CONTENTS Nuclear Power and Health H. R. Maxon L R. Solon and V. W. Side/ Training the Internist J. A. Barondess W. B. Bateman, Jr., H. G. Bloom, and J. I. Bou fiord Immunity in Hodgkin's Disease N. Gutensohn and P. Cole N. J. Vianna Irritable Bowel Syndrome W. G. Thompson and K. W. Heaton Cimetidine, Lupus Erythematosus, and Granulocytopenia G. O. Littlejohn and M. B. Urowitz Intravascular Coagulation and Ascitic-Fluid Infusion A. Via/let and J-P. Villeneuve W. M. Lee Potassium Tolerance in Sickle-Cell Hemoglobinopathy P. Mitnick, R. Sterns, and M. Cox Splenectomy in Sickle-Cell Disease P. W. Wilson, W. R. Berry, and W. F. Rosse Renal Excretion of Technetium-99m Diphosphonate in Osteomalacia /. Fogelman and R. G. Bessent

314 315 315 316 316 316 317 317 318 319 319 320


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 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 out style.

Nuclear Power and Health T o T H E EDITOR: In the March 1979 issue you published an editorial "Health Implications of Nuclear Power Production," by Leonard R. Solon and Victor W. Sidel (1). The underlying theme of the editorial seems to be that both the World Health Organization (WHO) Report, Health Implications of Nuclear Power Production, and the 1975 United States Nuclear Regulatory Commission ( N R C ) Reactor Safety Study represented efforts by "qualified and influential members of the nuclear establishment" to "minimize the current or potential dangers of the nuclear fuel cycle" for the purposes of "promoting the acceptability o f nuclear power. In their quotation from Bok and in their closing paragraph, they imply dishonesty, deception, and "a pattern of omission" that "may return to haunt us and untold generations of our offspring." The only documentation of such serious implications is their summary statement of criticisms of the original (not the final) draft of the N R C report by a special study group of the American Physical Society. There is no question that the initial draft included many serious errors. The N R C subsequently asked numerous "experts" to study specific health-effects problems. The final draft contained extensive revisions and new reports from each of these various groups, which even Solon and Sidel conceded were "serious and reasonably definite in their exploration of current knowledge in the field." Solon and Sidel also added an addendum to the editorial in which they stated that "the N R C now appears to agree with us that the uncertainties in the estimates of reactor risks are significantly greater than those cited in the 1975 study." The complete statement of the N R C on 18 January 1979 acknowledged 314

Danazol and Thyroid Function J. Worts man, J. Hirschowitz, and N. Soler 321 Adrenocorticotropin (ACTH) Test and Hyponatremia L. I. Rose 321 Spironolactone and Metabolic Acidosis D. W. Nierenberg 321 P. A. Gabow, S. Moore, andR. W. Schrier 322 Streptococcal Pharyngitis and Gram Stains R. A. Wright and E. N. Scholes 322 G. Crawford 323 Legionella pneumophila in Drinking Water of Guinea Pigs R. W. Connor and D. N. Gilbert 323 Treatment of Aspergillosis in Leukemia B. A. Ad elman, A. Bent man, P. Rosenthal, B. R. Smith, K. R. Bridges, and W. Holmes 323 Ocular Toxoplasmosis R. P. Handler 324 Ampicillin Rash and Hyperuricemia T. F. Murphy 324 Medical Education in Colombia A. F. Jacome-Roca 325 Library Resources on Alcoholism D. M. Novick and S. R. Yancovitz 325

that many of the criticisms of the 1975 study (particularly the executive summary and numerical estimates of accident probabilities) were valid. This statement was based on the Risk Assessment Review Group Report, which had been submitted to the N R C on 7 September 1978 by Chairman Harold Lewis. That same review-group report also concluded that the 1975 study was "a substantial advance over previous attempts to estimate the risks of the nuclear option." On Wednesday 14 March 1979, at the Annual Meeting of the National Council on Radiation Protection and Measurements in Washington, D.C., Dr. Paul Slovic presented a paper entitled "Images of Disaster: Perception and Acceptance of Risks from Nuclear Power." He concluded that the "fear of nuclear power stems in part from the recognition that there are important unresolved technical issues in the risk assessment process and in part from fundamental mental processes such as the use of imaginability and memorability as a basis for estimates of probability and frequency. Normal modes of thought, coupled with the special qualities of nuclear hazards that make them particularly memorable and imaginable yet hardly amendable to empirical verification, blur the distinction between the possible and the probable and produce an immense gap between the views of technical experts and a significant portion of the public." The editorial by Solon and Sidel seems to illustrate his point. That such a respected forum as the Annals of Internal Medicine should be used for the blanket condemnation of massive efforts by many members of our scientific community to achieve a realistic understanding of the health implications of nuclear power production, and for that matter, of any radiation exposure is regrettable. Although there is no question that many uncertainties remain in the assessment of risk, I do not believe that publication of poorly documented implications of dishonesty and deception represents the best interest of either the medical community or the public. I agree with Solon and Sidel that "physicians should be as aware of potential threats to the health of their patients and their communities as they are of clearly documented current sources of illness, injury, and disability." I also agree that "we should face the choices clearly." I do not think that their editorial has contributed to either of these goals.

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H A R R Y R. M A X O N , M . D .

Eugene L. Saenger Radioisotope Laboratory, Cincinnati General Hospital; Cincinnati, O H 45267

REFERENCE 1. SOLON LR, SIDEL VW. Health implications of nuclear power production. Ann Intern Med. 1979;90:424-6.

L E O N A R D R. S O L O N , P H . D .

Bureau for Radiation Control, Department of Health, New York, 10013 V I C T O R W. S I D E L , M . D .

In comment: Our editorial summarized accurately the editorial evolution and the scientific content of the 1975 Nuclear Regulatory Commission ( N R C ) study and the 1978 World Health Organization ( W H O ) report on the health implications of nuclear power production. Dr. Maxon does not, as far as we can see, disagree with the facts but rather with our interpretation of them. He does not choose to mention the additional fact, documented in the editorial, that every modification of the original N R C report (and the recent partial repudiation by the N R C of the revised report [1]) are based on estimates of increased, usually seriously greater, uncertainties and risks. This was part of the evidence for our suggestion of a systematic bias ("pattern of omission*') in these reports toward underestimation of the risks; to what extent the pattern of omission is conscious or unconscious in those who prepare such reports, many of whom in our view have a vested interest in the development of the "nuclear option" or at least in not blocking it, we did not and cannot judge. These inferences are of course our own, and your readers can determine for themselves whether they agree with our or Dr. Maxon's interpretation of the facts. A much more constructive criticism of our editorial has been received personally from colleagues who question another of our inferences: "Indeed, our society's energy requirements may be so severe that the quality of life, as we know or desire it, depends upon acceptance of the nuclear option irrespective of the health implications." This statement is based on our opinion that [1] increased use of fossil fuels would also have negative health implications; [2] large-scale introduction of physically and socially healthier types of energy, although urgently needed, seem to be still in the future due to technical or political barriers, or both; [3] the largest users of energy in the United States are industry and the affluent, neither of whom will substantially reduce their consumption voluntarily, or is there indication that they will be forced to do so in a socially constructive way; and [4] in a U.S. energy shortage those who will suffer the worst of the consequences are those who depend on the "trickle-down" in our development, the poor and the powerless. Already widely disparate straws blow in the wind: Senator Hayakawa, states that "a lot of the poor don't need gas because they're not working" and urges allowing the price of gasoline to rise ( H A Y A K A W A SI. Statement at the White House, 16 May 1979; wording verified by Senator Hayakawa's office, 30 May 1979); the board of directors of the National Association for the Advancement of Colored People specifically endorses nuclear energy because it meets the needs of the poor (2); and pictures of antinuclear rallies show largely white middle-class young people (3). We argued in the editorial that people (not experts) must deal with such Scylla and Charybdis choices and that they need reasonably unbiased estimates of the benefits, risks, and uncertainties of all of their options. We stand by our contention that the reports we reviewed have failed to do this adequately for the potential health risks of nuclear power production. In addition, our opinion is that those who have special expertise have special responsibilities. So long as the danger of radionuclide release exists, for example, and we fear it will continue to exist for some time whatever choices are made, ways must be developed to try to protect the population. We share the view adopted by some experts, to take a specific instance, that there should be stockpiling of potassium iodide and development of standby plans for its appropriate emergency use to attempt to block absorption of accidentally released iodine-131 into the thyroids of children (4). Would it not be more useful for a member of a medical radioisotope laboratory to discuss concretely some of the potential health risks and present and evaluate suggestions for protection of the population in the event of their occurrence than to attempt to defend a report minimizing the risks, a report even whose sponsors find largely indefensible?

Department of Social Medicine, Montefiore Hospital, Bronx, N Y 10467 REFERENCES 1. BURNHAM D. Nuclear agency revokes support for safety study. New York Times. 1979 Jan 20:1 (col. 2), 19 (col. 5-6). 2. JOHNSON TA. N A A C P reaffirms its support of development of nuclear energy. New York Times. 1979 May 19:8 (col. 1-2). 3. R A W L S W. JR. 65,000 demonstrate at Capitol to halt atomic power units. New York Times. 1979 May 7:1 (col. 6), 13 (col. 4-6). 4. Potassium iodide for use as a thyroid-blocking agent in a radiation emergency (Docket 76-0050). Federal Register. 1978 15 Dec.

