Limulus endotoxin assay and meningitis.

LETTERS AND CORRECTIONS

CONTENTS Living with the Drug Industry R. Brads Legionnaires' Disease and Acinetobacter Bacteremia P. Lerner and J. Kassan Rheumatic Fever in Adults D. J. Mund Cephalosporin and Aminoglycoside Nephrotoxic Interaction W. H. Greene Limulus Endotoxin Assay and Meningitis V. A. Spagna andR. B. Prior H. C. Neu Granulomatosis Treatment R. A. DeRemee A. S. Fauci, B. F. Haynes, and P. Katz Cerebritis in Lupus Erythematosus J. S. Goodwin and J. M. Goodwin Myocarditis of Lupus Erythematosus M. A. Varat T. W. Bunch and R. G. Tancredi M. B. Stevens and F C. Arnett, Jr. Aortic Stenosis and Echocardiography G. Nemana P. Vignola Menopause and Coronary-Artery Heart Disease F P. Zuspan T. Gordon Thyroid Disease and Alkaline Phosphatase D. V. Hamilton /. Potasman and T. Rosenfeld

434 434 435 435 436 436 436 437 437 438 438 439 439 439 439 440 440 440

Serum Angiotensin-Converting Enzyme in Granuloma Annulare M. S. Rohrbach, S. Kossard, and R. K. Winkelmann Pop-Top Finger R. J. Rapoport Ammonium Chloride Therapy in Liver Disease A. N. Bessman D. A. Bushinsky and F. J. Gennari Oxacillin and Hepatotoxicity L J. D'Angelo J. L Axelrod and I. M. Onorato Tamoxifen Hormonal Effects J. D. Veldhuis .... Phenylazopyridine (Pyridium®) and Acute Renal Failure N. Qureshi and R. W. Hedger Cholesterol Embolism in Bone Marrow A. M. Rywlin Itinerant Patient with Hematologic Abnormalities A. S. Bender Marxism V. Simko G. Jacobs Blood Samples for Progeria Study W. T. Brown Correction: Citation of Paper by Yeager and Associates H. Yeager, Jr. R. G. Crystal Correction: Middle Intitial Correction: Name in Index

441 441 442 442 442 442 443 443 443 444 444 444 445

445 445 445 445

Letters submitted for publication must be typed double-spaced. Text length must not exceed 500 words, and no more than five references may be used. Complete references must be furnished, as specified in "Information for Authors'* (page 1-6). Specific permission to publish should be appended as a postscript. Publication depends on availability of space: We give preference to comment on recent content and to new information. Letters for this section should be concise—the Editor reserves the right to shorten them and make changes that accord with our style.

may not be married, from all that is known they are at least happily living together.

Living with the Drug Industry

Legionnaires' Disease and Acinetobacter Bacteremia

R A Y M O N D BRACIS, M.D.

2800 North Vancouver, Suite 230; Portland, OR 97227 REFERENCE

1. K U N I N CM: Problems of antibiotic usage. Definitions, causes, and proposed solutions. Ann Intern Med 89(Part 2):802-805, 1978

T o T H E EDITOR: In his article "Problems of Antibiotic Usage"

T o T H E EDITOR: In the September 1978 issue (1) Kirby and

in the November 1978 issue (1), Dr. Kunin has articulated the sometimes cozy relationship between the pharmaceutical industry and the physician. But has he addressed the root of the problem? Perhaps an accurate analogy in this post-Watergate era would be to compare the physician with a Congressman. Put simply, both are chosen by the public to spend its money wisely. Would not the public be suspicious if a congressman had just returned from an all-expense-paid trip provided by a special interest group and then proceeded to cast a vote affecting the same special interest? Would not that congressman be accused of conflict of interest? While physicians repeatedly state that their acceptance of gifts has no effect on their practice habits, this seems to suggest that the very profitable pharmaceutical industry is being naive. Perhaps the shoe belongs on the other foot. Because the health-care consumer is eventually paying for the pharmaceutical industry's largess, perhaps we physicians should reconsider our current relationship with the drug industry. Although the pharmaceutical industry and the physician

colleagues describe endemic Legionnaires' disease at the Wadsworth Veterans Administration Hospital. One patient with coincident Klebsiella pneumoniae pneumonia remained ill until a course of erythromycin therapy was initiated 10 weeks later. Our following case strengthens their suggestion that chronic illness that sometimes follows Legionnaires' infection may coexist with and be confused by other nosocomial pathogens.

434

Downloaded from https://annals.org by Karolinska Institute user on 01/18/2019

A 76-year-old white woman was admitted on 29 July 1978 with back pain aggravated by coughing, sneezing, and straining. She was afebrile and her chest roentgenogram was clear. Bed rest and pelvic traction for radiculitis provided little relief, but a nerve block did. She was set to be discharged on 21 August when she complained of right chest pain and developed a fever (38.9°C) and tachycardia (130/min). Chest examination findings were normal; she was mildly short of breath. Her leukocyte count was 31 600/mm 3 (89% neutrophils, 5 % bands). Chest roentgenogram revealed an infiltrate occupying most of the right upper lobe (Figure 1) and a small pleural effusion. Despite the absence of significant cough or sputum production, she was treated for pneumonia with oral erythromycin because of a history of penicillin allergy, but she remained febrile. On 22 August two blood cultures grew Acinetobacter anitratus sensitive to tobramycin, initiated that day intravenously (80 mg every 8 h); within 36 h her temperature was normal, and

she was subjectively much improved. She received oral erythromycin for about 48 h. Although she was afebrile thereafter, her lungs cleared very slowly. Tobramycin was withdrawn on 2 September and the patient was discharged, although her leukocyte count was still elevated (16 000/mm 3 ). The consultant noted that "the pneumonia is remarkably asymptomatic for an infectious process, let alone a gram-negative bacillary process." She was readmitted on 18 September with fatigue, malaise, breathlessness, and fever (38.3°C). She denied chest pain or cough. Her lungs were clear, but chest roentgenogram again showed extensive pneumonia of the right upper lobe. On 20 September she was started on oral erythromycin therapy, 500 mg every 8 h. A small amount of expectorated sputum revealed many neutrophils but only a scattering of normal oral flora. Blood cultures were negative. Her temperature subsided gradually on erythromycin therapy. Bronchoscopy on 26 September revealed the right upper lobe bronchus (apical segment) to be edematous and thickened. Biopsy and cytologic studies were negative. She became completely afebrile after these procedures. Antibody titers for Legionnaires' disease were 1:2048 (acute) and 1:4096 (convalescent). Her lungs gradually cleared again but this time with residual pleuritis surrounding the right upper lobe.

This woman developed an acute right upper lobe pneumonia while confined for a noninfectious condition. Bacteremia due to Acinetobacter species prompted a change to intravenous tobramycin therapy after only 48 h of oral erythromycin therapy. Despite prompt defervescence, a chest roentgenogram showed slow and incomplete resolution. Fever, malaise, and pneumonia recurred 2 weeks later and responded, albeit slowly, to a full course of oral erythromycin. Noteworthy were involvement of only a single pulmonary lobe; the absence of significant cough or physical signs of pneumonia on both occasions; and the slow defervescence associated with erythromycin therapy. The characteristics so clearly delineated in the Wadsworth report are emphasized in this case, along with the fact that other opportunistic pathogens may coexist with or obscure the diagnosis of Legionnaires' disease pneumonia. PHILLIP LERNER, M.D. JULIAN KASSEN, M.D.

Mt. Sinai Hospital; Cleveland, OH 44106

REFERENCE 1. K I R B Y BD, SNYDER KM, M E Y E R R D , F I N E G O L D SM: Legionnaires'

disease: clinical features of 24 cases. Ann Intern Med 89:297-309, 1978

Rheumatic Fever in Adults T o THE EDITOR: I have read with great interest the article in the December 1978 issue on acute rheumatic fever in adults (1) and wish to add two cases to those presented. In the last 5 months I have seen two cases of acute rheumatic fever in adults with presentations and courses similar to those presented in the above paper. In each patient, a 25-year-old Yemenite man and a 22-year-old Jamaican woman, the initial presentation was one of high fever to 39.4°C accompanied by a rapidly additive migratory and symmetric polyarthritis mainly involving the lower extremities. The ankles and knees were involved in both patients, with the shoulders additionally involved and a tenosynovitis of the wrist additionally found in the male patient. Neither patient had evidence of erythema marginatum, subcutaneous nodules, or chorea. One patient had a 2 / 6 apical midsystolic murmur throughout his course, but both electrocardiographic and echocardiographic findings were normal. Both patients had evidence of preceding beta hemolytic streptococcus infection with high titer Streptozyme determinations (Wampole Laboratories, Cranbury, New Jersey). Negative throat cultures, moderately elevated peripheral leukocyte counts (12 000/mm 3 ) with a neutrophil predominance, and elevated sedimentation rates (52 and 67 mm) were found in both patients. Synovial fluid leukocyte counts were 7500/mm 3 and 9800/mm 3 with a 95% and 98% predominance of neutrophils. Marked response to aspirin with rapid defervescence and clinical improvement was noted within 24 to 48 h. Of interest was the history of the Jamaican woman who had had similar episodes of arthritis and fever lasting 2 to 3 weeks at ages 10 and 15. She had no recollection of rash, nodules, chorea, or cardiac disturbance during these episodes. The mimetic nature of these attacks are in keeping with the accepted pattern or repeated attacks of rheumatic fever. There is no doubt that acute rheumatic fever occurs in the adult. Larger studies with longer follow-up periods are needed, however, to define the true incidence of carditis. D O U G L A S J. M U N D , M . D .

