COMMENTS AND CORRECTIONS
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.
dividuals all of whom were female and young, but not all of whom—depending upon the Dick test result—received toxin. L. F R E D A Y V A Z I A N , M . D .
Pulmonary Disease Section Veterans Administration Hospital East Orange, New Jersey 07019 REFERENCES 1. WHITE CS, ADLER WH, MCGANN VG: Repeated immunization:
possible adverse effects. Ann Intern Med 81:594-600, 1974 2. AYVAZIAN LF, BADGER TL: Disseminated lupus erythematosus oc-
Risks of Repeated Immunization TO THE EDITOR: In their paper "Repeated Immunization: Possible Adverse Effects," White, Adler, and McGann (1) report on less than 10% of 700 male employees at Fort Derrick who since 1956 had received multiple immunizations; despite some interesting minor laboratory abnormalities in this group, the authors conclude that chronic stimulation of the immunoglobulin-stimulating system in the human seems to cause no adverse effects, unlike amyloid disease, myeloma, and hypersensitivity reported in laboratory animals. As in a similar study referred to, that is, the soldiers receiving influenza vaccine, the subjects studied were always or almost always men well above adolescent age. I wonder about morbidity and mortality among the large majority of the immunized group not studied, and whether some of those unincluded or unavailable for follow-up might not, indeed, represent those most likely to have suffered consequences. In 1948, Dr. Theodore L. Badger and I (2) reported from the Thorndike Memorial Laboratories of the Boston City Hospital the occurrence of fatal disseminated lupus erythematosus in 3 of 750 young student nurses (all women) being studied primarily to correlate tuberculin skin reactivity with the development of tuberculosis over a 15year interval. These represented 23 % of the total mortality, exceeded (by one case) only by tuberculosis. A search among unrelated hospital and clinic records, training-school files, and autopsy protocols indicated a common factor in that all three girls, aged 18 years old, had received multiple Schick and Dick tests, scarlet fever streptococcus toxin, and typhoid-paratyphoid vaccine, with reactions including serum sickness, arthralgia, fever, positive Hinton reaction, and bizarre illness progressive to death over periods of 1 year, 15 months, and 7 years. Onset of illness correlated well with the inoculations, each injection leading to a reaction of added severity. In one case the original erythema of the toxin injection over the deltoid area gradually transformed, without fading, into the chronic violaceous eruption characteristic of lupus erythematosus. Autopsy confirmed this diagnosis in all three patients. Detailed information is available in the original publication. In our discussions, we offered evidence and conjecture suggesting a link between allergens, particularly biologic substances derived from the streptococcus, and "hypersensitivity" disease. It may be of importance that our group represented a substantial number (750) of unselected in-
curring among student nurses. N Engl J Med 239:565-570, 1948
In comment: Dr. Ayvazian recounts his experience with three cases of lupus erythematosus in a group of student nurses in Boston (2 above). He also raises the question of morbidity and mortality in the immunized population not studied, and points out that this population was predominantly adult men and thus not entirely representative. The initial selection of the 99 hyperimmunized men was solely on the basis of duration and intensity of immunization ( 1 ) . As the authors observed that laboratory abnormalities were present on the two occasions that the immunized men were studied (1, 2 ) , this same group seemed most appropriate for detainled laboratory follow-up at 25 years. The remainder of the population was followed in a single clinic until 1971, but it was logically considered to be less likely to show adverse effects of immunization. The entire group of immunized workers is presently being evaluated by Drs. Robert Hoover and Thomas Mason of the Epidemiology Branch of the National Cancer Institute. The cases noted by Dr. Ayvazian are of interest in a group of persons immunized less intensively and for a shorter time. Such cases serve to show the lack of information about the effects of repeated immunization not only on adults, but on infants and children, the population at greatest risk. CHARLES S. WHITE III, M.D., F.A.C.P.
Division of Hematology and Oncology George Washington University Medical Center Washington, D.C. 20037 REFERENCES 1. PEELER RN, CLUFF LE, TREVOR RW: Hyperimmunization of
man. Bull Johns Hopkins Hosp (Baltimore) 103:183-198, 1958 2. PEELER RN, KADULL PJ, CLUFF LE: Intensive immunization of
man. Evaluation of possible adverse consequences. Ann Intern Med 63:44-57, 1965
Giardiat Infection from Water TO THE EDITOR: In a recent article (Ann Intern Med 81: 498-499, 1974), five cases of infections with Giardia lamblia were epidemiologically associated with drinking contaminated water from an underground cistern. This Comments and Corrections
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19496/ by a University of California San Diego User on 04/25/2017
589
association was strengthened by the microscopic identification of G. lamblia trophozoites in water samples taken from the implicated source. At the Center for Disease Control, working in conjunction with Colorado state health officials, I had the opportunity to investigate several clusters of giardiasis patients in Colorado between 1972 and 1974. Similar to the authors' findings, my investigations invariably identified a source of untreated water as the most likely vehicle of transmission of G. lamblia cysts*. Fresh fruits and vegetables were generally purchased from nationally known supermarkets, and close personal contact among known patients was rare. In addition, recent travel outside the state before the onset of illness was uncommon among the patients, and stools obtained from domestic animals of known cases were usually negative for Giardia organisms. However, the majority of patients had, on several occasions, drunk water from untreated wells or mountain streams within 1 month of their onset of illness. These water sources usually had an unsafe level of fecal coliforms at the time of the investigation. However, filtering at least 10 gallons of water through an eight-micron Millipore filter (Millipore Corporation, Bedford, Massachusetts) from each of these sources consistently failed to isolate Giardia cysts. (It was not unusual for diatomes to resemble Giardia cysts.) Although my experience is in agreement with the authors' conclusion that waterborne giardiasis is common, I feel that the evidence in their article is inconclusive. Although the three involved families did not live in close geographic proximity, frequent visits to each other's home or a single gathering at the implicated (parent's) home could have allowed ample time for person-to-person spread. No mention was made of any recent travel outside the country or ingestion of untreated water from either mountain streams or other untreated wells. In fact, the authors' evidence of waterborne giardiasis is entirely based on the identification of G. lamblia trophozoites in water samples obtained from a presumably contaminated cistern. Yet, bacteriologic evidence of fecal contamination of this water source was not provided. Because G. lamblia is an enteric pathogen, it would be unlikely for this organism to exist without fecal coliforms in an unchlorinated water supply, presumably contaminated by a nearby outhouse. Furthermore, evidence for cross-connection between the outhouse and the cistern was not provided, other than the fact that several visitors to the home had previously complained of diarrhea. Most distressing was the authors' failure to explicitly describe the methods used to isolate and identify G. lamblia organisms from the implicated water. Similar to Chang and Kubler ( 1 , t ) , I have been able to retrieve G. lamblia cysts from experimentally contaminated water samples with a Millipore filtering method. However, microbiologic evidence of waterborne giardiasis by identifying cysts in implicated sources has not been previously reported. Even in the ski-resort outbreak cited by the authors ( 2 ) , Giardia cysts were only microscopically identified in heavily contaminated sewage that was cross-connected to the town's main water supply. Finally, Giardia trophozoites, unlike the highly resistant cysts, are fragile organisms whose survival outside the gastrointestinal tract has never been shown. It is, therefore,
surprising that this particular developmental stage was identified in contaminated water. It would have been more appropriate if the authors had presented pictorial evidence of Giardia organisms in the water sample than in the duodenal aspirates.
* WRIGHT RA, SPENCER H, BRODSKY R: Giardiasis in Colorado: an epidemiologic study. Unpublished. t CHANG SL: Identification of G. lamblia in water and control of waterborne giardiasis. Personal correspondence, November 1969. 590
RICHARD A. WRIGHT, M.D.
