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Vitamin B12 Deficiency after Gastric Surgery

To the Editor: The study by Sumner and colleagues (1) con­firms such metabolic consequences of gastric surgery as vitamin B12 (cobalamin) and iron malabsorption. We agree with the editorial comment by Dr. Green (2) that achlorhydria and the intestinal blind loop could have caused bacterial overgrowth, resulting in malabsorption of vitamin B12. In addition, some study patients could have been receiving histamine-2-receptor antagonists or been using proton pump inhibitors, which would aggravate malabsorption of vitamin B12 (3). However, Sumner and colleagues did not report which medication patients were receiving. A food (protein-bound) cobalamin-absorption test could have resolved some of the issues by diagnosing cobalamin deficiency, but this test is not readily available.

Sumner and colleagues do not mention whether their patients were inpatients or outpatients. This information would have been helpful because receiving a hospital diet for a few days can normalize serum folate levels and erythrocyte folate levels. Eryth­rocyte folate levels reflect the tissue store more accurately than do serum folate levels (4). The authors do not provide their patients' history of alcohol intake; alcoholics can have normal serum folate levels but still have extreme folate deficiency. In some patients, cobalamin deficiency (as defined by Sumner and colleagues' second criterion under the definition of vitamin B12

deficiency) could have been caused by deficiency in tissue. Al­though the homocysteine levels of these patients decreased after cobalamin was administered, some of the patients could also have received folate supplementation. Combining levels of serum homocysteine and methylmalonic acid has a high sensitivity for diagnosing cobalamin deficiency (5).

Although cobalamin and iron are frequently malabsorped in patients who have had gastric surgery, the conclusions of Sumner and colleagues (that is, a suggestion that vitamin B12 replacement be used in patients who have had gastric surgery and who have vitamin B12 levels less than 221 pmol/L) indicate that overdiag-nosing cobalamin deficiency is still possible, especially in the absence of hematologic or neuropsychiatry manifestations.

G. Divakara Murthy, MD Hanumappa Visweswaraiah, MD Stratton Veterans Affairs Medical Center Albany, NY 12208

References 1. Sumner AE, Chin MM, Abrahm JL, Berry GT, Gracely EJ, Allen RH,

et al. Elevated methylmalonic acid and homocysteine levels show high prevalence of vitamin B12 deficiency after gastric surgery. Ann Intern Med. 1996;124:469-76.

2. Green R. Screening for vitamin B12 deficiency: caveat emptor [Edito­rial]. Ann Intern Med. 1996;124:509-11.

3. Marcuard SP, Albernaz L, Khazanie PG. Omeprazole therapy causes malabsorption of cyanocobalamin (vitamin B12). Ann Intern Med. 1994; 120:211-5.

4. Colon-Otero G, Menke D, Hook CC. A practical approach to the differential diagnosis and evaluation of the adult patient with macro­cytic anemia. Med Clin North Am. 1992;76:581-97.

5. Savage DG, Lindenbaum J, Stabler SP, Allen RH. Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnos­ing cobalamin and folate deficiencies. Am J Med. 1994;96:239-46.

In response: Our investigation confirms the known metabolic consequences of gastric surgery using the most sensitive available tests—measurement of serum methylmalonic acid and total homo­cysteine levels—to determine vitamin B12 deficiency. We did not determine the cause of vitamin B12 deficiency but agree with Drs. Murthy and Visweswaraiah that achlorhydria, intestinal blind-loop syndromes, and histamine-2 antagonist therapy could have caused some of the malabsorption. Histamine-2 antagonists are frequently prescribed and available over the counter. We did not test for food protein-bound cobalamin absorption. A limitation of all vitamin B12-absorption tests is that they only measure mal­absorption at the time of the test and not whether vitamin B12

deficiency is actually present. Further, the tests are not standard­ized.

Approximately 50% of the patients who had gastric surgery were inpatients and 50% were outpatients. Of the patients with vitamin B12 deficiency, 12 were outpatients, 5 were inpatients, and 2 were residents of a Veterans Affairs nursing home.

Participants were not treated simultaneously with vitamin B12

and folate. Because we used elevation of serum methylmalonic acid levels and low or normal vitamin B12 levels as our major criteria for defining vitamin B12 deficiency, we do not believe that intake or problems in measurement of either serum or erythro­cyte folate levels would have any effect on data. Only one case met the second definition of vitamin B12 deficiency (normal methylmalonic acid level and abnormal homocysteine level). Treatment with vitamin B12 decreased this patient's total homo­cysteine level from 22.8 ptmol/L to 10.9 /imol/L. In addition to problems in standardization of the erythrocyte folate test, the test cannot distinguish between folate or vitamin B12 deficiency. Therefore, the test would not add any diagnostic information to that discovered through methylmalonic acid and homocysteine assays.