Downstate Medical Center; Brooklyn, N Y 11203 REFERENCE

1. M C D A N A L D EC, WEISMAN MH: Articular manifestations of rheumatic fever in adults. Ann Intern Med 89:917-920, 1978

Cephalosporin and Aminoglycoside Nephrotoxic Interaction

Figure 1 . Chest roentgenogram most of the right upper lobe.

showing an Infiltrate

occupying

T o THE EDITOR: In the recent succinct review of cefazolin by Quintiliani and Nightingale (1), they briefly mention the possible interaction of cephalosporins and aminoglycosides, notably cephalothin and gentamicin, in causing nephrotoxicity. Although reliable data for cefazolin plus aminoglycosides are too limited for definitive evaluation, this interaction deserves greater emphasis than they have given it. The reference cited by Quintilliani and Nightingale, that of Bobrow and associates (2) was indeed one of the early reports of catastrophic renal failure associated with cephalothin and gentamicin administration. The anecdotal nature of such reports, the frequent coexistence of serious underlying disorders and other renal insults in patients with the purported toxicity, and the lack of laboratory animal evidence of "synergistic" renal effects lead to considerable uncertainty about the existence of the phenomenon. In the past several years, several controlled prospective studies of empiric antibiotic combinations have documented this interaction. Klastersky and colleagues (3), in a comparison of Letters and Corrections


435

cephalothin-tobramycin, ticarcillin-tobramycin, and cephalothin-ticarcillin, found renal toxicity (serum creatinine rise to > 2.0 mg/dl) in 21%, 6%, and 2%, respectively (P < 0.05 by their chi-square analysis). N o cause other than the variations in antibiotic therapy could be implicated as accounting for this disparity. Similarly, in a much larger trial of carbenicillin-gentamicin (CG), carbenicillin-cephalothin (CK), and gentamicincephalothin (GK) conducted by the EORTC (4), significantly (P < 0.05 by two-tailed Fisher's exact test) greater renal dysfunction was observed among those patients receiving G K (16%) than among those receiving either CK (6%) or CG (3%), with increasing age and initial creatinine level predictive of the greatest "excess" renal toxicity in the G K arm. Finally, very recently Wade and co-authors (5) reported the results of a prospective, randomized, double-blind trial designed to answer this precise question. In this study patients were assigned to one of four treatment regimens: cephalothin + gentamicin (KG), cephalothin + tobramycin (KT), methicillin + gentamicin (MG), or methicillin + tobramycin (MT). Nephrotoxicity was defined as an increase in serum creatinine of > 0.4 mg/dl for those with an initial level of < 3.0 mg/dl, or a rise of > 0.9 m g / dl if the initial creatinine was > 3.0 mg/dl. Such nephrotoxicity was ascribed to antibiotic use when no other cause could be identified in the 72 h before the serum creatinine rise. The incidence of antibiotic-associated nephrotoxicity was found to be 30.4%, KG; 20.8%, KT; 10%, MG; and 4.3%, MT. N o statistically significant difference in renal dysfunction was found between aminoglycosides, and therefore the arms were collapsed into a cephalothin plus aminoglycoside group, with 25.5% showing nephrotoxicity, and a methicillin plus aminoglycoside group, (7%) with nephrotoxicity. This difference was significant at a level of P = 0.017 by a one-tailed Fisher's exact test.

are surprised that there is no mention of the limulus endotoxin assay as a rapid (60 minute), reliable method in the initial evaluation of meningitis. After Levin and Bang (2) observed that minute amounts of endotoxin created by gram-negative bacteria produced gelation of amoebocytes from Limulus polyphemus (horseshoe crab), multiple studies confirmed the usefulness of the limulus assay as an aid in the diagnosis of gram-negative meningitis (3-5). In comparing limulus assays and Gram-stain smears on initial spinal fluid samples of patients with gram-negative meningitis, positive limulus assays were obtained in at least 97% of cases, whereas only 70% had organisms visible on smears (3-5). Although the counterimmunoelectrophoresis assay has the advantage of specifically indentifying some of the more common pathogens, it is limited in terms of available antibody preparations (6). The chief drawback of the limulus assay is that a negative test does not rule out the possibility of meningitis due to organisms other than gram-negative bacteria. With a thorough understanding of the advantages and limitations of the limulus assay, it can serve as a valuable adjunct to other diagnostic modalities in the initial clinical management of meningitis.

These studies are strong evidence for the potentiation of aminoglycoside nephrotoxicity by cephalothin. Such potentiation should be taken into account when designing "empiric" regimens of antibiotics for broad-spectrum coverage. This is particularly true because it is difficult to document a greater clinical efficacy of cephalothin plus an aminoglycoside compared to other logical combinations (3, 4). Further, careful observation and reporting of this potential interaction, or its absence, are needed for the less widely used or newer cephalosporins now available, including cefazolin, cefoxitin, and cefamandole. Indeed, should some of these newer agents prove less prone to inducing this toxicity (6), they would be additionally attractive as alternatives to cephalothin. W I L L I A M H. G R E E N , M . D .

Yale University School of Medicine; New Haven, CT 06510 REFERENCES

1. QUINTILLIANI R, NIGHTINGALE CH: Cefazolin. Ann Intern Med 89(Part l):650-656, 1978 2. BOBROW SN, JAFFE E, YOUNG RC: Anuria and acute tubular necrosis associated with gentamicin and cephalothin. JAMA 222:1546-1547, 1972 3. KLASTERSKY J, HENSGENS C, DEBUSSCHER L: Empiric therapy for cancer patients: comparative study of ticarcillin-tobramycin, ticarcillincephalothin, and cephalothin-tobramycin. Antimicrob Agents Chemother 7:640-645, 1975 4. E O R T C INTERNATIONAL ANTIMICROBIAL T H E R A P Y P R O J E C T G R O U P :

Three antibiotic regimens in the treatment of infection in febrile granulocytopenic patients with cancer. J Infect Dis 137:14-29, 1978 5. W A D E JC, SMITH CR, P E T T Y BG, LIPSKY JJ, C O N R A D G, E L L N E R J,

LIETMAN PS: Cephalothin plus an aminoglycoside is more nephrotoxic than methicillin plus an aminoglycoside. Lancet 2:604-606, 1978

V I N C E N T A. S P A G N A , M . D . R I C H A R D B. PRIOR, P H . D .

The Ohio State University; Columbus, OH 43210 REFERENCES

1. N E U HC: What should the clinician expect from the microbiology laboratory? Ann Intern Med 89(Part 2):781-784, 1978 2. LEVIN J, BANG FB: The role of endotoxin in the extracellular coagulation of limulus blood. Bull Johns Hopkins Hosp 115:265-274, 1964 3. JORGENSEN JH, L E E JC: Rapid diagnosis of gram-negative bacterial meningitis by the limulus endotoxin assay. J Clin Microbiol 7:12-17, 1978 4. N A C H U M R, LIPSEY A, SIEGEL SE: Rapid detection of gram-negative bacterial meningitis by the limulus lysate test. N Engl J Med 289:931934, 1973 5. Ross S, R O D R I G U E Z W, C O N T R O N I G, K O R E N G O L D G, W A T S O N S,

K H A N W: Limulus lysate test for gram-negative bacterial meningitis. JAMA 233:1366-1369, 1975 6. E D W A R D S EA, M U E H L PM, PECKINPAUGH RO: Diagnosis of bacterial

meningitis by counterimmunoelectrophoresis. / Lab Clin Med 80:449454, 1972

In comment: The comments by Drs. Spagna and Prior on my article in the November issue (1) are well taken. I should have mentioned the use of the limulus lysate assay in the diagnosis of meningitis. I agree with their comments that the assay is useful. However, I would point out that the test has been most useful in pediatric patients in whom Haemophilus influenzae and Neisseria meningitidis are more common causes of meningitis than they are in adults. The greatest use of the test is in the neonate, in whom Escherichia coli, serotype K„ is one of the two most common organisms causing neonatal meningitis. In the adult patient Streptococcus pneumoniae is the most important cause of meningitis, and this organism produces a negative test. Further, in my own experience, group B N. meningitidis, which is the cause of sporatic cases of meningitis, has often yielded a negative limulus lysate test. We do use the lumulus test in all cases of meningitis of the newborn and in other children. H A R O L D C. N E U , M . D .

Columbia-Presbyterian Medical Center; New York, N Y 10032

6. KLASTERSKY J, DEBUSSCHER L, W E E R T S - R U H L D, P R E V O S T JM: Car-

benicillin, cefazolin, and amikacin as an empiric therapy for febrile granulocytopenic cancer patients. Cancer Treat Rep 61:1433-1439, 1977

REFERENCE

1. N E U HC: What should the clinician expect from the microbiology laboratory? Ann Intern Med 89(Part 2):781-784, 1978

Limulus Endotoxin Assay and Meningitis Granulomatosis Treatment T o THE EDITOR: The article by Dr. Neu in the November issue (1) is a concise, well-organized review of the services available to the clinician from the microbiology laboratory. However, we 436

March 1979 • Annals of Internal Medicine • Volume 90 • Number 3


T o THE EDITOR: In reference to the N I H Conference on vasculitis in the November issue (1), I wish to make a few comments

and observations on the treatment of Wegener's granulomatosis and lymphomatoid granulomatosis. Our experience with Wegener's granulomatosis includes more than 90 cases (2). Cytotoxic agents appear to provide a real advance in treatment. However, the role of glucocorticoids has been inappropriately downgraded. We have maintained patients in a quiescent state solely on prednisone therapy in the range of 60 to 100 mg on alternate days. These patients either could not tolerate or would not use cytotoxic agents for various reasons. Although glucocorticoids can maintain remissions for prolonged periods, it appears that a cytotoxic agent such as Cytoxan® is needed to induce a permanent remission. Clinically measurable effects of Cytoxan have, in my experience, been delayed from 2 to 3 weeks. Hence, I question the need or desirability of altering the dose of Cytoxan at the 2-week interval suggested by Dr. Haynes. Further, I advise caution in using cytotoxic agents and glucocorticoids concomitantly in a fulminating patient lest the immune paralysis lead to death from sepsis, which is the second leading cause of death after renal failure. Regarding the treatment of lymphomatoid granulomatosis, it has been our experience that cytotoxic agents with or without glucocorticoids do not have a significant enduring therapeutic effect. We have recently published evidence linking lymphomatoid granulomatosis with polymorphic reticulosis or so-called lethal midline granuloma, Stewart type (3). Radiation therapy has been uniformally effective in polymorphic reticulosis when it is localized. This experience suggests that similar treatment could be used in selected cases of more widespread disease. It should also spur the chemotherapists to devise regimens that are more radiomimetic in their effects.