335 Frederick San Francisco, California 94117 REFERENCES 1. CHANG SL, KUBLER PW: Detection of cysts of E. histolytica in
tap water by the use of membrane filter. Am J Hyg 64:170-180, 1956 2. MOORE GT, CROSS WM, MCGUIRE D, et al: Epidemic giardiasis
at a ski resort. N Engl J Med 281:402-407, 1969
Prevention of Chloroquine-Resistant Falciparum Malaria TO THE EDITOR: Permit us to comment tardily on the article "Chemoprophylaxis of Malaria for Travelers" (Ann Intern Med 81:219-224, 1974). Dr. Barrett-Connor is wrong in her summation that weekly chloroquine and primaquine and daily dapsone is the best prophylaxis against chloroquine-resistant falciparum malaria. It is illogical because she is recommending chloroquine for chloroquine-resistance. Would she recommend chloramphenicol for chloramphenicol-resistant typhoid? The most promising compounds appear to be the combinations of dihydrofolate reductase inhibitors with a sulfonamide or sulfone for the chemosuppression of chloroquine-resistant falciparum malaria and vivax malaria (1-4). Thanh, Huan, and Tinh (3) showed in a 3-month study the value of monthly sulfadoxine-pyrimethamine (Fansidar®) over weekly chloroquine and primaquine plus daily dapsone in the chemosuppression of falciparum malaria. In this study only 1 of 205 Vietnamese soldiers who received sulfadoxine-pyrimethamine contracted falciparum malaria, while 104 of 1139 troops who received chloroquine and primaquine plus dapsone developed falciparum malaria ( X 2 Y = 16.8, P < 0.0005). Therefore, the monthly sulfadoxine-pyrimethamine combination was far superior, and obviously the drug compliance of a monthly medication is more practical. Dr. Barrett-Connor mentions several prophylactic studies with pyrimethamine and sulfadoxine including one in nonimmune persons in Laos ( 4 ) . She then precludes pyrimethamine-sulfadoxine prophylaxis because of potential toxicity that has not yet occurred in numerous studies and because of the paucity of field trials on nonimmune persons, although she has just mentioned such a study in Laos! Can she name a field trial with chloroquine-primaquine and dapsone in travelers? Her arguments for precluding short-term prophylaxis with pyrimethamine-sulfadoxine in travelers are not clear, and here we are speaking of chemoprophylaxis for perhaps 1 to 3 months on a monthly basis. The possible long-term dangers of long-acting sulfonamides (such as sulfadoxine) include the Stevens-Johnson syndrome, which has never been reported after the use of pyrimethamine-sulfadoxine for the chemoprophylaxis or chemotherapy of malaria ( 5 ) . Prolonged use of any drug (for example, chloroquine) or combination (for example, pyrimethamine-sulfadoxine) for the prophylaxis of malaria in a community probably stimulates the emergence of parasites resistant to the regimen. Thus the choice of a long-term prophylactic is diffi-
April 1975 • Annals of Internal Medicine • Volume 82 • Number 4
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19496/ by a University of California San Diego User on 04/25/2017
cult. A person traveling to a malarious country should probably be placed on a chemosuppressive agent. With the specter of chloroquine-resistance spreading very rapidly throughout Southeast Asia and the Americas, chloroquine should probably not remain the prophylactic drug of choice, unless the traveler is visiting the African continent or certain other areas. Thus, the summary of Dr. Barrett-Connor's article should be altered to read "currently the best prophylaxis for chloroquine-resistant falciparum malaria is the combination of pyrimethamine with sulfadoxine given every 2 or 4 weeks. Such a regimen can be recommended for a few months' prophylaxis. Long-term use is discouraged."
States. In view of the much more extensive experience with the chloroquine-primaquine-dapsone regimen, I would still consider this the preferred prophylaxis for nonimmune North Americans at risk. If further investigations confirm the efficacy and safety of the pyrimethamine-sulfadoxine combination, I will be happy to have a nontoxic and effective program to recommend for American travelers. ELIZABETH BARRETT-CONNOR, M.D.
Department of Community Medicine School of Medicine University of California, San Diego La Jolla, California 92037
ELIOT J. PEARLMAN, M.D., M A J , MC ANTHONY P. H A L L , M.D., F.A.C.P., COL, MC
Zollinger-Ellison Syndrome: Calcium, Secretin, Gastrin
U.S. Army Medical Component SEATO Medical Research Laboratory Rajavithi Road Bangkok, Thailand (APO SF 96346) REFERENCES 1. SEGAL HE, PEARLMAN EJ, THIEMANUN W, et al: The suppression
of Plasmodium falciparum and Plasmodium vivax parasitemias by a dapsone-pyrimethamine combination. / Trop Med Hyg 76: 285-290, 1973 2. PEARLMAN EJ, THIEMANUN W, CASTANEDA BF: The suppression
of P. falciparum parasitemias by a diformyldapsone-pyrimethamine combination, in Proceedings, 3rd International Congress of Parasitology. Munich, 1974, pp. 1305-1306 3. THANH PH, HUAN DH, TINH TV: Resultats preliminaries
de
chimioprophylaxie et de traitement du paludisme dans les forces arm6es de la republique du Vietnam par l'association sulfadoxine sulphormethoxine) pyrimethamine. J Milit Med Vietnam 40:3746, 1971 4. EBISAWA I, MUTO T, MITSUI G, et al: Malaria at Nam Dam
construction site in Laos. I. Suppression with combinations of sulfonamides and pyrimethamine. Jap J Exp Med 41:209-219, 1971 5. FERNEX M: Progress in the prophylactic use of Fansidar in regions where P. falciparum does not respond to chloroquine. See Reference 2, pp. 1303-1304
In reply: I disagree with the recommendation against chloroquineprimaquine and dapsone and in favor of pyrimethaminesulfadoxine. Experience with the former regimen in nonimmune persons has been several thousandfold more extensive. It is not irrational to expect that the chloroquineprimaquine combination will have some effect against chloroquine-resistant malaria for the following reasons. 1. Chloroquine resistance is usually relative, not total. 2. Chloroquine and primaquine act at different stages in malaria reproduction, and they can be expected to have additive, if not synergistic, effects. 3. A prophylactically effective regimen is not necessarily the same as a therapeutically effective regimen. 4. The field experience in Vietnam, as well as prison volunteer studies cited in my review, suggests that this combination does have some suppressive effect against chloroquine-resistant strains. Doctors Pearlman and Hall refer to a study that shows superior efficacy of pyrimethamine-sulfadoxine in partially immune Vietnamese soldiers; only two libraries in the United States have this journal, and I have been unable to obtain a copy. Therefore, I am unable to evaluate this trial regarding noncompliance, selection, or exposure bias. It should be noted, however, that neither dapsone nor sulfadoxine are commercially available in the United
TO THE EDITOR: In a recent issue Kolts, Herbst, and McGuigan (1) report on having administered intravenous calcium and secretin to 3 patients with the Zollinger-Ellison syndrome; they confirmed the results of others that administration of these agents resulted in hypergastrinemia. Isenberg and colleagues (2) suggested that the rise in serum calcium might be responsible for the increased level of gastrin. Despite the fact that after secretin infusion the serum calcium appeared to increase 1.0 mg/dl, 1.0 mg/dl, and 0.5 mg/dl in Patients 1, 2, and 3, respectively, Kolts, Herbst, and McGuigan chose to consider the increase as insignificant and then challenged Isenberg's claim based on a positive calcium-gastrin response in 12 patients. The stimulation of gastrin release and gastric secretion by calcium in man has recently been cited by Nordgren, Nyhus, and Bombeck ( 3 ) , who documented this effect experimentally in cats. On the other hand, calcitonin lowers serum calcium and also decreases gastrin and gastric secretion in normal man. These effects may or may not be coincidental, but these findings, plus the increased frequency of peptic ulcer in patients with hyperparathyroidism and other hypercalcemic states, should still raise the suspicion that serum calcium levels affects gastrin release, gastric secretion, and hence peptic ulcer. Since increased gastrin and gastric secretion are responsible for the major disability in the Zollinger-Ellison syndrome, any agent that can decrease blood gastrin would be of great benefit. Calcitonin is one such agent, and somatostatin is another. Indeed, somatostatin has greatly decreased gastrin and gastric secretin in one patient with Zollinger-Ellison syndrome, perhaps the first such case reported ( 4 ) . Both calcitonin and somatostatin deserve a trial in the Zollinger-Ellison syndrome before gastrectomy and other extensive surgery are carried out. CARL S. ALEXANDER, M.D.
