COMMENTS AND CORRECTION

Comments submitted for publication must be typed doublespaced, and text length must not exceed 500 words. 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. Tumor Registry: Immunodeficiency Disease and Cancer TO THE EDITOR: An international registry was established 3 years ago to collect clinical and pathological material on persons diagnosed as having naturally occurring immunodeficiency diseases who subsequently developed cancer. The Immunodeficiency-Cancer Registry (ICR) has used a system of voluntary reporting and literature review to collect the 200 cases on file at present. Because immunodeficiency diseases have become better known to the medical community in recent years, it is likely that many additional cases of cancer in immunodeficient patients have been diagnosed without being published or reported to the ICR. Physicans who have information on individuals with this rare association of diseases, and who wish to include them in the registry, are kindly requested to contact ICR personnel, John H. Kersey, M.D., or Ms. Beatrice D. Spector, at the address below. Physicians in the United States may call collect, (612) 373-2769. The majority of tumors that have been reported in immunodeficiency groups regardless of age, sex, or primary immunodeficiency diseases, are lymphoreticular malignancies. Similarly, lymphoid malignancies, particularly reticulum cell sarcomas, have been reported in excess of expected rates in immunosuppressed renal transplant recipients. The association of immunodeficiency, naturally or chemically induced, and an increased risk for developing lymphoreticular tumors is generally considered to be of etiological significance for oncogenesis, although the various mechanisms involved are not fully understood. Continuous reporting of new cancer cases among diagnosed immunodeficient patients is also of great importance because of the many persisting questions related to the classification of lymphomas, in general, and to the characterization of tumors from immunodeficient patients in particular. A detailed, systematic study of case material is in progress to examine the pathology, classification, and natural history of these malignant lymphomas, as well as other tumors which have been diagnosed in these patients. A standardized set of data will be made available from this study to physicians reporting cases so that they may compare the pooled findings with results obtained on their case(s). BEATRICE D. SPECTOR

Immunodeficiency-Cancer Registry Box 609 Mayo University of Minnesota Minneapolis, MN 55455

Midline Granuloma or Wegener's Granulomatosis TO THE EDITOR: Drs. Fauci, Johnson, and Wolff note in their recent paper "Radiation Therapy of Midline Granuloma" {Ann Intern Med 84:140-147, 1976) the debate and confusion in the literature in distinguishing lethal midline granuloma from Wegener's granulomatosis. They choose to be "splitters" in this regard, stating that the two entities are quite distinct. One of the authors has written elsewhere that primary vasculitis is not a feature of midline granuloma ( 1 ) . Nevertheless, one of the patients reported in his present series had histopathological findings of small vessel vasculitis and two others had biopsies showing endarteritis. How may one differentiate a "primary" from a "secondary" vasculitis when necrotizing inflammation is widespread? Early in the course of both of these diseases one is often confronted with an upper-respiratory-tract biopsy showing only nonspecific granulomatous inflammation and necrosis without evidence of vasculitis or plentiful giant cells. Some of these patients may actually have early Wegener's granulomatosis, which has yet to disseminate, rather than lethal midline granuloma, which will be more locally invasive. Such a misdiagnosis of early disease may explain one group's report of a 4 0 % conversion from lethal midline granuloma to generalized Wegener's granulomatosis ( 2 ) . Perhaps at this early stage both entities, if they are indeed separate, represent a granulomatous reaction (with or without vasculitis) that responds to high-dose irradiation therapy not unlike stage I Hodgkin's disease. By the same token more disseminated systemic Wegener's (including lung and kidney involvement) is more appropriately treated with cytotoxic therapy (3) as in stage III Hodgkin's disease. STEPHEN L. SCHECHTER, M.D.

Rackham Arthritis Research Unit Department of Internal Medicine The University of Michigan Medical Center Ann Arbor, MI 48109 REFERENCES 1. WOLFF SM: Midline granuloma, in Harrison's Principles of Internal Medicine, 7th ed., edited by WINTROBE MM, THORN GW, ADAMS RD, et al. New York, McGraw Hill, 1974 pp. 1071-1072 2. BYRD LJ, SHEARN MA, Tu WH: Relationship of lethal midline granuloma to Wegener's granulomatosis. Arthritis Rheum 12:247253, 1969 3. WOLFF SM, FAUCI AS, HORN RG, et al: Wegener's granuloma-

tosis. Ann Intern Med 81:513-525, 1974 In reply: Dr. Schechter suggests that we choose to be "splitters" because we stated that midline granuloma ("lethal" is no longer an appropriate adjective for this disease) and Wegener's granulomatosis are quite distinct entities. We did not arbitrarily decide to consider these diseases distinct. The reasons for this distinction based on clinical and pathological findings are clearly delineated in our paper ( 1 ) . With regard to the findings of vasculitis, it is difficult to differentiate a primary from a secondary

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vasculitis when necrosis is widespread. However, the vasculitis of Wegener's granulomatosis is a prevalent finding often seen in tissue without necrosis, and is obviously primary. The occasional finding of endarteritis obliterans in tissue specimens in midline granuloma is almost always associated with necrosis much the same as the endarteritis associated with the necrosis of severe tissue infection. We believe it to be exceedingly rare (if not, nonexistent) for a patient with Wegener's granulomatosis to develop only upper-airway disease that has progressed to the point of extensive tissue destruction and necrosis without manifestations of systemic disease such as pulmonary, renal, skin, or other findings. With regard to the irradiation of "early" upper-airway disease, we would not use local irradiation in a patient with only nonspecific upperairway inflammation without evidence of progressive tissue destruction. The patients with midline granuloma are distinctive because they have extensive tissue destruction of the upper airway without systemic manifestations or involvement of other organ systems. Local irradiation of the upper airway lesions in well-documented Wegener's granulomatosis should never be done. In addition, there is no evidence that irradiation (the serious side effects of which are emphasized in our paper) of upper airway granulomatous inflammation in early disease suspected of, but not proven to be Wegener's granulomatosis will alter the systemic manifestations of this disease. Aggressive workup to firmly establish the correct diagnosis and hence dictate appropriate therapy (2) is a much preferred approach. ANTHONY S. FAUCI, M.D. RALPH E. JOHNSON, M.D. SHELDON M. W O L F F , M.D., F.A.C.P.