Training the Internist T o T H E EDITOR: Active debate on the training of the internist is long overdue, has been increasingly prominent in the past few years, and will no doubt continue. One hopes the issues will be clarified as a result. I thank each of those who took the trouble to write (1) in response to my paper. I point out that the paper did not suggest that ambulatory care, chronic care, geriatrics, common disorders, or efficient work practices are unimportant. I have no argument with those who emphasize that all of these things should be done well, compassionately, and with an ongoing sophisticated interest in the management of both disease and illness at all levels of severity. Additionally, the paper is not concerned exclusively with the training of primary-care physicians but rather with the training of internists, who, while making a very great contribution to the delivery of primary care in this country, also provide high-grade secondary and often tertiary care after the now-standard 3 years of training in general internal medicine. Medicine is complex and getting more so all the time; training programs should recognize and address themselves to this fact. Important diagnostic issues must be resolved accurately and time- and cost-effectively in relation to almost any complaint presented by a patient, whether he is ambulatory or hospitalized. Work-up and management decisions are no less complex. Proper training of the internist should prepare him for the decisions integral to the mix of major and minor disorders that every internist sees. The argument of the paper is that our training programs must provide as much expertise as possible in the recognition and management of the whole spectrum, with the crucial caveat that major disease must be isolated and recognized when it is present. I argue further that high competence of a technical nature is a vital, though not exclusive, manifestation of the compassion of the physician. In addition, technical competence is cost-effective, as is indicated by preliminary data from the certifying examination of the American Board of Internal Medicine (unpublished data). It is by no means clear to me that high technical competence relative to major disease, or a deep knowledge of pathophysiology gained at the bedside, interfere with the proper care of ambulatory patients or with appreciation of psychosocial, preventive, or rehabilitative issues. I know of no evidence to support this view, and, as indicated in the paper, believe there are cogent reasons to think the opposite is the case. Inclusion in the training years of appropriate experience with ambulatory patients is specifically advocated in the article. It is the shift away from training in depth through erosion of experience with inpatients that is of such concern. Appropriate integration of the two is specifically indicated and called for if we are to turn out internists prepared for the array of clinical challenges they are certain to meet. Further, I point out that the article did not recommend 5 years of training for all internists but rather for a small number who are required to fill the need for consultants, teachers, and scholars in general internal medicine. As pointed out in the correspondence, more recent medical Letters

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graduates enter training in internal medicine than any other specialty; in recent years large numbers of these have gone on to subspecialty training, but Tarlov and associates' data (2) indicate that this trend has leveled off and in fact may be reversing. In any case, all general internists and most subspecialists in internal medicine deliver primary care to their patients much of the time (3). T h e opinion that internists do not represent a major primary care resource is fallacious, and obscures important training and manpower issues. T h e Federated Council for Internal Medicine has expressed itself on this issue (4), and on the necessity for training more generalists in internal medicine. J E R E M I A H A. BARONDESS, M . D .

449 East 68th Street, New York, N Y 10021 REFERENCES

1. Training the internist. Ann Intern Med. 1979;91:124-7. Letters. 2. T A R L O V AR, SCHLEITER MK, W E I L PA,. T H E ASSOCIATION O F P R O FESSORS O F M E D I C I N E T A S K F O R C E ON M A N P O W E R . National study of

internal medicine manpower: IV. Residency and fellowship training 1977-1978, 1978-1979. Ann Intern Med. 1979;91:295-300. 3. R E I T E N M E I E R RJ, S P I T T E L L JA J R , W E E K S RE, D A U G H E R T Y GW, N O -

BREGA FT, FLEMING RW. Participation by internists in primary care. Results of a survey of Mayo Clinical Alumni. Arch Intern Med. 1975;135:255-7. 4. F E D E R A T E D C O U N C I L FOR I N T E R N A L M E D I C I N E . Federated Council for

Internal Medicine 1979;90:108-9.





The letter below arrived too late for comment dess.



by Dr. Baron-

T o T H E EDITOR: As a group responsible for the training of internists, we began reading Dr. Barondess' article (1) with great interest. A s faculty in a primary-care internal medicine program, we finished it with great concern. Although we do support some of his arguments the necessary brevity of this reply does not allow for in-depth discussion. We will focus on only a few of the difficulties in his analysis of what good primary-care training ought to be and what it is. Training competent, high-quality, primary-care physicians requires that programs prepare graduates to provide excellent inpatient and ambulatory patient care. A good program will neither advocate nor allow the ambulatory component to dominate the inpatient component. However, we disagree with the simplistic concept put forth by Dr. Barondess that all of medicine—acute and chronic disease, psychosocial and community aspects of disease and health, and so forth—can be best learned by continuous exposure to hospitalized inpatients manifesting the extreme forms of a disease or illness. T h e goal of training physicians ought to extend well beyond concern with the acute hospital presentation of disease to consider the many factors affecting the health of patients before and after hospitalization. Such essential aspects of primary care as recognizing disease in an early, undifferentiated state and learning to treat conditions for which people are rarely admitted (for example, most thyroid conditions, major arthritides) are not as effectively learned in the hospital as in the ambulatory setting, where they are the focus of attention rather than simply an aspect of the patient's problem(s) that may or may not be discussed. "Major medicine" in this country, at least quantitatively, is ambulatory medicine. As reflected in a recent National Medical Ambulatory Care Survey, only 3 % of patient encounters with physicians result in hospitalization (2). The focus of the primary-care physician must also go far beyond the disease focus of inpatient care to effectively address issues of primary and secondary-disease prevention through health promotion and periodic examinations in asymptomatic patients (3). T o fill this role requires exposure and training as rigorous as those for any other aspect of practice. O n e wonders whether most physicians can clearly define primary, secondary, and tertiary prevention, or whether they understand the interrelation of such factors as sensitivity, specificity, incidence, and prevalence in assessing the usefulness of laboratory and other tests for disease screening. Dr. Barondess demonstrates a com316

mon deficiency in this regard. He refers to a British surgeon who viewed the first symptoms of colon cancer as a change in a patient's normal pattern of flatulence—a "change in the wind." A well-trained primary-care physician knows that the best periodic (yearly in persons older than age 40) screening for colon cancer in asymptomatic persons is doing stool hemoccults (two specimens from each of three separate stools while the patient is on a meat-free high-residue diet). This is a sensitive, relatively specific, noninvasive, low-cost method of initially detecting a malignant lesion that has a chance of cure (4). It is far better than waiting for the appearance of even the most subtle of symptoms. The primary-care physician requires training and supervised experience to recognize not only a biomedical but also a psychological and social origin to disease, and to integrate concern for these factors into effective health promotion, disease prevention, and management of acute and chronic disease. Traditionally trained physicians are usually underexposed to these factors and without skills to deal with them. If exposed to these origins only in the inpatient experience, physicians often tend to discount their importance. There is still relatively little modern medicine can do, despite heroic attempts, to extend the life of a hypertensive or diabetic patient with end-stage complications. There is, however, a great deal that a concerned, informed, sophisticated primary-care physician can do to help that patient. Developing these skills takes time, effort, and intelligence. It is time to put a stop to misconceptions that outpatient-oriented primary care is less sophisticated, less important, and less challenging than inpatient care. Good primary-care training emphasizes the difficulty, not the ease, of being a well-informed, curious, quality physician, both in and out of the hospital. O u r program (5) and others like it are working toward this end. W I L L I A M B. B A T E M A N , J R . , M . D . H A R R I S O N G. B L O O M , M . D .

JO IVEY BOUFFORD, M.D. Residency Program in Social Medicine, Montefiore Hospital and Medical Center; Bronx, N Y 10467 REFERENCES

1. BARONDESS JA. The training of the internist: with some messages from practice. Ann Intern Med. 1979;90:412-7. 2. N A T I O N A L C E N T E R FOR H E A L T H STATISTICS. The national

Immunity in Hodgkin's Disease T o T H E EDITOR: In a recent report on immunity in Hodgkin's disease in the October 1978 issue, Vianna and Polan (1) interpret their data as evidence that rates of Hodgkin's disease in childhood increases as sibship size increases. This is based on their comparison of the sibship size distribution of 90 children with Hodgkin's disease with an expected distribution of sibship sizes. However, their selection of the expected distribution of sibship sizes is incorrect, and, when corrected, their data show no association of risk with family size. In their Table 2, Vianna and Polan compare the family size distribution of children with Hodgkin's disease to the distribution of sizes of families in the population. (The distribution of sizes of families is estimated from the parity of women in the population.) This is an erroneous comparison as it does not take into account the obvious fact that a large family has more children in it than does a small family. An appropriate comparison would compare the distribution of family sizes among cases with the distribution of family sizes among children in the pop-

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medical care survey: 1973 summary: United States, May 1973-April 1974. Data from the National Health Survey, series 13, no. 21. Rockville, Maryland: Health Resources Administration; 1975. (DHEW publication no. [HRA] 76-1772). 3. NOBLE J. Comprehensive care and the primary health team. In: NOBLE, J, ed. Primary Care and the Practice of Medicine. Waltham, Massachusetts: Little, Brown, and Co., 1976:263-75. 4. Hemoccult II. Med Let. 1979;21:36. 5. BOUFFORD JI. Primary care residency training: the first five years. Ann Intern Med. 1977;87:359-68.