Cardiovascular Section Veterans Administration Hospital Minneapolis, Minnesota 55417 REFERENCES 1. KOLTS BE, HERBST CA, MCGUIGAN JE: Calcium and secretin-
stimulated gastrin release in the Zollinger-Ellison syndrome. Ann Intern Med 81:758-762, 1974 2. ISENBERG JI, WALSH JH, PASSARO E JR, et al: Unusual effect of
secretin on serum gastrin, serum calcium, and gastric acid secretion in a patient with suspected Zollinger-Ellison syndrome. Gastroenterology 62:626-631, 1972 3. NORDGREN CE, NYHUS LM, BOMBECK CT: The influenct of cal-
cium on gastric acid secretion and plasma gastrin level in intact and thyroidectomized thyroxin-substituted gastric fistula cats (abstract). Gastroenterology 64:779, 1973 Comments and Corrections
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19496/ by a University of California San Diego User on 04/25/2017
591
4. BLOOM SR, MORTIMER CH, THORNER MO, et al: Inhibition of
gastrin and gastric-acid secretion by growth-hormone release-inhibiting hormone. Lancet 2:1106-1109, 1974
In
comment:
In o u r study referred t o b y D r . Alexander, serum gastrin and calcium concentrations were m e a s u r e d a n d c o m p a r e d before a n d after calcium a n d secretin infusion in patients with t h e Zollinger-Ellison s y n d r o m e a n d c o m p a r e d with control subjects. C a l c i u m infusion induced significant increases in both s e r u m calcium a n d s e r u m gastrin concentrations in t h e patients with t h e Zollinger-Ellison s y n d r o m e . C a l c i u m infusion induced significant increases in calcium levels in t h e control subjects a n d slight increases in their serum gastrin concentration. I n each patient with the Zollinger-Ellison s y n d r o m e w h o received calcium infusion there w a s a significant (P < 0.001) positive correlation (r from + 0.91 to + 0 . 9 5 ) between serum gastrin a n d calcium levels. I n t r a v e n o u s secretin also p r o d u c e d significant increases in both s e r u m gastrin a n d serum calcium concentrations in each patient with t h e Zollinger-Ellison s y n d r o m e ; however, there w a s n o t a positive correlation between serum gastrin concentrations. T h e s e studies confirmed secretin-induced paradoxical a u g m e n t a t i o n of serum gastrin in patients with t h e Zollinger-Ellison s y n d r o m e a n d showed significant increases in calcium levels in these patients. T h e failure, however, t o show positive correlation between serum gastrin a n d calcium with secretin administration did n o t support a role for s e r u m calcium as a m e c h a n i s m by which s e r u m gastrin is increased p a r a doxically after secretin infusion in patients with t h e Zollinger-Ellison s y n d r o m e . Therefore, c o n t r a r y t o t h e reader's conclusions, w e did n o t conclude that t h e increases in serum calcium with secretin infusion were insignificant, nor d o these d a t a in a n y w a y challenge o r contradict t h e observations of Isenberg a n d colleagues ( 2 above), with which w e completely agree.
colitis for 2 years before we saw her. She had had intermittent episodes of bloody diarrhea, treated with corticosteroids and salicylazosulfapyridine (Azulfidine®, Pharmacia Laboratories, Piscataway, New lersey) during this time with moderate success, and had been started anew on high-dose intravenous, and then oral, corticosteroids (40 mg to 60 mg daily) for 2 weeks before her coming in with an exacerbation of her symptoms. She came to our hospital on 21 October 1974 with sudden prostration, fever of 38.3 °C [101 °F], and blood pressure of 4 0 / 0 mm Hg unresponsive to volume expansion and pressors. She was then transferred to Kansas University Medical Center for a total colectomy with Hartmann's pouch, ileostomy, cholecystectomy, and incidental splenectomy. The pathologic report on the edematous hyperemic colon was "ulcerative colitis." After a benign postoperative course, she was transferred back to us; on 2 November, 12 days postoperative, her cardiac silhouette was noted to be enlarging, and spiking fevers became evident (the steroids already had been completely withdrawn). She was once again transferred back to Kansas University Medical Center. On the 17th day after colectomy a pericardiocentesis was performed, and an indwelling pericardial catheter was placed for 2 days and drained 1100 ml of fluid with a hematocrit reading of 1 2 % , 3500 leukocytes/mm 3 with 47% polymorphonuclear cells. All microbiologic and viral studies were negative. Lupus erythematosus preparations, complement measurements, and antinuclear antibody and rheumatoid factor studies on the pericardial fluid and on the blood were all unremarkable. Although the fluid did not reaccumulate, the fever continued, and a gallium-67 scan showed a pelvic abscess that was drained surgically; an abdominal-peroneal proctectomy was then done. The patient is now asymptomatic.
W e believe from o u r o w n observations a n d those of others, that serum calcium does affect both s e r u m gastrin levels a n d gastric acid secretion. A t t h e present time there are insufficient d a t a o n t h e efficacy of calcitonin a n d somatostatin in patients with t h e Zollinger-Ellison synd r o m e t o w a r r a n t delay in a p p r o p r i a t e surgery for these patients. J A M E S E. M C G U I G A N , M.D.
Division of Gastroenterology College of Medicine University of Florida Gainesville, Florida 32610
This case shows t h e d e v e l o p m e n t of pericardial inflamm a t i o n after colectomy; it regressed with pericardial drainage, without steroid therapy, a n d before t h e r e m a i n ing rectal s t u m p was removed. A s D r . Breitenstein suggests, the diagnosis of pericarditis should n o t b e overlooked in patients with inflammatory bowel disease, especially n o w that t w o of t h e five patients reported developed t a m p o n a d e (2-4). O W E N J. R H E I N G O L D , M . D . , C A P T , M C
Department of Internal Medicine U.S. Munson Army Hospital Fort Leavenworth, Kansas 66027 REFERENCES 1. BREITENSTEIN RA, SALEL AF, WATSON DW:
Chronic
inflam-
matory bowel disease: acute pericarditis and pericardial tamponade (letter). Ann Intern Med 81:406, 1974 2. MUKHOPADHYAY D, NASR K, GROSSMAN BJ, et al: Pericarditis
associated with inflammatory bowel disease. JAMA 1542, 1970
211:1540-
3. GROSSMAN BJ, DEBENNEDETTI BS: Extraintestinal manifestations
of chronic inflammatory bowel disease in children (abstract). Proc Inst Med Chic 28:119, 1970 4. YOUNG PC: Colonic and systemic manifestations of chronic ulcerative colitis. Med Clin North Am 51:1011-1013, 1967
Inflammatory Bowel Disease and Pericarditis Aspirin Hepatotoxicity T O T H E EDITOR: I read with interest t h e recent report by Breitenstein, Salel, a n d W a t s o n ( 1 ) of a patient with chronic inflammatory bowel disease w h o developed pericarditis a n d pericardial t a m p o n a d e . T h e y speculated whether t h e pericarditis would b e relieved by colectomy, which could n o t be predicted from available experience. I present here a n additional case a n d t h e first reported instance of pericarditis with pericardial t a m p o n a d e o c curring subsequent to colectomy.
TO T H E EDITOR: T h e p a p e r s b y S e a m a n , Ishak, a n d Plotz ( 1 ) , Wolfe, Metzger, a n d Goldstein ( 2 ) , a n d t h e letter by G o l d e n b e r g ( 3 ) have described five patients with systemic lupus erythematosus w h o developed aspirin-induced h e p a totoxicity. W e have recently seen a patient with n o u n d e r lying connective tissue disease w h o developed aspirin hepatitis after prolonged heavy ingestion of aspirin for relief of tension headaches a n d cold s y m p t o m s .
The patient was a 28-year-old white woman with ulcerative
A 26-year-old nurse was admitted to the neurology service
592
Apr/7 1975 • Annals of Internal Medicine • Volume 82 • Number 4
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19496/ by a University of California San Diego User on 04/25/2017
because of slurred speech, ataxia, confusion, and somnolence. N o history of seizure or progressive neurologic impairment was obtained. The patient admitted to past alcoholic intake but denied drinking in the 3 weeks before admission. In the past 8 months she had been taking aspirin and Coricidin® for tension headaches and cold symptoms. The total amount of aspirin from both sources was 9.0 g daily. During this period she experienced tinnitus and persistent headaches. At admission the physical examination was unremarkable. The serum glutamic oxalacetic transaminase (SGOT) was 273 M U / m l (normal, 0 to 40 M U / m l ) ; the alkaline phosphatase, 108 M U / m l (normal, 30 to 85 M U / m l ) ; and serum glutamic pyruvic transaminase ( S G P T ) , 111 M U / m l (normal, 5 to 35 M U / m l ) . Brain scan, electroencephalogram, oral cholecystogram, upper gastrointestinal films, and skull films were normal. Admission blood alcohol was 0 % , and a screening test for urine secobarbital and amobarbital was positive. The heterophil antibody test and lupus erythematosus-cell preparation were negative. Studies for hepatitis B antigen, and antimitochondrial, antismooth muscle and antinuclear antibodies were negative. The patient had no history of blood transfusions. She had been exposed to hepatitis, but she denied any episode of jaundice, malaise, or dark urine. Two days after admission, while off aspirin, the neurologic symptoms disappeared and the SGOT value decreased to 66 M U / m l . On the 4th day after admission, liver biopsy showed findings consistent with a mild toxic hepatitis {see Figure 1 ) .
Figure 1 . Photomicrograph of needle liver biopsy shows focal cellular necrosis and neutrophil infiltrate near the central vein. (Hematoxylin and eosin; magnification, x 1100.)