National Institutes of Health Bethesda, Maryland 20014 REFERENCES

1. FAUCI AS, JOHNSON RE, WOLFF SM: Radiation therapy of mid-

line granuloma. Ann Intern Med 84:140-147, 1976 2. FAUCI AS, WOLFF SM: Wegener's granulomatosis: studies in eighteen patients and a review of the literature. Medicine (Baltimore) 52:535-561, 1973

proliferative glomerulonephritis followed for at least 5 years. Our protocol differs in several aspects from the studies recently reported in this journal. Corticosteroid therapy, in single daily high dosage, 60 mg per day, was limited to 16 weeks. Thereafter it was tapered to an alternate day, low-dose schedule as rapidly as extrarenal symptoms permitted. In this way the physical disfigurement of iatrogenic Cushing's disease was avoided and the incidence of steroid toxicity, such as aseptic necrosis, septicaemia, or spinal fracture, was apparently reduced. The daily dose of azathioprine was limited to 200 mg per day as a maximum, which may explain the relatively slight increase in tumor incidence. Deaths, in less than 15% of the total cases, occurred exclusively in patients who entered the study with long-standing serum creatinine values greater than 3.0 mg/dl. Patients with mild disease or with nephritis who responded to high dose corticosteroid therapy alone, without iatrogenic Cushing's disease, did not receive combination therapy and are not included in our reports. Our attempts to initiate controlled comparative studies of corticosteroids versus cytotoxic drugs alone have been thwarted because of a failure of cytotoxic drugs by themselves to provide anti-inflammatory control of extrarenal symptoms and by the neutrotopenia produced. Both of these phenomona were apparently avoided by concomitant corticosteroid therapy. Clinical status after the first year of combination therapy was characterised by few extrarenal symptoms while on low alternate-day corticosteroids with or without continuing azathioprine. Exacerbations of extrarenal or renal symptoms usually responded to short courses of higher dose corticosteroids alone. Azathioprine was reinstituted for those whose renal exacerbations did not respond to corticosteroids within 12 weeks. Although the studies recently reported in this journal have not shown clinical synergism or steroid-sparing effects, they have not excluded them. Improved patient survival achieved by combination of drugs in cancer chemotherapy provides an excellent precedent for optimism as to the results of combination therapy in lupus nephritis. E. V. BARNETT, M.D.

Lupus Erythematosus: Immunosuppressive Therapy TO THE EDITOR: I wish to contradict the pessimistic impression placed on combination therapy and to emphasize that there is a great deal of anecdotal and controlled data supporting a clinical synergism for corticosteroids and cytotoxic drugs. We all agree that their use should continue to be investigational. I emphasize that the investigational design should include dosage schedules that avoid the toxic effects of both drugs and not include patients with persistent uremia. Your journal's recent reports ( 1 , 2 ) and accompanying editorial (3) on the immunosuppressive therapy in lupus erythematosus fail to explain the improved survival of patients treated in a number of uncontrolled studies with combinations of corticosteroids and cytotoxic drugs as compared to previous reports on survival of patients treated with corticosteroids alone. These differences admittedly may be attributed to, inter alia, differences in patient selection, concomitant antibiotic therapy, or methods of clinical and laboratory assessment. Our own uncontrolled experience at UCLA with corticosteroid-azathioprine combinations (4-6) resulted in no deaths due to renal disease in 55 patients with diffuse proliferative and membrano610

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Department of Medicine, UCLA Medical School, Los Angeles, CA 90024 REFERENCES

1. HAHN BH, KANTOR OA, OSTERLAND CK: Azathioprine plus

prednisone compared with prednisone alone in the treatment of systemic lupus erythematosus. Ann Intern Med 83:597-605, 1975 2. DECKER JL, KLIPPEL JH, PLOTZ PH, et al: Cyclophosphamide or

azathioprine in lupus glomerulonephritis. Ann Intern Med 83:606615, 1975 3. ROTHFIELD NF: Immunosuppressive therapy in lupus erythematosus. Ann Intern Med 83:727-728, 1975 4. DRINKARD JP, STANLEY TM, DORNFIELD L, et al: Azathioprine

and prednisone in the treatment of adults with lupus nephritis. Medicine (Baltimore) 49:411-432, 1970 5. DORNFELD L, PEARSON CM, GONICK HC, et al: Long-term fol-

low-up of systemic lupus erythematosus glomerulonephritis treated with prednisone and azathioprine. Presented at the 13th International Congress of Rheumatology, 30 September 1973, Tokyo, Japan 6. BARNETT EV: Action of immunosuppressive drugs. Dialysis Transplant 4:38-39, 1975 Medical Costs TO THE EDITOR: With reference to "Health Care 1976: Costs and Consequences" (Ann Intern Med 84:211-212, 1976) may I make two comments? While all that Dr.

Herman Somers says is true, it is seldom pointed out that medical insurance and rising medical care costs feed upon each other. Thus the more insurance, the more utilization, thereby increasing the total dollar expenditure. Likewise the higher these expenditures, the more urgent it is to get insurance coverage. National health insurance with all its proposed constraints, review procedures, and quality controls, will increase the total dollar expenditure on health care. Witness Medicare, Medicaid, and Great Britain! If National Health Insurance is a national priority, so be it, but the public must appreciate the universal coverage and lower total dollar expenditure cannot be achieved simultaneously. Finally, all of the fiddling with the organization and reorganization of health care delivery, and all of the various alterations in financing mechanisms will, in my opinion, make for little real change as compared with technological breakthroughs. For instance, a preventive vaccine against common respiratory infections would make a great difference in the number of patients needing primary care, reducing the sale of cold remedies, antibiotics, and so on. In this sense I agree with Dr. Somers that an ounce of prevention is worth a pound of cure. However, it seems unlikely that life styles are going to change radically (R. J. Reynolds just reported banner earnings!) but taking the handle off the pump, chlorinating the water, and Jenner's breakthrough still look like the way to go. WILLIAM A. STEIGER, M.D., F.A.C.P.