We agree with the concerns of Drs. Murthy and Visweswaraiah that tests for serum vitamin B12 level are not specific and that if this level alone is relied on, vitamin B12 deficiency could be overdiagnosed. In our study, only 2 of 22 controls with low vitamin B12 levels had metabolic evidence of vitamin B12 defi­ciency. Because patients who have had gastric surgery have an increased risk for vitamin B12 malabsorption, the number who were deficient was much higher; therefore, fewer patients with normal vitamin B12 levels would be treated on the basis of only the serum vitamin B12 level. Further, overtreatment with vitamin B12 would not be harmful, and it seems unwise to risk having a patient develop possibly irreversible demyelinating disease of the nervous system or anemia. Our investigation shows the advantage of using measurement of serum methylmalonic acid and homo­cysteine levels with the measurement of serum vitamin B12 and folate levels to gain specificity of diagnosis and to maximize the benefits of treatment.

1 December 1996 • Annals of Internal Medicine • Volume 125 • Number 11 937

Anne E. Sumner, MD Medical College of Pennsylvania and Hahnemann University Philadelphia, PA 19129

Janet L. Abrahm, MD Philadelphia Veterans Affairs Medical Center Philadelphia, PA 19104

Sally P. Stabler, MD University of Colorado Health Sciences Center Denver, CO 80262

Aspirin after Myocardial Infarction in the Elderly

To the Editor: In their article, Krumholz and colleagues (1) stated that aspirin was not prescribed at discharge for 24% of elderly patients who did not have a contraindication to aspirin after they had been hospitalized for acute myocardial infarction. Because daily use of nonsteroidal anti-inflammatory drugs (NSAIDs) is common in this population, and because these drugs (except for nonacetylated agents) have significant antiplatelet activity (2, 3), it may be reasonable and preferable not to add aspirin to the regimen of patients taking other NSAIDs. How many patients in the nonaspirin group were taking NSAIDs regularly?

Bruce L. Ring, MD Goddard Medical Associates, PC Brockton, MA 02401

References 1. Krumholz HM, Radford MJ, Ellerbeck EF, Hennen J, Meehan TP,

Petrillo M, et al. Aspirin for secondary prevention after acute myocar­dial infarction in the elderly: prescribed use and outcomes. Ann Intern Med. 1996;124:292-8.

2. Rajah SM, Nair V, Rees M, Saunders M, Walker D, Williams G, et al. Effects of antiplatelet therapy with indobufen or aspirin—dipyridamole on graft patency one year after coronary artery bypass grafting. J Tho-rac Cardiovasc Surg. 1994;10:1146-53.

3. Brochier ML. Evaluation of flurbiprofen for prevention of reinfarction and reocclusion after successful thrombolysis or angioplasty in acute myocardial infarction. The Flurbiprofen French Trial. Eur Heart J. 1993;14:951-7.

In response: Dr. Ring raises an interesting question, but our database is not currently configured to determine how many patients in the group not prescribed aspirin were taking NSAIDs. However, although NSAIDs may have antiplatelet activity, their value in reducing mortality after acute myocardial infarction is less well established than that of aspirin (1). Because adminis­tration of aspirin in medium-sized dosages (75 to 325 mg/d) results in a substantial reduction in risk for subsequent adverse cardiac events, it is appropriate to consider aspirin the standard of care. Moreover, current guidelines from the American Heart Association on secondary prevention for patients with coronary artery disease recommend the daily use of aspirin for patients with coronary artery disease (2). For these reasons, we believe that it is reasonable to focus on the use of aspirin in this group. Studies should be done to test the therapeutic efficacy of NSAIDs after acute myocardial infarction before such therapy is accepted as an adequate substitute for aspirin.

Harlan M. Krumholz, MD Yale School of Medicine New Haven, CT 06520-8017

References 1. Collaborative overview of randomised trials of antiplatelet therapy. I.

Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Tri-alists' Collaboration. BMJ. 1994;308:81-106.

2. Smith S, Blair S, Criqui M, Fletcher G, Fuster V, Gersh B, et al. Preventing heart attack and death in patients with coronary disease. Circulation. 1995;92:2-4.