we recognize this and have previously discussed these difficulties (1, 4). It should be pointed out that we are recommending brief courses of glucocorticoid therapy during the early fulminant stage. This regimen is rapidly tapered to an alternate day regimen and then to discontinuance. Alternate day therapy does not carry an increased risk of infection. This has clearly been shown (4). Further, we strongly recommend that in using cyclophosphamide, the dose be continuously titrated to maintain the leukocyte count above 3000/mm 3 and the neutrophil count above 1000 to 1500 per mm3. If this is done, there is very little, if any, increased risk of infection (5). Using this approach, we have had no evidence of increased risk of infection in large numbers of patients followed over several years. If daily divided doses of glucocorticoids are used along with a cyclophosphamide regimen that renders the patient markedly neutropenic, we would of course expect a severe host-defense defect, which is why we avoid such regimens, particularly for extended periods. Concerning the last point on the treatment of lymphomatoid granulomatosis, we have found that the early treatment of this disease with cyclophosphamide and alternate day glucocorticoid before the development of fulminant and often lymphomatous dissemination results in complete remissions in a large percentage of cases. The important point is to treat the disease early with cyclophosphamide and not to wait until it is widely disseminated, at which point treatment is relatively ineffective (1, 6). A N T H O N Y S. F A U C I , M . D . B A R T O N F. H A Y N E S , M.D. P A U L KATZ, M.D.

National Institutes of Health; Bethesda, M D 20014

R I C H A R D A. D E R E M E E , M . D .

Mayo Clinic; Rochester, M N 55901

REFERENCES

1. FAUCI AS, HAYNES BF, KATZ P: The spectrum of vasculitis. Clinical, REFERENCES

1. FAUCI AS, HAYNES BF, KATZ P: The spectrum of vasculitis. Clinical,

pathologic, immunologic, and therapeutic considerations. Ann Intern Med 89(Part l):660-676, 1978 2. DEREMEE RA, MCDONALD TJ, HARRISON EG JR, COLES DT: Wegen-

er's granulomatosis. Anatomic correlates, a proposed classification. Mayo ClinProc 51:777-781, 1976 3. DEREMEE RA, WEILAND LH, MCDONALD TJ: Polymorphic reticulosis,

lymphomatoid granulomatosis. Two diseases or one? Mayo Clin Proc 53:634-640, 1978

pathologic, immunologic, and therapeutic considerations. Ann Intern A/ed89(Part l):660-676, 1978 2. FAUCI AS, WOLFF SM: Wegener's granulomatosis: studies in eighteen patients and a review of the literature. Medicine (Baltimore) 52:535-561, 1973 3. REZA MJ, DORNFELD L, GOLDBERG LS, BLUESTONE P, PEARSON CM:

Wegener's granulomatosis. Long-term follow-up of patients treated with cyclophosphamide. Arthritis Rheum 18:501-506, 1975 4. FAUCI AS: Alternate-day corticosteroid therapy (editorial). Am J Med 64:729-731, 1978 5. DALE DC: Abnormalities of leukocytes, in Harrison's Principles of Internal Medicine, 8th ed., edited by THORN GW, ADAMS RD, BRAUNWALD E, ISSELBACHER KJ, PETERSDORF RG. New York, McGraw-Hill, 1977,

In comment: Dr. DeRemee suggests that we are inappropriately downgrading the role of glucocorticosteroids in the treatment of Wegener's granulomatosis. On the contrary, we have delineated those circumstances in which corticosteroids, along with cyclophosphamide, are clearly indicated (1, 2). However, it is quite clear and extremely well documented in several studies that glucocorticoid therapy alone is ineffective in inducing or maintaining long-term remissions in Wegener's granulomatosis, particularly when clinically apparent renal disease ensues. On the contrary, cyclophosphamide has been shown to consistently induce long-term and even permanent remissions in this disease even after the drug has been withdrawn (1-3). Thus, with regard to Dr. DeRemee's comment on maintaining patients in a quiescent state solely on 60 to 100 mg of prednisone on alternate days, we must disagree. The danger in assuming that glucocorticoids can maintain remissions in Wegener's granulomatosis is that renal disease can smolder and insidiously progress while many of the peripheral manifestations of disease are masked by steroid. We have seen several patients who had been maintained in a "quiescent" state with glucocorticoids alone, who in reality had insidious progression of renal disease and in some cases abrupt relapse with fulminant renal disease, such that by the time cyclophosphamide could be effectively instituted, severe and irreversible renal damage had occurred. It is for this reason that we are extremely skeptical about the use of corticosteroids alone in this disease, even to "maintain" remission. With regard to Dr. DeRemee's second comment on the dangers of using glucocorticoids and cyclophosphamide together,

pp. 404-411 6. FAUCI AS: Granulomatous vasculitides: distinct but related (editorial). Ann Intern Med 87:782-783, 1977

Cerebritis in Lupus Erythematosus T o THE EDITOR: The most common neurologic manifestation of systemic lupus erythematosus is organic brain disease, which occurs in about 20% of patients (1). This high incidence of organic brain disease has been thought to be the result of episodes of cerebral vasculitis. We show here that scores of mental status testing in patients with lupus erythematosus decrease as a function of disease duration but are not related to whether the patient had a previous episode of clinical cerebritis. This would suggest that a chronic subclinical cerebritis might occur in many patients with lupus erythematosus. We have studied 22 patients in a lupus erythematosus clinic. Each patient was given the Cognitive Capacity Screening Examination (2) in his or her native language (Spanish or English). We reviewed the charts of these patients and recorded age, duration of disease, and whether the patient had ever been diagnosed as having cerebritis. All of the patients had normal serum electrolytes and creatinine at the time of study. Subjects can score from zero to 30 on the Cognitive Capacity Screening Examination, a simplified mental status examination that correlates well with more extensive mental status testing (2). Letters and Corrections


437

The mean score for the 10 patients with a documented history of cerebritis was 24.6 + 6.6; mean for 12 patients without a history of cerebritis was 25.2 ± 5.0 (mean ± SD, P > 0.6 by t test). However, scores on mental status testing did correlate with duration of disease. The longer the patient had had lupus erythematosus, the lower the mental status score (r = —0.59, P < 0.01). There was no correlation between mental status score and patient's age (r = — 0.13, P > 0.6). It appears, then, that mental function gradually deteriorates in patients with lupus erythematosus as the disease progresses but that the deterioration is not due to recognized episodes of cerebritis. These findings could be explained by a chronic subclinical cerebritis in many or all patients with lupus erythematosus, resulting in gradual intellectual impairment. This concept of a chronic subclinical cerebritis is supported by the recent finding of Pinching and co-workers (3). These workers used oxygen-15 brain scanning to detect cerebral involvement in lupus erythematosus. Of 47 patients studied, only four had normal scans. What was particularly interesting was that 11 of 12 patients without any clinical evidence of central nervous system involvement still had abnormal scans. Earlier autopsy studies also support the concept of unsuspected subclinical central nervous system involvement in patients with lupus erythematosus (4). Organic brain syndromes in patients often go unrecognized by their physicians (5). Physicians should suspect an organic brain syndrome in all patients with systemic lupus erythematosus, and the index of suspicion should increase with increasing duration of the disease. J A M E S S. G O O D W I N , M . D . J E A N M. G O O D W I N , M . D .

University of New Mexico School of Medicine; Albuquerque, N M 87131 REFERENCES 1. G A N Z VH, G U R L A N D BJ, DEMING WE, FISHER B: The study of the

psychiatric symptoms of systemic lupus erythematosus. Psychosom Med 34:207-220, 1972 2. JACOBS JW, BERNHARD MR, DELGADO A, STRAIN JJ: Screening for

organic mental syndromes in the medically ill. Ann Intern Med 86:40-46, 1977 3. PINCHING AJ, TRAVERS RL, H U G H E S GRV, JONES T, Moss S: Oxygen-

15 brain scanning for detection of cerebral involvement in systemic lupus erythematosus. Lancet 1:898-900, 1978 4. GLASER GH: Lesions of central nervous system in disseminated lupus erythematosus. Arch Neurol Psychiatry 67:745-753, 1952 5. KNIGHTS EB, FOLSTEIN MF: Unsuspected emotional and cognitive disturbance in medical patients. Ann Intern Med 87:723-724, 1977

[Readers of this letter will probably be interested in the editorial note by Appenzeller and Williams, Cerebral Lupus Erythematosus, on pp. 430-431 in this issue—The Editor.]

would expect a correspondingly low level of CK-MB release into the blood. This amount would be rapidly cleared (6), and no prominent serum CK-MB elevation would be detected. Therefore serum CK-MB levels seem to be of little value in diagnosing lupus myocarditis or other histologically similar types of myocarditis. M U R R A Y A. V A R A T , M . D .