1732 Sir William Osier Drive Virginia Beach, VA 23454 TO THE EDITOR: In regard to Professor Herman M. Somers* editorial, "Health Care 1976: Costs and Consequences," in the February issue, it is interesting to observe that he, like so many others, fails to touch upon the cause of the inflation of not only health care costs, but also all other costs. The cause of inflation is the United States Government, and all the regulation and enslavement of individual Americans that any bureaucrat may contemplate will not correct it. If anything, medical costs have simply gone up at a rate commensurable with this general inflation. In 1975, to achieve the purchasing power of a $5.00 house call made in 1945, one would have to charge $38.00. As long as Keynesian un-economics hold sway, one may confidently look forward to the collapse of our debased coinage and currency. Exhorting physicians to ignore the effects of inflation in their economic lives is about as useful as breaking the thermometer because it indicates a fever. Every physician, and especially every professor, should read Irwin A. SchifFs The Biggest Con: How the Government is Fleecing You, which will be published in early March by Arlington House. It is as necessary to know the etiology of economic ills, as it is of medical ones in order to do anything effectual about them. STUART RAGLAND, JR., M.D., F.A.C.P.

Colebrook, CT 06021

trauma, copper intoxication, exposure to hypotonic dialysis solution, use of well water (nitrates) or tap water (chloramines) for dialysis, or development of idiopathic hypersplenism. This report documents a case of delayed hemolytic anemia in a hemodialysis patient briefly exposed to an overheated dialysis bath, a complication that has been only rarely described ( 1 ) . A 22-year-old patient complained of a progressive feeling of unbearable warmth developing over 15 minutes during hemodialysis. Dialysis fluid was noted to be scalding to the touch (exact temperature not recorded; faulty temperature alarm system subsequently discovered). Dialysis was discontinued immediately. The patient's temperature was reported as 37 °C. Several hours later, fever (38.6 °C), chills, and rigors developed. Physicial findings were unremarkable. Hemoglobin was stable at the predialysis level of 6.2 g/dl. Twenty hours after dialysis, hemoglobin was noted to be 5.1 g/dl, and 8 hours later this value had fallen further to 4.0 g/dl. Fever and malaise continued, and progressive enlargement of the spleen was observed. Serum was pink and tested positively for free hemoglobin. A blood smear showed spherocytes and fragmented erythrocytes. Serum haptoglobin and serum hemopexin were markedly decreased. Platelet count, prothrombin time, partial thromboplastin time, and plasma fibrinogen concentration were normal. Serum potassium concentration remained constant at 4.2 meq/litre. Transfusion with 2 units of washed, frozen packed cells restored the hemoglobin to 6.0 g/dl. The patient became afebrile and was discharged 48 hours after the initial event. Although it has been known since 1865 that hemolytic anemia may occur secondary to thermal injury to erythrocytes ( 2 ) , this phenomenon achieved wide clinical recognition only with publication in 1943 of studies on the burned victims of the Cocoanut Grove disaster in Boston (3). Thermal injury produces hemolysis marked by increased erythrocyte osmotic and mechanical fragility and is associated, as in this patient, with the appearance of spherocytes and fragmented erythrocytes in the peripheral blood smear. Damaged cells, along with the products of their breakdown, are removed by the spleen, resulting in progressive splenomegaly. In-vitro studies have shown that heating of erythrocytes to 46 °C for up to 1 hour does not lead to damage; progressive changes in erythrocyte structure and function occur, however, wth lengthening exposure to higher temperatures ( 4 ) . This case shows not only that thermal hemolysis may occur as an accident of hemodialysis therapy, but that any patient exposed to this complication should be admitted to hospital for careful observation. The onset of thermal hemolysis may be delayed many hours, and, superimposed on the anemia of chronic renal failure, may lead to both hyperkalemia (1) and a critical further reduction in hemoglobin. This case also is a reminder of the importance of perodic inspection and testing of both thermostats and temperature alarm systems on hemodialysis machines. ROBERT A. BEAR, M.D., F . R . C . P . ( C )

Department of Nephrology St. Michael's Hospital Toronto, ON, Canada REFERENCES

Thermal Hemolysis in Hemodialysis

1. FORTNER RW, NOWAKOWSKI A, CARTER CB, et al: Death due

TO THE EDITOR: Hemolytic anemia may occur as a complication of hemodialysis therapy secondary to mechanical

overheated dialysate during dialysis. Ann Intern Med 73:443-444, 1970 2. SCHULTZE M, as quoted by DACIE JV, in The Hemolytic Anemias, part III. New York, Grune and Stratton, 1967, p. 950 Comments and Correction

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3. SHEN SC, HAM TH, FLEMING EM: Studies on the destruction of

red blood cells. III. Mechanisms and complications of hemoglobinemia in patients with thermal burns: spherocytosis and increased osmotic fragility of red blood cells. N Engl J Med 229:701-713, 1943 4. HAM TH, SHEN SC, FLEMING EM, et al: Studies on the destruc-

tion of red blood cells. IV. Thermal injury. Blood 3:373-403, 1948

L. RUILOPE, M.D. J. RODICIO, M.D.

Servicio de Nefrologia Departmento de Medicina Interna C.S. "1 de Octubre" Madrid, Spain REFERENCES