Table 1. Expected Versus Observed Distribution of Family Sizes Sibship Size

Parity distribution of mothers, % Children per 100 mothers, no. Distribution of children, % Expected distribution of cases, no. Observed distribution of cases, no. Relative incidence (observed/expected)







































100.0 317


ulation as shown in our Table 1. These data show no consistent relation between family size and the incidence of Hodgkin's disease among children. NANCY GUTENSOHN, S.M. PHILIP COLE, M.D., DR. P.H. Harvard School of Public Health; Boston, M A 02115

Drossman (1) draws attention to our study (2) in which certain symptoms were found to be more characteristic of the irritable bowel syndrome than of organic disease. We have since surveyed 301 apparently healthy people in an attempt to ascertain the prevalence of functional gut symptoms (3). We found that 13.6% had symptoms characteristic of the irritable bowel, 7% had dyspepsia, 6% had constipation (frequent straining at stool), and 3.7% had painless diarrhoea. Thus, 30% suffered functional abdominal gastrointestinal symptoms. Only 20% of these patients had seen a doctor in the past year and then not necessarily for their gastrointestinal symptoms. Apparently then, most people suffer such symptoms in silence, as part of life. The few that seek medical aid become patients and may be submitted to extensive and repeated investigation, which simply reinforces their belief that "something must be wrong." Therefore, we echo Dr. Grossman's call for an accurate and positive diagnosis of the irritable bowel from the history backed up by physical examination and a few selected tests. More work is necessary to allow the clinician to diagnose the irritable bowel with confidence and without extensive referral and repeated roetgenograms. Also, some thought should be given to the question "Why do some subjects with gut dysfunction seek medical attention, whilst most do not?" Perhaps free medical care and media-inspired cancer phobia are factors. In any case, the problem cannot be swept under the rug; such subjects are worried about their symptoms and are seeking out their doctors in increasing numbers. W.


1. VIANNA NJ, POLAN AK. Immunity in Hodgkin's disease: importance of age at exposure. Ann Intern Med. 1978;89:550-6.



In comment: Gutensohn and Cole have calculated sibship size per child. We calculated sibship size per family, which is a more familiar concept as indicated in demography texts ("children per family with children . . . for selected countries" [1] or "own children per married couple with children" [2]). We calculated the mean sibship size per family in New York State (excluding New York City) to be 3.1. For the same population, their approach would result in a mean sibship size of 4.3. This appears high in comparison with values shown in demography texts (for example, 2.37 for children younger than 18 living at home in the United States 1960 [1] or 3.2 as calculated from U.S. Bureau of Census data) for children per family with children (3). These figures show the fundamental difference between our approach and that used by Gutensohn and Cole. One family of five siblings would be counted as one sibship by us, but as five sibships of five by them. The only problem that could have arisen with our approach would be the situation in which more than one child with Hodgkin's Disease came from the same family. If that situation did occur (which it did not) we would have counted that as one family. N I C H O L A S J. V I A N N A , M . D . ,


Bureau of Environmental Epidemiology and Occupational Health, New York State Department of Health Office of Public Health; Albany, N Y 12237 REFERENCES

1. SHRYOCK HS, SIEGEL JS. Marital characteristics and family groups. In: STOCKWELL EG, ed. The Methods and Materials of Demography. New York: Academic Press; 1976:173. 2. SPIEGELMAN M. Family formation, composition, and dissolution. In: Introduction to Demography. Chicago: The Society of Actuaries; 1955:144. 3. U.S. BUREAU OF T H E CENSUS. Current Population Reports. Fertility of American women: June 1977. Series P-20, no. 325, Washington, D.C.: Goverment Printing Office; 1978:54.

Irritable Bowel Syndrome T o THE EDITOR: In his editorial note in the March 1979 issue,




Bristol Royal Infirmary, University of Bristol; Bristol, England REFERENCES

1. DROSSMAN DA. Diagnosis of the irritable bowel syndrome. Ann Med. 1979;90:431-2. Editorial note.


2. M A N N I N G AP, T H O M P S O N WG, H E A T O N KW, M O R R I S A F . Towards

positive diagnosis of the irritable bowel. Br Med J. 1978;2:653-4. 3. THOMPSON WG, H E A T O N KW. Functional bowel disorder: a new perspective. Gut. 1978;19:975. Abstract.

Cimetidine, Lupus Erythematosus, and Granulocytopenia T o T H E EDITOR: The association between cimetidine and agranulocytosis has recently been reviewed (1). We report a patient with systemic lupus erythematosus who developed this complication. An 18-year-old Chinese woman with a 4-month history of Raynaud's phenomenon was admitted to another hospital on 29 December 1978 with fever, sore throat, photosensitivity rash, and a butterfly facial rash. The antinuclear antibody titre was 1:160 with an homogenous pattern, lupus erythematosus-cell phenomenon positive and DNA-binding 9 7 % . Initial haemoglobin was 12.0 g/dL; platelet count, 137 000/mm 3 ; and leukocyte count, 1500/mm 3 with a normal differential (Figure 1). Bone-marrow examination on 8 January 1979 was normal. Because of severe leukopenia and systemic illness, prednisone, 40 mg/d, was begun on 10 January. The leukocyte (and granulocyte) counts rose progressively. In mid-February Coombs'-positive haemolytic anaemia, Staphylococcus aureus septicaemia (treated with cloxacillin, 4 g/d) and lupus cerebritis developed. Prednisone was increased to 60 mg/d. From 25 February to 28 February cimetidine, 1200 mg/d, was given because of persistent epigastric discomfort. The absolute neutrophil count fell transiently. On 1 March transfer to Wellesley Hospital was made after a rapid progression of cerebritis. Haemoglobin was 8.0 g / d L with 18% reticulocyte count, and platelet counts were normal. Steroids equivalent to prednisone 200 m g / d were given with steady improvement in cortical signs and cessation of haemolysis. Staphylococcus aureus bacteraemia on 14 March resulted in reintroduction of cloxacillin. Cimetidine, 1200 mg/d, was begun on 16 March as part of management of steroid-induced pancreatitis and for recurrence of epigastric symptoms. Two units of matched packed cells were given on 19 March. Letters

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Ottawa Civic Hospital, University of Ottawa; Ottawa, O N K1Y 4E9 Canada


Figure 1 . Absolute neutrophil counts during course of illness. (C4, normal: 15 to 5 4 m g / d L ; C3, normal: 7 0 to 2 2 0 m g / d L ; CH50, normal: 1 4 0 to 2 2 0 U/mL; DNA binding, normal < 2 5 % ; prednisone maximum, 2 0 0 mg.)

Cimetidine was withdrawn on 26 March when severe agranulocytosis developed. Haemoglobin and platelet count were normal, and bone-marrow examination showed a left shift of granulopoiesis with 12% promyelocytes. Serologic and clinical status indicated that the lupus erythematosus was controlled. No sepsis was found. Management was otherwise unaltered and absolute neutrophil counts gradually rose to previous levels during the next 21 d.

tribute to understanding of these underlying mechanisms.

The initial granulocytopenia was present when the systemic lupus erythematosus was serologically and clinically active. It was part of a general depression of all white-cell elements characteristic of systemic lupus erythematosus and responded to steroids. The degree of agranulocytosis on presentation was unusually severe (2). The mechanism of neutropenia in systemic lupus erythematosus is presumed to be due to the presence of anticell antibodies or to circulating immune complexes that have bound to neutrophils. With treatment, the serologic and clinical manifestations resolved. Granulocytopenia that subsequently developed was temporally related to cimetidine therapy and responded to its withdrawal. The cause of cimetidine-induced agranulocytosis is also unknown. Proposed effects of cimetidine on bone-marrow kinetics (3) may be enhanced if pre-existing active granulopoiesis is present. In the case of systemic lupus erythematosus, this would result from destruction of this cell line by immunologic mechanisms. Alternatively, if the granulocytopenic action of cimetidine is peripherally mediated, patients with systemic lupus erythematosus and leukopenia may represent a group at higher risk for developing this complication. Further observations in such susceptible patients may con-

1. FRESTON JW. Cimetidine and granulocytopenia. Ann 1979;90:264-65. Editorial.


G E O F F R E Y O. LITTLEJOHN, M.B., B.S. M U R R A Y B. U R O W I T Z , M . D .

The Wellesley Hospital; Toronto, Ontario M4Y 1J3 Canada REFERENCES



EH. Systemic lupus erythematosus: review of the literature and clinical analysis of 138 cases. Medicine (Baltimore). 1954;33:291-437. 3. BYRON JW. Cimetidine and bone-marrow toxicity. Lancet. 1977;2:555-6.