Outpatient Management of HIV-Related Pneumonia

To the Editor: The editorial by Masur and Shelhamer (1) is an important addition to the developing literature on practice guide­lines for the human immunodeficiency virus (HIV). One point deserves further attention. If sputum studies do not provide a diagnosis and bronchoscopy is planned, transbronchial biopsy and bronchoalveolar lavage should also be done. In cases in which bronchoscopy is required for diagnosis, Pneumocystis carinii pneumonia is not the usual cause and biopsy will also be neces­sary to establish the diagnosis. In many institutions, bronchoal­veolar lavage without transbronchial biopsy is a routine proce­dure for the diagnosis of P. carinii pneumonia. At our institution, we recently saw cases of so-called classic P. carinii pneumonia (with dyspnea, interstitial infiltrates, hypoxemia, and elevated lactate dehydrogenase levels) that were subsequently proven by biopsy to have been caused by cytomegalovirus, Mycobacterium tuberculosis, lymphocytic interstitial pneumonitis, and coccid-ioides.

As the natural history of HIV infection continues to change, different and perhaps new opportunistic diseases can be ex­pected. Our diagnostic approaches must evolve to keep up with the changes in the underlying disease.

Stephen L. Becker, MD California Pacific Medical Center San Francisco, CA 94107

Reference 1. Masur H, Shelhamer J. Empiric outpatient management of HTV-related

pneumonia: economical or unwise? [Editorial] Ann Intern Med. 1996; 124:451-3.

In response: Dr. Becker raises two issues that were not explic­itly addressed in our editorial. First, if the result of an induced-sputum examination is negative for P. carinii, what diagnosis is likely? Second, if the result of an induced-sputum examination is negative for P. carinii, what diagnostic procedures should be used?

Regarding the first issue, we believe that at many institutions, induced sputum examination has a high sensitivity for P. carinii pneumonia in patients who are and are not receiving prophylaxis for P. carinii pneumonia (sensitivity, >60% and >90%, respec­tively) (1). However, we do not agree that a negative result of induced-sputum examination in this setting makes other pulmo­nary diagnoses substantially more likely than a diagnosis of P. carinii pneumonia. Huang and colleagues (2) reported that in patients who have HIV infection, low CD4 counts, a clinical picture typical of P. carinii pneumonia, and a negative result of an induced-sputum examination, the most likely diagnosis is P. carinii pneumonia. In that study (2) (which was done at an institution with considerable experience assessing induced-spu­tum samples), 192 of 602 (31%) patients with negative results of induced-sputum examinations were found to have P. carinii pneu­monia at bronchoscopy. This diagnosis was substantially more common than that of M. tuberculosis infection (<5%) or fungal infection (<5%).

The second issue raised by Dr. Becker is what procedures should be done to establish the diagnosis of pulmonary disease when the result of an induced-sputum examination is negative. Depending on the reliability of the laboratory and the quality of the specimen, a second induced-sputum sample might be useful. Most clinicians would do bronchoalveolar lavage after the initial induced-sputum analysis and consider the merit of transbronchial biopsy during the initial bronchoscopy. Transbronchial lung bi­opsy is associated with a slightly increased sensitivity of the bronchoscopic procedure for P. carinii pneumonia and may ei­ther enhance the sensitivity or be required to establish a diag­nosis of tuberculosis, cytomegalovirus pneumonia, fungal pneu­monia, or such noninfectious processes as lymphocytic interstitial pneumonitis or some pulmonary cancers (3, 4). It is reasonable, as Dr. Becker has done, to advocate a diagnostic procedure that includes bronchoscopy, bronchoalveolar lavage, and transbron­chial lung biopsy during the initial bronchoscopic procedure for

938 1 December 1996 • Annals of Internal Medicine • Volume 125 • Number 11

patients who present with a clinical picture that suggests P. carinii pneumonia and a negative result of induced-sputum ex­amination. However, our general practice is to do only bronchos­copy and bronchoalveolar lavage. If those procedures fail to indicate a diagnosis, we repeat them, adding the transbronchial biopsy.

In geographic areas where tuberculosis, histoplasmosis, or coc-cidiomycosis is especially common or in health care settings where induced-sputum evaluation is insensitive, a different algo­rithm encouraging bronchoscopy with or without transbronchial biopsy may be indicated.

Henry Masur, MD James H. Shelhamer, MD National Institutes of Health Bethesda, MD 20892

References

1. Gill V, Quinn T, Crawford S, Kovacs J, Masur H, Ognibene F, et al. Diagnosis of pulmonary opportunistic infections. Ann Intern Med. 1996;124:585-99.

2. Huang L, Hecht F, Stansell J, Montanti R, Hadley W, Hopewell P. Suspected Pneumocystis carinii pneumonia with a negative induced spu­tum examination. Am J Respir Crit Care Med. 1995;151:1866-71.

3. Barnes P, Steele M, Young S, Vachon L. Tuberculosis in patients with human immunodeficiency virus infection. Chest. 1992;102:428-32.