University of Pittsburgh; Pittsburgh, PA 15213 REFERENCES 1. BORENSTEIN DG, F Y E WB, A R N E T T FC, STEVENS MB: The myocardi-

tis of systemic lupus erythematosus. Association with myositis. Ann Intern Med 89(Part 1):619-624, 1978 2. YASMINEH WG, IBRAHIM GA, ABBASNEZHAD M, A W A D EA: Isoen-

zyme distribution of creatine kinase and lactate dehydrogenase in serum and skeletal muscle in Duchenne muscular dystrophy, collagen disease and other muscle disorders. Clin Chem 24:1985-1989, 1978 3. VARAT MA, MERCER DW: Cardiac specific creatine phosphokinase isoenzyme in the diagnosis of acute myocardial infarction. Circulation 51:855-859, 1975 4. A H M E D SA, WILLIAMSON JR, ROBERTS R, CLARK RE, SOBEL BE: The

association of increased plasma MB CPK activity and irreversible ischemic myocardial injury in the dog. Circulation 54:187-193, 1976 5. BRIGDEN W, BYWATERS EGL, LESSOFF MH, ROSS JP: The heart in

systemic lupus erythematosus. Br Heart J 22:1-16, 1960 6. SMITH LR, ROGERS WJ, M C D A N I E L HG, TURNER ME, BLACKSTONE

EH, RACKLEY CE: Two compartmental models for enzymatic assessment of infarct size. Circulation 58(suppl II): 186, 1978

T o THE EDITOR: The article by Borenstein and associates (1) in the November issue presented the case of a patient with systemic lupus erythematosus associated with skeletal muscle myositis and myocarditis; data on four similar patients were also reviewed. On reading the article, we believe that there is not unequivocal evidence that each of these patients had myocarditis. In the index case, there were only "rare foci of inflammation" in the heart at autopsy; this patient had a restrictive lung disorder with prominence of the pulmonary artery on roentgenogram, and pathologic examination raised the possibility of coronary artery embolization. Perhaps the cardiac abnormalities in this patient were not all secondary to the minimal inflammatory disease seen pathologically. The criteria that the authors propose for the diagnosis of "definite myocarditis" may actually reflect the presence of a myocardiopathy with or without true myocarditis. Cardiac inflammatory changes similar to those seen in lupus erythematosus have been noted in polymyositis, and we recently studied, at autopsy, the hearts of 20 patients with polymyositis. The existence of true myocarditis, determined pathologically, could not be predicted from clinical evidences of congestive heart failure, ventricular dysrhythmias, or nonspecific ST-T changes on the electrocardiogram ( D E N B O W CE, T A N C R E D I RG, B U N C H TW:

Unpublished data). The causation of the cardiac functional abnormalities seen in connective tissue diseases associated with skeletal myositis seems complex. For example, Gottdiener and co-authors (2) in a prospective study found hyperdynamic hearts in patients with polymyositis, but none of their patients showed poor left ventricular performance, as was seen in three of five patients with lupus erythematosus in Borenstein's paper (1). Myocarditis is a pathologic disorder. Until we can establish clinical criteria that adequately separate true myocarditis from other forms of cardiomyopathies, we should not assume that patients with electrocardiographic abnormalities or congestive heart failure associated with active skeletal myositis have myocarditis.

Myocarditis of Lupus Erythematosus T o T H E EDITOR: The association between lupus myositis and myocarditis reported by Borenstein and co-workers in the November issue (1) is very interesting. I wish to comment on the significance of the serum creatine kinase (CK)-cardiac (MB) isoenzyme elevation in their patient and on their suggestion that CK isoenzyme determination may be of value in the diagnosis of lupus myocarditis. A small amount of CK-MB is found in skeletal muscle by tissue analyses (2). In addition, in healthy control subjects, up to 2 % of serum CK may be in the MB form (3). Therefore, the total CK of 1730 U/litre reported in their patient could contain up to 35 U/litre of MB. This amount of MB would be read as "positive*' by the electrophoretic method but could still be consistent with necrosis of skeletal muscle only. It appears likely that CK-MB is released from heart muscle only with necrosis of cells (4). In lupus myocarditis, cell necrosis is not prominent (5) and probably occurs very slowly. One 4 3 8

March 1979 • Annals of Internal Medicine • Volume 90 • Number


T H O M A S W. B U N C H , M . D . R O B E R T G. T A N C R E D I , M . D .

Mayo Clinic; Rochester, M N 55901 REFERENCES 1. BORENSTEIN DG, F Y E WB, A R N E T T FC, STEVENS MB: The myocardi-

tis of systemic lupus erythematosus. Association with myositis. Ann Intern Med 89(Part l):619-624, 1978 3

2. G O T T D I E N E R JS, SHERBER HS, H A W L E Y RJ, E N G E L WK: Cardiac man-

ifestations in polymyositis. Am J Cardiol 41:1141-1149, 1978

In comment: We do not share Dr. Varat's pessimism about the potential value of serum creatine phosphokinase (CPK)-cardiac (MB) isoenzyme in differentiating myositis from myocarditis, since his own elegant studies have shown that only 2% of serum CPK-MB can be attributed to skeletal muscle (his Reference 2). Therefore, with a more quantitative method, for example, ion exchange chromatography, a CPK-MB exceeding 2 % of total serum CPK should alert one to possible myocardial involvement. We agree that CPK-MB is released only from necrotic cardiac muscle. The data are inadequate for determining the degree of myocardial necrosis in systemic lupus erythematosus, for thus far, and including the study quoted by Varat (his Reference 3), histopathologic studies of cardiac muscle have not focused on those with clear myocarditis clinically. Further, the interval between diagnosis of myocarditis and death has almost universally been characterized by suppressive corticosteroid therapy. The judgment of degree of myocardial cell necrosis after steroid therapy becomes difficult, if not impossible, at autopsy when significant dosages of corticosteroids have been administered for a significant period of time. We agree with Drs. Bunch and Tancredi that the distinctions between "myocarditis'* and "myocardiopathy" can be difficult. In our patients with systemic lupus erythematosus, no cause other than the basic disease could be established for myocardial dysfunction, and pathologic findings compatible with healing myocarditis were present at postmortem examination. Again, the modifying role of corticosteroids should be expected to alter degree of pathologic change in cardiac as well as skeletal muscle. A s clinicians, we believe that relying on definitions rather than likelihoods can deny patients adequate therapy of lifethreatening organ involvement since the consequence of not treating active inflammation in myocardium is disastrous. Clearly, prospective studies in patients with systemic lupus erythematosus are needed—and such studies are in progress. M A R Y BETTY STEVENS, M.D. F R A N K C. A R N E T T , JR., M . D .

The Johns Hopkins University School of Medicine; Baltimore, M D 21239

Aortic Stenosis and Echocardiography T o THE EDITOR: I read with interest the article "Echocardiographic Estimation of Aortic-Valve Gradient in Aortic Stenosis'* in the September issue (1). It is surprising that the authors have chosen to include four patients who were found to have no gradient across the aortic valve on left heart catheterization. Even if the condition is clinically suspected, absence of gradient across the aortic valve eliminates the diagnosis. This error, I presume, will not add the same statistical significance that the authors claim. The paper is based on the assumption that normal left ventricle maintains a constant wall stress when faced with chronic pressure load. However, a number of clinical characteristics of their patients (their Table 1), for example, aortic regurgitation and mitral regurgitation, can change the left ventricular internal dimension both echocardiographically and angiographically. Trivial gradients of 10 to 15 mm across the aortic valve are not uncommonly seen in severe aortic insufficiency during cardiac catheterization. This is due to a large volume of flow across the aortic valve and may not in itself represent true organic aortic valvular stenosis (2). If the equation based on the abovementioned assumption is correct, then this should particularly hold true in the two cases of discrete subaortic stenosis that the authors have quoted, wherein chronic pressure load should result in constant wall stress. Yet, their equation 4 has failed to prove the concept in these two cases. Clearly more data should be made available to apply M mode

echocardiography to quantify gradients in aortic stenosis. There is very little doubt, however, about the usefulness of echocardiography in a qualitative sense. GOPALARAO N E M A N A , M.D.

Kaiser-Permanente Medical Center; Sacramento, CA 95825 REFERENCES 1. S C H W A R T Z A, VIGNOLA PA, W A L K E R HJ, K I N G ME, G O L D B L A T T A:

Echocardiography estimation of aortic-valve gradient in aortic stenosis. Ann Intern Med 89:329-335, 1978 2. H U R S T JW, L O G U E RB, SCHLANT RC, W E N G E R NK (eds.): The Heart,

4th ed. New York, McGraw-Hill, 1978, p. 1052

In comment: It is not surprising at all that four patients with clinically suspected aortic stenosis were shown to have no gradient at the time of cardiac catheterization. In children and elderly adults the diagnosis of aortic stenosis can be extremely difficult because clinical clues frequently are misleading or inconclusive. Many large series of catheterized patients with clinically suspected aortic stenosis contain persons with small or absent gradients across the aortic valve (1). Obviously the absence of a pressure gradient across the aortic valve at the time of cardiac catheterization excludes the diagnosis of aortic stenosis. However, the point of our paper was that these patients can be reliably identified using the echocardiography wall stress technique, therefore obviating the need for the invasive study. The presence of aortic or mitral regurgitation does not invalidate the basic assumption of the constant wall stress technique (2). Our experience with this technique in discrete subaortic stenosis is limited to two patients. Therefore we do not believe that our data are sufficient to assess its usefulness in this disease state. However, investigators studying larger numbers of patients with discrete subaortic stenosis have successfully predicted left ventricular outflow gradients using the echocardiographic wall stress technique ( H E L L E N B R A N D WE: Personal communication.) We and others continue to believe that the echocardiography method can be used as a screening procedure to help select those patients who should undergo diagnostic cardiac catheterization and to identify those patients with insignificant left ventricular outflow obstruction, thereby obviating the need for invasive studies in such patients. P A U L VIGNOLA, M.D.