One week after admission all the liver enzymes values returned to normal. Because of t h e elevated serum liver-enzymes values, t h e history of repeated ingestion of large doses of aspirin, a n d clinical findings consistent with mild salicylate intoxication, the diagnosis of aspirin hepatitis w a s considered. T h e liver biopsy s u p p o r t e d this diagnosis. As in t h e cases reported ( 1 - 3 ) , t h e t r a n s a m i n a s e levels rapidly r e t u r n e d t o n o r m a l after withdrawal of t h e drug. This patient h a d , however n o features of connective tissue diseases. W h e t h e r this patient's alcohol o r b a r b i t u r a t e intake h a s increased h e r susceptibility to aspirin is speculative. T h e factors that m a y contribute to a n d modify aspirin hepatotoxicity r e m a i n t o b e delineated. E L A Y N E G A R B E R , B.A. R O B E R T M. CRAIG, M.D.
Gastroenterology Service Department of Medicine Northwestern University Chicago, Illinois 60611 R A J A M. BAHU, M.D.
Department of Pathology Northwestern University Chicago, Illinois 60611 REFERENCES 1. SEAMAN WE, ISHAK KG, PLOTZ PH: Aspirin-induced hepatotox-
icity in patients with systemic lupus erythematosus. Ann Intern Med 80:1-8, 1974 2. WOLFE JD, METZGER AL, GOLDSTEIN RC: Aspirin hepatitis. Ann
Intern Med 80:74-76, 1974 3. GOLDENBERG DL: Aspirin hepatotoxicity. Ann Intern Med 80: 773, 1974
"Munchausen" Coronary Artery Disease TO T H E EDITOR: W e wish to r e p o r t t h e case of a patient with " M u n c h a u s e n s y n d r o m e " w h o presented with cardiovascular complaints indicative of severe c o r o n a r y artery disease. A 46-year-old white man was transferred to The George Washington University Hospital ( G W U H ) 5 days before Christmas 1974 because of preinfarction angina. H e gave a history of typical angina for the past 2 months, w r ' : h had become worse 10 days ago when he collapsed and was admitted to a local hospital. His angina did not respond to sublingual nitroglycerin, oral isosorbide dinitrate, and oral propranolol. The only medication that seemed to offer relief was intramuscular meperidine injections. After transfer to G W U H he continued to complain of angina at rest, relieved by no medications other than intravenous morphine sulfate; however, placebo injections seemed to offer equal relief as long as they were given in Tubex® form. Electrocardiograms were repeatedly normal during and between attacks of pain. Serum glutamic oxalacetic transaminase, lactic dehydrogenase, and creatinine phosphokinase enzyme values on the day of transfer were mildly elevated, probably because of intramuscular meperidine injections received at the other hospital. Subsequent serum enzyme values were all normal. He gave a past history of rheumatic fever and scarlet fever as a child, with later development of nephritis. Labile hypertension was noted a year ago. He gave a strong family history of fatal heart attacks among his parents and grandparents. He had several healed incisional scars: bilateral supraclavicular, right antecubital, and appendectomal. Bilateral supraclavicular incisional scars were from scalene node biopsies done at District of Columbia General Hospital in 1972. Scars in the right antecubital fossa were said by the patient to have resulted from operative repair of the brachial artery injured in an automobile accident many years ago. The right brachial and right radial pulses were barely palpable. It was decided to gradually withdraw propranolol and to do coronary arteriography after a few days. While being observed in the coronary-care unit, he was recognized by one of us (JM) as having been previously admitted to G W U H in May 1973 under another name with identical complaints. At that time coronary arteriography, done by the Sones method in the right arm by one of us ( G K ) , showed mild narrowings in the right coronary artery and in the left circumflex artery that were believed not to be severe enough to account for his angina. When confronted with these revelations 2 days before Christmas 1974, he promptly signed out of G W U H , presumably to return to his home in Pennsylvania. This patient m a y n o w b e in a c o r o n a r y - c a r e unit o r cardiac catheterization l a b o r a t o r y of another hospital being Comments and Corrections
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19496/ by a University of California San Diego User on 04/25/2017
593
GUNNAR KRAAG, M.D., F.R.C.P.(c)
cared for as a case of preinfarction angina. The obvious benefit to the patient, housestaff, and hospital from early recognition of this patient is apparent. We hope physicians warned of this story will be able to spare the patient another coronary arteriography, a potentially hazardous procedure, which he appears to be willing to undergo again.
ANTHONY J. RICHARDS, M.B., M.R.C.P. DUNCAN A. GORDON, M.D., F . R . C . P . ( C ) , F.A.C.P.
McMaster University Medical Centre Rheumatology Area 2F-26 1200 Main Street West Hamilton, Ontario, Canada
TSUNG O. CHENG, M.D., F.A.C.P. JERRY F. MEYER, M.D. GEORGE A. KELSER, JR., M.D., F.A.C.P.
REFERENCES
1. UHL GS, WILLIAMS JE, ARNETT FC: Intracerebral lymphoma
in a patient with central nervous system lupus on cyclophosphamide. J Rheum 1:282-286, 1974 2. LIPSMEYER EA: Development of malignant cerebral lymphoma in a patient with systemic lupus erythematosus treated with immunosuppression. Arthritis Rheum 15:183-186, 1972
The George Washington University Medical Center 2150 Pennsylvania Avenue, N.W. Washington, D.C. 20037 NYAB A L I , M.D.
District of Columbia General Hospital Washington, D.C. 20003 Correction: Grant Support TO THE EDITOR: In my paper "A Hypothesis to Account for the Mary Walker Phenomenon" (Ann Intern Med 82:411-415, 1975), I failed to acknowledge grant support from the Muscular Dystrophy Associations of America through its Houston chapter.
Brain Scanning in Lupus Erythematosus TO THE EDITOR: We read with interest the paper by Drs. Bennahum, Messner, and Shoop, "Brain Scan Findings in Central Nervous System Involvement by Lupus Erythematosus" (Ann Intern Med 81:763-765, 1974). They have shown brain scanning to be a safe and useful tool for diagnosis and evaluation of therapy. They excluded patients with purely psychiatric symptoms, but it would be interesting to know if a brain scan could help in differentiating true central nervous system involvement in lupus erythematosus, from psychiatric symptoms induced by corticosteroid therapy. This is a frequent dilemma for the practicing physician who must decide whether to increase the corticosteroid or incriminate it. We suggest some caution in interpreting brain scan abnormalities in lupus erythematosus. There have been recent reports of intracerebral lymphoma developing in patients receiving immunosuppressive therapy. Uhl, Williams, and Arnett (1) recently described a case of intracerebral lymphoma in a patient with central nervous system lupus erythematosus on cyclophosphamide, and Lipsmeyer (2) reported a case of intracranial reticulum cell sarcoma after only 2 months of azathioprine therapy. Many patients with lupus erythematosus are now receiving immunosuppressive therapy, and the development of an abnormal brain scan with neurologic manifestations should alert the clinician to this possibility. As Uhl points out, this is especially true when neurologic signs and brain scan abnormalities are not accompanied by clinical and laboratory findings that suggest a general flare of the lupus erythematosus. Unlike the clearning of brain scan abnormalities in Bennahum's report, in Uhl's patient the scan abnormalities progressed even though there was slight improvement in weakness on increasing the steroid dosage. Lipsmeyer (2) has suggested that a tumour registry of malignancies arising in patients who have rheumatic disorders and who receive immunosuppressives might put this potential toxicity into proper perspective, but until then one must remain aware of this complication.
594
A p r / / 1 9 7 5 • Annals of Internal Medicine • Volume 82 • Number
BERNARD M. PATTEN, M.D.
Department of Neurology Baylor College of Medicine Houston, Texas 77025
Correction: Nocardial Infection TO THE EDITOR: We wish to point out our error in "Nocardia Infection in Heart Transplant Patients" (Ann Intern Med 82:18-26, 1975). In the discussion section on "Host Defenses against Nocardia," page 25, first paragraph, line 20, the sentence reads: "Experimental evidence in support of the hypothesis has recently been published by Bourgeois and Beaman (25)." This should be corrected: "Experimental evidence in support of the hypothesis (4) that cellular immunity is of major importance in defense against Nocardia in the normal host has recently been published by Bourgeois and Beaman (25)." JAMES H. KRICK, M.D.
Palo Alto Medical Research Foundation 860 Bryant Street Palo Alto, California 94301
Correction: Mithramycin Dosage We call attention to the notice on page 421 in the March 1975 issue of an error in dosage of mithramycin for treatment of hypercalcemia.—The Editor
4
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19496/ by a University of California San Diego User on 04/25/2017
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.
dividuals all of whom were female and young, but not all of whom—depending upon the Dick test result—received toxin. L. F R E D A Y V A Z I A N , M . D .