4. Kennedy D, Lewis W, Barnes P. Yield of bronchoscopy for the diag­nosis of tuberculosis in patients with human immunodeficiency virus infection. Chest. 1992;102:1040-4.

Cost-Effectiveness of Detecting and Treating Diabetic Retinopathy

To the Editor: The carefully conducted and clear cost-utility analysis by Javitt and Aiello (1) provides useful information on the economics of diabetic retinal screening for different popula­tions from the perspective of a health insurance agency. There are, however, two major limitations to the application of the study findings to decision making.

The valuation of sight considers two levels of outcome, de­pending on whether the affected person is well or poorly adjusted to his or her disability. The proportion of patients reaching these end points is estimated from national figures on the outcome of rehabilitation. This estimate assumes that blind diabetic patients have an outcome from rehabilitation similar to that of other blind persons. This assumption is probably untrue because dia­betic persons often have other disabilities when severe eye dis­ease develops. Loss of light, discriminatory touch, and joint po­sition sense is particularly common. It is uncertain how this difference in outcome affects valuation of sight; the complications of the condition mean that these patients are likely to start with a worse quality of life but tend to value their sight more. This makes interpreting comparisons of the costs per quality-adjusted year of life with those of other interventions particularly difficult.

In determining the costs of the intervention, however, it ap­pears from the assumptions of Javitt and Aiello's model that the averted cost of the state of a blind person was subtracted from the cost of delivering the intervention. This confuses the picture because this realm no longer belongs just to the health insurer. Much of the cost of blindness will result from making social rather than health care provisions.

Mark Lambert, MB, BS University of York Heslington, York YOl 5DD, United Kingdom

Reference 1. Javitt JC, Aiello LP. Cost-effectiveness of detecting and treating dia­

betic retinopathy. 1996;124(1 pt 2):164-9.

In response: We appreciate Dr. Lambert's interest in our work. However, contrary to his assertion, neither of the issues he raises limits the application of our study results to decision making.

Dr. Lambert challenges our assumption that persons with di­

abetes who lose their sight are as likely to be rehabilitated as visually disabled persons in the rest of the population. He sug­gests that loss of proprioception and touch sensation associated with diabetes might cause persons with diabetes to value their sight more highly than do those without the disease. Although he presents no data to support this proposition, we can see the logic in the argument. However, increasing the value in quality-ad­justed years of life associated with vision in our model, as Dr. Lambert suggests, only increases the estimated cost-effectiveness of screening for and treating diabetic eye disease. This certainly does not limit the value of our study.

Dr. Lambert also infers that we subtracted the averted finan­cial cost associated with blindness from the health care cost of delivering the intervention. We have not done so in this or any other article that addresses cost-effectiveness, and we agree that it would be improper to do so. We have previously discussed the cost savings associated with detecting and treating eye disease from the federal perspective; in that model we appropriately considered costs associated with blindness (1).

Jonathan C. Javitt, MD, MPH Georgetown University Medical Center Washington, DC 20007

Lloyd Paul Aiello, MD, PhD Joslin Diabetes Center Boston, MA 02215

Reference 1. Javitt JC, Aiello LP, Ferris FL, Canner JK, Chiang YP, Greenfield SR.

Preventive eye care in people with diabetes is cost-saving to the federal government: implications for health-care reform. Diabetes Care. 1994; 17:909-17.

Uveitis Associated with Rifabutin Prophylaxis and Itraconazole Therapy

To the Editor: Although anterior uveitis is a frequent compli­cation of rifabutin therapy (1), it occurs infrequently with rifabu­tin prophylaxis (300 mg/d) (2). This condition, however, has been seen during concomitant administration of rifabutin and either fluconazole or clarithromycin; this suggests that a drug interac­tion may be responsible for this complication (3). We describe a patient with human immunodeficiency virus infection who devel­oped anterior uveitis while receiving rifabutin prophylaxis during itraconazole therapy.

A 49-year-old man with a history of Pneumocystis carinii pneu­monia and bilateral cytomegalovirus retinitis was hospitalized with anterior uveitis of the left eye. He had been receiving rifabutin prophylaxis (300 mg/d) for 6 months. One month before hospitalization, treatment with itraconazole (600 mg/d) was ini­tiated for Aspergillus fumigatus pneumonia. Because of low itra­conazole plasma levels after 3 weeks of treatment, the dose was increased to 900 mg/d 1 week before the onset of ophthalmic symptoms. At admission, trough serum levels of itraconazole and its metabolite were appropriate (516 /xg/L and 645 /ig/L, respec­tively). As expected, trough serum levels of rifabutin and its LM565 metabolite (153 ng/mL and 50 ng/mL, respectively) were higher (serum levels of rifabutin are usually lower than 50 ng/mL 24 hours after oral administration of 300 mg of the drug). Ri­fabutin prophylaxis was discontinued, and the patient was treated with topical steroids and a cycloplegic agent. Results of ophthal­mic examination returned to normal after 5 days.