Intravascular Coagulation and Ascitic-Fluid Infusion T o THE EDITOR: In their very informative paper in the May 1979 issue, Harmon and coworkers (1) have described their findings of disseminated intravascular coagulation in cirrhotic patients in whom a peritoneovenous shunt was installed. In their discussion, they state that extracorporeal ultrafiltration devices for the reinfusion of ascitic fluid have not been associated with laboratory evidence of disseminated intravascular coagulation. In 1977, we reported our findings (2) in eight patients, with diuretic-resistant ascites due to cirrhosis, treated 11 times by reinfusion of concentrated ascitic fluid (Rhodiascit, Rhone-Pou-

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lenc, France). Coagulation abnormalities were found during 10 procedures. Significant drops of the platelet count and of the fibrinogen concentration were noted, whereas fibrin degradation products were markedly elevated. T h e prothrombin time was prolonged compared with values observed before reinfusion on eight occasions. All of these coagulation variables returned to previous levels within 48 hours after the end of reinfusion. The degree of changes observed in our patients was less marked than those documented by Harmon and coworkers. The mean duration of the procedure in our patients was 21.9 h and the coagulation studies were done 6 h after the start of the reinfusion; in Harmon's study, the coagulation measurements were obtained after the peritoneovenous shunt had been functioning for at least 24 hours. Thus, the difference in intensity of the disseminated intravascular coagulation observed in the two studies could be explained by the time factor. Reinfusion of tissue thromboplastin from the cellular component of the ascitic fluid or reinfusion of activated coagulation factors could be responsible for this type of disseminated intravascular coagulation. A N D R £ VIALLET, M.D. J E A N - P I E R R E V I L L E N E U V E , M.D., M.SC.

to normal over the next 4 to 6 days. Because the Rhodiascit machine concentrates the ascitic fluid three-to-fourfold and still introduces large volumes (300 m L / h ) into the circulation, the clotting changes with it may, in fact, be more abrupt and more severe than with the LeVeen shunt. Reinfusion by extracorporeal machine or LeVeen shunt is a powerful new method for controlling ascites, but the potential hazards of bleeding may limit the widespread application of either method. Ascites reinfusion by machine is of limited duration and can be stopped instantly in the event of complications. It may therefore be a useful model for the study of methods to control the intravascular coagulation that occurs in this setting. W I L L I A M M.


College of Physicians and Surgeons of Columbia University; New York, N Y 10032 REFERENCES 1. H A R M O N DC, D E M I R J I A N Z, E L L M A N L, FISCHER JE. Disseminated

intravascular coagulation with the peritoneovenous shunt. Ann Med. 1979;90:774-6.


Clinical Research Center, Hopital Saint-Luc; Montreal, P Q H 2 X 3J4 Canada

2. P A R B H O O SP, A J D U K I E W I C Z A, SHERLOCK S. Treatment of ascites by


3. L E V Y VG, O P O L O N P, P A U L E A U N, C A R O L I J. Treatment of ascites by

1. H A R M O N DC, D E M I R J I A N Z, E L L M A N L, FISCHER JE. Disseminated

intravascular coagulation with the peritoneovenous shunt. Ann Med. 1979;90:774-6.


2. V I L L E N E U V E JP, T H U O T C, M A R L E A U D, JOLY JG, H U E T PM, V I A L -

LET A. Treatment of resistant ascites by continuous ultrafiltration-reinfusion of ascitic fluid. Can Med Assoc J. 1977;117:1296-8.

T o T H E EDITOR: T h e statement by H a r m o n and associates in

the May 1979 issue (1) that extracorporeal ascites reinfusion has not been associated with evidence of disseminated intravascular coagulation is not accurate. Data subsequent to the 1974 article quoted (2) from our own group and others (3, 4) support the idea that ascites infusion of any sort frequently results in disseminated intravascular coagulation. An example of this is shown in Figure 1. In this patient in whom the Rhodiascit ascites reinfusion machine was used for 12 h, clotting variables were altered significantly from preinfusion values and returned

Figure 1 . Coagulation data before and after Rhodiascit ascites reinfusion. Changes are most severe on the day after reinfusion and return to near normal by the sixth day after infusion. PT = prothrombin time, PLTS = platelets FDP = fibrinogen degredation products.

continuous ultrafiltration and reinfusion of protein concentrate. 1974;1:949-52.

reinfusion of concentrated peritoneal fluid-review of 318 procedures in 210 patients. Postgrad Med J. 1975;51:564-6. 4. W I L K I N S O N SP, D A V I D S O N AR, H E N D E R S O N J, W I L L I A M S R. Ascites

reinfusion using the Rhodiascit appartus: clinical experience and coagulation abnormalities. Postgrad Med J. 1975;51:583-7.

Potassium Tolerance in Sickle-Cell Hemoglobinopathy T o T H E EDITOR: De Fronzo and associates in the March 1979

issue (1) have described a K + secretory defect in six patients with sickle-cell hemoglobinopathy but hyperkalemia (even during acute and chronic potassium loading) was notably absent. However, these authors made note of an abstract (2) describing hyperkalemia in a patient with sickle-cell hemoglobinopathy and commented that they have seen a chronically hyperkalemic patient with HbSS disease. We have recently studied a patient with documented HbSS disease who developed life-threatening hyperkalemia while receiving only modest amounts of potassium. A 25-year-old black woman underwent cesarean section at 36 weeks with uncomplicated delivery of twins. Six days after operation a paralytic ileus developed, which was treated with nasogastric suction and intravenous fluids. Fluid intake during 3 d consisted of 9.5 L of 5 % dextrose in l / 2 normal saline containing a total of 300 meq of K.C1, during which time urinary output and nasogastric drainage were 7 and 1.5 L, respectively. At the end of this 3 d period the serum potassium concentration was 7.4 meq/L and markedly peaked T waves were present on the electrocardiogram. Studies at this time showed a serum creatinine concentration of 0.5 to 1.0 mg/dL, a normal platelet count, the absence of acidemia or hemolysis, and urinary electrolyte concentrations (in meq/L) as follows: K + , 46; Na + , 120; and CI, 152. The patient's response to conventional therapy was uncomplicated and she was admitted to the Clinical Research Center for further study. The plasma Cortisol and aldosterone responses to the administration of cosyntropin (Cortrosyn) (0.25 mg intramuscularly) were normal. After 3 d on a 25-meq Na + , 60-meq K + diet and after the oral administration of 50 mg of ethacrynic acid, supine and 2-h erect plasma renin and aldosterone concentrations were measured (aldosterone; 50 and 98 ng/dL, supine and erect, respectively; renin; 7.3 and 15.6 ng angiotensin I / m L / h , supine and erect, respectively). Twenty-four-hour urinary aldosterone excretion was 19.8 u.g. The patient's renin-aldosterone axis was therefore normal in all respects. The patient was allowed to come into balance on a 130-meq Na + , 60-meq K-t- diet and then underwent a 2-h intravenous infusion of KC1 in '/ 2 normal saline at a rate of 0.375 meq K + / k g / b o d y weight *h. Urinary K-|excretory rates before the infusion and during the first and second hours of the infusion were 22, 145, and 209 u.eq/min, respectively. The fraction of infused K + excreted was 4 8 % (1 h) and 52% (2 h). These values compare favorably with those seen in normal subjects (1). The infusion was repeated Letters

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after the administration of 9-a-fluorohydrocortisone (0.1 mg orally three times a day for 3 d). Urinary K + excretory rates were 233 and 342 fieq/min at 1 and 2 h, respectively, and the fraction of infused K + excreted was 79% (1 h) and 100% (2 h). The serum K-f concentration remained within the normal range during both infusions. Although the two studies were not strictly comparable, in that the N a + excretory rate was higher during the second study, tabular K + secretion in response to an acute KC1 load was clearly normal in this patient.

d, and by the carbon monoxide technique, erythrocyte survival was 16 d. Hemoglobin electrophoresis at the time of follow-up studies was Hb S, 8 5 % ; Hb F, 11%; Hb A; 0%, and Hb A2, 3 % . After surgery the patient continued to have frequent abdominal pains at the rate of about once a week, but now in the right upper quadrant and accompanied by moderate hepatomegaly. Six months after operation the hemoglobin stabilized at 8 g/dL with 600 000 platelets/mm 3 . Thereafter she was lost to follow-up.

Apparently, therefore, the K + secretory defect in HbSS disease may present either as a defect in chronic K + handling with a normal response to acute K + loading (as in our patient) or as a defect in K + secretion after acute K + loading (as in the patients reported by DeFronzo and associates, [1]). Although the physiologic implications of these differences are uncertain, their clinical significance is clear. Whether or not the response to an acute K + load is abnormal, some patients with HbSS disease may develop severe hyperkalemia when chronically loaded with modest amounts of K + . Caution is therefore advisable whenever the K + secretory system is stressed in patients with sickle-cell hemoglobinopathy. Whether the stress in our patient was related to the chronicity of the K + administration or to the presence during pregnancy of high circulating levels of progesterone, an aldosterone antagonist (3), is unclear.

This case and that reported by Balleston and Warth share several interesting features. Both patients were young adult women who had hypofunction on spleen scan as described by Pearson, Spencer, and Cornelius (4) in pediatric sickle-cell patients and had no attacks of left-upper-quadrant pain after splenectomy. Our patient showed splenic sequestration preoperative^ and improvement of erythrocyte survival after surgery, supporting the diagnosis of hypersplenism. Rather than having a benign postoperative course, she developed hepatic and painful right-upper-quadrant crises after splenectomy. Our results showed that an enlarged spleen that shows hypofunction by "mTc scanning techniques may selectively sequester erythrocytes and destroy them, a form of hypersplenism. In this setting, splenectomy may improve the hematologic measures or abdominal symptoms, but the overall result may depend on other factors.