Pulmonary Disease Section Veterans Administration Hospital East Orange, New Jersey 07019 REFERENCES 1. WHITE CS, ADLER WH, MCGANN VG: Repeated immunization:
possible adverse effects. Ann Intern Med 81:594-600, 1974 2. AYVAZIAN LF, BADGER TL: Disseminated lupus erythematosus oc-
Risks of Repeated Immunization TO THE EDITOR: In their paper "Repeated Immunization: Possible Adverse Effects," White, Adler, and McGann (1) report on less than 10% of 700 male employees at Fort Derrick who since 1956 had received multiple immunizations; despite some interesting minor laboratory abnormalities in this group, the authors conclude that chronic stimulation of the immunoglobulin-stimulating system in the human seems to cause no adverse effects, unlike amyloid disease, myeloma, and hypersensitivity reported in laboratory animals. As in a similar study referred to, that is, the soldiers receiving influenza vaccine, the subjects studied were always or almost always men well above adolescent age. I wonder about morbidity and mortality among the large majority of the immunized group not studied, and whether some of those unincluded or unavailable for follow-up might not, indeed, represent those most likely to have suffered consequences. In 1948, Dr. Theodore L. Badger and I (2) reported from the Thorndike Memorial Laboratories of the Boston City Hospital the occurrence of fatal disseminated lupus erythematosus in 3 of 750 young student nurses (all women) being studied primarily to correlate tuberculin skin reactivity with the development of tuberculosis over a 15year interval. These represented 23 % of the total mortality, exceeded (by one case) only by tuberculosis. A search among unrelated hospital and clinic records, training-school files, and autopsy protocols indicated a common factor in that all three girls, aged 18 years old, had received multiple Schick and Dick tests, scarlet fever streptococcus toxin, and typhoid-paratyphoid vaccine, with reactions including serum sickness, arthralgia, fever, positive Hinton reaction, and bizarre illness progressive to death over periods of 1 year, 15 months, and 7 years. Onset of illness correlated well with the inoculations, each injection leading to a reaction of added severity. In one case the original erythema of the toxin injection over the deltoid area gradually transformed, without fading, into the chronic violaceous eruption characteristic of lupus erythematosus. Autopsy confirmed this diagnosis in all three patients. Detailed information is available in the original publication. In our discussions, we offered evidence and conjecture suggesting a link between allergens, particularly biologic substances derived from the streptococcus, and "hypersensitivity" disease. It may be of importance that our group represented a substantial number (750) of unselected in-
curring among student nurses. N Engl J Med 239:565-570, 1948
In comment: Dr. Ayvazian recounts his experience with three cases of lupus erythematosus in a group of student nurses in Boston (2 above). He also raises the question of morbidity and mortality in the immunized population not studied, and points out that this population was predominantly adult men and thus not entirely representative. The initial selection of the 99 hyperimmunized men was solely on the basis of duration and intensity of immunization ( 1 ) . As the authors observed that laboratory abnormalities were present on the two occasions that the immunized men were studied (1, 2 ) , this same group seemed most appropriate for detainled laboratory follow-up at 25 years. The remainder of the population was followed in a single clinic until 1971, but it was logically considered to be less likely to show adverse effects of immunization. The entire group of immunized workers is presently being evaluated by Drs. Robert Hoover and Thomas Mason of the Epidemiology Branch of the National Cancer Institute. The cases noted by Dr. Ayvazian are of interest in a group of persons immunized less intensively and for a shorter time. Such cases serve to show the lack of information about the effects of repeated immunization not only on adults, but on infants and children, the population at greatest risk. CHARLES S. WHITE III, M.D., F.A.C.P.
Division of Hematology and Oncology George Washington University Medical Center Washington, D.C. 20037 REFERENCES 1. PEELER RN, CLUFF LE, TREVOR RW: Hyperimmunization of
man. Bull Johns Hopkins Hosp (Baltimore) 103:183-198, 1958 2. PEELER RN, KADULL PJ, CLUFF LE: Intensive immunization of
man. Evaluation of possible adverse consequences. Ann Intern Med 63:44-57, 1965
Giardiat Infection from Water TO THE EDITOR: In a recent article (Ann Intern Med 81: 498-499, 1974), five cases of infections with Giardia lamblia were epidemiologically associated with drinking contaminated water from an underground cistern. This Comments and Corrections
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19496/ by a University of California San Diego User on 04/25/2017
589
association was strengthened by the microscopic identification of G. lamblia trophozoites in water samples taken from the implicated source. At the Center for Disease Control, working in conjunction with Colorado state health officials, I had the opportunity to investigate several clusters of giardiasis patients in Colorado between 1972 and 1974. Similar to the authors' findings, my investigations invariably identified a source of untreated water as the most likely vehicle of transmission of G. lamblia cysts*. Fresh fruits and vegetables were generally purchased from nationally known supermarkets, and close personal contact among known patients was rare. In addition, recent travel outside the state before the onset of illness was uncommon among the patients, and stools obtained from domestic animals of known cases were usually negative for Giardia organisms. However, the majority of patients had, on several occasions, drunk water from untreated wells or mountain streams within 1 month of their onset of illness. These water sources usually had an unsafe level of fecal coliforms at the time of the investigation. However, filtering at least 10 gallons of water through an eight-micron Millipore filter (Millipore Corporation, Bedford, Massachusetts) from each of these sources consistently failed to isolate Giardia cysts. (It was not unusual for diatomes to resemble Giardia cysts.) Although my experience is in agreement with the authors' conclusion that waterborne giardiasis is common, I feel that the evidence in their article is inconclusive. Although the three involved families did not live in close geographic proximity, frequent visits to each other's home or a single gathering at the implicated (parent's) home could have allowed ample time for person-to-person spread. No mention was made of any recent travel outside the country or ingestion of untreated water from either mountain streams or other untreated wells. In fact, the authors' evidence of waterborne giardiasis is entirely based on the identification of G. lamblia trophozoites in water samples obtained from a presumably contaminated cistern. Yet, bacteriologic evidence of fecal contamination of this water source was not provided. Because G. lamblia is an enteric pathogen, it would be unlikely for this organism to exist without fecal coliforms in an unchlorinated water supply, presumably contaminated by a nearby outhouse. Furthermore, evidence for cross-connection between the outhouse and the cistern was not provided, other than the fact that several visitors to the home had previously complained of diarrhea. Most distressing was the authors' failure to explicitly describe the methods used to isolate and identify G. lamblia organisms from the implicated water. Similar to Chang and Kubler ( 1 , t ) , I have been able to retrieve G. lamblia cysts from experimentally contaminated water samples with a Millipore filtering method. However, microbiologic evidence of waterborne giardiasis by identifying cysts in implicated sources has not been previously reported. Even in the ski-resort outbreak cited by the authors ( 2 ) , Giardia cysts were only microscopically identified in heavily contaminated sewage that was cross-connected to the town's main water supply. Finally, Giardia trophozoites, unlike the highly resistant cysts, are fragile organisms whose survival outside the gastrointestinal tract has never been shown. It is, therefore,
surprising that this particular developmental stage was identified in contaminated water. It would have been more appropriate if the authors had presented pictorial evidence of Giardia organisms in the water sample than in the duodenal aspirates.
* WRIGHT RA, SPENCER H, BRODSKY R: Giardiasis in Colorado: an epidemiologic study. Unpublished. t CHANG SL: Identification of G. lamblia in water and control of waterborne giardiasis. Personal correspondence, November 1969. 590
RICHARD A. WRIGHT, M.D.