Itraconazole, an orally active triazole antifungal drug, appears to be well tolerated but can inhibit the metabolism of other drugs, such as digoxin and cyclosporine. No interaction between rifabutin and itraconazole has been reported. Our case report suggests a kinetic interaction between itraconazole and rifabutin that resulted in an increase in serum rifabutin levels and a risk for developing uveitis. Serum levels of rifabutin should be closely monitored in patients receiving rifabutin prophylaxis during itra­conazole therapy. If uveitis develops in such patients, rifabutin-

1 December 1996 • Annals of Internal Medicine • Volume 125 • Number 11 939

related uveitis should be suspected and rifabutin therapy should be stopped immediately.

Agnes Lefort, MD Odile Launay, MD Claude Carbon, MD Hopital Bichat-Claude Bernard Paris, France

References

1. Shafran SD, Deschenes J, Miller M, Phillips P. Toma E. Uveitis and pseudojaundice during a regimen of clarithromycin, rifabutin, and ethambutol [Letter]. MAC Study Group of the Canadian HIV Trials Network. N Engl J Med. 1994;330:438-9.

2. Nightingale SD, Cameron DW, Gordin FM, Sullam PM, Cohn DL, Chaisson RE, et al. Two controlled trials of rifabutin prophylaxis against Mycobacterium avium complex infection in AIDS. N Engl J Med. 1993;329:828-33.

3. Trapnell CB, Narang PK, LR, Lavelle JP. Increased plasma rifabutin levels with concomitant fluconazole therapy in HIV-infected patients. Ann Intern Med. 1996;124:573-6.

Use of the Rumack-Matthew Nomogram in Cases of Extended-Release Acetaminophen Toxicity

To the Editor: A 17-year-old healthy girl presented to the hospital after a suicidal ingestion of 13 g of Extended-Relief Tylenol (McNeil Consumer Products Co., Fort Washington, Pennsylvania). She was asymptomatic, and vital signs and physi­cal examination findings were normal. Acetaminophen levels were obtained 3 hours and 5 hours after ingestion. Both values were below the Rumack-Matthew nomogram (Figure). While the patient awaited psychiatric consultation, the acetaminophen level was measured for the third time 11 hours after ingestion. The level was 79.8 /Ltg/mL and was in the toxic range when plotted on the nomogram. Oral N-acetylcysteine therapy was begun, and the patient received the standard 72-hour regimen. Liver function test results were monitored every 12 hours and remained normal for the next 89 hours. Results of serum and urine toxicology screens were negative.

Extended-relief acetaminophen is available in 650-mg caplets intended to release 325 mg immediately and 325 mg more slowly. Although a few published case reports have described acetamin­ophen overdose (1, 2), it is unclear how and whether the differ­ent toxicokinetics of extended-relief acetaminophen will affect use of the Rumack-Matthew nomogram.

Figure. Acetaminophen levels after suicidal ingestion of 13 g of the drug. NAC = N-acetylcysteine.

What does the nomogram line represent? Does it indicate the total area under the curve, and is this the important factor in the development of toxicity? Is it some threshold serum value that, when surpassed, results in saturation of sulfation and glucu-ronidation and depletion of glutathione? Prescott and colleagues' report (3) of hepatic failure in untreated acetaminophen over­doses showed early prolongation of apparent acetaminophen half-lives before hepatotoxicity occurred, probably as a result of saturation pharmacokinetics. Late crossing of the nomogram line after a single acute overdose of extended-relief acetaminophen may simply reflect slow ongoing absorption rather than saturation pharmacokinetics. Unless some threshold value has been reached, toxicity might be unlikely. Further research and a thoughtful ratio­nal approach to acetaminophen overdose is needed.

Susi Vassallo, MD Abu N.G.A. Khan, MD Mary Ann Howland, PharmD New York Regional Poison Control Center New York, NY 10016

References 1. Cetaruk EW, Dart RC, Horowitz RS, Hurlbut KM. Extended-release

acetaminophen overdose [Letter]. JAMA. 1996;275:686. 2. Graudins A, Aaron CK, Linden CH. Overdose of extended-release

acetaminophen [Letter]. N Engl J Med. 1995;333:196. 3. Prescott LF, Wright N, Roscode P, Brown SS. Plasma-paracetamol

half-life and hepatic necrosis in patients with paracetamol overdose. Lancet. 1971;1:519-22.

