. Our limited epidemiologic study revealed that a recently hired employee, who was an infected HBsAg and HBeAg carrier, was most likely the source of the outbreak. The virus may have been transmitted either through contact between knives contaminated with his blood and other employees with hand cuts or through puncture of other employees' skin by knives contaminated with his blood. Both routes would permit his blood to enter their bodies. The mode of transmission, therefore, was probably parenteral or horizontal via open wounds. Vaccination of the general population against HBV is not the current policy in the Western world. It is given only to highrisk populations, such as health care workers, whose risk for infection correlates with their degree of exposure to blood (3, 4). Our findings, together with similar observations from Europe (5), may reveal that butchers are a high-risk group. Dror Mevorach, MD Rami Eliakim, MD Mayer Brezis, MD Hadassah University Hospital Jerusalem 91240, Israel References 1. Franks AL, Bery JC, Kane MA, et al. Hepatitis B virus infection among children born in the United States to Southeast Asian refugees. N Engl J Med. 1989;321:1301-5. 2. Gray DL, Weber JD, Lemon MS. Horizontal transmission of hepatitis B virus. Lancet. 1989;1:889-93. 3. Hoofnagle JH. Towards universal vaccinations against hepatitis B virus. N Engl J Med. 1989;321:1333-4. 4. Lewis JL, Alter HJ, Chalmers TC. A comparison of the frequency of hepatitis B antigen and antibody in hospital and non-hospital personnel. N Engl J Med. 1973;289:647-51. 5. Much AM, Barnes R, Crowe SM, Dimitrakakis M, Lucas CR. An outbreak of hepatitis B and D in butchers. Scand J Infect Dis. 1987;19:179-84.
Testing Remedies for the Shortage of Organs To the Editors: Despite great efforts based on voluntarism and altruism, a severe shortage of organs plagues transplantation today (1). The waiting list of potential recipients continues to grow steadily, and some will die before a suitable organ can be found (2). Many of these deaths are preventable; we are recruiting only a small fraction of eligible donors (3). Several alternative systems of organ procurement have been proposed, including presumed consent, mandated choice, conscription by the state, state-supplied financial incentives, organ sales, and giving higher priority to potential recipients who have previously expressed a willingness to donate. The risks and benefits of each proposal have already been debated extensively. Rather than debate them, I am calling for pilot studies to see just how these proposals would work. Only through trials can the practical value of any proposed solution be determined. For example, required request legislation seemed sensible when it was first proposed, and it was rapidly adopted in most states without trials. Unfortunately, this innovative approach has fallen short of expectations (4). Why wasn't the effect of this legislation in Oregon (where it was first enacted) evaluated before other states followed suit? Whereas required request legislation did not appear to cause damage, other legislation might. I suggest the following approach. First, review the various proposals to see which are ethically acceptable. Second, determine which of the acceptable proposals has the greatest
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chance for benefit and the least for harm as demonstrated here or in other countries with other organ procurement systems in place (5). Third, choose the proposal that seems most simple to implement and evaluate it in a pilot study in one or several small areas before implementing it broadly. Aaron Spital, MD University of Maryland School of Medicine Baltimore, MD 20742 References 1. Spital A. The shortage of organs for transplantation: where do we go from here? N Engl J Med. 1991;325:1243-6. 2. Randall T. Too few human organs for transplantation, too many in need. . . and the gap widens. JAMA. 1991;265:1223-7. 3. Spital A. Locked in dialysis—turning the transplant key. Semin Dial. [In press]. 4. Caplan AL, Welvang P. Are required request laws working? Altruism and the procurement of organs and tissues. Clin Transplant. 1989;3: 170-6. 5. Childress J F . Ethical problems and policies in obtaining and distributing organs for transplantation. Crit Care Clinics. 1986;2:133-48.
" A Poisoned Tooth" To the Editors: Human bite wounds are notoriously prone to the development of infection. The combination of trauma to tissues and deep inoculation of the abundant and varied microorganisms present in the oral cavity often tips the balance in favor of the invaders (1). Recent studies have emphasized the polymicrobial nature of these infections, from which an average of five or six bacterial species, including both aerobic and anaerobic types, is isolated (2, 3). Suppurative tenosynovitis, septic arthritis, or osteomyelitis develop in half the cases, and, before the development of antibiotics, bacteremic infections were occasionally fatal (4).
An early case of fatal infection following a human bite wound is described in Orkneyinga Saga, the history of the earls of Orkney, written around 1200 (5). The Orkney Islands, which lie just off the northern coast of Scotland, were settled by Norsemen in the late eighth and early ninth centuries. They were ruled by Norway and Denmark until 1472, when they were taken over by Scotland. A chapter entitled " A Poisoned Tooth" describes an encounter between the forces of Sigurd the Powerful, the first earl of Orkney, and Maelbrigte, an earl of Scots, which probably took place early in the tenth century (5): There was a fierce fight, but it wasn't long before Maelbrigte and his men were dead. Sigurd had their heads strapped to the victors' saddles to make a show of his triumph, and with that they began riding back home, flushed with their success. On the way, as Sigurd went to spur his horse, he struck his calf against a tooth sticking out of Maelbrigte's mouth and it gave him a scratch. The wound began to swell and ache, and it was this that led to the death of Sigurd the Powerful. He lies buried in a mound on the bank of the River Oykel.