Miami Heart Institute; Miami Beach, FL 33140 REFERENCES 1. E D D L E M A N

EE J R , F R O M M E Y E R

WB, L Y L E DP, BANCROFT WH,

T W E N E R ME: Critical analysis of clinical factors in estimating severity of aortic valve disease. Am J Cardiol 31:687-695, 1973 2. B E N N E T T D H , E V A N S DW, R A J MVJ: Echocardiography left ventricu-

lar dimensions in pressure and volume overload. Their use in assessing aortic stenosis. Br Heart J 37:971-977, 1975

Menopause and Coronary-Artery Heart Disease T o T H E EDITOR: The article by Gordon and colleagues (1) in the August 1978 issue, "Menopause and Coronary Heart Disease. The Framingham Study," contained wording in the abstract that seemed inappropriate. Were the particular values arrived at from the statement, *\ . . whether menopause was natural or surgical. In surgical menopause there was excess incidence whether the ovaries were removed or notV It is impossible to have a surgical menopause unless the ovaries are removed, hence their statement needs further clarification, as does their data. Table 1, column 1, indicates the type of menopause, and under the headings are listed surgical (all), uterus only, uterus plus unilateral oophorectomy, bilateral oophorectomy, oophorectomy unknown. Whether the uterus remains or is absent has Letters and Corrections


439

nothing to do with menopause. The presence or absence of a surgical menopause is based on the presence or absence of functioning ovaries. There are appropriate methods to measure the presence or absence of estrogen and the presence or absence of functioning gonadal tissue. Since the thesis is based on the presence or absence of ovaries, it would appear that estrogen is what is being written about. How are the extra gonadal sources of estrogen and their effect upon the individual accounted for? The current data based on the classification types of menopause under the listing of surgical is meaningless, and I hope that these data can be clarified more meaningfully with criteria taking into account the presence or absence of ovaries. F R E D E R I C K P. Z U S P A N , M . D .

The Ohio State University; Columbus, OH 43210 REFERENCE 1. GORDON T, K A N N E L WB, HJORTLAND MC, M C N A M A R A PM: Meno-

pause and coronary heart disease. The Framingham study. Ann Intern Med 89:157-161, 1978

In reply: Our designation of "surgical menopause" referred to any surgical procedure that led to cessation of menstruation. Since hysterectomy satisfied that criterion, we included it under the heading. We recognize that the decline of ovarian function is a critical factor in natural menopause, but we were not implying that surgical menopause provided an exact counterpart to natural menopause. Even in natural menopause a lot of hormonal and physiologic changes are going on at the same time, and there is something to be said for attending to all of these, rather than focusing exclusively on estrogen. Definitions aside, we hope Dr. Zuspan will concede us our facts. The Framingham data appear to show that a woman with intact ovaries loses her protection against coronary heart disease when her uterus is removed. We do not know, and cannot guess, why this is so, but so it is. Incidentally, this finding does raise the question of whether estrogen has anything to do with the relative immunity against coronary heart disease in premenopausal women. It certainly does not appear to be the sole factor. It may be worth noting in this connection both the strength and weakness of our study and similar epidemiologic investigations. Although it may seem straightforward to measure estrogen output in women, to do so repeatedly in a large number of women is a formidable undertaking. Nonetheless we would have been delighted to undertake repeated hormone studies on both men and women in our study cohort except for one thing: it was well beyond what our finding would allow. Thus we settled for simpler and more economical sources of information. What we found by this means—that hysterectomy with or without oopherectomy leads to an increased risk of coronary heart disease—was unexpected and is unexplained. It is a "lead," a "clue.*' Other investigators, using more sophisticated techniques, such as those alluded to by Dr. Zuspan, will have to take it from there. We hope they will. TAVIA

GORDON

National Heart, Lung, and Blood Institute; Bethesda, M D 20014

Table 1 . Blood Investigations

Thyroxine

SGPTf

IU/litre —

nmol/litre Case 1 4 May 28 May 9 Jun 30 Jun 8 Sep Case 2 23 Jan 3 Apr 22 May 17 Jul 16 Oct Normal range

SGOT*

Alkaline Phosphatase

168 337 167 77 111

102 255 187 108 68

280 90 123 88 119 40 - 140

157 666 200 125 124 30 - 100

11 36 40 19 13 73 109 75 48 52 9-27

> 12 54 67 20 12 95 190 105 51 67 4-24

* SGOT = serum glutamic oxalacetic transaminase. t SGPT = serum glutamic pyruvic transaminase. zymes were elevated. One month later liver function test findings were normal (except for a slightly elevated alkaline phosphatase) and serum thyroxine was normal. Extensive viral studies failed to elucidate the cause of the subacute thyroiditis. An autoantibody screen was negative. A 35-year-old woman presented with a 4-month history of weight loss, trembling hands, sweating, diarrhea, and pruritus. At examination, she was thin, with sweaty hands and tremor. She had a tachycardia of 140/min and brisk reflexes. Investigations (see Table 1) revealed a markedly elevated serum thyroxine and abnormal hepatic enzymes (serum bilirubin was normal). Thyroid microsomal antibodies were positive in a titer of 1:1600. She was treated with carbimazole (initial dose, 10 mg three tiime daily). Within 4 months she was euthyroid, but abnormalities of liver function persisted. A liver biopsy showed mild centrilobular congestion. Her present treatment is carbimazole, 5 mg/day; liver function test findings remain abnormal.

In previous reports of raised alkaline phosphatase and subacute thyroiditis (1-4), abnormalities have been present on diagnosis. In my first case above, the alkaline phosphatase rose and fell concomitantly with the serum thyroxine. In the second case abnormalities of liver function are still present despite adequate treatment of thyrotoxicosis. Mild nonspecific abnormalities of liver function and liver histology have been reported in patients with thyrotoxicosis. The cause of these abnormalities is believed to be due to ischemia or necrosis of some hepatic cells (5). In subacute thyroiditis the cause is unknown. One current theory is that there may be subclinical hepatitis induced by the same virus responsible for the subacute thyroiditis. Two of the reported cases of subacute thyroiditis and raised alkaline phosphatase were associated with infectious mononucleosis (1, 2). Subclinical hepatitis is a wellknown complication of infectious mononucleosis. Alternatively, the cause of the abnormal liver function test findings in subacute thyroiditis may be akin to that in thyrotoxicosis, although as yet there is no satisfactory explanation for these changes. A liver biopsy in a patient with subacute thyroiditis may provide the answer. D A V I D V. H A M I L T O N , M . B . , B . C H I R .

Norfolk and Norwich Hospital; Norwich, Norfolk, England Thyroid Disease and Alkaline Phosphatase

REFERENCES 1. DALOVISIO JR, BLONDE L, CORTEZ LM, PANKEY GA: Subacute thy-

T o THE EDITOR: Following the recent reports in your journal of raised alkaline phosphatase levels in patients with subacute thyroiditis (1-4), I wish to report an additional case in which initial liver function test findings were normal. I also wish to report a case of thyrotoxicosis in which liver function test findings have remained abnormal for 9 months. A 38-year-old woman presented with a 2-week history of painful swelling of her thyroid gland, which on examination was tender. Investigations (see Table 1) were essentially normal apart from an elevated erythrocyte sedimentation rate and serum thyroxine. She was treated with indomethacin. Two weeks later serum thyroxine was markedly elevated and hepatic en4 4 0



roiditis with increased serum alkaline phosphatase. Ann Intern Med 88:505-507, 1978 2. FENNELL JS: Alkaline phosphatase and thyroiditis (letter). Ann Intern Med 89:143, 1978 3. LEWIS DA: Alkaline phosphatase and thyroiditis (letter). Ann Intern Med 89:143-144, 1978 4. KASPA RT, NAPARSTEK Y: Thyroiditis and alkaline phosphatase (letter). Ann Intern Med 89:578, 1978 5. DOONER HP, PARADA J, ALIAGA C, HOYL C: The liver in thyrotoxico-

sis. Arch Intern Med 120:25-32, 1967

T o THE EDITOR: We have read with great interest the recent

article by Dalovisio and co-authors (1) and the letters of Fennell and Lewis (2, 3) on subacute thyroiditis with increased alkaline phosphatase. Since it is routine practice in our hospital to measure the alkaline phosphatase of every patient, we wished to ascertain whether the results obtained in our patients with subacute thyroiditis concurred with those of Dalovisio. We retrospectively analyzed the files of 15 patients whose diagnosis of subacute thyroiditis was made according to accepted criteria. The results follow. Alkaline phosphatase level (normal, 0.8 to 3.0 U) was found to be elevated in three patients: 4.6, 4.8, and 6.6 U, respectively. Three additional patients had values at the upper limit of normal (3.0 U). Glutamic oxalacetic transaminase was elevated in three patients, all of whom had high levels of alkaline phosphatase as well. Several other laboratory test abnormalities were found. High levels of T 3 or T 4 were noted in five of 15 patients; low levels of T 3 were found in five. Antithyroglobulin antibodies were positive in two and negative in five patients. Viral study findings (adenovirus, herpes, mumps) in three patients (those with high alkaline phosphatase) were negative. Serologic tests {Brucella, Weil-Felix, Widal, Paul-Bunnell) in 10 of 15 patients were negative. The length of the prodromal signs was longer by 3 5 % in the group with normal alkaline phosphatase values.

High levels of alkaline phosphatase have been described in many diseases (4). The work of Dalovisio and colleagues (1) suggests yet another disease. Our data support their finding that the source of the alkaline phosphatase in subacute thyroiditis is hepatic and not osseous. Further studies should be undertaken to verify this finding. The occurrence of high levels of thyroid hormones is less common in our patients (30% versus 90% by Dalovisio), but this finding is variable in any case. This is also true for the low levels of T3. Viral and serologic tests were negative in all patients, and we did not find, in our cases, any substantiation to the points of Fennell (2) or Volpe (5) for the possible viral causation in subacute thyroiditis. The point we wish to stress is the time factor. Our findings are not unequivocal, but it seems that the duration of the prodromal symptoms and stage in the course of the illness at which the serum alkaline phosphatase and glutamic oxalacetic transaminase are estimated may have relevance to the frequency of positive results. We found a large range of duration of prodromata, and we think that in some cases the estimation may have been done when high levels were declining. ISRAEL POTASMAN, M.D. TLBERIO R O S E N F E L D , M . D .