Coma from the Health Food Store: Interaction between Kava and Alprazolam

To the Editor: Millions of Americans use drugs sold in health food stores, yet most of these agents are unregulated. The po­tential for drug interactions is great. We report an interaction between kava and alprazolam that caused a semicomatose state.

A 54-year-old man was hospitalized at our center in a lethargic and disoriented state. His medications included alprazolam, ci-metidine, and terazosin. His vital signs and results of laboratory studies were normal. His alcohol level was negative, and a drug screen was positive for benzodiazepines. He became more alert after several hours and stated that he had been taking a "natural tranquilizer" called kava for the past 3 days, bought from a local health food store. He denied overdosing on the kava or alpra­zolam.

The kava plant (Piper methysticum) is a perennial shrub be­longing to the Piperaceae family (1). The plant is indigenous to Oceania and is used widely in the South Pacific for its intoxicat­ing effects (1). Kava is marketed as a mild anxiolytic in European countries. In the United States, kava is sold in health food stores as a natural alternative to antianxiety drugs and sleeping pills.

The active component of kava belongs to a group called a-py-rones and is present in the root extract (2). In a 1992 Australian study, Davies and colleagues (3) investigated the neuropharma-cologic interactions of a-pyrones with central nervous system receptors and found weak effects on 7-amino butyric acid (GABA) or benzodiazepine receptors in vitro. Their findings were verified in a 1994 German study by Jussofie and associates (4) that also showed synergism between a-pyrones and other GABA-active sedatives.

Pharmacologic studies indicate additive effects between kava a-pyrones, pentobarbital, and pregnane steroids (4). These inves­tigational studies suggest that kava might have additive effects with benzodiazepines, given that they act on the same receptor and on the same areas of the central nervous system with in­creased GABA receptors (4). We believe that these findings may explain the mechanism governing the possible interaction be­tween kava and alprazolam.

This report of a possible drug interaction between kava a-py­rones and a benzodiazepine (alprazolam) signals the potential for dangerous interactions between kava and prescription drugs. The growing popularity of kava increases the danger.

940 1 December 1996 • Annals of Internal Medicine • Volume 125 • Number 11

Joenie C. Almeida, MD Edwin W. Grimsley, MD Memorial Medical Center Savannah, GA 31403

References 1. Singh YN. Kava: an overview. J Ethnopharmacol. 1992;37:13-45. 2. Schelosky L, Raffauf C, Jendroska K, Poewe W. Kava and dopamine

antagonism [Letter]. J Neurol Neurosurg Psychiatry. 1995;58:639-40. 3. Davies LP, Drew CA, Duffield P, Johnston GA, Jamieson DD. Kava

pyrones and resin: studies on GABAA, GABAB and benzodiazepine binding sites in rodent brain. Pharmacol Toxicol. 1992;71:120-6.

4. Jussofie A, Schmiz A, Hiemke C. Kavapyrone enriched extract from Piper methysticum as modulator of GABA binding site in different regions of rat brain. Psychopharmacology (Berlin). 1994;116:469-74.

Bias in Observational Studies of Treatment

To the Editor: In their recent article, Glesby and Hoover (1) cite our paper on changes in survival among patients with the acquired immunodeficiency syndrome (AIDS) (2) as an analysis subject to selection bias. We agree that this is a potentially important bias, but we were surprised that they ignored our explicit concern about this effect. We noted that "because sub­jects with rapid CD4 lymphocyte loss were removed from the cohorts by death at a disproportionately high rate during the early years of followup . . . subjects dying early in follow-up or progressing rapidly had less chance to receive therapy" (2).

We do not believe our results are attributable to selection bias. Glesby and Hoover suggest that our conclusions are based on a proportional hazards model. We concluded that treatment and prophylaxis for Pneumocystis carinii pneumonia had a larger ef­fect on improved survival than did antiretroviral therapy because we saw improved survival over the decade only in men with a diagnosis of P. carinii pneumonia, an outcome that is hard to explain if antiretroviral therapy were responsible. We suggested, with qualification by the recognition of possible bias, that the proportional hazards model showed a lack of survival benefit from initiation of zidovudine therapy at higher CD4 lymphocyte counts. This was subsequently found in clinical trials of early compared with late initiation of zidovudine therapy.

Glesby and Hoover hypothesized that "those who received little or no benefit from antiretroviral therapy would have died sooner and, by default, would never have used the prophylaxis." We observed almost no deaths among human immunodeficiency virus positive-patients with CD4 counts greater than 200 cells/ mm3; by 1991, nearly all cohort members with CD4 counts less than 200 cells/mm3 reported some use of antiretroviral and prophy­lactic therapies (90% and 92%, respectively) (3). We believe that the effect of zidovudine use on survival has been modest, but that, in the early years of the epidemic, survival was improved with treating and preventing P. carinii pneumonia.