W. Edmund Farrar, MD Medical University of South Carolina Charleston, SC 29425 References 1. Farmer CB, Mann RJ. Human bite infections of the hand. South Med J. 1966;59:512-8. 2. Goldstein EJ, Citron DM, Wield B, et al. Bacteriology of human and animal bite wounds. J Clin Microbiol. 1978;8:667-72. 3. Brook I. Microbiology of human and animal bite wounds in children. Pediatr Infect Dis J. 1987;6:29-32. 4. Mason ML, Koch SL. Human bite infections of the hand. Surg Gynecol Obstet. 1930;51:591-625. 5. Orkneyinga Saga: The History of the Earls of Orkney. Palsson H, Edwards P, translators. New York: Penguin Books; 1981:27-8.
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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. The Nicotine Transdermal Patch: A Cautionary Note To the Editors: The nicotine transdermal patch, the newest pharmacologic adjunct for smoking cessation, has recently been introduced in the United States. Two recent reviews of this product concluded that it is effective (1, 2). The reviewers raised concerns about its long-term effectiveness and the generalizability of results (1), and they pointed out the importance of concomitant behavioral modification (2). Based on our experience with nicotine gum, we would add an additional concern: its potential for misuse. The results of early nicotine gum trials raised unrealistic expectations (3, 4). Nicotine replacement was often overprescribed or used without behavioral modification. Disappointing results followed, and perceptions of the product appeared to swing in the opposite direction, leading to underestimation of its efficacy. Fueled by promising research and aggressive marketing by three competing pharmaceutical companies, media and public attention about the patch has already surpassed that accompanying the release of nicotine gum. This initial enthusiasm for the patch, however, may presage difficulties similar to those encountered with the gum. The patch is simpler to use than the gum, which should enhance adherence. Nevertheless, patient expectations, motivation, and compliance will still influence its utility. Many patients look toward using the patch to break the habit; they must be informed that nicotine replacement alone is ineffective for smoking cessation. Practitioners are urged to advise all smokers to quit, to select patients carefully, to combine pharmacotherapy with behavioral interventions, and to monitor patients' progress after smoking cessation. Patients should be encouraged to set a quit date, to plan strategies for coping with urges, and to anticipate and prepare for relapse situations. The time constraints of a busy practice necessitate selecting patients for smoking interventions carefully. Good candidates are those who have shown their motivation by previously trying to quit, who commit to a quit date, and who agree to a follow-up appointment. Finally, nicotine replacement should be used only for those whose smoking reflects addiction according to the Fagerstrom Tolerance Scale or similar instruments (5). If transdermal nicotine is used in conjunction with these timehonored smoking cessation strategies, the product will enhance quit rates and past errors with nicotine replacement will not be repeated.
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References 1. Prochazka A. Commentary on "Transdermal nicotine patch for smoking cessation." ACP J Club. 1991;Nov-Dec:85. (Ann Intern Med. vol 115, suppl 1). Comment on: Tonnesen P, Norregaard J, Simonsen K, Sawe U. A double-blind trial of a 16-hour transdermal nicotine patch in smoking cessation. N Engl J Med. 1991;325:311-5. 2. Schorling JB. Commentary on "Transdermal nicotine delivery for smoking cessation." ACP J Club. 1991;Sep-Oct:51. (Ann Intern Med. vol 115, suppl 2). Comment on: Daughton DM, Heatly SA, Prendergast JJ, et al. Effect of transdermal nicotine delivery as an adjunct to low-intervention smoking cessation therapy: a randomized, placebo-controlled, double-blind study. Arch Intern Med. 1991; 151:749-52. 3. Lam W, Sze P, Sachs HS, Chalmers TC. Meta-analysis of randomized controlled trials of nicotine chewing-gum. Lancet. 1987;2:27-9. 4. Hughes JR, Gust SW, Keenan RM, Fenwick JW, Healey ML. Nicotine vs placebo gum in general medical practice. JAMA. 1989;261: 1300-5. 5. Fagerstrom KO, Schneider NG. Measuring nicotine dependence: a review of the Fagerstrom tolerance questionnaire. J Behav Med. 1989;12:159-82.
Wilson Disease—Penicillamine Therapy and Late Presentation To the Editors: The review by Stremmel and colleagues (1) is informative and provides a significant analysis of the presentation, evaluation, and long-term course of Wilson disease using current therapies. Their conclusion that the calculated serum free-copper concentration is the most reliable finding for the initial diagnosis and is the best indicator of the effectiveness of copper-reducing therapy is noteworthy. Of specific interest is the significantly reduced incidence of severe side effects of D-penicillamine compared with the incidence reported in previous studies of its use in rheumatoid arthritis, systemic sclerosis, and primary biliary cirrhosis. Current package labeling states "Because of the potential for serious hematological and renal adverse reactions to occur at any time, routine urinalysis, white and differential blood cell count, hemoglobin determination, and direct platelet count must be done every two weeks for at least the first six months of penicillamine therapy and monthly thereafter." These recommendations appear to be based on experience with penicillamine therapy for treatment of rheumatologic disorders. I have questioned the necessity of monthly monitoring in stable patients with Wilson disease after years of uncomplicated therapy. Current recommendations about monitoring of penicillamine therapy in patients with Wilson disease are difficult to find in the literature, and I would appreciate the recommendations of those with more experience with the use of long-term penicillamine therapy in patients with Wilson disease. Mark B. Skeen, MD Duke University Medical Center Durham, NC 27710 Reference 1. Stremmel W, Meyerrose K, Niederau C, Hefter H, Kreuzpaintner G, Strohmeyer G. Wilson disease: clinical presentation, treatment, and survival. Ann Intern Med. 1991;115:720-6.