Renal Failure and Cephalothin TO THE EDITOR: The recent "Letter" by Engle and associates "Reversible Acute Renal Failure Following Cephalothin" (Ann Intern Med 83:232-233, 1975) reports a case very similar to one of ours. In our case, we have obtained renal biopsy specimens and studied the histologic and immunofluorescent characteristics. A 70-year-old man was admitted to the Department of Nephrology because of acute renal failure that had developed in another hospital, where he had been treated for bilateral pneumonia and congestive heart failure. He had no past history of renal disease, and his blood urea level was reported as normal. He received cephalothin 16 g/day, for 12 days. After 10 days of this therapy, his blood urea and serum creatinine levels started to rise and, at the same time, oliguria was noted. He did not develop any cutaneous rash. When we admitted the patient, his urine volume was 50 ml/24 h, and his temperature, 40 °C; he had generalized edema and his blood pressure was 140/90 mm Hg. Hematocrit value was 47%; hemoglobin, 16 g/dl; leukocyte count, 19 000/mm3 without eosinophils; blood urea, 1.92 g/litre; serum creatinine, 9 mg/dl; Na+, 135 meq/litre; K+, 6.0 meq/litre; pH, 7.29; Pco2, 44.7 mm Hg; bicarbonate 20 meq/litre; and Po2, 70 mm Hg. Urinary electrolytes were Na + , 53 meq/litre; K + , 53 meq/litre; and urine osmolality, 350 mosmol/kg of water; urinalysis showed 2+ of protein and clumps of leukocytes in the sediment. Repeated blood cultures were negative, and clotting studies, including tests for fibrin degradation products, were normal. X-ray films of the chest showed bilateral pneumonic infiltrates. Cystoscopy and right retrograde urography findings were normal. After three periods of hemodialysis, on the seventh day of admission the patient underwent a cardiac arrest without response to conventional treatment. A renal biopsy showed 30 normal glomeruli; the tubules were dilated with epithelial necrosis and mitosis; the interstitium was edematous with a very slight infiltration of lymphocytes and plasma cells; no eosinophils were seen; immunofluorescence to IgG, IgA, IgM, IgE, fibrinogen, and C3 was negative. Our patient had a typical pathologic pattern of acute tubular necrosis. We consider the cephalothin therapy to have been the cause, as he did not receive any other drugs and all the other possible causes, such as hypotension, dehydration, or obstruction, were ruled out. At our patient's age, one would expect some degree of involution of the renal function, which, in conjunction with heart failure at the time he was admitted to the first hospital, could in some way have enhanced the cephalothin nephrotoxicity at the doses prescribed. The mechanism by which cephalothin can produce acute renal failure is not clear. Histologic and immunofluorescent characteristics in our case do not favor an allergic mechanism, as that claimed for methicillin ( 1 , 2 ) . In the latter, it has been shown that IgG, C3 and dimethoxyphenylpenicilloyl hapten are deposited in a continuous linear pattern in the tubular basement membrane. A. BARRIENTOS, M.D. I. BELLO, M.D. V. GUTIERREZ-MILLET, M.D. 512

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1. BORDER WA, LEHMAN DH, EGAN JD, et al: Antitubular base-

ment-membrane antibodies in methicillin-associated interstitial nephritis. N Engl J Med 291:381-384, 1974 2. BALDWIN DS, LEVINE BB, MCCLUSKEY RT, et al: Renal failure

and interstitial nephritis due to penicillin and methicillin. N Engl J Med 279:1245-1252, 1968

Dyazide® and Hyperkalemia TO THE EDITOR: The article by McDonald (Ann Intern Med 84:162-167, 1976) implies that triamterene and Dyazide® are equivalent. Dyazide consists of both triamterene and hydrochlorothiazide. Thus, Dyazide is a preparation intended to alleviate potassium changes. The physicians caring for the patients, therefore, may have had this in mind when not making adjustments in medication based solely on serum potassium changes. It is certainly true that hyperkalemia may be seen with Dyazide treatment, as Dr. McDonald implied ( 1 , 2 ) . A. G E N E PETERSEN, M.D.

411 Nichols Road Kansas City, MO 64112 REFERENCES

1. BENDER AD, CARTER CL, HANSEN KB: Use of a diuretic combina-

tion of triamterene and hydrochlorothiazide in elderly patients. / Am Geriatr Soc 15:166-173, 1967 2. HANSEN KB, BENDER AD: Changes in serum potassium levels occurring in patients treated with triamterene and a triamterenehydrochlorothiazide combination. Clin Pharmacol Ther 8:392399, 1967 In comment: I did not intend to imply that Dyazide® was a pure preparation of triamterene but agree that such an inference could be drawn from my paper and appreciate Dr. Petersen's clarification. As he notes, Dyazide is a combination of 25 mg of hydrochlorothiazide and 50 mg of triamterene. The combination of these two drugs with opposing actions is reputed to maintain a balance between their respective potassium wasting and potassium sparing effects with resulting normokalemia. This balance was tipped toward hyperkalemia in 2 6 % of our patients on Dyazide. All patients with hyperkalemia had some degree of azotemia, which suggests that renal failure was responsible for this higher-than-expected occurrence of hyperkalemia, and that Dyazide should be used only with great caution in the face of renal failure. I agree that it is likely that the normokalemic reputation of Dyazide plays some role in physician nonresponsiveness to Dyazideinduced hyperkalemia. Nonetheless, hyperkalemia is a direct contraindication to the continuance of treatment with Dyazide, and the manufacturer recommends substituting a pure wasting diuretic under these circumstances ( 1 ) .

C L E M E N T J. MCDONALD, M.D.

Indiana University School of Medicine Indianapolis, IN 46202

4. TUAZON CU, HILL R, SHEAGREN JN: Microbiologic study of

street heroin and injection paraphernalia. J Infect Dis 129:327329, 1974

REFERENCE

1. Physicians Desk Reference, Baker CE (p 1359) Publisher, Medical Economics Co., Oradell, New Jersey, 1974

Regional Pathogens in Endocarditis? TO THE EDITOR: A S information on infective endocarditis in intravenous drug users accumulates, its character as an illness with a regional flora becomes increasingly apparent. The recent report of Mills and Drew (Ann Intern Med 84:29-35, 1976) from San Francisco is remarkable for several reasons. First, it adds Serratia to coagulase positive staphylococci ( 1 ) , Pseudomas aeruginosa ( 2 ) , and Candida sp. as common or predominant regional pathogens causing endocarditis in intravenous drug users. Second, it depicts similarities between the clinical picture of serratia and pseudomonas infections ( 2 ) , in that these patients present with infections of both right and left sides of the heart. Those patients with right-sided infections are observed to have a better clinical course compared with those with left-sided disease. However, the overall prognosis is poor, with a dismal medical cure-rate in those patients with left-sided infections with either Serratia or Pseudomonas. A recent review (3) of endocarditis in intravenous drug users in Cleveland has turned up additional information to further characterize this illness as one with a regional flora. During the past 5 years, 24 cases of endocarditis in intravenous drug users have been identified. Of these, 14 were due to enterococci, for an overall frequency of 58.3%. Clinical features of enterococcal endocarditis in this population were characterized by exclusively left-sided disease in patients with an absence of antecedent valvular disease. In comparison with the course of those patients infected with Pseudomonas and Serratia, the outcome of these cases of enterococcal infection in addicts was relatively good: 10 of 14 patients cured medically, 2 required valve resection for refractable congestive heart failure, and 2 died from embolic complications. Combinations of penicillin or ampicillin with streptomycin or ampicillin alone formed the mainstay of therapy. Attempts to explain the regional flora of this illness by culturing street heroin and injection paraphernalia have met with little success in recovery of responsible pathogens ( 4 ) . On only two occasions has there been an opportunity to culture heroin and paraphernalia from our patients; however, in both instances enterococci were recovered in abundance. Further efforts to define the pathogenesis of this illness are warranted. N E I L E. REINER, M.D.