335 Frederick San Francisco, California 94117 REFERENCES 1. CHANG SL, KUBLER PW: Detection of cysts of E. histolytica in
tap water by the use of membrane filter. Am J Hyg 64:170-180, 1956 2. MOORE GT, CROSS WM, MCGUIRE D, et al: Epidemic giardiasis
at a ski resort. N Engl J Med 281:402-407, 1969
Prevention of Chloroquine-Resistant Falciparum Malaria TO THE EDITOR: Permit us to comment tardily on the article "Chemoprophylaxis of Malaria for Travelers" (Ann Intern Med 81:219-224, 1974). Dr. Barrett-Connor is wrong in her summation that weekly chloroquine and primaquine and daily dapsone is the best prophylaxis against chloroquine-resistant falciparum malaria. It is illogical because she is recommending chloroquine for chloroquine-resistance. Would she recommend chloramphenicol for chloramphenicol-resistant typhoid? The most promising compounds appear to be the combinations of dihydrofolate reductase inhibitors with a sulfonamide or sulfone for the chemosuppression of chloroquine-resistant falciparum malaria and vivax malaria (1-4). Thanh, Huan, and Tinh (3) showed in a 3-month study the value of monthly sulfadoxine-pyrimethamine (Fansidar®) over weekly chloroquine and primaquine plus daily dapsone in the chemosuppression of falciparum malaria. In this study only 1 of 205 Vietnamese soldiers who received sulfadoxine-pyrimethamine contracted falciparum malaria, while 104 of 1139 troops who received chloroquine and primaquine plus dapsone developed falciparum malaria ( X 2 Y = 16.8, P < 0.0005). Therefore, the monthly sulfadoxine-pyrimethamine combination was far superior, and obviously the drug compliance of a monthly medication is more practical. Dr. Barrett-Connor mentions several prophylactic studies with pyrimethamine and sulfadoxine including one in nonimmune persons in Laos ( 4 ) . She then precludes pyrimethamine-sulfadoxine prophylaxis because of potential toxicity that has not yet occurred in numerous studies and because of the paucity of field trials on nonimmune persons, although she has just mentioned such a study in Laos! Can she name a field trial with chloroquine-primaquine and dapsone in travelers? Her arguments for precluding short-term prophylaxis with pyrimethamine-sulfadoxine in travelers are not clear, and here we are speaking of chemoprophylaxis for perhaps 1 to 3 months on a monthly basis. The possible long-term dangers of long-acting sulfonamides (such as sulfadoxine) include the Stevens-Johnson syndrome, which has never been reported after the use of pyrimethamine-sulfadoxine for the chemoprophylaxis or chemotherapy of malaria ( 5 ) . Prolonged use of any drug (for example, chloroquine) or combination (for example, pyrimethamine-sulfadoxine) for the prophylaxis of malaria in a community probably stimulates the emergence of parasites resistant to the regimen. Thus the choice of a long-term prophylactic is diffi-
April 1975 • Annals of Internal Medicine • Volume 82 • Number 4
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19496/ by a University of California San Diego User on 04/25/2017
cult. A person traveling to a malarious country should probably be placed on a chemosuppressive agent. With the specter of chloroquine-resistance spreading very rapidly throughout Southeast Asia and the Americas, chloroquine should probably not remain the prophylactic drug of choice, unless the traveler is visiting the African continent or certain other areas. Thus, the summary of Dr. Barrett-Connor's article should be altered to read "currently the best prophylaxis for chloroquine-resistant falciparum malaria is the combination of pyrimethamine with sulfadoxine given every 2 or 4 weeks. Such a regimen can be recommended for a few months' prophylaxis. Long-term use is discouraged."
States. In view of the much more extensive experience with the chloroquine-primaquine-dapsone regimen, I would still consider this the preferred prophylaxis for nonimmune North Americans at risk. If further investigations confirm the efficacy and safety of the pyrimethamine-sulfadoxine combination, I will be happy to have a nontoxic and effective program to recommend for American travelers. ELIZABETH BARRETT-CONNOR, M.D.
Department of Community Medicine School of Medicine University of California, San Diego La Jolla, California 92037
ELIOT J. PEARLMAN, M.D., M A J , MC ANTHONY P. H A L L , M.D., F.A.C.P., COL, MC
Zollinger-Ellison Syndrome: Calcium, Secretin, Gastrin
U.S. Army Medical Component SEATO Medical Research Laboratory Rajavithi Road Bangkok, Thailand (APO SF 96346) REFERENCES 1. SEGAL HE, PEARLMAN EJ, THIEMANUN W, et al: The suppression
of Plasmodium falciparum and Plasmodium vivax parasitemias by a dapsone-pyrimethamine combination. / Trop Med Hyg 76: 285-290, 1973 2. PEARLMAN EJ, THIEMANUN W, CASTANEDA BF: The suppression
of P. falciparum parasitemias by a diformyldapsone-pyrimethamine combination, in Proceedings, 3rd International Congress of Parasitology. Munich, 1974, pp. 1305-1306 3. THANH PH, HUAN DH, TINH TV: Resultats preliminaries
de
chimioprophylaxie et de traitement du paludisme dans les forces arm6es de la republique du Vietnam par l'association sulfadoxine sulphormethoxine) pyrimethamine. J Milit Med Vietnam 40:3746, 1971 4. EBISAWA I, MUTO T, MITSUI G, et al: Malaria at Nam Dam
construction site in Laos. I. Suppression with combinations of sulfonamides and pyrimethamine. Jap J Exp Med 41:209-219, 1971 5. FERNEX M: Progress in the prophylactic use of Fansidar in regions where P. falciparum does not respond to chloroquine. See Reference 2, pp. 1303-1304
In reply: I disagree with the recommendation against chloroquineprimaquine and dapsone and in favor of pyrimethaminesulfadoxine. Experience with the former regimen in nonimmune persons has been several thousandfold more extensive. It is not irrational to expect that the chloroquineprimaquine combination will have some effect against chloroquine-resistant malaria for the following reasons. 1. Chloroquine resistance is usually relative, not total. 2. Chloroquine and primaquine act at different stages in malaria reproduction, and they can be expected to have additive, if not synergistic, effects. 3. A prophylactically effective regimen is not necessarily the same as a therapeutically effective regimen. 4. The field experience in Vietnam, as well as prison volunteer studies cited in my review, suggests that this combination does have some suppressive effect against chloroquine-resistant strains. Doctors Pearlman and Hall refer to a study that shows superior efficacy of pyrimethamine-sulfadoxine in partially immune Vietnamese soldiers; only two libraries in the United States have this journal, and I have been unable to obtain a copy. Therefore, I am unable to evaluate this trial regarding noncompliance, selection, or exposure bias. It should be noted, however, that neither dapsone nor sulfadoxine are commercially available in the United
TO THE EDITOR: In a recent issue Kolts, Herbst, and McGuigan (1) report on having administered intravenous calcium and secretin to 3 patients with the Zollinger-Ellison syndrome; they confirmed the results of others that administration of these agents resulted in hypergastrinemia. Isenberg and colleagues (2) suggested that the rise in serum calcium might be responsible for the increased level of gastrin. Despite the fact that after secretin infusion the serum calcium appeared to increase 1.0 mg/dl, 1.0 mg/dl, and 0.5 mg/dl in Patients 1, 2, and 3, respectively, Kolts, Herbst, and McGuigan chose to consider the increase as insignificant and then challenged Isenberg's claim based on a positive calcium-gastrin response in 12 patients. The stimulation of gastrin release and gastric secretion by calcium in man has recently been cited by Nordgren, Nyhus, and Bombeck ( 3 ) , who documented this effect experimentally in cats. On the other hand, calcitonin lowers serum calcium and also decreases gastrin and gastric secretion in normal man. These effects may or may not be coincidental, but these findings, plus the increased frequency of peptic ulcer in patients with hyperparathyroidism and other hypercalcemic states, should still raise the suspicion that serum calcium levels affects gastrin release, gastric secretion, and hence peptic ulcer. Since increased gastrin and gastric secretion are responsible for the major disability in the Zollinger-Ellison syndrome, any agent that can decrease blood gastrin would be of great benefit. Calcitonin is one such agent, and somatostatin is another. Indeed, somatostatin has greatly decreased gastrin and gastric secretin in one patient with Zollinger-Ellison syndrome, perhaps the first such case reported ( 4 ) . Both calcitonin and somatostatin deserve a trial in the Zollinger-Ellison syndrome before gastrectomy and other extensive surgery are carried out. CARL S. ALEXANDER, M.D.