Glen D. Morgan, PhD Wyoming Valley Family Practice Kingston, PA 424
Victor G. Villagra, MD Geisinger Medical Center Danville, PA
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To the Editors: We read with great interest the article by Stremmel and colleagues (1) about patients with Wilson Disease. Of note, the median age of these patients at symptom onset was 15.5 years. Although Wilson disease presents more often in adolescence, patients with primarily neurologic disease may present much later in life. We report the case of a man who presented in the fifth decade. This 41-year-old petrochemical worker reported to his company medical department with complaints of right-handed tremor and metallic taste on the tongue for 9 months. He had been diagnosed as having benign essential tremor by a movement disorder clinic. The patient was subsequently hospitalized for evaluation of progressive manic symptoms and disabling tremor. His serum copper level was 63 /ig/dL (normal range, 70 to 155 /xg/dL), and his ceruloplasmin level was 110 mg/L (normal range, 210 to 530 mg/L). Further examination confirmed Kayser-Fleischer rings, and a liver biopsy revealed a copper content of 961 /xg/g of dry weight. Treatment with D-penicillamine was initiated, and the mania improved, although the tremor initially worsened. The patient returned to work 5 months after the initiation of therapy and now has normal neuropsychologic examination results.
Bruce W. Brown, MD James A. Palmier, MD 2955 Harrison #300 Beaumont, TX 77702
Reference 1. Stremmel W, Meyerrose K, Niederau C, Hefter H, Kreuzpaintner G, Strohmeyer G. Wilson disease: clinical presentation, treatment, and survival. Ann Intern Med. 1991;115:720-6.
In response: In our experience, side effects of D-penicillamine are less frequent in patients with Wilson disease (10% to 20%) than in other patients, such as those with rheumatoid arthritis (20% to 30%), possibly because of its copper-binding capacity in these patients. Some serious and frequently observed side effects are a slowly emerging sensory polyneuropathy, autoimmune disease, nephropathy, thrombocytopenia, and bone marrow aplasia. In stable patients with Wilson disease after years of uncomplicated therapy, we monitor renal status, the presence of autoimmune antibodies in plasma, blood cell count, and we conduct a neurologic examination every third month. In our series, we did not observe any patient with Wilson disease whose onset of symptoms occurred after the age of 40 years. We nevertheless strongly recommend that Wilson disease be excluded in patients with classical clinical symptoms even with onset after 40 years of age; exceptional cases can occur.
Wolfgang Stremmel, MD University of Diisseldorf 4000 Diisseldorf, Germany
Serum Cholesterol as a Prognostic Factor after Myocardial Infarction To the Editors: In men with baseline cardiovascular disease, there appears to be a direct relation between increasing cholesterol levels and subsequently increasing cardiovascular and all-cause mortality (1). In contrast, according to the Framingham data presented by Wong and colleagues (2), the relative risk for both coronary death and all-cause death in women who recovered from myocardial infarction was lower in those with cholesterol levels between 5.17 and 7.11 mmol/L (200 and 274 mg/dL) than in those with levels of less than 5.17 mmol/L (200 mg/dL) (P > 0.05). In a large population study conducted in Scotland (3), which did not show a relation between all-cause mortality and cho-
lesterol levels in women, there was a trend for lower all-cause mortality in those with cholesterol levels between 6.1 and 7.2 mmol/L. A study of elderly female nursing home residents showed that the relation between cholesterol levels and subsequent all-cause death was J-shaped; the lowest relative risk was associated with cholesterol levels of 7 mmol/L (4). Women with cholesterol levels between 5.17 and 7.11 mmol/L comprise a significant segment of our population. Additionally, elderly women may be more susceptible to the adverse effects of hypolipidemic agents (5). Well-designed clinical trials are needed to advance the primary and secondary prevention of coronary disease in women. Mark R. Goldstein, MD Crozer-Chester Medical Center Upland, PA 19013
References 1. Pekkanen J. Relation of cholesterol level to cardiovascular mortality among men with and without preexisting cardiovascular disease. N Engl J Med. 1991;324:61. 2. Wong ND, Wilson PW, Kannel WB. Serum cholesterol as a prognostic factor after myocardial infarction: the Framingham Study. Ann Intern Med. 1991;115:687-93. 3. Isles CG, Hole DJ, Gillis CR, Hawthorne VM, Lever AF. Plasma cholesterol, coronary heart disease, and cancer in the Renfrew and Paisley survey. BMJ. 1989;298:920-4. 4. Forette B, Tortrat D, Wolmark Y. Cholesterol as a risk factor for mortality in elderly women. Lancet. 1989;1:868-70. 5. Goldstein MR. Myopathy and rhabdomyolysis with lovastatin taken with gemfibrozil. JAMA. 1990;264:2991.