Department of Medicine Case Western Reserve University School of Medicine Cleveland, OH 44106 REFERENCES

1. BANKS T, FLETCHER R, ALI N: Infective endocarditis in heroin addicts. Am J Med 55:444-451, 1973 2. REYES MP, PALUTKE WA, WYLIN RF, et al: Pseudomonas

endocarditis in the Detroit Medical Center 1969-1972. Medicine (Baltimore) 52:173-194, 1973 3. REINER NE, GOPALKRISHNA KV, LERNER PI: JAMA, in press

Trimethoprim-Sulfamethoxazole for Meningitis TO THE EDITOR: On reason that there is an increasing frequency of collisions between ethicists and physicians might be illustrated by the letter from Farid and associates ( 1 ) , who used trimethoprim-sulfamethoxazole for the treatment of pneumococcal and meningococcal meningitis. Since the overwhelmingly proved drug of choice for either disease is penicillin G, and since meningitis is not an innocuous disease, one wonders whether any semblance of informed consent was obtained from relatives ("three patients were drowsy and two were unconscious"). Since the authors state that the patients had not responded to "routine therapy," either they are reporting five cases of penicillin-resistant pneumococcal and meningococcal meningitis or penicillin was never used. If the latter was the case, the only possible reason to consider trimethoprimsulfamethoxazole therapy would be a history of significant penicillin hypersensitivity; if so, this should have been mentioned in the communication. JOHN A. ROBINSON, M.D.

Clinical Immunology Section Department of Medicine Loyola University-Foster G. McGaw Hospital Maywood, IL 60153 REFERENCE

1. FARID Z, GIRGIS NI, YASSIN W, et al: Trimethoprim-sulfameth-

oxazole and bacterial meningitis. Ann Intern Med 84:50-51, 1976 In reply: We are disappointed with both the tone and the implications of Dr. Robinson's letter, and we hope that both our methods and our intentions were more clearly understood by the majority of readers. We have been treating patients with bacterial meningitis for over a decade ( 1 ) , and we are not aware of any group in the United States with more extensive clinical experience with the disease (1768 cases of bacterial meningitis from 1 January 1971 to 31 December 1975). We cannot believe that we are alone in recognizing the need for the development of new drugs for the treatment of this serious illness and the need for well-controlled clinical trials conducted by experienced physicians. The following points are germane to the reported series of cases. 1. Before using any treatment that may in any way be considered unusual, we give a full and detailed explanation to the patient, or his relatives, or to both, and obtain written consent. 2. Before the start of the reported trial, trimethoprimsulfamethoxazole was known to have already been used successfully in the treatment of bacterial meningitis (2, 3) and bacterial brain abscess (4). It was not, therefore, an untried form of treatment into which we blindly embarked. 3. Before starting the reported trial, we and others (2) had ascertained that trimethoprim-sulfamethoxazole was sufficiently concentrated in the cerebrospinal fluid (CSF), and that its level was above the minimum inhibitory concentration of pneumococcal and meningococcal isolates obtained from cases of bacterial meningitis. 4. All patients in the reported trial were carefully monitored Comments and Correction

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by one of us for the first 24 hours, and treatment was continued only when clinical improvement was apparent, and the CSF mirrored that improvement. In fact, we did not set out to treat "pneumococcal and meningococcal meningitis" with trimethoprim-sulfamethoxazole. We set out to treat patients admitted with signs and symptoms of acute bacterial infections of the central nervous system. All patients had received inadequate, or inappropriate, antibiotics before admission (which, unfortunately, is the "routine therapy" to which we referred). We cannot demand an identification of the causative organism before initiating treatment; however, we do carefully monitor the distribution of organisms in our cases. We are now seeing a statistically significant increase in meningitis due to Hemophilus influenza (15.4% of cases in 1975), of which 5 of 13 were resistant to penicillin and ampicillin. This situation prompts us to continue our study and the search for alternative therapies. Perhaps we have erred in expecting all of our readers to understand the problems of dealing with an extremely heavy case load of infectious diseases in a developing country where facilities and nursing care are scarce. To us, the fact that trimethoprim-sulfamethoxazole was also effective when given intravenously every 12 hours is extremely important and a great advantage over penicillin, which must be given intravenously every 4 hours. Finally, we respectfully refer Dr. Robinson to Dr. Ingelfinger's recent article in this journal regarding medical ethics ( 5 ) . ZOHEIR FARID, M.D., D.T.M.&H. (ENG.) NABIL I. GlRGIS, M.D. W A L T E R F. M I N E R , M.D., M . P . H . D A V I D C. E D M A N , P H . D .

U.S. Naval Medical Research Unit No. 3 Cairo, Egypt REFERENCES 1. HASSAN A, ABDEL WAHAB MF, FARID Z, et al: Acute pyogenic

meningitis in Cairo, Egypt 1961-1966. J Trop Med Hyg 74:141144, 1971 2. LAFAIX C: Proceedings of the 7 th International Congress of Chemotherapy. Prague, 1 1227, 1971

bronchoscope ( 2 ) . The detection and quantitation of elements with an atomic number greater than 10 can be done on isolated cells by X-ray energy spectrometry. Material is processed for scanning electron microscopy, and the X rays emitted by different elements in the sample are quantified and their distribution revealed. This method has recently been applied to alveolar macrophages from smokers, asbestos fibers, and lung biopsies (3-5). There are, however, some problems with this approach. Precise quantitation of the concentration of elements is not easy because of self-adsorption of X rays and the geometry of the sample. As Dr. Bouhuys pointed out in his editorial, the presence of a substance in the lung does not mean that it caused the disease. One would expect any defect in clearance of particles of a very large dust load to result in an accumulation of a substance in the lung. The appeal of this approach is that it is very general (any element with an atomic number greater than 10 will be displayed), does not require open lung biopsy, and may produce new information about elements that accumulate in macrophages in relation to industrial exposure and cigarette smoking. Patients who might be examined include those with pulmonary fibrosis or lung tumor who are having bronchoscopy for diagnostic evaluation. ROBERT J. MASON, M.D.