Cardiovascular Section Veterans Administration Hospital Minneapolis, Minnesota 55417 REFERENCES 1. KOLTS BE, HERBST CA, MCGUIGAN JE: Calcium and secretin-
stimulated gastrin release in the Zollinger-Ellison syndrome. Ann Intern Med 81:758-762, 1974 2. ISENBERG JI, WALSH JH, PASSARO E JR, et al: Unusual effect of
secretin on serum gastrin, serum calcium, and gastric acid secretion in a patient with suspected Zollinger-Ellison syndrome. Gastroenterology 62:626-631, 1972 3. NORDGREN CE, NYHUS LM, BOMBECK CT: The influenct of cal-
cium on gastric acid secretion and plasma gastrin level in intact and thyroidectomized thyroxin-substituted gastric fistula cats (abstract). Gastroenterology 64:779, 1973 Comments and Corrections
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19496/ by a University of California San Diego User on 04/25/2017
591
4. BLOOM SR, MORTIMER CH, THORNER MO, et al: Inhibition of
gastrin and gastric-acid secretion by growth-hormone release-inhibiting hormone. Lancet 2:1106-1109, 1974
In
comment:
In o u r study referred t o b y D r . Alexander, serum gastrin and calcium concentrations were m e a s u r e d a n d c o m p a r e d before a n d after calcium a n d secretin infusion in patients with t h e Zollinger-Ellison s y n d r o m e a n d c o m p a r e d with control subjects. C a l c i u m infusion induced significant increases in both s e r u m calcium a n d s e r u m gastrin concentrations in t h e patients with t h e Zollinger-Ellison s y n d r o m e . C a l c i u m infusion induced significant increases in calcium levels in t h e control subjects a n d slight increases in their serum gastrin concentration. I n each patient with the Zollinger-Ellison s y n d r o m e w h o received calcium infusion there w a s a significant (P < 0.001) positive correlation (r from + 0.91 to + 0 . 9 5 ) between serum gastrin a n d calcium levels. I n t r a v e n o u s secretin also p r o d u c e d significant increases in both s e r u m gastrin a n d serum calcium concentrations in each patient with t h e Zollinger-Ellison s y n d r o m e ; however, there w a s n o t a positive correlation between serum gastrin concentrations. T h e s e studies confirmed secretin-induced paradoxical a u g m e n t a t i o n of serum gastrin in patients with t h e Zollinger-Ellison s y n d r o m e a n d showed significant increases in calcium levels in these patients. T h e failure, however, t o show positive correlation between serum gastrin a n d calcium with secretin administration did n o t support a role for s e r u m calcium as a m e c h a n i s m by which s e r u m gastrin is increased p a r a doxically after secretin infusion in patients with t h e Zollinger-Ellison s y n d r o m e . Therefore, c o n t r a r y t o t h e reader's conclusions, w e did n o t conclude that t h e increases in serum calcium with secretin infusion were insignificant, nor d o these d a t a in a n y w a y challenge o r contradict t h e observations of Isenberg a n d colleagues ( 2 above), with which w e completely agree.
colitis for 2 years before we saw her. She had had intermittent episodes of bloody diarrhea, treated with corticosteroids and salicylazosulfapyridine (Azulfidine®, Pharmacia Laboratories, Piscataway, New lersey) during this time with moderate success, and had been started anew on high-dose intravenous, and then oral, corticosteroids (40 mg to 60 mg daily) for 2 weeks before her coming in with an exacerbation of her symptoms. She came to our hospital on 21 October 1974 with sudden prostration, fever of 38.3 °C [101 °F], and blood pressure of 4 0 / 0 mm Hg unresponsive to volume expansion and pressors. She was then transferred to Kansas University Medical Center for a total colectomy with Hartmann's pouch, ileostomy, cholecystectomy, and incidental splenectomy. The pathologic report on the edematous hyperemic colon was "ulcerative colitis." After a benign postoperative course, she was transferred back to us; on 2 November, 12 days postoperative, her cardiac silhouette was noted to be enlarging, and spiking fevers became evident (the steroids already had been completely withdrawn). She was once again transferred back to Kansas University Medical Center. On the 17th day after colectomy a pericardiocentesis was performed, and an indwelling pericardial catheter was placed for 2 days and drained 1100 ml of fluid with a hematocrit reading of 1 2 % , 3500 leukocytes/mm 3 with 47% polymorphonuclear cells. All microbiologic and viral studies were negative. Lupus erythematosus preparations, complement measurements, and antinuclear antibody and rheumatoid factor studies on the pericardial fluid and on the blood were all unremarkable. Although the fluid did not reaccumulate, the fever continued, and a gallium-67 scan showed a pelvic abscess that was drained surgically; an abdominal-peroneal proctectomy was then done. The patient is now asymptomatic.
W e believe from o u r o w n observations a n d those of others, that serum calcium does affect both s e r u m gastrin levels a n d gastric acid secretion. A t t h e present time there are insufficient d a t a o n t h e efficacy of calcitonin a n d somatostatin in patients with t h e Zollinger-Ellison synd r o m e t o w a r r a n t delay in a p p r o p r i a t e surgery for these patients. J A M E S E. M C G U I G A N , M.D.
Division of Gastroenterology College of Medicine University of Florida Gainesville, Florida 32610
This case shows t h e d e v e l o p m e n t of pericardial inflamm a t i o n after colectomy; it regressed with pericardial drainage, without steroid therapy, a n d before t h e r e m a i n ing rectal s t u m p was removed. A s D r . Breitenstein suggests, the diagnosis of pericarditis should n o t b e overlooked in patients with inflammatory bowel disease, especially n o w that t w o of t h e five patients reported developed t a m p o n a d e (2-4). O W E N J. R H E I N G O L D , M . D . , C A P T , M C
Department of Internal Medicine U.S. Munson Army Hospital Fort Leavenworth, Kansas 66027 REFERENCES 1. BREITENSTEIN RA, SALEL AF, WATSON DW:
Chronic
inflam-
matory bowel disease: acute pericarditis and pericardial tamponade (letter). Ann Intern Med 81:406, 1974 2. MUKHOPADHYAY D, NASR K, GROSSMAN BJ, et al: Pericarditis
associated with inflammatory bowel disease. JAMA 1542, 1970
211:1540-
3. GROSSMAN BJ, DEBENNEDETTI BS: Extraintestinal manifestations
of chronic inflammatory bowel disease in children (abstract). Proc Inst Med Chic 28:119, 1970 4. YOUNG PC: Colonic and systemic manifestations of chronic ulcerative colitis. Med Clin North Am 51:1011-1013, 1967
Inflammatory Bowel Disease and Pericarditis Aspirin Hepatotoxicity T O T H E EDITOR: I read with interest t h e recent report by Breitenstein, Salel, a n d W a t s o n ( 1 ) of a patient with chronic inflammatory bowel disease w h o developed pericarditis a n d pericardial t a m p o n a d e . T h e y speculated whether t h e pericarditis would b e relieved by colectomy, which could n o t be predicted from available experience. I present here a n additional case a n d t h e first reported instance of pericarditis with pericardial t a m p o n a d e o c curring subsequent to colectomy.
TO T H E EDITOR: T h e p a p e r s b y S e a m a n , Ishak, a n d Plotz ( 1 ) , Wolfe, Metzger, a n d Goldstein ( 2 ) , a n d t h e letter by G o l d e n b e r g ( 3 ) have described five patients with systemic lupus erythematosus w h o developed aspirin-induced h e p a totoxicity. W e have recently seen a patient with n o u n d e r lying connective tissue disease w h o developed aspirin hepatitis after prolonged heavy ingestion of aspirin for relief of tension headaches a n d cold s y m p t o m s .
The patient was a 28-year-old white woman with ulcerative
A 26-year-old nurse was admitted to the neurology service
592
Apr/7 1975 • Annals of Internal Medicine • Volume 82 • Number 4
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19496/ by a University of California San Diego User on 04/25/2017
because of slurred speech, ataxia, confusion, and somnolence. N o history of seizure or progressive neurologic impairment was obtained. The patient admitted to past alcoholic intake but denied drinking in the 3 weeks before admission. In the past 8 months she had been taking aspirin and Coricidin® for tension headaches and cold symptoms. The total amount of aspirin from both sources was 9.0 g daily. During this period she experienced tinnitus and persistent headaches. At admission the physical examination was unremarkable. The serum glutamic oxalacetic transaminase (SGOT) was 273 M U / m l (normal, 0 to 40 M U / m l ) ; the alkaline phosphatase, 108 M U / m l (normal, 30 to 85 M U / m l ) ; and serum glutamic pyruvic transaminase ( S G P T ) , 111 M U / m l (normal, 5 to 35 M U / m l ) . Brain scan, electroencephalogram, oral cholecystogram, upper gastrointestinal films, and skull films were normal. Admission blood alcohol was 0 % , and a screening test for urine secobarbital and amobarbital was positive. The heterophil antibody test and lupus erythematosus-cell preparation were negative. Studies for hepatitis B antigen, and antimitochondrial, antismooth muscle and antinuclear antibodies were negative. The patient had no history of blood transfusions. She had been exposed to hepatitis, but she denied any episode of jaundice, malaise, or dark urine. Two days after admission, while off aspirin, the neurologic symptoms disappeared and the SGOT value decreased to 66 M U / m l . On the 4th day after admission, liver biopsy showed findings consistent with a mild toxic hepatitis {see Figure 1 ) .
Figure 1 . Photomicrograph of needle liver biopsy shows focal cellular necrosis and neutrophil infiltrate near the central vein. (Hematoxylin and eosin; magnification, x 1100.)