In response: The findings that Dr. Goldstein refers to in our report—those showing lower relative risks for coronary death and all-cause death among women with moderately elevated levels of total cholesterol (5.17 to 7.11 mmol/L [200 to 274 mg/dL]) than among women with lower levels (less than 5.17 mmol/L [200 mg/dL])—must be interpreted with caution (1). They are based on a small number of events and do not reach statistical significance. A possible explanation is that high-density-lipoprotein (HDL) cholesterol, which is generally higher in women, could offer protection even in conjunction with total cholesterol levels of up to 7.11 mmol/L (275 mg/dL). Conversely, those in the reference group may have had particularly low levels of HDL cholesterol, thus placing this group at a risk similar to that of those in the middle two total cholesterol level categories. Unfortunately, lipoprotein levels were not available for the majority of participants in our study, so this possibility cannot be confirmed. The fact that these moderate cholesterol levels were associated with an increased risk for reinfarction, on the other hand, suggests that in women who have had a myocardial infarction, such levels of cholesterol might influence the risk for a cardiac event but not necessarily the risk for death. These inconsistent findings, nevertheless, suggest the need for clinical trials among persons with only moderate elevations of total and low-density-lipoprotein cholesterol. Such persons account for a much greater segment of the population than do those with very high levels, as has been noted in previously reported trials. We agree with Dr. Goldstein about the need for clinical trials of lipid intervention in women and the elderly. These groups, already sizable, will only become greater in future years as a result of the aging of the baby boomers and better health care. In addition to new federal initiatives, pharmaceutical companies have an important obligation to justify claims about hypolipidemic agents' effects in reducing cardiovascular events. They have thus far reported only the results of studies in men. Although a recently reported regression trial showed beneficial results of lipid-lowering in reversing atherosclerosis, relatively few women were included (2). An important National Heart, Lung and Blood Institute-funded trial conducted in the elderly is currently in a pilot phase. If expanded to a full-scale trial, it will examine the lipid hypothesis with respect to primary prevention of cardiovascular disease.
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of amyloid suppression and may reverse even the nephrotic syndrome.
Nathan D. Wong, PhD University of California Irvine, CA 92717
Deborah Zemer, MD Avi Livneh, MD Pnina Langevitz, MD The Heller Institute of Medical Research Tel Aviv, Israel
Peter W. F. Wilson, MD William B. Kannel, MD The Framingham Heart Study Framingham, MA 01701
References 1. Wong ND, Wilson PW, Kannel WB. Serum cholesterol as a prognostic factor after myocardial infarction: the Framingham Study. Ann Intern Med. 1991;115:687-93. 2. Kane JP, Malloy MJ, Ports TA, Phillips NR, Diehl JC, Havel RJ. Regression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens. JAMA. 1990; 264:3007-12.
References 1. Zemer D, Pras M, Sohar E, Modan M, Cabili S, Gafni J. Colchicine in the prevention and treatment of the amyloidosis of familial mediterranean fever. N Engl J Med. 1986;314:1001-5. 2. Livneh A, Zemer D, Siegal B, Laor A, Sohar E, Pras M. Colchicine prevents kidney-transplant amyloidosis in familial mediterranean fever. Nephron. [In press].
Angioedema after Substituting Lisinopril for Captopril Reversal of the Nephrotic Syndrome by Colchicine in Amyloidosis of Familial Mediterranean Fever To the Editors: Preventive long-term treatment with colchicine (using an appropriate daily dosage) may reduce kidney damage to minimal proteinuria in patients with familial mediterranean fever, even when it is introduced in the nephrotic stage of this amyloidotic renal disease. We are writing to correct our previous statement that colchicine does not affect amyloidotic kidney disease once it has reached the nephrotic stage (1). We report three cases in which colchicine treatment reduced such kidney damage. We treated a 40-year-old man of Jewish Sephardi origin who has had febrile attacks since the age of 6 months. In 1981, colchicine treatment, 1 mg/d, was recommended, but the patient took only 0.5 mg/d. Three years later, he developed peripheral edema, and his 24-hour urinary protein excretion was 13.5 g. Biopsy confirmation was not sought because, in all our young patients with familial mediterranean fever, persistent proteinuria has resulted from renal amyloidosis (1). The dose of colchicine was increased to 2 mg/d. In the following year, the patient's edema gradually disappeared, and his 24hour urinary protein excretion decreased to 3 g. Since 1987, he has been in stable condition with a 24-hour urinary protein excretion of 0.4 to 0.7 g and normal kidney function. We treated a 30-year-old man of Jewish Sephardi origin who has had febrile attacks since the age of 9 years. In 1981, the patient's parents refused colchicine treatment. In 1983, the nephrotic syndrome was evidenced by peripheral edema, hypoalbuminemia (2.2 g%), and proteinuria (24-hour urinary protein