Cardiovascular Research Institute Department of Medicine University of California School of Medicine San Francisco, C A 94143 REFERENCES

1. SOROKIN SP, BRAIN JP: Pathways of clearance in mouse lungs exposed to iron oxide aerosols. Anat Rec 181:581, 1975 2. REYNOLDS HV, NEWBALL HH: Analysis of proteins and respiratory

cells obtained from human lungs by bronchial lavage. / Lab Clin Med 84:559, 1974 3. BRODY AR, CRAIGHEAD JE: Cytoplasmic inclusions in pulmonary

macrophages of cigarette smokers. Lab Invest 32:125, 1975 4. LANGER AM, RUBIN IB, SELIKOFF IJ: Chemical characterization

of asbestos body cores by electron microprobe analysis. J Histochem Cytochem 20:723-734, 1972 5. SIEGESMUND KA, FUNAHASHI A, PINTAR K: The identification of

silicon in the lung by energy-dispersive x-ray analysis. Am Rev RespDis 111:903, 1975

3. SABEL KG, BRANDBERG A: Treatment of meningitis and septicemia

in infancy with a sulphamethoxazole/trimethoprim combination. Acta Paediatr Scand 64:25-32, 1975 4. GREENE BM, THOMAS PE, ALFORD RH: Trimethoprim-sulfameth-

oxazole and brain abscess. Ann Intern Med 82:812-813, 1975 5. INGELFINGER FJ: The unethical in medical ethics. Ann Intern Med 83:264-269, 1975

Identifying Foreign Matter in Pulmonary Macrophages TO THE EDITOR: The recent editorial, "Fibers and Fibrosis" by Bouhuys (Ann Intern Med 83:898-899, 1975), reviews the value of lung biopsy and analysis of fibers for diagnosis of selected occupational lung diseases. I wish to suggest an alternative investigative method for diseases produced by inhalation of insoluble particles (especially inorganic dusts). This method is based on the biology of alveolar macrophages and the development of recent technology for elemental analysis, and this suggestion may stimulate research. The method requires a major piece of equipment and is not a proved alternative to current clinical methods. Alveolar macrophages ingest and store indigestible particulate material for years ( 1 ) . Pulmonary macrophages can be obtained from patients by lavage through a fiberoptic 514

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Placidyl® and Pulmonary Edema TO THE EDITOR: In the January issue, two cases of pulmonary edema associated with intravenous Placidyl® injection were reported by Glauser and associates (Ann Intern Med 84:46-48, 1976). The symptoms and hospital course of the two patients were very similar and suggest features of a syndrome that one may use in practice to differentiate the cause of respiratory distress syndrome in young adults. Particularly, the patients noted a minty taste in the mouth, immediate shortness of breath, nonproductive cough, and a period of unconsciousness lasting from 17 to 20 hours. The hospital course was one of rapid improvement through 24 hours. I would like to report a similar case of intravenous Placidyl-associated pulmonary edema, with a few different manifestations. A 26-year-old man injected the contents of two 750 mg Placidyl capsules into an antecubital vein. He immediately felt a severe pain in his anterior chest that was constant and not aggravated by respiration. He had immediate shortness of breath and began vomiting in what was described to be a

projectile manner. He vomited several times during the next 4 hours. He did not describe a minty taste in his mouth and did not lose consciousness. He was brought to the emergency room about 12 hours after the injection. Chest auscultation revealed diffuse mid- to end-expiratory rales but no wheezing. He was markedly dyspneic, complained of severe chest pain, and had a nonproductive cough. Cardiac findings were normal. His blood pressure was 112/88 mm Hg. Laboratory findings: ECG, sinus tachycardia at 140/min; and serum electrolytes, NA+, 139 meq and K+, 4.1 meq; chest X ray showed diffuse fluffy pulmonary infiltrates in all lung fields. Initial blood gas analyses (patient breathing room air) revealed pH 7.42; Pco,, 30.3; Po 2 , 41.5; and saturation, 65%. The patient was begun on 35% venturimask, intermittent positive pressure breathing with 0 2 , and Lasix®, 40 mg (one dose), was given. Because of the profuse vomiting and suspected aspiration, the patient was also given intravenous steroids and penicillin. He rapidly improved clinically but still complained of severe chest pain until 48 hours after admission, when the chest pain gradually resolved. Blood gas values improved slowly: six hours after admission, they were pH 7.45; Poo*, 32.4; Po2, 49.6; and saturation, 87%. Fortyeight hours after admission, pH was 7.46; Pco*, 39.0; Po2, 61.6; and saturation, 93 %. Seventy-two hours after admission, breathing room air, the pH was 7.49; Pco*, 33.7; Po,, 80.2; and saturation, 97%. Chest X ray during this period showed rapid resolution of the infiltrates. This case reflects several differences from those reported by Glauser and co-workers, notably the lack of hypotension, coma, and bradycardia. Also of interest was the immediate vomiting and chest pain in this case. P. VAN SWEARINGEN, M.D.

940 Margaret Place Shreveport, LA 71101

Phenformin and Lactic Acidosis TO THE EDITOR: We wish to correct a statement that appeared in our recent "Letter" (Ann Intern Med 84:55-56, 1976). In our discussion of a patient with phenforminrelated lactic acidosis, we indicated that the increase in phosphofructokinase activity, and hence the increase in glycolytic production of lactic acid, was caused by a fall in cytosolic ATP concentration. This is probably not true. Current biochemical evidence suggests that intracellular ATP levels do not regulate glycolysis because they change very little, even under anoxic conditions, and that increases or decreases in phosphofructokinase activity are closely related to concordant changes in cytosolic A M P concentration ( 1 ) . A decline in ATP concentration that was sufficient to stimulate phosphofructokinase activity, if it were not completely incompatible with life, would probably suppress lactic acid production by inhibiting the hexokinase reaction. The foregoing comment in no way alters the basic conclusion of our letter, that is, that phenformin is a profoundly toxic drug clinical use of which can no longer be justified. STANLEY A. BLUMENTHAL, M.D., F.A.C.P. DAVID H. P. STREETEN, M.B., D.PHIL., F.R.C.P.