One week after admission all the liver enzymes values returned to normal. Because of t h e elevated serum liver-enzymes values, t h e history of repeated ingestion of large doses of aspirin, a n d clinical findings consistent with mild salicylate intoxication, the diagnosis of aspirin hepatitis w a s considered. T h e liver biopsy s u p p o r t e d this diagnosis. As in t h e cases reported ( 1 - 3 ) , t h e t r a n s a m i n a s e levels rapidly r e t u r n e d t o n o r m a l after withdrawal of t h e drug. This patient h a d , however n o features of connective tissue diseases. W h e t h e r this patient's alcohol o r b a r b i t u r a t e intake h a s increased h e r susceptibility to aspirin is speculative. T h e factors that m a y contribute to a n d modify aspirin hepatotoxicity r e m a i n t o b e delineated. E L A Y N E G A R B E R , B.A. R O B E R T M. CRAIG, M.D.
Gastroenterology Service Department of Medicine Northwestern University Chicago, Illinois 60611 R A J A M. BAHU, M.D.
Department of Pathology Northwestern University Chicago, Illinois 60611 REFERENCES 1. SEAMAN WE, ISHAK KG, PLOTZ PH: Aspirin-induced hepatotox-
icity in patients with systemic lupus erythematosus. Ann Intern Med 80:1-8, 1974 2. WOLFE JD, METZGER AL, GOLDSTEIN RC: Aspirin hepatitis. Ann
Intern Med 80:74-76, 1974 3. GOLDENBERG DL: Aspirin hepatotoxicity. Ann Intern Med 80: 773, 1974
"Munchausen" Coronary Artery Disease TO T H E EDITOR: W e wish to r e p o r t t h e case of a patient with " M u n c h a u s e n s y n d r o m e " w h o presented with cardiovascular complaints indicative of severe c o r o n a r y artery disease. A 46-year-old white man was transferred to The George Washington University Hospital ( G W U H ) 5 days before Christmas 1974 because of preinfarction angina. H e gave a history of typical angina for the past 2 months, w r ' : h had become worse 10 days ago when he collapsed and was admitted to a local hospital. His angina did not respond to sublingual nitroglycerin, oral isosorbide dinitrate, and oral propranolol. The only medication that seemed to offer relief was intramuscular meperidine injections. After transfer to G W U H he continued to complain of angina at rest, relieved by no medications other than intravenous morphine sulfate; however, placebo injections seemed to offer equal relief as long as they were given in Tubex® form. Electrocardiograms were repeatedly normal during and between attacks of pain. Serum glutamic oxalacetic transaminase, lactic dehydrogenase, and creatinine phosphokinase enzyme values on the day of transfer were mildly elevated, probably because of intramuscular meperidine injections received at the other hospital. Subsequent serum enzyme values were all normal. He gave a past history of rheumatic fever and scarlet fever as a child, with later development of nephritis. Labile hypertension was noted a year ago. He gave a strong family history of fatal heart attacks among his parents and grandparents. He had several healed incisional scars: bilateral supraclavicular, right antecubital, and appendectomal. Bilateral supraclavicular incisional scars were from scalene node biopsies done at District of Columbia General Hospital in 1972. Scars in the right antecubital fossa were said by the patient to have resulted from operative repair of the brachial artery injured in an automobile accident many years ago. The right brachial and right radial pulses were barely palpable. It was decided to gradually withdraw propranolol and to do coronary arteriography after a few days. While being observed in the coronary-care unit, he was recognized by one of us (JM) as having been previously admitted to G W U H in May 1973 under another name with identical complaints. At that time coronary arteriography, done by the Sones method in the right arm by one of us ( G K ) , showed mild narrowings in the right coronary artery and in the left circumflex artery that were believed not to be severe enough to account for his angina. When confronted with these revelations 2 days before Christmas 1974, he promptly signed out of G W U H , presumably to return to his home in Pennsylvania. This patient m a y n o w b e in a c o r o n a r y - c a r e unit o r cardiac catheterization l a b o r a t o r y of another hospital being Comments and Corrections
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19496/ by a University of California San Diego User on 04/25/2017
593
GUNNAR KRAAG, M.D., F.R.C.P.(c)
cared for as a case of preinfarction angina. The obvious benefit to the patient, housestaff, and hospital from early recognition of this patient is apparent. We hope physicians warned of this story will be able to spare the patient another coronary arteriography, a potentially hazardous procedure, which he appears to be willing to undergo again.
ANTHONY J. RICHARDS, M.B., M.R.C.P. DUNCAN A. GORDON, M.D., F . R . C . P . ( C ) , F.A.C.P.
McMaster University Medical Centre Rheumatology Area 2F-26 1200 Main Street West Hamilton, Ontario, Canada
TSUNG O. CHENG, M.D., F.A.C.P. JERRY F. MEYER, M.D. GEORGE A. KELSER, JR., M.D., F.A.C.P.
REFERENCES
1. UHL GS, WILLIAMS JE, ARNETT FC: Intracerebral lymphoma
in a patient with central nervous system lupus on cyclophosphamide. J Rheum 1:282-286, 1974 2. LIPSMEYER EA: Development of malignant cerebral lymphoma in a patient with systemic lupus erythematosus treated with immunosuppression. Arthritis Rheum 15:183-186, 1972
The George Washington University Medical Center 2150 Pennsylvania Avenue, N.W. Washington, D.C. 20037 NYAB A L I , M.D.
District of Columbia General Hospital Washington, D.C. 20003 Correction: Grant Support TO THE EDITOR: In my paper "A Hypothesis to Account for the Mary Walker Phenomenon" (Ann Intern Med 82:411-415, 1975), I failed to acknowledge grant support from the Muscular Dystrophy Associations of America through its Houston chapter.
Brain Scanning in Lupus Erythematosus TO THE EDITOR: We read with interest the paper by Drs. Bennahum, Messner, and Shoop, "Brain Scan Findings in Central Nervous System Involvement by Lupus Erythematosus" (Ann Intern Med 81:763-765, 1974). They have shown brain scanning to be a safe and useful tool for diagnosis and evaluation of therapy. They excluded patients with purely psychiatric symptoms, but it would be interesting to know if a brain scan could help in differentiating true central nervous system involvement in lupus erythematosus, from psychiatric symptoms induced by corticosteroid therapy. This is a frequent dilemma for the practicing physician who must decide whether to increase the corticosteroid or incriminate it. We suggest some caution in interpreting brain scan abnormalities in lupus erythematosus. There have been recent reports of intracerebral lymphoma developing in patients receiving immunosuppressive therapy. Uhl, Williams, and Arnett (1) recently described a case of intracerebral lymphoma in a patient with central nervous system lupus erythematosus on cyclophosphamide, and Lipsmeyer (2) reported a case of intracranial reticulum cell sarcoma after only 2 months of azathioprine therapy. Many patients with lupus erythematosus are now receiving immunosuppressive therapy, and the development of an abnormal brain scan with neurologic manifestations should alert the clinician to this possibility. As Uhl points out, this is especially true when neurologic signs and brain scan abnormalities are not accompanied by clinical and laboratory findings that suggest a general flare of the lupus erythematosus. Unlike the clearning of brain scan abnormalities in Bennahum's report, in Uhl's patient the scan abnormalities progressed even though there was slight improvement in weakness on increasing the steroid dosage. Lipsmeyer (2) has suggested that a tumour registry of malignancies arising in patients who have rheumatic disorders and who receive immunosuppressives might put this potential toxicity into proper perspective, but until then one must remain aware of this complication.
594
A p r / / 1 9 7 5 • Annals of Internal Medicine • Volume 82 • Number
BERNARD M. PATTEN, M.D.
Department of Neurology Baylor College of Medicine Houston, Texas 77025
Correction: Nocardial Infection TO THE EDITOR: We wish to point out our error in "Nocardia Infection in Heart Transplant Patients" (Ann Intern Med 82:18-26, 1975). In the discussion section on "Host Defenses against Nocardia," page 25, first paragraph, line 20, the sentence reads: "Experimental evidence in support of the hypothesis has recently been published by Bourgeois and Beaman (25)." This should be corrected: "Experimental evidence in support of the hypothesis (4) that cellular immunity is of major importance in defense against Nocardia in the normal host has recently been published by Bourgeois and Beaman (25)." JAMES H. KRICK, M.D.
Palo Alto Medical Research Foundation 860 Bryant Street Palo Alto, California 94301
Correction: Mithramycin Dosage We call attention to the notice on page 421 in the March 1975 issue of an error in dosage of mithramycin for treatment of hypercalcemia.—The Editor
4
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19496/ by a University of California San Diego User on 04/25/2017