excretion, 4.2 g). Colchicine treatment, 2 mg/d, was started. In 1985, the patient's 24-hour urinary protein excretion decreased to 2.2 g, and his albumin blood level was 3.3 g%. At present, his albumin blood level and kidney function are normal, and his 24-hour urinary protein excretion is 0.750 g. We also treated a 62-year-old man of Jewish Ashkenazi origin who has had recurrent febrile attacks of abdominal and chest pains since childhood. In 1953, the patient was found to have proteinuria, but familial mediterranean fever was excluded because of his Ashkenazi origin. In 1984, the full-blown nephrotic syndrome developed: The patient had peripheral edema, proteinuria (24-hour urinary protein excretion, 6 g), and hypoalbuminemia (2 g%). A rectal biopsy specimen indicated amyloidosis. He was diagnosed as having familial mediterranean fever with amyloidotic kidney disease, and colchicine treatment, 1 g/d, was instituted. In 1986, the patient's nephrotic syndrome started to regress, and, since 1988, his 24-hour urinary protein excretion is approximately 0.540 g. His blood albumin level and renal function are normal. The minimal daily dose of colchicine for prevention of amyloidosis in patients with familial mediterranean fever is 1 mg/d, even if attacks are suppressed with a smaller dose. Patients with clinical evidence of amyloidotic kidney disease and kidney transplant recipients should receive daily doses of between 1.5 and 2 mg/d, regardless of the intensity or frequency of attacks, age, or weight. Such treatment improves the chances 426
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To the Editors: Angiotensin-converting enzyme inhibitors are now among the ten most frequently prescribed drugs in the United States (1). Increased prescription of these inhibitors has exposed more persons to the possibly life-threatening side effect of angioedema (2). The risk for angioedema is estimated to be between 0.1% and 0.2% in patients receiving an angiotensin-converting enzyme inhibitor (3). Angioedema commonly involves the face and oropharyngeal tissues and can result in acute airway obstruction that necessitates emergency intervention. Such obstruction has been reported with the three most commonly prescribed of these inhibitors: captopril, enalapril, and lisinopril (2, 3). Other investigators have reported this effect with a first dose as well as after prolonged exposure (4, 5). To our knowledge, our patient's case is the first angioedema with lisinopril treatment documented in a patient who previously received captopril treatment without side effects. A 20-year-old man with a recent history of progressively worsening congestive heart failure consistent with idiopathic cardiomyopathy was being evaluated for heart transplantation. He had been taking captopril, 50 mg every 8 hours, for the past 4.5 weeks for severe congestive heart failure and pulmonary hypertension. The patient developed a nonproductive cough while taking captopril, and his therapy was modified to lisinopril, 10 mg twice a day. Two hours after administration of the first dose of lisinopril, the patient noticed that his throat felt dry and that his tongue was swelling. When his tongue became too edematous to retract into his mouth, he called for his nurse. During this event, he had no pain or shortness of breath. His past history was remarkable only for penicillin allergy. He had no known food allergies. On physical examination, the patient had good breath sounds without wheezes and a swollen tongue, but no swollen nodes. He was treated with diphenhydramine, 25 mg intravenously, and dexamethasone, 8 mg intravenously. Within 1 hour, the swelling subsided. Steroid treatment was continued and tapered over 48 hours because of the long-acting nature of lisinopril. The next day, captopril treatment was reinstituted without event. A biologic assay of Q esterase inhibitor activity and C 4 levels, which may reflect a hereditary propensity toward angioedema, had normal results. Presently, seven angiotensin-converting enzyme inhibitors are on the market in the United States. As a group, they are ordinarily well tolerated for the treatment of hypertension and heart failure. However, with so many agents now available to prescribing physicians, the likelihood of changing from one such inhibitor to another has increased substantially in the past year. This case demonstrates that previous tolerance does not exclude the risk for angioedema when one angiotensin-converting enzyme inhibitor is substituted for another. Sean McElligott, PharmD Mark Perlroth, MD Linda Raish, PharmD Stanford University Hospital Stanford, CA 94305
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References 1. Simonsen LL. What are pharmacists dispensing most often? Pharmacy Times. 1991;57-71. 2. Barna JS, Frable MS. Life-threatening angioedema. Otolaryngol Head Neck Surg. 1990;103:795-8. 3. Orfan N, Patterson R, Dykewicz MS. Severe angioedema related to ACE inhibitors in patients with a history of idiopathic angioedema. JAMA. 1990;264:1287-9. 4. Gannon TH, Eby TL. Angioedema from angiotensin converting enzyme inhibitors: a cause of upper airway obstruction. Laryngoscope. 1990;100:1156-60. 5. Chin HL, Buchan DA. Severe angioedema after long-term use of an angiotensin-converting enzyme inhibitor [Letter]. Ann Intern Med. 1990;112:312-3.
