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Vitamin B 12 Deficiency after Gastric Surgery

To the Editor: The study by Sumner and colleagues (1) confirms such metabolic consequences of gastric surgery as vitamin
B 12 (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 B 12 . 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 B 12 (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 B 12
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 B 12 replacement
be used in patients who have had gastric surgery and who have
vitamin B 12 levels less than 221 pmol/L) indicate that overdiagnosing 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
testsmeasurement of serum methylmalonic acid and total homocysteine levelsto determine vitamin B 12 deficiency. We did not
determine the cause of vitamin B 12 deficiency but agree with Drs.
Murthy and Visweswaraiah that achlorhydria, intestinal blindloop 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 B 12
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 B 12 deficiency, 12 were outpatients, 5 were inpatients,
and 2 were residents of a Veterans Affairs nursing home.
Participants were not treated simultaneously with vitamin B 12
and folate. Because we used elevation of serum methylmalonic
acid levels and low or normal vitamin B 12 levels as our major
criteria for defining vitamin B 12 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 B 12 deficiency (normal
methylmalonic acid level and abnormal homocysteine level).
Treatment with vitamin B 12 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 B 12 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 B 12 level are not specific and that if
this level alone is relied on, vitamin B 12 deficiency could be
overdiagnosed. In our study, only 2 of 22 controls with low
vitamin B 12 levels had metabolic evidence of vitamin B 12 deficiency. Because patients who have had gastric surgery have an
increased risk for vitamin B 12 malabsorption, the number who
were deficient was much higher; therefore, fewer patients with
normal vitamin B 12 levels would be treated on the basis of only
the serum vitamin B 12 level. Further, overtreatment with vitamin
B 12 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 B 12 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

Outpatient Management of HIV-Related

Pneumonia

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

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 coccidioides.
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.

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 aspirindipyridamole
on graft patency one year after coronary artery bypass grafting. J Thorac 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 Trialists' 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.

938

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 inducedsputum 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

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 coccidiomycosis 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 diabetic 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.

940

1 December 1996 Annals of Internal Medicine

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 glucuronidation 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, cimetidine, 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-pyrones and is present in the root extract (2). In a 1992 Australian
study, Davies and colleagues (3) investigated the neuropharmacologic 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.

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 GABA A , GABA B 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/
m n r 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.
J A M A 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 Americans. 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-

942

1 December 1996 Annals of Internal Medicine

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 cm 3 ), the students and housestaff were asked to identify the ellipsoid that best represented
normal adult testicular size. Normal testicular size was defined as
larger than 15 cm 3 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 cm 3 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 examinationfrequently 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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