Grant support: in part by N I H grant 5-MO1-RR00040. P A U L MITNICK, M.D. R I C H A R D STERNS, M . D . MALCOLM COX, M.D.

Hospital of the University of Pennsylvania, and Philadelphia Veterans Administration Hospital; Philadelphia, Pa 19104 REFERENCES 1. D E F R O N Z O RA, T A U F I E L D PA, BLACK H, M C P H E D R A N P, C O O K E CR.

Impaired renal tubular potassium secretion in sickle cell disease. Ann Intern Med. 1979;90:310-6. 2. R O S E M A N MK, SEHY JT, A R R U D A JAL, K U R T Z M A N NA. Studies on

the mechanism of hyperkalemic distal renal tubular acidosis (dRTA): gradient type dRTA in SC hemoglobinopathy. In: Proceedings of the Tenth Meeting of the American Society of Nephrology. Washington, D.C.: American Society of Nephrology; 1977:21. Abstract. 3. E H R L I C H EN, L I N D H E I M E R M D . Effect of administered mineralocorti-

coids or ACTH in pregnant women: attenuation of kaliuretic influence of mineralocorticoids during pregnancy. J Clin Invest. 1972;51:1301-9.

Splenectomy in Sickle-Cell Disease T o T H E EDITOR: In the March 1979 Balleston and Warth (1) describe the case of an adult with sickle-cell anemia and splenomegaly who profited from splenectomy. We describe a similar case and relate a different experience. A 20-year-old woman was seen at the Duke University Medical Center because of recurrent left-upper-quadrant pain and persistent swelling in that area. History showed sickle-cell anemia with hepatosplenomegaly diagnosed at age 3 at the same medical center. Results of physical examination on presentation were remarkable for a protuberant and tender spleen, which extended to the left anterior iliac crest; no hepatomegaly or ascites were present. Laboratory data showed hemoglobin, 7.0 g/dL; reticulocyte count, 35 dL; leucocyte count, 9200/1111^; and platelet count, 135 0 0 0 / m m \ Hemoglobin electrophoresis on cellulose acetate by the Helena method showed Hb S, 75%; Hb A, 20%; and Hb F, 4.4% after a recent transfusion. No hemoglobin biosynthetic studies were done. Total serum complement, G 6 P D screen results, and quantitative serum immunoglobulins were all normal. A liverspleen scan with "mTc sulfur colloid showed a slight increase in the liver size and generalized hypofunction of a massively enlarged spleen. The Cr51 autologous erythrocyte survival was 7 d, and body counting showed sequestration in the spleen. Serial organ counting over the spleen and liver during 5 d showed a spleen/liver uptake maximum of 1/3.0 on Day 2 (upper normal, 1/2.0, with values greater than 1/2.5 suggestive of splenic sequestration) (2). Erythrocyte survival estimated by endogenous carbon monoxide production was 8.8 d (3). Splenectomy and cholecystectomy were done after an exchange transfusion. At surgery the splenic artery was patent and the spleen weighed 2250 g. Microinfarctions, giant cell reactions, and splenic congestion were seen on histologic examination. No large area of splenic infarction was present. Five months after splenectomy Cr51 autologous erythrocyte survival was 13 to 14 320

P E T E R W. W I L S O N , M . D .

National Heart, Lung, and Blood Institute, National Institutes of Health; Bethesda, M D 20205 W I L L I A M R. B E R R Y , M . D . W E N D E L L F. R O S S E , M . D .

Duke University Medical Center; Durham, N C 27710 REFERENCES

1. BALLESTER OF, W A R T H J. Sickle cell anemia: recurrent splenic pain relieved by splenecromy. Ann Intern Med. 1979;90:349-50. 2. HATHORN M. Patterns of red cell destruction in sickle-cell anemia. Br J Haematol. \%7; 13:746-51. 3. L O G U E GL, ROSSE W F , SMITH WT, SALTZMAN HA, G U T T E R M A N LA.

Endogenous carbon monoxide production measured by gas-phase analysis: an estimation of heme catabolic rate. J Lab Clin Med. 1971;77:86776. 4. PEARSON HA, SPENCER RP, C O R N E L I U S EA. Functional asplenia in

sickle-cell anemia. N Engl J Med. 1969;281:923-6.

Renal Excretion of Technetium-99m Diphosphonate in Osteomalacia T o T H E EDITOR: We read with interest the article in the March 1979 issue by McFarlane and associates (1) in which 24-h renal excretion of technetium-99m diphosphonate was used as a measure of the whole-body retention in a patient with osteomalacia. Whole-body retention of diphosphonate at 24 h after injection reflects the total skeletal uptake of tracer and provides a simple method for assessing current skeletal metabolic activity (2). It is therefore of considerable clinical value, but we believe measuring the whole-body retention directly is important, because the accuracy of any urinary collection must always be suspect unless the patient is catheterised. If a normal result is obtained for a patient, then this would exclude certain diseases, for example, renal osteodystrophy, osteomalacia, and, probably, primary hyperparathyroidism; but if the result is elevated, would this then mean that there was organic disease present or simply that an incomplete urine collection had been obtained? A whole-body monitor is required for direct whole-body retention estimates, and, although this may not be widely available at present, by today's standards it cannot be considered an expensive piece of equipment. IGNAC FOGELMAN R O D N E Y G.

REFERENCES 1. M A C F A R L A N E , J D , K H A I R I M R A , R I C C I A R D O N E M, W E L L M A N , H,

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University Departments of Medicine and Nuclear Medicine, Royal Infirmary, Glasgow, G 4 OSF Scotland

JOHNSTON CC JR. Renal excretion of 99mTc-diphosphonate in osteomalacia. Ann Int Med. 1979;90:350-1.

JACOBO W O R T S M A N , M . D . JACK H I R S C H O W I T Z , M . D . N O R M A N SOLER, M . D .


G R E I G WR. The use of whole-body retention of Tc-"m diphosphonate in the diagnosis of metabolic bone disease. J Nucl Med. 1978;19:270-5.

Southern Illinois University School of Medicine; Springfield, IL 62708

Danazol and Thyroid Function REFERENCES

T o THE EDITOR: Dr. Spaulding has reported in the May 1979 issue (1) a patient with hereditary angioedema who developed a rise in the level of creatine phosphokinase during treatment with danazol. We have recently reported our experience with this drug in 19 patients with endometriosis (2) but our total experience to date covers 27 patients. When using danazol in doses ranging from 400 to 800 mg daily, clinically significant side-effects were few and affected only three women. One patient developed severe acne, another a transient rash, and a third patient complained of hot flashes and a decrease in the size of her breasts. None of our patients complained of muscular cramps or weakness. We also observed a significant increase in the serum concentrations of estradiol and testosterone when patients were receiving danazol, but the basal concentration of pituitary gonadotropins remained unchanged. Treatment with danazol was commonly associated with a decrease in the thyroxine T4 index (measured by a dual competitive protein-binding assay, Abbott Laboratories, Chicago, Illinois). Thyrotropin levels were normal at the time of diagnosis (3) and remained unchanged during treatment with danazol. On the other hand, the T4 index was generally lower when the patients were receiving the drug, and in some cases the decrease was marked (Figure 1). After we noticed this phenomenon we measured the T4 index in a few patients after danazol was stopped; T4 was found to be within normal limits. Danazol can block the ovulatory peak of the gonadotropins (4), and therefore possibly interferes with hypothalamic-pituitary control of thyroid-stimulating hormone. We suggest that reversible hypothyroidism may be the cause for the increase in creatine phosphokinase (CPK) found during treatment with danazol. A variable increase in CPK is a well-recognized abnormality in hypothyroidism, which may or may not be associated with muscle cramps or weakness (5).

1. SPAULDING WB. Myalgia and elevated creatine phosphokinase with Danazol ® in hereditary angioedema. Ann Intern Med. 1979;90:854. Letter. 2. H I R S C H O W I T Z J, SOLER N G , W O R T S M A N J. Sex steroid levels during

treatment of endometriosis. Obstet Gynecol. 1979. In press. 3. H I R S C H O W I T Z JS, SOLER N G , W O R T S M A N J The galactorrhea-endome-

triosis syndrome. Lancet. 1970;1:896-8. 4. POTTS GO. Pharmacology of danazol. J Int Med Res. 1977; 5(suppl 3):114. 5. G O L D M A N J, M A T Z R, M O R T I M E R R, F R E E M A N R. High elevations of

creatine phosphokinase in hypothyroidism. An isoenzyme analysis. JAMA. 1977;238:325-6. Adrenocorticotropin ( A C T H ) Test and Hyponatremia

T o THE EDITOR: I read with interest the paper in the May 1979 issue by Sheeler and Schumacher (1) concerning hyponatremia during adrenocorticotropin (ACTH) infusions. They postulated that ACTH might be contaminated by antiduretic hormone (ADH). Baumann and associates (2) showed that natural ACTH is indeed contaminated by A D H , but that synthetic ACTH does not contain A D H . In the 48-h ACTH test (3) we now use 50 U of cosyntropin per 24 hours. After several hundred infusions we have not encountered hyponatremia. L E S L I E I. R O S E , M . D .