Rheumatoid Arthritis-like Disease after Alpha-Interferon Therapy To the Editors: We read with great interest the article by Ronnblom and colleagues (1) describing the development of autoimmune diseases after alpha-interferon therapy for malignant carcinoid tumors. We extend the scope of alpha-interferon-induced autoimmune diseases by reporting the cases of three patients with rheumatoid arthritis-like disease. Two men and one woman (64, 52, and 42 years of age, respectively) with chronic myeloproliferative disorders (two patients) and chronic active autoimmune hepatitis (one patient) developed symptoms and signs consistent with acute (one patient) or chronic (two patients) polyarthritis during treatment with recombinant alpha-interferon (alpha-2a, Roferon, Roche, Nutley, New Jersey; or alpha-2b, Intron-A, Schering, Kenilworth, New Jersey). Symmetrical polyarthritis affected the wrists, metacarpal phalanges, proximal intraphalangial joints, knees, and ankles with inflammatory synovial fluid in two patients. Rheumatoid factor (latex to rheumatoid factor titer, 1:640) was present in one patient during therapy. Antinuclear antibodies (IIF titer, 1:500) were detected in another patient before therapy and increased to 1:1000 after a 6-week course of alpha-interferon therapy (3 x 106 units three times per week). Wrist radiographs were consistent with early erosive rheumatoid arthritis in one patient with a positive test result for rheumatoid factor. Symptoms improved in two patients after discontinuation of interferon therapy and administration of corticosteroids. Polyarthritis remained active in the third patient despite oral therapy with prednisone (20 mg/d) and azathioprin (100 mg/d). The causative role of recombinant alpha-interferon is likely, even if autoantibodies and rheumatic disorders have been associated with either chronic active hepatitis or myeloproliferative disorders (2). These case reports extend the spectrum of autoimmune disorders induced by alpha-interferon therapy (3). We recommend the testing of sera for autoantibodies before the start of alpha-interferon therapy and the reconsideration of this treatment for malignant as well as nonmalignant disorders in patients with serologic abnormalities at baseline. Pascal Chazerain, MD Olivier Meyer, MD Marcel-Francis Kahn, MD Xavier Bichet Medical School 75018 Paris, France References 1. Ronnblom LE, Aim GV, Oberg KE. Autoimmunity after alpha-interferon therapy for malignant carcinoid tumors. Ann Intern Med. 1991; 115:178-83. 2. Rondeau E, Solal-Celigny P, Dherm Y, Boivin P. Immune disorders in a gnogenic myeloid metaplasia: relations to myelofibrosis. Br J Haematol. 1983;53:467-75. 3. Conlon KC, Urba WJ, Smith JW, Steis RG, Longo DL, Clark JW. Exacerbation of symptoms of autoimmune disease in patients receiving alpha-interferon therapy. Cancer. 1990;65:2237-42.
Hepatitis C Virus Testing in African Sera To the Editors: Esteban and colleagues (1) reported that in Spain a large proportion (about 70%) of blood donors who are
found to be reactive for antibodies to hepatitis C virus (HCV) by enzyme-linked immunosorbent assay (ELISA) are confirmed to be positive by a second-generation recombinant immunoblot assay (RIBA-2). We recently evaluated the ELISA's specificity in normal donors living in tropical communities. For this purpose, sera specimens from 90 African donors (33 from Mogadishu, Somalia; 25 from Mbalmayo, Cameroon; and 22 from Mbabane, Swaziland) that were found by ELISA (Ortho HCV ELISA Test System 2nd Generation, Raritan, New Jersey) to be repeatedly reactive for anti-HCV were selected for confirmatory testing with RIBA-2 (Chiron RIBA HCV Test System 2nd Generation, Emeryville, California). None had a history of parenteral exposure to blood or blood products, a clinical or pathologic picture compatible with viral hepatitis, or another apparent cause of liver disease. Of the ELISA-positive serum specimens, 30 had an absorbance value of more than 2.4 and were scored as strongly reactive; 30 had a value between 2.4 and 1.1 and were scored as intermediately reactive; and 30 had a value of less than 1.1 and were scored as weakly reactive. According to RIBA-2 testing, 23 (25.6%) sera specimens were positive (reacting with two or more viral antigens), 4 (4.4%) were indeterminate (reacting with only one band), and 63 (70%) were negative (reacting with no bands). The RIBA-2 results correlated with ELISA values. The RIBA-2 positivity rate was 67% in ELISA strongly reactive sera, 10% in ELISA intermediately reactive sera, and 0% in ELISA weakly reactive sera (P < 0.000001, chi-square analysis). No difference was found among donors from different countries. Because RIBA is a very reliable confirmatory test (1), the data are consistent with a high rate of anti-HCV false positivity in African sera with an intermediately or weakly positive ELISA result. Reliance on a single screening ELISA to estimate the prevalence of anti-HCV in sera from tropical communities may lead to gross over-estimation of prevalence. Epidemiologic analysis of HCV prevalence in developing countries will have to await the development of low-cost, more specific assays. Antonio Aceti, MD Gloria Taliani, MD Institute for Tropical and Infectious Diseases La Sapienza University 00161 Rome, Italy Reference 1. Esteban JI, Lopez-Talavera JC, Genesca J, et al. High rate of infectivity and liver disease in blood donors with antibodies to hepatitis C virus. Ann Intern Med. 1991;115:443-9.
Mortality Rate of Community-acquired Pneumonia: 1944 and Today To the Editors: Some old data seem to have been overlooked in the literature. In their article, Farr and colleagues (1) discussed pneumonia mortality, quoting the usual rates of 6% to 24%. In 1946, we reported a mortality rate of 2.6% among 543 cases of acute pneumonia, all of which were presumed to be pneumococcal, with positive roentgenographic findings (2). This finding was of the same order of magnitude as the 1.5% reported by Collen and colleagues (3). The U.S. Army reported case fatality rates of 1.8% among officers and of 0.6% among enlisted men (4). Now many cases are treated without hospitalization. Only more seriously ill patients, many of whom are elderly, are admitted. Perhaps the prepaid insurance of the "shipyard" days, and the approach to medical care in the Army led to earlier hospitalization and treatment. Charles Grossman, MD 622 Oregon National Building Portland, OR 97205 References 1. Farr BM, Sloman AJ, Fisch MJ. Predicting death in patients hospitalized for community-acquired pneumonia. Ann Intern Med. 1991; 115:428-36.