Dennis H. Osmond, MD Edwin Charlebois, MD Andrew R. Moss, MD University of California, San Francisco San Francisco, CA 94341

References

1. Glesby MJ, Hoover DR. Survivor treatment selection bias in observa­tional studies: examples from the AIDS literature. Ann Intern Med. 1996;124:999-1005.

2. Osmond DH, Charlebois E, Lang W, Shiboski S, Moss A. Changes in AIDS survival time in two San Francisco cohorts of homosexual men, 1983 to 1993. JAMA. 1994;271:1083-7.

3. Lang W, Osmond D, Page-Bodkin K, Moss A, Winkelstein W. Popula­tion-based estimates of antiretroviral therapy and anti-pneumocystis prophylaxis in San Francisco: 1991. JAcquir Immune Defic Syndr. 1993;6:191-3.

In response: Osmond and colleagues make several points about our use of their paper (1) as an example of survivor treatment selection bias. First, although they express concern about this bias in their paper, such a caveat, in our opinion, should not substitute for the use of appropriate statistical models that can address this bias.

Second, the authors state that their conclusions were based on survival comparisons between men with and those without diag­noses of P. carinii pneumonia rather than the (biased) propor­tional hazards model. In fact, survival in their subgroup with P. carinii pneumonia as an initial AIDS-defining diagnosis did not change significantly over the decade (P > 0.2). In addition, their comparisons of survival beyond CD4 counts less than 200 cells/ mnr according to type of initial AIDS-defining illness are also biased. Patients receiving prophylaxis for P. carinii pneumonia who nevertheless develop pneumonia tend to do so at very low CD4 counts (2) and therefore would have survived relatively longer (regardless of treatment) than would patients not receiv­ing prophylaxis who develop pneumonia. Please note that Figure 1 of their paper (1) was mislabeled, and median survival beyond a CD4 count of 200 cells/mm3 in those with P. carinii pneumonia was less (not greater) in the later time period.

Third, Osmond and colleagues cite data on the use of antiret­roviral agents and P. carinii pneumonia prophylaxis that were obtained from a cross-sectional (prevalence) survey (3) and ex­trapolate these data to their cohort study. This extrapolation may be misleading, given that cross-sectional samples reflect the use of treatment in patients with longer survival. Those who die quickly are under-represented in a sample that is taken at a single time point. The authors should instead investigate use of these drugs in the same cohort of men with incident CD4 counts less than 200 cells/mm3 on which they based their original anal­yses.

We stand by our contention that survivor treatment bias may have influenced the conclusions of the study by Osmond and associates (1). The issue could be settled by reanalysis of their data using time-dependent covariates for treatment initiation, as recommended in our report.

We also note an error that occurred in our paper. The study of differences in survival between men and women after AIDS diagnosis, reported by Lemp and colleagues (4), was cited incor­rectly as an example of how survivor treatment bias could lead to misleading conclusions. Lemp and coworkers restricted their analyses of the treatment effect of zidovudine to the time period after the availability of zidovudine (1987 to 1991). Thus, any differential survivor bias between men and women that may have been present in the analysis was greatly overstated in our paper and probably would not have affected the conclusions of Lemp and colleagues.

Marshall J. Glesby, MD Community Research Initiative on AIDS New York, NY 10001

Donald R. Hoover, PhD Johns Hopkins University School of Hygiene and Public Health Baltimore, MD 21205

References 1. Osmond D, Charlebois E, Lang W, Shiboski S, Moss A. Changes in

AIDS survival time in two San Francisco cohorts of homosexual men, 1983 to 1993. JAMA. 1994;271:1083-7.

2. Saah AJ, Hoover DR, Peng Y, Phair JP, Visscher B, Kingsley LA, et al. Predictors for failure of Pneumocystis carinii pneumonia prophylaxis. JAMA 1995;273:1197-202.

3. Lang W, Osmond D, Page-Bodkin K, Moss A, Winkelstein W. Popula­tion-based estimates of antiretroviral therapy and anti-pneumocystis prophylaxis in San Francisco: 1991. JAcquir Immune Defic Syndr. 1993;6:191-3.

4. Lemp GF, Hirozawa AM, Cohen JB, Derish PA, McKinney KC, Her­nandez SR. Survival for women and men with AIDS. J Infect Dis. 1992;166:74-9.

Fatalism and Breast Cancer in Black Women

To the Editor: Moormeier (1) recently summarized the avail­able data on the greater morbidity and mortality of black women with breast cancer. Although we agree with the need for screen­ing and early detection in black women, we believe the problem is more complex than economics and knowledge of the disease.