Hahnemann Medical College & Hospital; Philadelphia, PA 19102 REFERENCES

1. SHEELER LR, SCHUMACHER OP. Hyponatremia during ACTH infusions. Ann Intern Med. 1979;90:798-9. 2. B A U M A N N G, R A Y F I E L D EJ. R O S E LI, W I L L I A M S , G H , D I N G M A N J F .

"Trace" contamination of corticotropin and human growth hormone with vasopressin-clinical significance. J Clin Endocrinol. 1972;34:801-4. 3. R O S E LI, W I L L I A M S G H , J A G G E R PI, L A U L E R DP. The 48-hour adreno-

corticotrophin infusion test for adrenocortical insufficiency. Ann Intern Med. 1970;73:49-54. Spironolactone and Metabolic Acidosis

Figure 1 . Thyroxine T 4 index during treatment with danazol in endometriosis, nl = normal range; B = basal levels; on Rx = during treatment with danazol.

T o THE EDITOR: In their excellent article in the March 1979 issue, Gabow, Moore, and Schrier (1) describe six cirrhotic patients with ascites who developed reversible hyperchloremic metabolic acidosis without significant anion gaps when treated with spironolactone. A s the authors point out, patients with severe liver disease are likely to develop a low serum-bicarbonate concentration for several reasons, including renal acidification defects, respiratory alkalosis, and alcoholic diarrhea. We recently were asked to see a similar patient, a 67-year-old woman with alcoholic cirrhosis, ascites, and normal renal function, who developed a severe hyperchloremic acidosis (HC0 3 , 8 meq/L; pH, 7.20) with no anion gap while being treated with spironolactone, 150 m g / d , and acetazolamide, 250 mg four times a day. The acetazolamide, ordered for her glaucoma, was stopped, but the patient remained severely acidotic until the spironolactone was withdrawn as well. I mention this case because in our search of the literature in this area, we were able to find a previously described case of severe metabolic acidosis induced by spironolactone. In 1978, Feinfeld and Carvounis (2) described a 63-year-old man with chronic alcoholism and normal renal function who was placed on spironolactone, 300 mg/d, and hydrochlorothiazide, 50 m g / d, for treatment of ascites. After several weeks of therapy he was admitted, confused and lethargic, with results of chemistries showing severe hyperkalemia and a severe hyperchloremic metabolic acidosis, with no anion gap. Despite vigorous therapy, the patient died. The authors claimed that this was the first Letters

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reported case of spironolactone-associated fatal acidosis and hyperkalemia in a patient with apparently intact renal function. Thus, although Gabow, Moore, and Schrier are not the first to describe metabolic acidosis as a complication of spironolactone therapy, their series of six cases is certainly the largest in the literature. Because this drug is so often used to reduce ascites in cirrhotic patients, one wonders what the frequency of this complication of therapy truly is. D o the authors know the frequency of this complication? How were their six patients identified? Their paper serves to nicely re-emphasize that no diuretic treatment of ascites in a cirrhotic patient is free from serious adverse effects. D A V I D W. N I E R E N B E R G , M . D .

University of California, San Francisco; San Francisco, C A 94143 REFERENCES 1. G A B O W PA, M O O R E S, SCHRIER RW. Spironolactone-induced hyper-

chloremic acidosis in cirrhosis. Ann Intern Med. 1979;90:338-40. 2. F E I N F E L D DA, C A R V O U N I S CP. Fatal hyperkalemia and hyperchloremic

acidosis: association with spironelactone in the absence of renal impairment. JAMA. 1978;240:1516.

In reply: The observation that the article "Fatal Hyperkalemia and Hyperchloremic Acidosis: Association wih Spironolactone in the Absence of Renal Impairment" by Feinfeld and Carvounis appeared before publication of our paper is well taken. We apologize for this oversight, which no doubt related to the fact that our paper was submitted to Annals of Internal Medicine before publication of this article. It should be noted, however, that the case of Feinfeld and Carvounis reports only a temporal association of hyperkalemia, hypobicarbonatemia, and spironolactone. Because the patient entered the emergency room after a several months' hiatus in follow-up with a sine wave pattern on ECG and was not resuscitated, it was not possible in that patient to verify a causal relation by discontinuation of spironolactone with subsequent normalization of the serum-bicarbonate and serum-potassium concentration. The patients reported by us came to our attention through the renal consultation service. We have not prospectively evaluated the effects of spironolactone in a large group of hospitalized patients with decompensated cirrhosis. Therefore we cannot comment on the frequency of the complications of hyperkalemia and hyperchloremic acidosis. PATRICIA A. G A B O W , M . D . SCOTT M O O R E , M . D . R O B E R T W. SCHRIER, M . D .

Department of Health and Hospitals, City and County of Denver; Denver, CO 80204 Streptococcal Pharyngitis and Gram Stains T o THE EDITOR: When the rising cost of health care appears insurmountable, seeing health professionals attempting to implement more cost-effective means of delivering health care is encouraging. In an article by Crawford and colleagues in the March 1979 issue (1) "Streptococcal Pharyngitis: Diagnosis by Gram Stains," a cost-effective method of identifying group A streptococcal pharyngitis was proposed. The authors showed that the most cost-effective approach was when diagnostic methods were targeted to high-risk patients. Indeed, selective screening for streptococcal pharyngitis is supported by this country's low rate of acute rheumatic fever and rare occurrence of epidemic streptococcal disease (2). In fact, Tompkins and colleagues went so far as to consider a low disease prevalence ( < 5 % ) to obviate any diagnostic or therapeutic intervention (3). In our clinic population, with a 10%-to-20% prevalence of streptococcal pharyngitis, implementation of a clinical algorithm limiting throat culturing to select patients with high-risk indicators resulted, during a 2-year period, in a 30% reduction in throat cultures done, with a savings in laboratory costs of 322

$23 754 ($6.00 per culture). The absolute number of cases detected, however, did not change significantly (unpublished data). In addition to culturing high-risk groups, Crawford and colleagues further minimized laboratory costs by doing Gram stains of pharyngeal exudate. They claimed that the identification of typical streptococci on Gram stains allows for immediate therapy and obviates confirmatory throat cultures and second clinic visit. Based on the authors data, however, usefulness of Gram stains cannot be accepted without some reservation. The importance of expertise in the interpretations of such stains cannot be underestimated. Because normal oral flora is laden with gram-positive cocci and coccobacilli, which may morphologically simulate streptococci, frequent overreading (false-positives) or underreading (false-negatives) seems unavoidable. This situation is analogous to difficulties posed by endocervical Gram stains for Neisseria gonorrhoeae, and recent reports have re-emphasized the difficulty in identifying respiratory pathogens in sputum Gram stains (4, 5). Therefore, the proclamation that proficiency in Gram-stain reading can be acquired with ease and minimal training must be viewed with skepticism. Additionally, with the observed predicted value of 7 1 % , the authors failed to provide an explanation for the 29% of positive Gram stains associated with negative cultures. Was this primarily due to false-negative cultures, false-positive gram stains, or both? Even if Gram stains of pharyngeal exudate are reliable, the procedure, like throat cultures, does not distinguish between colonization and infection, a problem to which the authors alluded. The magnitude of this problem is strengthened by recent evidence that hints at a possible decrease in rheumatogenicity and virulence of group A streptococcal strains (6), a phenomenon that will significantly increase the ratio of colonized-to-infected patients and overtreatment. Thus, we urge that present attempts at diagnosing streptococcal pharyngitis be based on careful patient selection and that therapeutic intervention be based on clinical findings and a cautious interpretation of Gram stains or culture results. R I C H A R D A. W R I G H T , M . D . E L A I N E N O R M A N SCHOLES, M.D.

Eastside Neighborhood Health District, Denver Health and Hospitals; Denver, CO 80205 REFERENCES 1. C R A W F O R D G, B R A N C A T O F, H O L M E S K K . Streptococcal pharyngtitis:

diagnosis by Gram stain. Ann Intern Med. 1979;90:293-7. 2. M C C A R T Y M. The streptococcus and human disease. Am J Med. 1978;65:717-8. 3. T O M P K I N S R K , B U R N E S DC, C A B L E WE. An analysis of the cost-effec-

tiveness of pharyngitis management and acute rheumatic fever prevention. Ann Intern Med. 1977;86:481-92. 4. VAN SCOY RE. Bacterial sputum cultures: a clinician's viewpoint. Mayo ClinProc. 1977;52:39-41. 5. D I P O A L A JA. Prognosis of pneumonia: sputum culture and Gram stain. NY State J Med. 1977;77:1259-62. 6. STOLLERMAN G.H. The relative rheumatogenicity of strains of group A streptococci. Mod Cone Cardiovasc Dis. 1975;44:35-40.