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2. Grossman CM. Lobar pneumonia in the shipbuilding industry. J Ind Hyg Tox. 1946;28:233-6. 3. Collen MF, Sellers AL, Cast EC. Combined penicillin and sulfadiazine therapy in pneumococcal pneumonia. Am J Med Sci. 1946;211: 299-306. 4. Review of Morbidity and Mortality from Respiratory Diseases; 1930 through June 1944. Army in the Continental United States. Washington, DC: Office of the Surgeon General; 15 December 1944: Report 2-MS.
In response: We enjoyed Dr. Grossman's letter and the cited articles by Collen and coworkers (1) and Grossman (2). That lower pneumonia case fatality rates were observed in these two studies than in more recent studies may relate, at least in part, to the healthy worker effect (that is, persons who work in a shipyard are probably younger and healthier, and therefore have a lower frequency of underlying disease or less severe underlying disease than do other persons who are hospitalized for pneumonia). The article by Collen and colleagues (1) demonstrates a younger age distribution and a lower frequency of underlying illness than have been demonstrated in recent studies, including our own (3), of patients hospitalized for pneumonia. Barry Farr, MD, MSc Michael Fisch, MD University of Virginia Health Sciences Center Charlottesville, VA 22908 References 1. Collen MF, Sellers AL, Kast EC. Combined penicillin and sulfadiazine therapy in pneumococcic pneumonia. Am J Med Sci. 1946;211: 299-306. 2. Grossman CM. Lobar pneumonia in the shipbuilding industry. J Ind Hyg Tox. 1946;28:233-6. 3. Farr BM, Sloman AJ, Fisch MJ. Predicting death in patients hospitalized for community-acquired pneumonia. Ann Intern Med. 1991; 115:428-36.
Hepatitis B—An Occupational Risk for Butchers? To the Editors: Hepatitis B virus (HBV) infection, for which preventive vaccination is still the best available therapy, has significant morbidity and mortality. We report the outbreak of hepatitis B in a butchery in which four of the five employees as well as their spouses snowed evidence of HBV infection. The means of transmission of HBV are discussed. A 57-year-old man was hospitalized for management of excessive hypertension that was resistant to metoprolol and diltiazem. Physical examination revealed no relevant findings except for high blood pressure (180 to 200/120). A complete blood count and the results of liver enzyme and kidney function tests were normal. On day 7 of hospitalization, he complained of arthralgia, nausea, and fever, and he developed jaundice. His aspartate aminotransferase level increased to 1610 IU/L (normal range, 5 to 40 IU/L), his alanine aminotransferase level increased to 3470 IU/L (normal range, 5 to 53 IU/L), his alkaline phosphatase level increased to 250 IU/L (normal range, 45 to 115 IU/L), his gamma-glutamyl transpeptidase level increased to 255 IU/L (normal range, 11 to 40 IU/L), and his total bilirubin level increased to 280 /tmol/L (normal range, 0 to 17 /xmol/L). HBeAg and HBsAg tests were positive; Anti-HBc (IgM) was detected at the initial examination, but not 6 weeks later, while the patient developed antibodies to HBe and HBsAg. No serologic evidence of acute delta or hepatitis A virus infection was found. The patient recovered uneventfully. Because the patient was heterosexual and denied abusing drugs, and had received no injections or blood transfusions, the source of his infection was fully investigated. He was a butcher working with four employees. His work involved cutting meat with sharp knives that were often exchanged among the butchers. Small hand cuts were a frequent occurrence. One employee in the butchery was an intravenous drug addict with asymptomatic hepatitis; his sera was positive for HBsAg and HBeAg. This employee had been hired approximately 5 months before the development of hepatitis in the index case. Another two butchers had serologic evidence of exposure to 428
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the virus: One had antibodies to HBs, HBe, and HBc (IgG), and the other had positive HBsAg, HBeAg, and anti-HBc antibodies. The sexual partners of the infected butchers had asymptomatic infection with HBV (they had anti-HBs and HBc IgG antibodies). Except for the drug abuser, none of the employees and none of their spouses had risk factors for HBV infection. At least four modes of transmission of HBV are known (1, 2): parenteral, perinatal, sexual, and "horizontal." Horizontal transmission includes all other modes of transmission and accounts for 50% of hepatitis B infection cases. Most such transmission is through open wounds and, perhaps, saliva. Our limited epidemiologic study revealed that a recently hired employee, who was an infected HBsAg and HBeAg carrier, was most likely the source of the outbreak. The virus may have been transmitted either through contact between knives contaminated with his blood and other employees with hand cuts or through puncture of other employees' skin by knives contaminated with his blood. Both routes would permit his blood to enter their bodies. The mode of transmission, therefore, was probably parenteral or horizontal via open wounds. Vaccination of the general population against HBV is not the current policy in the Western world. It is given only to highrisk populations, such as health care workers, whose risk for infection correlates with their degree of exposure to blood (3, 4). Our findings, together with similar observations from Europe (5), may reveal that butchers are a high-risk group. Dror Mevorach, MD Rami Eliakim, MD Mayer Brezis, MD Hadassah University Hospital Jerusalem 91240, Israel References 1. Franks AL, Bery JC, Kane MA, et al. Hepatitis B virus infection among children born in the United States to Southeast Asian refugees. N Engl J Med. 1989;321:1301-5. 2. Gray DL, Weber JD, Lemon MS. Horizontal transmission of hepatitis B virus. Lancet. 1989;1:889-93. 3. Hoofnagle JH. Towards universal vaccinations against hepatitis B virus. N Engl J Med. 1989;321:1333-4. 4. Lewis JL, Alter HJ, Chalmers TC. A comparison of the frequency of hepatitis B antigen and antibody in hospital and non-hospital personnel. N Engl J Med. 1973;289:647-51. 5. Much AM, Barnes R, Crowe SM, Dimitrakakis M, Lucas CR. An outbreak of hepatitis B and D in butchers. Scand J Infect Dis. 1987;19:179-84.