Rothschild University Hospital; Haifa, Israel REFERENCES 1. DALOVISIO JR, B L O N D E L, C O R T E Z LM, P A N K E Y G A : Subacute thy-

2. 3. 4. 5.

roiditis with increased serum alkaline phosphatase. Ann Intern Med 88:505-507, 1978 F E N N E L JS: Alkaline phosphatase and thyroiditis (letter) Ann Intern Med 89:143, 1978 L E W I S DA: Alkaline phosphatase and thyroiditis (letter). Ann Intern Med 89:143-144, 1978 WALLACH J: Interpretation of Diagnostic Tests, 3rd ed. Boston, Little, Brown & Co., 1978, p. 53 VOLPE R, R O W VV, EZRIN C: Circulating viral and thyroid antibodies in subacute thyroiditis. / Clin Endocrinol 27:1275-1284, 1967

migration inhibiting factors have been seen in both (2). Although cutaneous sarcoidosis and generalized granuloma can usually be differentiated clinically, the two conditions may coexist or overlap (3). We have measured the serum angiotensin-converting enzyme level (4) in five patients with generalized granuloma annulare without evidence of sarcoidosis. The mean level of 42.0 ( ± 9.4 s o ) U / m l for these patients was within the normal range of 40.2 ( i 8.6) U / m l previously determined for 60 healthy normal adult subjects. Whether the lack of elevation of serum angiotensin-converting enzyme in granuloma annulare merely represents differences in granuloma mass in the two conditions and hence serum levels or a more fundamental difference is unknown. The measurement of angiotensin-converting enzyme may also be of some diagnostic value in patients in whom this differential is being considered. M I C H A E L S. R O H R B A C H , P H . D . S T E V E N K O S S A R D , M.B., PH.D.

R. K. WlNKELMANN, M.D. Mayo Clinic; Rochester, M N 55901 REFERENCES

1. LIEBERMAN J, R E A TH: Serum angiotensin-converting enzyme in leprosy and coccidioidomycosis. Ann Intern Med 87:422-425, 1977 2. U M B E R T P, B E L C H E R RW, W I N K E L M A N N RK: Lymphokines (MIF) in

serum of patients with sarcoidosis and cutaneous granuloma annulare. Br J Dermatol 95:481-485, 1976 3. U M B E R T P, W I N K E L M A N N RK: Granuloma annulare and sarcoidosis. Br

J Dermatol 97:481-486, 1977 4. ROHRBACH MS: (Glycine-1- 14 C) Hippuryl-L-histidyl-L-levucine: a substrate for the radiochemical assay of angiotensin converting enzyme. AnalBiochem 84:272-276, 1978

Pop-Top Finger T o THE EDITOR: A 30-year-old rheumatology fellow developed severe joint tenderness and ecchymotic lesion over the flexor surface of the right second distal interphalangeal joint. The lesion appeared abruptly, about 20 minutes before evaluation. He denied constitutional symptoms except fatigue; findings in a limited physical examination were normal except for facial hirsutism and (male pattern) alopecia. The patient adamantly refused biopsy but consented to be photographed (see Figure 1). After extensive evaluation over the next 30 minutes, a specific cause could not be found. Immune complexes, however, were not sought. A short time later, over a can of beer, the etiologic agent was identified—a pop-top tab. It was painfully clear that grasping the pop-top tab with the afflicted joint had reproduced the pain precisely. Since this transmissible agent reproduced the initial symptoms after rechallenge, we believe it fulfills Koch's postulate. R O N A L D J. R A P O P O R T , M . D .

The Medical College of Wisconsin; Milwaukee, WI 53226

Serum Angiotensin-Converting Enzyme in Granuloma Annulare T o THE EDITOR: Lieberman and Rea (1) have recently shown that elevated levels of serum angiotensin-converting enzyme are not confined to patients with sarcoidosis but can also be found in patients with leprosy and Gaucher's disease. In contrast, patients with deep fungal granulomas and tuberculosis usually have normal levels of this enzyme. Granuloma annulare is a cutaneous disorder that shares some of the characteristics of sarcoidosis. Both are granulomas of unknown cause, and elevated levels of serum macrophage

Figure 1 . Pop-top finger showing ecchymotic lesion over the flexor surface of the right second distal interphalangeal joint. Letters and Corrections


441

Ammonium Chloride Therapy in Liver Disease T o I H E EDITOR: 1 read with great interest the article in the November issue entitled "Life-Threatening Hyperkalemia Induced by Arginine" by Bushinsky and Gennari (1). In the article one of the named contraindications to the use of arginine was the presence of liver disease. A listed alternative therapy to arginine for metabolic alkalosis, presumably in patients with liver disease, was the infusion of ammonium chloride. A 1943 reference was cited. The role of ammonia intoxification in the genesis of hepatic encephalopathy was developing in 1955 (2). After the finding of this relationship, ammonium chloride by mouth or by infusion was believed to be contraindicated in liver failure because of its propensity to precipitate hepatic encephalopathy. Would the authors care to comment on this? A L I C E N. BESSMAN, M . D .

Rancho Los Amigos Hospital; Douney, C A 90242

one I have commented on are important so that the "most likely" candidates can be recognized, allowing physicians to make an intelligent choice when dealing with potentially drug-induced injury. Unfortunately, these choices, as any based on odds, will not always be correct. L A W R E N C E J. D ' A N G E L O , M . D .

2475 Echo Drive, Atlanta, G A 30345 REFERENCES

1. ONORATO IM, AXELROD JL: Hepatitis from intravenous high-dose oxacillin therapy. Findings in an adult inpatient population. Ann Intern Med 89:497-500, 1978 2. MECHANIC RC, MEYERS L: Chloromazine-type cholangitis. Report of a

case occurring after the administration of prochlorperazine. N Engl J Med 259:778-780, 1958 3. KLAISKIN G: Toxic and drug-induced hepatitis, in Diseases of the Liver, 5th ed., edited by SCHIFF L. Philadelphia, J.B. Lippincott Co., 1975, pp. 604-710 4. MITCHELL JR, NESLON WL, POTTER WZ, SASAME HA, JOLLOW DJ:

REFERENCES 1. BUSHINSKY DA, GENNARI FJ: Life-threatening hyperkalemia induced

by arginine. Ann Intern Med 89(Part l):632-634, 1978 2. BESSMAN AN, BESSMAN S: The cerebral and peripheral uptake of ammonia in liver disease with an hypothesis for the mechanism of hepatic coma. / Clin Invest 34:622, 1955

In reply: We agree, of course, with the comments of Dr. Bessman. In our original manuscript, the last sentence read, "An alternative treatment for severe metabolic alkalosis in patients who cannot tolerate sodium chloride or potassium chloride is the infusion of dilute hydrochloric acid or, in patients without hepatic encephalopathy, ammonium chloride." In response to the Editor's request that we shorten the paper, we deleted the phrase indicating that hepatic encephalopathy was a contraindication to ammonium chloride administration. We believed we could make this deletion with impunity since it is so well known and accepted that ammonium chloride should not be given to patients with liver failure. D A V I D A. B U S H I N S K Y , M . D . F. JOHN G E N N A R I , M . D .

Tufts-New England Medical Center Hospital; Boston, M A 02111

Oxacillin and Hepatotoxicity T o THE EDITOR: The report of Onorata and Axelrod in the October issue (1) emphasizes the otherwise poorly recognized risk of hepatotoxicity from high-dose intravenous oxacillin. However, while I agree that this was probably the agent that induced the observed abnormalities in liver function, the authors' unfortunate statement that none of the other agents their patients were taking "have been associated with hepatic dysfunction" ironically makes them guilty of the same lack of vigilence that made their paper possible. Of the eight patients cited, six were taking other drugs theoretically capable of inducing injury similar to that seen in these cases. These drugs are prochlorperazine (Case 1)(2), meprobamate (Case 4)(3), furosemide (Cases 6 and 7)(4), and acetominophen (Cases 3, 7, and 8). Although hepatotoxicity secondary to all of these is presumably rare, and in the case of acetominophen questionable in usual therapeutic doses (although Case 8 was probably on a low-protein diet postoperatively, which, when combined with phenobarbital treatment, has been shown to drastically reduce the toxic threshold for acetominophen [5]), they cannot be dismissed out-of-hand as nonhepatotoxins. The challenge of trying to identify an agent responsible for hepatic dysfunction in this era of polypharmacy is indeed formidable. Recently, a textbook was written in response to the multitude of agents that induce liver injury (6). Reports such as the 4 4 2

Metabolic activation of furosemide to a chemically reactive, hepatotoxic metabolite. J Pharmacol 199:41-52, 1976 5. MCLEAN AEM, D A Y PA: The effect of diet on the toxicity of paracetamol and the safety of paracetamol-methionine mixtures. Biochem Pharmacol 24:37-42, 1975 6. ZIMMERMAN HJ: Hepatotoxicity: The Adverse Effects of Drugs and Other Chemicals on the Liver. New York, Appleton-Century-Crofts, 1978, p. 577

In comment: With respect to prochlorperazine, the patient referred to, and several others referenced by McFarland (1), had typical features of cholestatic jaundice. Our patients had a distinct clinical syndrome of anicteric hepatitis. Concerning meprobamate, the cases referred to (2) also had cholestatic jaundice that occurred after 25 days in one patient and 6 months in two others. Biopsies revealed typical features of cholestatic hepatitis. Furosemide has indeed caused hepatic necrosis but (as noted in Dr. D'Angelo's Reference 4) after 300 mg/kg intraperitoneally in mice. Neither Klatskin (2) nor Zimmerman (Dr. D'Angelo's Reference 6) mentioned any instance of hepatic necrosis in humans. Finally, hepatic necrosis following acetominophen therapy has been described after massive doses taken with suicidal intent (2) and after chronic use (3). With respect to diet, the article referred to by Dr. D'Angelo describes a study in rats in which, after 1 week of a low protein diet, the LD*, of acetominophen decreased from 5.2 g A g to 0.9 g/kg. This would correspond to 63 g in a 70-kg man. Postoperative patients 7 and 8 received a total of 1.8 g and 2.4 g, respectively, in the form of suppositories. The new textbook by Zimmerman is a welcome addition to the medical literature and supports the above statements. We therefore disagree with Dr. D'Angelo's comment that six of our cases were taking other drugs "capable of inducing injury similar to that seen in these cases'* We do agree, however, that our sentence on hepatic dysfunction of other drugs (p. 498, column 1) should be amended and propose this manuscript correction: "Drugs received concomitantly with oxacillin are noted in Table 1. In the doses used in our patients, none have been associated with a similar picture of anicteric hepatitis"



J U D I T H L. A X E L R O D , M . D .