VA Hospital; and Department of Medicine State University of New York Upstate Medical Center Syracuse, NY 13210

REFERENCE

1. NEWSHOLME EA, START C: Regulation in Metabolism. London, John Wiley & Sons, 1973, pp. 105-132 TO THE EDITOR: I have been a fan of this journal for many years. Therefore I note regretfully an editorial in the October 1975 issue entitled "Farewell to Phenformin for Treating Diabetes Mellitus" ( 1 ) . It is not so much the content of this editorial that is disturbing, as the omissions. The emphasis in diabetes practice for many years has been on the later stages of diabetes, and clinical research on early stages has been limited largely to prediabetes. Clinical research dedicated to the person with subclinical diabetes (British term, "latent diabetes") and chemical diabetes (British term, "asymptomatic diabetes") has been conspiciously minimal. A number of publications have indicated that shortterm use of a biguanide drug such as phenformin may be of value here (2-5). In addition, some clinical and experimental evidence indicates that lowering of glucose levels during the incipient stages of diabetes may forestall or prevent advancing metabolic deterioration (6-8). The controversy surrounding the U.G.D.P. studies continues. These studies indicate, however, an increased mortality in persons taking oral hypoglycemic agents continuously over several years. But there is no evidence of significant detrimental effect when oral hypoglycemic agents are administered in properly selected patients in intermittent short-term courses. Furthermore, the editorial would bid a farewell to one class of oral hypoglycemic, while suggesting the continued use of another. I believe that many conscientious physicians will go on using phenformin in properly selected patients for short periods of time in certain diabetic subjects free of complications or other significant organic disease. It will probably continue to be used on a short-term basis in those subjects in whom diet and exercise have failed, or where the will of the patient cannot be mobilized to follow such treatment effectively. Finally, in contrast with other editorial comment ( 9 ) , there was no comment calling for closer attention to the early phases of diabetes mellitus. More study is required in these areas, and a well-defined role for the short-term use of a biguanide such as phenformin may yet be clearly defined. DOUGLAS L. WILANSKY, M.D.

Department of Medicine Etobicoke General Hospital Toronto (Rexdale), ON, Canada REFERENCES

1. WILLIAMS RH, PALMER JP: Farewell to phenformin for treating diabetes mellitus. Ann Intern Med 83:567-568, 1975 2. WILANSKY DL, HAHN I: Modification of latent diabetes by shortterm phenformin administration. Metabolism 16:199-203, 1967 3. FALUDI G, BENDERSKY G, GERBER P: Functional hypoglycemia in

early latent diabetes. Ann NY Acad Sci 148:868-874, 1968 4. BERGER S, DOWNEY JL, TRAISMAN HS: Effect of phenformin on

the cortisone glucose tolerance test. Ann NY Acad Sci 148:859867, 1968 5. ARKY RA, ABRAHAMSON EA: Insulin response to glucose in the presence of oral hypoglycemics. Ann NY Acad Sci 148:768-777, 1968 6. LUKENS FDW, DOHAN FC, WOLCOTT MW: Pituitary diabetes in

the cat: recovery following phloridzin treatment. Endocrinology 32:475-487, 1943 7. STOWERS JM, BEWSHER PD, BRACKENRIDGE RC: Trial of chloComments and Correction

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propamide in subclinical diabetes. Diabetes ll(suppl): 127-130, 1962 8. WILANSKY DL, SHOCHAT G: The course of latent diabetes. Ann NY Acad Sci 148:848-858, 1968 9. CRAWFORD JD, BODE HH: Diabetes and the amplifier hypothesis. N Engl J Med 282:1266-1267, 1970

Weir and associates reached the conclusion: "This elevation [of PTH] was probably consistent with the degree of hypocalcemia seen since there was a significant inverse correlation with ionized calcium values." This conclusion would appear unjustified with the data available for the reasons outlined above. GILES M. ROBERTSON, JR., M.D. KARL E. PEACE

Hypocalcemia and Parathyroid Hormone in Pancreatitis TO THE EDITOR: In the August issue (Ann Intern Med 83:185-189, 1975), Weir and associates reported studies on 11 patients with acute pancreatitis; 8 patients had decreased serum ionized calcium, and parathyroid hormone (PTH) concentrations were elevated in 6 and undetectable in 5. They state, "the data obtained from our study indicate that hypocalcemia in acute pancreatitis is not the result of abnormalities of secretion of gastrin, glucagon, or parathyroid hormone." Their conclusion regarding PTH seems to be based upon the demonstration of significant correlation (r = 0.487 and P < 0.025) between ionized calcium (Ca ++ ) and PTH and assuming a simple linear regression exists. It appears that the Pearson product moment estimate of correlation was used with a subsequent transformation of this to the f-statistic for the test of significance. This analysis assumes independence of the observations which is clearly violated by including the multiple observations on Patient 8. Additionally, the inclusion of these multiple observations increases the number of degrees of freedom thereby enhancing the likelihood of the computed correlation being found significant, and necessarily biases the conclusion reached toward whatever the true state of nature between PTH and (Ca ++ ) is for Patient 8. Data from any experiment should be used if possible in the analysis but not using the multiple observations on Patient 8 is clearly justified because to do otherwise is to make no conclusion valid from the analysis. Concerning the calculation of r, arbitrary values for five patients with undetectable levels of PTH must be supplied and thus casts doubt on the validity of both r and the corresponding P value. Therefore, it is difficult to understand how significance can be claimed by the authors when 5 of 11 crucial determinations are assigned arbitrary values. Even if this criticism were not justified, and an assignment of 10 is made where less than 10 is indicated by the table (p. 186), a recalculation (1) using only the single observations on the 11 patients yields r = 0.541 (P = 0.0859 for a two-sided alternative and P = 0.043 for the appropriate one-sided alternative) neither of which is significant at any level smaller than the computed P value. Thus, a nonparametric measure of association based upon ranks may be more appropriate with the data available. The use of parametric versus nonparametric methods is still a much debated issue. However, the data available (not including the multiple observations) tend to demand a nonparametric analysis because of the lack of known concentrations of PTH in the five patients alluded to above. Using Kendall's tau (2, 3) (r), modified for ties, produces the nonparametric estimate of correlation, r = 0.4513, with P = 0.05 for the one-sided alternative of negative correlation between Ca++ and PTH. Thus, the hypothesis of independence (no relationship) between Ca++ and PTH cannot be rejected at the 0.05 or lower levels. 615