Testing Remedies for the Shortage of Organs To the Editors: Despite great efforts based on voluntarism and altruism, a severe shortage of organs plagues transplantation today (1). The waiting list of potential recipients continues to grow steadily, and some will die before a suitable organ can be found (2). Many of these deaths are preventable; we are recruiting only a small fraction of eligible donors (3). Several alternative systems of organ procurement have been proposed, including presumed consent, mandated choice, conscription by the state, state-supplied financial incentives, organ sales, and giving higher priority to potential recipients who have previously expressed a willingness to donate. The risks and benefits of each proposal have already been debated extensively. Rather than debate them, I am calling for pilot studies to see just how these proposals would work. Only through trials can the practical value of any proposed solution be determined. For example, required request legislation seemed sensible when it was first proposed, and it was rapidly adopted in most states without trials. Unfortunately, this innovative approach has fallen short of expectations (4). Why wasn't the effect of this legislation in Oregon (where it was first enacted) evaluated before other states followed suit? Whereas required request legislation did not appear to cause damage, other legislation might. I suggest the following approach. First, review the various proposals to see which are ethically acceptable. Second, determine which of the acceptable proposals has the greatest
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chance for benefit and the least for harm as demonstrated here or in other countries with other organ procurement systems in place (5). Third, choose the proposal that seems most simple to implement and evaluate it in a pilot study in one or several small areas before implementing it broadly. Aaron Spital, MD University of Maryland School of Medicine Baltimore, MD 20742 References 1. Spital A. The shortage of organs for transplantation: where do we go from here? N Engl J Med. 1991;325:1243-6. 2. Randall T. Too few human organs for transplantation, too many in need. . . and the gap widens. JAMA. 1991;265:1223-7. 3. Spital A. Locked in dialysis—turning the transplant key. Semin Dial. [In press]. 4. Caplan AL, Welvang P. Are required request laws working? Altruism and the procurement of organs and tissues. Clin Transplant. 1989;3: 170-6. 5. Childress J F . Ethical problems and policies in obtaining and distributing organs for transplantation. Crit Care Clinics. 1986;2:133-48.
" A Poisoned Tooth" To the Editors: Human bite wounds are notoriously prone to the development of infection. The combination of trauma to tissues and deep inoculation of the abundant and varied microorganisms present in the oral cavity often tips the balance in favor of the invaders (1). Recent studies have emphasized the polymicrobial nature of these infections, from which an average of five or six bacterial species, including both aerobic and anaerobic types, is isolated (2, 3). Suppurative tenosynovitis, septic arthritis, or osteomyelitis develop in half the cases, and, before the development of antibiotics, bacteremic infections were occasionally fatal (4).
An early case of fatal infection following a human bite wound is described in Orkneyinga Saga, the history of the earls of Orkney, written around 1200 (5). The Orkney Islands, which lie just off the northern coast of Scotland, were settled by Norsemen in the late eighth and early ninth centuries. They were ruled by Norway and Denmark until 1472, when they were taken over by Scotland. A chapter entitled " A Poisoned Tooth" describes an encounter between the forces of Sigurd the Powerful, the first earl of Orkney, and Maelbrigte, an earl of Scots, which probably took place early in the tenth century (5): There was a fierce fight, but it wasn't long before Maelbrigte and his men were dead. Sigurd had their heads strapped to the victors' saddles to make a show of his triumph, and with that they began riding back home, flushed with their success. On the way, as Sigurd went to spur his horse, he struck his calf against a tooth sticking out of Maelbrigte's mouth and it gave him a scratch. The wound began to swell and ache, and it was this that led to the death of Sigurd the Powerful. He lies buried in a mound on the bank of the River Oykel.
W. Edmund Farrar, MD Medical University of South Carolina Charleston, SC 29425 References 1. Farmer CB, Mann RJ. Human bite infections of the hand. South Med J. 1966;59:512-8. 2. Goldstein EJ, Citron DM, Wield B, et al. Bacteriology of human and animal bite wounds. J Clin Microbiol. 1978;8:667-72. 3. Brook I. Microbiology of human and animal bite wounds in children. Pediatr Infect Dis J. 1987;6:29-32. 4. Mason ML, Koch SL. Human bite infections of the hand. Surg Gynecol Obstet. 1930;51:591-625. 5. Orkneyinga Saga: The History of the Earls of Orkney. Palsson H, Edwards P, translators. New York: Penguin Books; 1981:27-8.
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