St. Luke's Hospital Center; New York, N Y 10025 I D A M. O N O R A T O , M . D .

Mt. Sinai Hospital; New York, N Y 10029 REFERENCES

1. MCFARLAND RB: Fatal drug reaction associated with prochlorperazine (Compazine). Report of a case characterized by jaundice, thrombocytopenia, and agranulocytosis. Am J Clin Pathol 40:284, 1963 2. KLATSKIN G: Toxic and drug-induced hepatitis, in Diseases of the Liver, 5th ed., edited by SCHIFF L. Philadelphia, J.B. Lippincott Co., 1975, pp. 604-710 3. JOHNSON GK, TOLMAN KG: Chronic liver disease and acetominophen. Ann Intern Med 87:302-304, 1977

Tamoxifen Hormonal Effects T o THE EDITOR: The report by Patterson and colleagues in the December issue (1) provides access to clinical data on adverse drug effects occasionally reported in association with tamoxifen use, but unfortunately is subject to the well-recognized limitations of ascertainment bias produced by a spectrum of factors (frequency of specific sampling for hypercalcemia, tumor estradiol receptor status, inclination to report or register the adverse effect, and so on). More important, however, their perspective neglects certain fundamental, current concepts in the molecular endocrinology of hormone action. These concepts may clarify some of the ostensibly confusing and seemingly unrelated effects occasionally noted during initiation of the clinically effective "antiestrogen" tamoxifen. In addition to transient hypercalcemia, moderate acute increases in bone pain or soft-tissue metastatic breast-cancer lesions have been described (2) during initiation of tamoxifen. Contrary to the allegation of Patterson and co-workers (1), tamoxifen has been shown to have unequivocol estrogen agonist effects at low concentrations or during initial administration but subsequent, effective inhibitory action at higher concentrations (that is, a biphasic action). Specifically, in human breast cancer cells maintained under defined conditions in vitro, low concentrations of tamoxifen (10 • molar) produce dose-dependent cell proliferation and induce the progesterone receptor (3)! Tamoxifen binds to the native estradiol cytoplasmic receptor and undergoes nuclear translocation, where it subsequently interferes with some distal step in the cytoplasmic estrogen-receptor replenishment cycle (3), rendering the tissue unresponsive to further hormone (or antiestrogen) stimulation. This biphasic stimulation followed by inhibition, we believe, provides a testable hypothesis to explain the transient hypercalcemia or "tumor flare" reported. J. D . V E L D H U I S , M . D .

Milton S. Hershey Medical Center; Hershey, PA 17033 REFERENCES 1. PATTERSON JS, FURR BJA, BATTERSBY LA: Tamoxifen and hypercalce-

mia (letter). Ann Intern Med 89:1013, 1978 2. PLOTKIN D, LECHNER JJ, JUNG WE, ROSEN PJ: Tamoxifen flare in

advanced breast cancer. JAMA 240:2644-2646, 1978 3. HORWITZ KG, KOSEKI Y, M C G U I R E WL: Estrogen control of proges-

terone receptor in human breast cancer: role of estradiol and antiestrogens. Endocrinology 103:1742-1751, 1978

ficiency due to drug toxicity. Serial BUN and creatinine measurements declined, and her daily urine output remained more than 1500 ml. On the 13th hospital day, a percutaneous kidney biopsy was done. Light microscopy of the tissue showed distal and collecting tubules with degenerative and regenerative activity, the latter characterized by hyperchromatic mitotically active epithelium. Pigmented granular casts and orange cystalline material was seen inside some of the tubules. Interstitial fibrosis and a mononuclear inflammatory infiltrate were also noted. When the patient was discharged on the 18th hospital day, she was ambulatory and had a BUN level of 13 mg/dl and a creatinine level of 1.0 mg/dl.

Phenylazopyridine in the usual recommended oral dose is relatively innocuous. In one study (2), 13% of cases developed mild gastrointestinal discomfort and 3 % required withdrawal of the drug. Heinz-body hemolytic anemia, methemoglobinemia (3), and acute hepatoxicity have been described (4). In 1970, two cases were reported in this journal (1); both were in patients older than 75 years of age who had pre-existing renal disease. The syndrome presented with acute renal failure, oliguria, and yellow skin discoloration after the patients ingested a larger than usual dose of pyridium. One patient refused a kidney biopsy; the other patient's kidneys were studied at autopsy after a fatal pulmonary embolus. These sections showed pigmented tubular casts in collecting ducts with degenerating epithelial cells. Ours is a case of phenylazopyridine-induced renal failure in the presence of normal renal function. It is reversible and the pathologic changes are similar to previous reports. The presenting findings, however, did not include skin discoloration, oliguria, or an abnormal urinary sediment, as has been previously described. NAUMAN QURESHI, M.D. ROBERT W. HEDGER, M.D. Columbus Hospital and University of Illinois Abraham Lincoln School of Medicine; Chicago, IL 60614

REFERENCES

1. ALANO FA JR, WEBSTER G D JR: Acute renal failure and pigmentation due to phenylazopyridine (Pyridium*). Ann Intern Med 72:89-91, 1970 2. G O U L D S: Urinary tract disorders. Clinical comparison of flavoxate and phenylazopyridine. Urology 5:612-615, 1975 3. GREENBERG MS, WONG H: Methemoglobinemia and Heinz body hemolytic anemia due to phenylazopyridine hydrochloride. N Engl J Med 271:431-435, 1964 4. HOOD JW, TOTH WN: Jaundice caused by phenylazopyridine hydrochloride. JAMA 198:1366-1367, 1966

Cholesterol Embolism in Bone Marrow Phenylazopyridine (Pyridium®) and Acute Renal Failure T o T H E EDITOR: Pyridium® (phenylazopyridine) is a urinarytract analgesic that can cause acute renal insufficiency in people with pre-existing renal damage. We report here the case history and renal biopsy of a young woman with normal renal status who ingested an overdose of phenylazopyridine and developed acute renal failure. The histologic findings are similar to autopsy findings previously described by Alano and Webster (1) in the January 1970 issue. A 20-year-old woman was admitted with a 3-day history of nausea and vomiting after ingesting a single 4-g dose of phenylazopyridine, with suicidal intentions. There was no history of yellow skin discoloration, oliguria, or cyanosis. Her past records showed emotional instability and recurrent urinary-tract infections. She had normal intravenous pyelogram results the previous year. One day before ingesting the drug, her blood urea nitrogen (BUN) level was 8 mg/dl; creatinine level was 0.6 mg/dl, and uric acid level 2.8 mg/dl. Pertinent laboratory data on admission include BUN, 36 mg/dl; creatinine, 5 mg/dl; uric acid, 9.8 mg/dl. Repeated urinalyses showed a few erythrocytes and leukocytes, without any pigmented casts or crystals and isothenuria. An intravenous pyelogram failed to visualize the kidneys. Tomograms and ultrasonography showed slightly enlarged, smooth kidneys. On the seventh hospital day, creatinine clearance was 26 ml/min and urinary electrolytes were NA + , 42 meq/litre; K + , 36 meq/litre; CI, 39 meq/litre. She was managed conservatively as having a nonoliguric acute renal insuf-

T o THE EDITOR: In "Cholesterol Embolism: Diagnosis Antemortem by Bone Marrow Biopsy," in the December 1978 issue (1), Pierce and associates state that cholesterol emboli diagnosed by bone marrow biopsy have not been previously reported. I have seen cholesterol emboli in histologic preparations of aspirated and biopsied marrow on several occasions and have reported it (2). A word of caution is in order. The finding of atheromatous emboli in the bone marrow does not necessarily mean that the patient is suffering from widespread manifestations of this process. It may be an incidental finding of minor clinical significance indicating that the patient has ulcerating aortic arteriosclerosis. Vessels are invariably seen in histologic sections of aspirated or biopsied bone marrow. Because of its simplicity and safety, bone marrow aspiration or biopsy is a good way to document the presence of a systemic vascular disease. A R K A D I M. R Y W L I N , M . D .

Mount Sinai Medical Center and University of Miami School of Medicine; Miami, F L 33140 REFERENCES 1. PIERCE JR JR, W R E N MV, COUSAR JB JR: Cholesterol embolism: diag-

Letters and Corrections


443

nosis antemortem by bone marrow biopsy. Ann Intern Med 89:937-938, 1978 2. RYWLIN A: Histopathology of the Bone Marrow. Boston, Little, Brown and Company, 1976, p. 181

Itinerant Patient with Hematologic Abnormalities T o T H E EDITOR: The patient with "Munchausen's syndrome" previously described in your journal (1, 2) in the August and November 1976 issues remains active. He was recently admitted to the Martha Jefferson Hospital in Charlottesville, Virginia, with symptoms of ureteral colic, claiming to be a safety engineer for Boeing Aircraft. During his brief hospitalization his attending urologist received a call from the "medical director" of Boeing Aircraft requesting that the patient be released from the hospital to investigate an airline crash. Subsequent evaluation revealed that the patient had never been employed by Boeing, and the patient later admitted that he had made this call himself. Additional evaluation was undertaken because of his leukocyte count of 62 000, the differential and leukocyte alkaline phosphatase being entirely consistent with chronic myelocytic leukemia. Chromosome analysis of a bone marrow specimen by the University of Virginia Cytogenetics Laboratory showed 46 XY Ph consistent with chronic myelocytic leukemia. This observation had not been noted previously. The patient remained in the hospital for several days while his hematuria and leukocytosis were investigated. When no stone was found and his identity was questioned, he left abruptiy. Physicians should be aware of a patient presenting with the above symptom complex. A R T H U R S. B E N D E R , M . D .