In comment: I am pleased that Drs. Wright and Scholes share my concern over the costs of diagnosing streptococcal pharyngitis. Their ability to reduce the cost of evaluation by selective culturing, based on clinical criteria, agrees with the experience of others (1). I agree that expertise in the interpretation of the Gram stain is vital to our technique, and this expertise is not universal among physicians. However, skepticism with regard to the ability of experienced observers to distinguish gram-positive pathogens from normal oral flora is not warranted by the cited references. Dr. Van Scoy's study correlates the number of polymorphonuclear cells and epithelial cells present in sputum specimens with the number of "pathogens" isolated on culture and does not examine the value of Gram stain (2). Dr. DiPoala does compare the results of Gram stain and culture of sputum and concludes that the Gram stain is of value in predicting the pres-

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ence of pneumococci, which are of course, gram-positive (3). This conclusion is supported by Rein, who has shown that with proper attention to the morphology of the positive cocci associated with polymorphonuclear cells, the Gram stain is a reliable guide to the diagnosis of pneumococcal pneumonia (4). The requirement for skill in interpretation is not limited to the Gram stain. The accuracy of throat-culture interpretation may be unacceptable in private office settings (5), and most clinicians would agree that experience and judgement are needed in evaluating the clinical criteria used in clinical algorithms. Although some of our "false-positive'* Gram stains were accounted for by isolations of non-group-A beta-hemolytic streptococci, in the absence of serologic data, it is speculative whether the remainder were "false-positive" Gram stains or "false-negative" cultures. Similarly, any ability of the Gram stain to distinguish streptococcal colonization from streptococcal infection must await further studies correlating serology, culture and Gram stain. GEORGE CRAWFORD, M.D.

Wilford Hall Medical Center; Lackland Air Force Base, TX 78236

water supply. N o illness occurred during an additional 10 d of observation. Subsequently, cimetidine and L. pneumophila administration was stopped, and the animals have remained well during a subsequent 21-d observation period. The aqueous test suspension of L. pneumophila was repeatedly culture-positive and direct fluorescent antibody-positive for the organism. The stool of the test animals was positive for Legionnaires' bacterium by direct fluorescent antibody technique for at least 4 days after exposure to the contaminated water was discontinued. One month after termination of Legionnaires' bacterium exposure, all guinea pigs remained seronegative, and L. pneumophila was no longer demonstrable in the stool by direct immunofluorescence. Thus, under the conditions used, L. pneumophila administered orally did not produce disease in guinea pigs. R O D N E Y W. C O N N E R , M . D . D A V I D N. G I L B E R T , M . D .

Providence Medical Center & The University of Oregon Health Sciences Center, Portland, OR 97201 REFERENCES


1. SKALIY P, M C E A C H E R N HV. Survival of the Legionnaires' disease bacterium in water. Ann Intern Med. 1979;90:662-3.

1. H O N I K M A N LH, M A S S E L L BF. Guidelines for the selective use of throat

2. M O R R I S G K , P A T T O N CM, F E E L E Y JC. et al. Isolation of the Legion-

culture in the diagnosis of streptococcal respiratory tract infection. Pediatrics. 1971;48:573-81. 2. VAN SCOY RE. Bacterial sputum cultures: a clinician's viewpoint. Mayo Clin Proc. 1977;52:39-41. 3. D I P O A L A JA. Prognosis of pneumonia: sputum culture and gram stain. NY State J Med. 1977;77:1259-62.

naires' disease bacterium from environmental samples. Ann Intern Med. 1979;90:664-6.

4. R E I N M F , G W A L T N E Y JM J R , O ' B R I E N WM, J E N N I N G S RH, M A N D E L L

GL. Accuracy of Gram's stain in identifying pneumococci in sputum. JAMA. 1978;239:2671-3. 5. M O N D Z A C AM. Throat culture processing in the office: a warning. JAMA. 1967;200:1132-3. Letter.

3. W A N G WLL, BLASER, MJ, C L A V E N S J, JOHNSON MA. Growth, surviv-

al, and resistance of the Legionnaires' disease bacterium. Ann Intern Med. 1979;90:614-8. 4. C H A N D L E R FW, M C D A D E JE, H I C K L I N M D , BLACKMON JA, T H O M A -

SON BM, E W I N G EP. Pathologic findings in guinea pigs inoculated intraperitoneally with the Legionnaires' disease bacterium. Ann Intern Med. 1979;90:671-5.

Treatment of Aspergillosis in Leukemia Legionella pneumophila in Drinking Water of Guinea Pigs T o THE EDITOR: After reviewing the recently published proceedings of the International Symposium on Legionnaires' Disease in the April 1979 issue, we thought readers of your journal might be interested in our attempt to produce Legionnaires' disease in susceptible guinea pigs by contaminating their drinking water. Several observations reported in the symposium supported the hypothesis that some cases of Legionnaires' disease could result from ingestion of water containing Legionella pneumophila. Legionella pneumophila has been isolated from surface water and can survive in tap water for as long as a year (1, 2). Legionella pneumophila is relatively resistant, in vitro, to acid and hence might survive exposure to gastric acidity (3). Furthermore, the reduced gastric acidity associated with aging may be a factor in the increased incidence of Legionnaires' disease in older persons. Survival of ingested L. pneumophila may provide a pathogenic clue to the gastrointestinal symptoms often observed during the early stages of Legionnaires' disease. Finally, guinea pigs given L. pneumophila intraperitoneal^ develop peritonitis and a patchy pneumonitis, which is histologically similar to the pneumonia produced by inhalation of the organism (4). Perhaps some cases of pneumonitis occur via hematogenous spread from the gastrointestinal tract. To test the per-os hypothesis, we added the Philadelphia-1 strain of L. pneumophila (supplied by the Center for Disease Control) to the drinking water of three nonimmune (seronegative by immunofluorescent antibody assay) female albino guinea pigs. The organism was cultivated on IsoVitaleX-supplemented chocolate agar, harvested daily, and added to sterile distilled water in a final concentration approximating 105 to 106 bacteria per millilitre. The guinea pigs ingested between 150 and 200 mL of water per day. They were observed daily for signs of illness. After 7 d of exposure, no adverse effects were observed. At this time, in an attempt to ascertain whether reducing gastric acid secretion would increase susceptibility, we added cimetidine, 40 mg/kg body weight d, to the L. p/zew/nopA/Va-contaminated

T o THE EDITOR: We read with interest the paper by Aisner and associates in the January 1979 issue (1), which reports the predictive value of positive nasal cultures for Aspergillus species in the diagnosis of invasive aspergillosis in patients with acute leukemia. We wish to report the successful treatment of a patient based on their data. A 48-year-old woman with acute nonlymphocytic leukemia in relapse was admitted to the Peter Bent Brigham Hospital for evaluation of fever and a pulmonary infiltrate. The patient had been severely granulocytopenic (neutrophils, < 500/mm 3 ) for 8 weeks before admission. On admission, the temperature was 38 °C, results of physical examination were unremarkable, leukocyte count was 470/mm J (neutrophils, 10%; lymphocytes, 36%; monocytes, 1%; blasts, 53%), and a chest roentgenogram showed a right-middlelobe infiltrate. There was no sputum production. After appropriate culture material was obtained, the patient was begun on broad-spectrum antibiotics (tobramycin, cephalothin, and erythromycin). Despite this therapy, there was no change in the temperature curve, and a new infiltrate developed in the left-lower-lung field. On the sixth hospital day, a nose bleed developed, and a large friable clot was removed from the right nostril. Histologic examination of this clot showed it to be a large mass of aspergillus hyphae. At this point, the patient refused a transbronchial biopsy for definitive diagnosis. Amphotericin B was administered via a subclavian catheter, and all other antibiotics were withdrawn at this time. By Day 7 of amphotericin B therapy, the pulmonary lesions seemed to be resolving. On Day 13 of therapy, rifampin, 300 mg twice a day, was added because of its possible activity against Aspergillus (2). After receiving 600 mg of amphotericin B, the dosage schedule was changed to 40 mg four times a day. Amphotericin B therapy was discontinued at a total dose of 1.3 g. Currently, the chest roentgenogram shows only a fibrotic scar in the right middle lobe. Throughout the entire period, the patient's total neutrophil count remained less than 500/ mm1.

We believe that the successful outcome in this patient is quite instructive. Based upon Aisner's observations, we presumed that the pulmonary infiltrates in this patient were due to invasive aspergillosis and proceeded with amphotericin B therapy. Our successful therapeutic experience with this patient further confirms the effectiveness of amphotericin B therapy in the neutropenic patient (3). Letters

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REFERENCES 1. G U M P DW, H O L D E N RA. Acquired chorioretinitis due to toxoplasmosis.

B R I A N R. S M I T H , M . D .

Ann Intern Med. 1979;90:58-60. 2. K R I C K JA, R E M I N G T O N JS. Current concepts in parasitology. Toxoplasmosis in the adult: an overview. N Engl J Med. 1978;298:550-5.

K E N N E T H R. B R I D G E S , M . D .

3. R Y N I N G FW, M C L E O D R, M A D D O X J D , H U N T S, R E M I N G T O N JS.


Probable transmission of Toxoplasmagondii Ann Intern Med. 1979;90:47-9.