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Department of Biostatistics Medical College of Virginia Richmond, VA 23298 REFERENCES

1. FREUND JE: Mathematical Statistics. Englewood Cliffs, New Jersey, Prentice-Hall, Inc., 1962, p. 310 2. CONOVER WJ: Practical Nonparametric Statistics. New York, John Wiley and Sons, 1971, p. 249 3. KENDALL MG: Rank Correlation Methods. Riverside, New Jersey, Hafner Publishing Company, 1962, p. 35 In reply: The comments by Robertson and Peace bring up some interesting statistical points about the negative correlation we reported between ionized calcium and parathyroid hormone (PTH). It may be reasonable to criticize the inclusion of the multiple observations on Patient 8, even though the samples were drawn at different points during the time course of the patient's illness. Because of the small number of patients, it is not surprising that statistical significance is lacking when the multiple observations of Patient 8 are eliminated. Despite the above criticisms, our fundamental point about PTH secretion does not appear to be weakened. 1. If our study population was larger and included patients with mild pancreatitis and normal calcium levels, one would expect the negative correlation in question to be highly significant. 2. Of the eight patients with low ionized calcium values, five had elevated PTH levels. We can not explain why PTH increases were not seen in three patients, but perhaps slight elevations were not detected by the radioimmunoassay. There are very little data available about the levels of immunoreactive PTH reached during mild hypocalcemia. We were cautious in indicating that we could not be certain that the PTH elevation was consistent with the degree of hypocalcemia. 3. Because clear PTH elevations were seen in most of the patients with hypocalcemia, we feel it is highly unlikely that the hypocalcemia of acute pancreatitis is the result of abnormal parathyroid hormone secretion. Conceivably the PTH response was not maximal, but it seems hard to accept deficient PTH secretion as a major mechanism. As we mentioned in our discussion, bone may for unknown reasons, be unresponsive to PTH. For these reasons we believe our conclusions are supported by our data. GORDON C. WEIR, M.D. PAUL B. LESSER, M.D. ANDREW L. WARSHAW, M.D.

Massachusetts General Hospital Boston, MA 02114

Soviet Antisemitism TO THE EDITOR: During the past several months, there has been increasing world concern over the fate of Soviet

Jewish physicians, scientists, and intellectuals who have sought to emigrate to Israel and elsewhere. Often dismissed from their jobs, barred from their laboratories, or demoted to menial tasks, they live with the fear that they will be arrested or imprisoned, perhaps in a mental hospital ( 1 ) , or that permission to emigrate will never be granted to them. Some case histories will illustrate: Dr. Mikhail Shtern, former Chief of Endocrinology at Vinnitsa Hospital in the Ukraine, was recently sentenced to 8 years' imprisonment for accepting "bribes" from his patients. Leading Western jurists have stated that the fact that Shtern's two sons had applied to go to Israel had much more to do with his conviction than any violation of Soviet law (2). Dr. Ilya Glezer, noted neuroanatomist, is now serving the last 3 years of a 6-year prison term for alleged "anti-Soviet propaganda." His crime consisted of writing a letter concerning Soviet antisemitism (3). There are other physicians imprisoned, and still more denied the right to practice since requesting exit visas. The Western medical community must now demand the rights of free emigration and freedom to practice without harrassment because of one's personal beliefs for their colleagues in the Soviet Union. Western physicians planning to travel to Russia can be particularly effective by raising these issues with their Russian hosts, and by pointing out that if scientific and technical interchange is to continue with the West, it must be based on the principle of respect for human rights, not on intimidation. Further information concerning these and other violations of the rights of Soviet Jews, as well as suggestions for action, may be obtained from the Medical Mobilization for Soviet Jewry, 233 Bay State Road, Boston, MA. 02215.

2. Soviet Jewish doctor gets 8 years in a bribery case. NY Times 1 January 1975, p. 38 3. SATTIN A, AXELROD J, KOPIN IJ, et al: Ilya Glezer's struggle

(letter). Science 187:902, 1975

Blue Hands and Pseudocyanosis TO THE EDITOR: I wish to call attention to an unusual case recently seen at our hospital. A 35-year-old man was admitted to the hospital for evaluation of a fever of unknown origin. Mid-course in the hospital he suddenly developed striking bluish coloration ^of his hands. He had no associated pain and the discoloration did not respond to simple washing. He had no other discoloring of skin or mucous membranes, and his hands were warm. Both the patient and his family were distraught, and observers were unable to explain his cyanotic-appearing hands. The differential diagnosis was proliferating when this blue coloring was noted to be alcohol soluble. It was then immediately obvious that his blue hands were the result of contact with his blue flannel bathrobe worn constantly during his fever. This might be termed the "new blue garment pseudoacrocyanosis syndrome". JEFFREY C. DARNELL, M.D.

Department of Medicine Wishard Memorial Hospital Indianapolis, IN 46202

Correction and Apology: MKSAP IV Infectious Disease Committee

LAURO F. CAVAZOS, PH.D., Dean

Tufts University School of Medicine 136 Harrison Avenue Boston, MA 02111 PAUL REICH, M.D.

Department of Medicine Harvard Medical School 25 Shattuck St. Boston, MA 02115 REFERENCES

1. CHODOFF P: Involuntary hospitalization of political dissenters in the Soviet Union. Psych Opinion 11:5, 1974

The list of names of Members of the Infectious Disease Committee of the American College of Physicians' Medical Knowledge Self-Assessment Program IV that accompanied "Infectious Disease: An Annotated Bibliography of Recent Literature" in "The Literature of Medicine" section of the February issue (Ann Intern Med 84:228-232, 1976) should have included Herbert L. DuPont, M.D., F.A.C.P.; and Ralph R. Tompsett, M.D., M.A.C.P. This error was a result of an oversight in copy editing. The Editorial Office apologizes to Drs. DuPont and Tompsett for this error.

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