Martha Jefferson Hospital; Charlottesville, VA 22901 REFERENCES 1. ALLEGRA D, WOODWARD J, CHANDLER J: Munchausen as physician

and patient. Ann Intern Med 85:262-263, 1976 2. JUSTUS PG, KITCHENS CS: Secondary leukemia with Munchausen's filariasis Ann Intern Med 85:685, 1976

Marxist party, a totalitarian power, solely controls health institutions, stratification of workers, access of students to medical schools, and the placement of physicians. With this in mind I consider it a gross distortion of facts to blame the "capitalist" society for limited mobility in health professions. The fee-for-service system, although not officially approved, is burgeoning in Marxist health care in its most primitive form of a barter trade. Workers who wish more personal care on the part of a physician have to bring with them a variety of bribes. Not infrequently such barter includes a permit to travel into the denounced capitalist hell or Western currency to buy sophisticated medicines from the free world. Under the Marxists health insurance is mandatory and uniform, and its returns to patients depend on the priorities determined by the ruling circle of the Marxist party. The patient and the citizenship have absolutely no feedback into shaping of the national health and insurance policies. In this context any "interest group politics" blamed by Dr. Waitzkin as affecting the U.S. health system should be considered an asset and a part of a laudable democratic mechanism. His lamentations on state invervention into health care in a "capitalist" society are also ludicrous when projected on the background of the party-state system in a Marxist-ruled country. Dr. Waitzkin's Marxist pamphlets have been supported by the National Institutes of Health, by funds from the National Center for Health Services Research, and by funds from the Massachusetts General Hospital. Would a Marxist country provide funds for publishing a paper highly critical of the Marxist view of medical care? If anything, it seems that our federal and state bureaucracy is taking a close look to learn from nationalized systems of health care delivery. Last but not least, the Marxist term "imperialism" is grossly misleading and it does not belong in a serious article published in a scientific journal (compare Soviet expansion in Central Europe, Africa, and Asia). The contemporary Marxist followers are the ones who should first "demystify current ideologic patterns." It is hard to believe that they have not yet noted the tremendous gap between the romantic Marxist dreams of the 19th century and the reality we live in. They should get a political lesson from their disenchanted fellow Eurocommunists. Any discussion on the influence of different political systems on health care should be based on facts and thus have a scientific basis. V L A D O SIMKO, M.D.

Marxism

University of Cincinnati College of Medicine; Cincinnati, OH 45267

T o THE EDITOR: Having spent 15 years in a Marxist-dominated health care system, I wish to disagree with the extensive article by Dr. Waitzkin (1), for which this journal provided such a generous space in the August 1978 issue. Alarming to me is the "scientific" facade of this paper, which may hide for an unexperienced reader the notorious papier-mache of doctrinarian citations. Political power and economic dominance is mirrored by the health system in Marxist-dominated countries much more than in a free-market society. The class structure of a Marxist society is best exemplified by the fact that best health institutions are set aside for the Party apparatchiks. Not a worker with whose exploitation the Marxist state purchases the modern Western health technology, but only the Party hierarchy can enter these exclusive health institutions. The rest of the population is regimented to mandatory and uniform health care, which is, by all measures, below the standards of the big city hospitals for indigenous populations in the United States. The real control over every health institution is exerted not by a "corporate and upper-middle-class professionals" but by a Party committee that is usually manned by domineering individuals with little professional experience, poor formal education, and no peer control. The political and economic monopoly of the Marxist party allows investments in health care that are based more on voluntary decisions of a few individuals than on a sound social and economic analysis. Compared with the free world, the trade unions in their feedback to the health care system are only a paper tiger, completely obedient to the Party whistle. The 444



REFERENCE

1. WAITZKIN H: A Marxist view of medical care. Ann Intern Med 89:264278, 1978 T o T H E EDITOR: If a sincere and honorable intellectual proposed a fascist analysis of medical care systems and why a fascist state would produce a better one, the least we would expect from her or him is an apologia explaining why the proposed changes would not again produce the horrors and murders of the previous fascist states. I looked carefully at Isaac's letter (1) in the December 1978 issue and Waitzkin's article (2) in the August 1978 issue and could find no evidence that they recognized a similar obligation. Considering the barbarism of Marxist states, I for one cannot honor Marxist analysis with seriousness anymore. Not until the Marxists furnish us with something akin to our Federalist Papers should we even begin to treat Marxism with any respect. The Federalist Papers are the backbone of our protection from the state. Those papers are not a paragraph or two of automatic language but 85 papers of careful analysis. And we still have difficulty protecting the individual from the state. While we wait for some Marxist to turn his or her fantastic energy from repetitive, automatic language to some creative and original thinking regarding civil rights, I go with Revel (3) who would probably predict that if a Marxist medical system came to the U.S.A., it would be "oppressive in its domination [of

patient and doctor] and liberating in its propaganda". G E R S O N JACOBS, M.D.

599 Sir Francis Drake Boulevard; Greenbrae, CA 94904

three names are listed incorrectly. A similar error is made on page 465, left-hand side, line 52. The correct listing of our work should be: Y E A G E R H J R , W I L L I A M S MC, B E E K M A N J F , BAYLY TC, B E A M A N BL,

REFERENCES

1. ISAACS E: Marxist view of medicine (letter). Ann Intern Med 89:1005, 1978 2. WAITZKIN H: A Marxist view of medical care. Ann Intern Med 89:264278, 1978 3. R E V E L J: The Totalitarian Temptation. New York, Penguin Books, 1977, p. 303

Blood Samples for Progeria Study T o T H E EDITOR: The New York Hospital-Cornell Medical Center and The Sloan-Kettering Institute are studying patients with progeria and Werner's syndrome. These studies require a small sample of heparinized blood. We can transport such a sample from any area of the United States for study in our laboratories. If progeric patients cannot give a fresh blood sample or have died, a 2- to 3-ml serum specimen would be helpful. Please contact Dr. Ted Brown; New York Hospital-Cornell Medical Center; 525 East 68 Street; New York, N Y 10021; or call collect (212)472-8070. W. T E D B R O W N , M . D . , P H . D .

The New York Hospital-Cornell Medical Center; New York, N Y 10021

H A W L E Y RJ: Sarcoidosis: analysis of cells obtained by bronchial lavage. Am Rev Resp Dis 116:951-955, 1977 H E N R Y YEAGER, JR., M.D.

Georgetown University Hospital; Washington, D C 20007 REFERENCE 1. W E I N B E R G E R SE, K E L M A N JA, ELSON NA, Y O U N G RC J R , R E Y N O L D S HY, F U L M E R JD, CRYSTAL RG: Bronchoalveolar lavage in interstitial

lung disease. Ann Intern Med 89:459-466, 1978

In comment: Dr. Yeager is correct. We recognize the importance of his paper and apologize for the typographic errors. R O N A L D G. C R Y S T A L , M . D .

National Heart, Lung, and Blood Institute, National Institutes of Health; Bethesda, M D 20014 Correction: Middle Initial The correct name of the second author in the article in the January 1979 issue, "Occurrence of Immunoglobulin G-Alkaline Phosphatase Complexes in Human Serum" (1), is Tony F. Mets, not Tony E. Mets. REFERENCE 1. D E B R O E ME, M E T S T[F], L E R O U X - R O E L S G G , W I E M E RJ: Occurrence

of immunoglobulin G-alkaline phosphatase complexes in human serum. Ann Intern Med 90:30-35, 1979

Correction: Citation of Paper by Yeager and Associates Correction: Name in Index T o THE EDITOR: I write to request that you print a correction concerning a citation in the October 1978 issue to work from our laboratory. The paper from Dr. Ronald Crystal's laboratory (1) lists as Reference 22 a work of ours, but the names of three of the six authors are not given, and two of the remaining

The first initial of Dr. Paulshock whose name is indexed on p. 1032 of the December 1978 issue as author of a book review on "Drug Information for Patients" is B, not P. We apologize to Dr. Paulshock for this error.

Letters and Corrections


445

Rapid diagnosis of gram-negative bacterial meningitis by the Limulus endotoxin assay.

Legionella pneumophila and limulus endotoxin assay: recent findings.

Limulus test and meningitis.

Specific assay for endotoxin using immobilized histidine, Limulus amoebocyte lysate and a chromogenic substrate.

Quantitative Limulus lysate assay for endotoxin and the effect of plasma.

Adaptation of a microdilution procedure to the Limulus lysate assay for endotoxin.

A novel endotoxin-specific assay by turbidimetry with Limulus amoebocyte lysate containing beta-glucan.

Inactivation of endotoxin by Limulus amoebocyte lysate.

Binding and neutralization of endotoxin by Limulus antilipopolysaccharide factor.

Endotoxin shedding by enterobacteria: free and cell-bound endotoxin differ in Limulus activity.

Penicillins and the limulus amoebocyte lysate test for endotoxin.

Discrimination between endotoxin and (1----3)-beta-D-glucan using turbidimetric kinetic assay with Limulus amebocyte lysate.

Limulus antilipopolysaccharide factor protects rabbits from meningococcal endotoxin shock.

Inhibitory effect of heparin on the Limulus test for endotoxin.

Diagnostic limulus lysate assay for endophthalmitis and keratitis.

Plasma endotoxin and glycolipid antibodies in children with meningitis.

Comparison of the histamine hypersensitivity and the Limulus amoebocyte lysate tests for endotoxin activity.

Dissociation between Limulus neutralisation and in vivo protection in monoclonal antibodies directed against endotoxin core structures.

Endotoxin measurement: aerosol sampling and application of a new Limulus method.

Statistical determination of endotoxin content in influenza virus vaccine by the limulus amoebocyte lysate test.

Comparative evaluation of the Limulus assay and the direct Gram stain for detection of significant bacteriuria.

Combination of conventional and endotoxin-specific limulus tests for measurement of polysaccharides in sera of rabbits with experimental systemic candidiasis.

A new sensitive microplate assay of plasma endotoxin.

Limulus amebocyte lysate testing: adapting it for determination of bacterial endotoxin in 99mTc-labeled radiopharmaceuticals at a hospital radiopharmacy.