Peter Bent Brigham Hospital; Boston, M A 02115

by organ


Ampicillin Rash and Hyperuricemia

REFERENCES 1. A I S N E R J, M U R I L L O J, S C H I M P F F SC, S T E E R E AC. Invasive aspergillosis

in acute leukemia: correlation with nose cultures and antibiotic use. Ann Intern Med. 1979;90:4-9. 2. K I T A H A R A M, S E T H VK, M E D O F F G, KOBAYASHI GS. Activity of am-

photericin B, 5-fluorocytosine, and rifampin against six clinical isolates of Aspergillus. Antimicrob Agents Chemotherapy. 1976;9:915-9. 3. PENNINGTON JE. Successful treatment of aspergillus pneumonia in hematologic neoplasia. N Engl J Med. 1976;295:426-7.

Ocular Toxoplasmosis T o THE EDITOR: A case of acquired chorioretinitis due to toxoplasmosis was reported in the January 1979 issue (1). I agree with the author that chorioretinitis does occur with acquired toxoplasmosis. It may be more common than realized, perhaps because physicians in primary care do not frequently contribute to journals. In 3 years of private practice of internal medicine, I have managed five cases of toxoplasmosis of which four were definitely acquired and in which in one case the patient developed loss of central vision in the right eye due to chorioretinitis. This case was confirmed by appropriate serologic tests and funduscopic examination, and the patient was treated in a manner identical to that described by Drs. Gump and Holden. An additional case of confirmed chorioretinitis from toxoplasmosis occurring in a 20-year-old woman was treated but could not be proved to be acquired rather than congenital. Toxoplasmosis in the adult was recently reviewed (2), and overwhelming fatal disease acquired by cardiac transplantation documented (3). An unusual sequella not to my knowledge previously reported is loss of vision due to clouding of the anterior chamber. In December 1977 a 35-year-old woman developed pain and swelling in the right eye. Complete blood count, sedimentation rate, and thyroxine, RT3, blood urea nitrogen and electrolyte levels were normal. She was referred to an ophthalmologist, who made the diagnosis of anterior uveitis. A toxoplasmosis titer (the New York State Department of Health) was 1:16. The patient went on to lose vision in her right eye despite treatment with topical dexamethasone (Decadron). Until that time at which anterior chamber clouding completely prevented funduscopic examination, the retina had been normal. In April 1978, the same laboratory reported a toxoplasmosis titer of 1:256. The patient noted cervical lymphadenopathy. When the patient was first seen in this office in February 1979, positive findings included only complete clouding of the right anterior chamber and a slightly tender 2cm mobile left-anterior cervical node. Complete blood count, sedimentation rate, 12-channel chemistry profile, VDRL, urinalysis, chest roentgenogram, and ECG findings were all negative or normal. Because of the history of recurrent diarrhea, she was evaluated for inflammatory bowel disease. A sigmoidoscopy, barium enema, upper gastrointestinal* small-bowel series, radiographic appearance of the sacroiliac joints, and tests for lymphocyte B27 surface antigen were all negative or normal. The toxoplasmosis titer had returned to 1:16. Microscopic examination of the enlarged lymph node showed reactive hyperplasia morphologically consistent with toxoplasmosis.

Because removing material from the patient's right eye is not now clinically indicated, the presence of organisms in the anterior chamber has not been confirmed. Nevertheless, the concurrence of severe anterior-chamber inflammation with acquired toxoplasmosis and the absence of any other discernible cause suggests a causal relation. It would be interesting to know if other readers have seen any similar cases. R I C H A R D P. H A N D L E R , M . D .

Medical Associates of Saranac Lake, P.C.; Saranac Lake, N Y 12983 324

T o THE EDITOR: In his excellent review on the management of gout in the May 1979 issue (1), Dr. Simkin discusses the approach to asymptomatic hyperuricemia. A related consideration for clinicians to be aware of in caring for these patients is the increased incidence of rash associated with ampicillin administration. The Boston Collaberative Drug Surveillance Program reported a 22.4% incidence of rash in patients receiving ampicillin and allopurinol concomitantly (2). The explanation for this observation is not known, but an altered immunologic reactivity in hyperuricemic persons may be responsible (3). This is particularly applicable to patients with tumors undergoing chemotherapy, because these patients are frequently hyperuricemic and receive allopurinol. The chemotherapy-induced leukopenia and immunosuppression predispose to opportunistic infections that require treatment with antibiotics. Ampicillin should be avoided in such patients if an acceptable alternative antibiotic can be used. Whether the increased incidence of ampicillin rash is related to concomitant administration of allopurinol or to hyperuricemia is not clear. Until the precise association is established, ampicillin should be avoided in both instances as well as in infectious mononucleosis (4), cytomegalovirus infection (5), and lymphocytic leukemias (6) because of the increased risk of rash. T I M O T H Y F. M U R P H Y , M . D .

Tufts New England Medical Center; Boston, M A 02111 REFERENCES

1. SIMKIN PA. Management of gout. Ann Intern Med. 1979;90:812-6. 2. BOSTON C O L L A B E R A T I V E D R U G S U R V E I L L A N C E P R O G R A M . Excess of

ampicillin rashes associated with allopurinol or hyperuricemia. N Engl J Med. 1972;286:505-7. 3. FESSEL WJ. Immunologic reactivity in hyperuricemia. N Engl J Med. 1972;286:1218. Letter. 4. P U L L E N H, W R I G H T N, M U R D O C H JM. Hypersensitivity reactions to

antibacterial drugs in infectious mononucleosis. Lancet. 1967;2:1176-8. 5. KLEMORA E. Hypersensitivity reactions to ampicillin in cytomegalovirus mononucleosis. Scand J Infect Dis. 1970;2:29-31. 6. C A M E R O N SJ, R I C H M O N D J. Ampicillin hypersensitivity in lymphatic

leukaemia. Scott Med J. 1971;16:425-7.

Medical Education in Colombia T o THE EDITOR: I read with interest the paper by G. T. Harrell in the August 1978 issue, "Medical Education in Colombia" (1). His overall view of the problem is good and one should not expect every single subject in such a complicated field to be covered with detail. I have a few comments to make. With regard to faculty members, I should point out that at least in some Colombian schools there are a good number of U.S.-trained specialists; they count on private practice as a major source of income just as locally trained faculty members do. The number of schools in Colombia is likely greater than needed, but pressure from candidates who are probably as competent as those entering long-established schools and, furthermore, willing to pay high tuition fees if necessary, has pushed up the number. Dr. Harrell says little about political activity in schools but at least in one good school owned by the government (University of Antioquia), leftist students took over. I am sorry to say that that school is now run down. Its best faculty members have founded a new private medical school in Medellin. Medical education in Colombia has frequently moved in a

August 1979 • Annals of Internal Medicine • Volume 91 • Number 8

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direction that may be wrong for the real situation in the country: low personal incomes, poor resources, broke hospitals, concentration of population in large centers, and the Social Security Institute as the main medical recruiting agency. Steps are being taken, however, to make curriculae go along with reality, to train good general practitioners who are willing to stay where they are needed (2). A L F R E D O F. J A C O M E - R O C A , M . D .

Javeriana University School of Medicine, Bogota, Colombia REFERENCES 1. H A R R E L L GT. Medical education in Colombia. Ann Intern Med. 1978;89:283-4. 2. PAREDES R, et al. Reorientacion de la educacion medica en Colombia. ASCOFAME, ed. Bogota, Colombia; 1970.

Library Resources on Alcoholism T o T H E EDITOR: The excellent list of books and journals, "A Library For Internists III," in the March 1979 issue (1) contained no specific references on alcoholism and drug abuse. Inasmuch as these are widespread problems that will be encountered by almost all internists, references on alcoholism and drug abuse in future versions of the list would seem appropriate. We have found the following books and journals useful.


Drug Abuse: A Guide for the Clinician. 443 pp. Sapira JD, Cherubin CE. Excerpta Medica, Amsterdam, 1975. $84.50. A Treatment Manual for Acute Drug Emergencies. 178 pp. Bourne PE (ed.). National Institute on Drug Abuse, Rockville, Maryland, 1975. The Biology of Alcoholism. Vol. 1, 630 pp.; Vol. 2, 552 pp.; Vol. 3, 673 pp.; Vol. 4, 643 pp.; Vol. 5, 631 pp. Kissin B, Begleiter H (eds.). Plenum Press, New York, 1971-1977. Vol. 1-3, 37.50; Vol. 4-5, 39.50. The Pharmacological Basis of Therapeutics. 5th ed. 1704 pp. Goodman LS, Gilman A (eds.). Macmillan Publishing Company, Inc., New York, 1975. $34.00. JOURNALS

American Journal of Drug and Alcohol Abuse $50.00 Journal of Studies on Alcohol Monthly, $35.00


D A V I D M. N O V I C K , M . D . S T A N L E Y R. Y A N C O V I T Z , M . D .

Morris J. Bernstein Institute, Beth Israel Medical Center, New York, N Y 10003 REFERENCE 1. A L L Y N R. A Library for Internists III: recommended by the American College of Physicians. Ann Intern Med. 1979;90:446-77.


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Intravascular coagulation and ascitic-fluid infusion.

LETTERS CONTENTS Nuclear Power and Health H. R. Maxon L R. Solon and V. W. Side/ Training the Internist J. A. Barondess W. B. Bateman, Jr., H. G. Blo...
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