1 December 1996 • Annals of Internal Medicine • Volume 125 • Number 11 941

We previously postulated that the poor outcome among black women was caused solely by relative unavailability of medical care and the cost of methods of detection. However, when we provided medical care and screening procedures for free, few patients belonging to a minority group participated. Because one third of black patients presenting with breast cancer to our institution have stage III or IV disease, an incomplete-sentence technique was used among patients with breast cancer to deter­mine the reasons for this lack of participation. Most responses described elements of fatalism. Often, this fatalism had religious connotation; some of these respondents believed that one's ac­tions cannot influence outcome or that cancer was a punishment for wrongdoings.

An instrument was developed to collect information on edu­cation, income, race or ethnicity, sex, age, and health practices; an inventory of 10 questions was also developed to quantify responses indicating fatalism. Information was collected from healthy volunteers at marketplaces and malls that were patron­ized by a mixture of ethnic groups. The mean age was 54 years. Data were collected from 600 persons, 68% of whom were fe­male. Black persons had a higher mean fatalism score than whites, and women were more fatalistic than men. Age, educa­tion, and economic status were each significant factors in this survey. When white and black persons who had similar education and economic status were paired, the difference in fatalism scores based on ethnicity or race was markedly diminished. We con­cluded that fatalism is prevalent in poor and less educated pop­ulations and that this factor is an important reason why some persons fail to seek medical care at an early stage of disease and do not use methods for early detection of cancer. Methods of interdiction and education need further study.

Our conclusion and observations are similar to those reported by Powe (2) in the Charleston, South Carolina, area. Whether fatalism is primarily a problem in southern United States and whether it is a significant problem in other minority populations are not known.

Marcel E. Conrad, MD Patricia Brown, BS Marcia G. Conrad, MSN, MPH University of South Alabama Mobile, AL 36688

References 1. Moormeier J. Breast cancer in black women. Ann Intern Med. 1996;

124:897-905. 2. Powe BD. Cancer fatalism among elderly Caucasians and African Amer­

icans. Oncology Nursing Forum. 1995;22:1355-9.

Underestimation of Testicular Size by Medical Students and Housestaff

To the Editor: Recent reports (1, 2) have addressed deficiencies in medical education, especially education for physical examina­

tion. Improper examination techniques, omissions, detection fail­ures, and errors in interpreting physical findings can often affect diagnosis (3). This is particularly true for testicular examination, where identifying small size can lead to the clinical diagnosis of hypogonadism and its important treatable causes (such as pitu­itary disease) and sequelae (including osteoporosis, anemia, and infertility).

We questioned 81 third- and fourth-year medical students and internal medicine housestaff at four major teaching hospitals in the Washington, D.C., area about testicular examination. By examining a Prader orchidometer (which consists of 12 ellipsoids that vary in volume from 1 to 25 cm3), the students and house-staff were asked to identify the ellipsoid that best represented normal adult testicular size. Normal testicular size was defined as larger than 15 cm3 on the basis of data that correlated testicular size, as measured by orchidometer, with testicular function (4). Estimates of normal testicular size had a wide range. Residents in internal medicine were less accurate (4 of 24 [17%] made correct estimates) than were interns (9 of 24 [37%]) or medical students (9 of 33 [27%]). Eight of 81 (10%) participants regarded prepubertal testes as normal for an adult, but only 27% (22 of 81) identified testes larger than 15 cm3 as normal.

To improve education in physical examination skills, the nature and frequency of errors must be determined (1). We found that most internal medicine housestaff and students could not identify normal adult testicular size. We recommend that attending phy­sicians question a reported normal testicular size at least once during rounds and show normal size either at the bedside or through use of an orchidometer. Increased attention to testicular examination and wider availability of orchidometers would pro­mote awareness of normal testicular size and should result in more frequently correct clinical diagnoses of hypogonadism.

Note: The views expressed in this letter are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, or the U.S. Government.

Brian S. Aprill, MD Rodney D. Michaels, MD KM. Mohamed Shakir, MD National Naval Medical Center Bethesda, MD 20889-5600

References 1. Johnson JE, Carpenter JL. Medical housestaff performance in physical

examination. Arch Intern Med. 1986;146:937-41. 2. Wray NP, Friedland JA. Detection and correction of housestaff error in

physical diagnosis. JAMA. 1983;249:1035-7. 3. Weiner S, Nathonson M. Physical examination—frequently observed

errors. JAMA. 1976;236:852-5. 4. Takihara H, Costentino MJ, Sakatoko J, Cochett AT. Significance of

testicular size measurement in andrology. II. Correlation of testicular size with testicular function. J Urol. 1987;137:416-9.

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