Behr syndrome

INTRODUCTION

Bone marrow transplantation is used to treat an increasing number of patients and diseases (1, 2). As it is among the most recent of advances in transplant medicine, the impact of lifetime substance abuse by recipients on bone marrow transplantation outcome has yet to be systematically addressed.

In contrast, alcoholism and liver transplantation have been considered from both medical and ethical aspects. Since alcoholic liver disease causes end-stage liver failure, concerns about unsatisfactory rates of posttransplant survival if alcohol use is resumed, persist. Recently, however, Starzl, et al. have found that posttransplant results with alcoholic patients are comparable to those with other adult patients with other hepatic diseases (3,4,5,6).

The purpose of this retrospective study is to test the hypothesis that lifetime substance abuse will have an adverse impact on survival after bone marrow transplantation when other factors including disease and procedure are equal. Substance abuse or dependence is defined according to the criteria established by the American Psychiatric Association in the Diagnostic and Statistical Manual of Mental Disorders, Third Edition--Revised (DSM-III-R, 7), and does not include individuals with insignificant or trivial use.

METHODS

Subjects

Study subjects were selected from 468 patients admitted since January 1990 to the Brigham and Women's Hospital in Boston for bone marrow transplantation. Subjects were eligible for inclusion if they were identified by nursing and physician staff to have a lifetime substance abuse problem at admission.

Study Design

Comparison patients were selected from the BMT admissions roster without knowledge of the study endpoint, survival time, by the first author. Criteria for matching included diagnosis and stage, pretransplant BMT conditioning regimen, BMT type (allogeneic, autologous, or matched unrelated), and age. Pretransplant conditioning regimen may consist of either chemotherapy or chemotherapy with radiation to ablate the patient's own marrow. Matches were then reviewed and approved by the BMT Medical Director for medical comparability.

The medical records of patients with and without substance abuse problems were then reviewed and abstracted by the first author, certified in Addiction Psychiatry, or the certified addictions counselor for confirmation of the patients' substance abuse status, course of transplant, outcome, and demographic information. This study was approved by the Human Research Committee of the Brigham and Women's Hospital.

Data Analysis

Simple descriptive statistics comparing patients with and without substance abuse were calculated. Results are reported as percentages or as means with standard deviations.

Survival times were calculated from the date of admission to the date of last follow up. Failure was defined as death; patients still alive at last follow up were censored. Survival data were then analyzed using the SAS Lifetest procedure (8) to compute Kaplan Meier survival distributions and log rank tests for association of survival time with lifetime substance abuse. A second survival analysis was performed with stratification by history of cigarette smoking to test for its potential association with survival time and to adjust for the effect of cigarette smoking before assessing the effect of lifetime substance abuse on survival. Finally, a third survival analysis was performed with stratification by type of bone marrow transplant to test the association of survival time with type of bone marrow transplant, and to adjust for type of transplant before assessing the effect of lifetime substance abuse on survival. All reported probability values are two-sided.

RESULTS

Seventeen patients were identified by BMT nursing and physician staff to have either current or remote substance abuse at admission. The positive substance abuse assessment was confirmed in all 17 cases by the expert substance abuse reviewers. Medical record data included comprehensive physician and nursing preadmission, admission and hospital assessments which ask for history, frequency and quantity of alcohol and substance use, evaluations completed by psychiatrists and social workers, and documented reports of patient substance abuse given to staff by patient's family members. Eleven of the 17 (65%) patients acknowledged using substances up to the day of admission, such as drinking 6 to 12 beers daily, smoking marijuana daily, or "eating" 30 percocets daily. Some patients reported having blackouts and arrests for driving while intoxicated prior to admission, and one, who drank up to a fifth of spirits daily, was detoxified just two months prior to transplant admission. Duration of substance use ranged from regular use for a year, to 3habitual use for many years.

The diagnostic impression was based on all available information on chart review, and the probable DSM-III-R diagnoses are as follows: alcohol abuse or dependence, current, n = 6; alcohol abuse or dependence, in remission, n = 6; cocaine abuse, in remission, n = 1; marijuana abuse, current, n = 5; opiate abuse or dependence, current, n = 2; opiate abuse or dependence, in remission, n = 3; benzodiazepine abuse, current, n = 1; polysubstance abuse or dependence (alcohol, opiate, and benzodiazepine simultaneously), current, n = 1. Of note, 14 of the 17 patients with lifetime substance abuse or dependence were also cigarette smokers, with an average of 19.3 [+ or -] 10.2 pack years. None of the 17 comparison patients was found to have lifetime substance abuse or dependence. In contrast to the substance abusers, only 3 of these patients were cigarette smokers, with an average of 7.0 [+ or -] 3.6 pack years.

Both groups of patients were otherwise very similar at admission. All were Caucasian with insurance. The mean age of patients with SA was 38.1 years and 36.1 years for patients without SA. The proportion of male and female patients in each group was likewise comparable. Both groups were equally matched for type of bone marrow transplant, disease, stage, and pretransplant conditioning regimen. Table 1 summarizes the overall comparisons.

(*) Total exceeds 100% because individuals used more than one but fewer than three substances. Simultaneous abuse/dependence of three or more substances meets DSM-III-R diagnostic criteria for polysubstance abuse/dependence.

Figure 1 summarizes the probability of survival after admission for transplant for patients with and without substance abuse. Two of 17 (12%) patients with substance abuse were censored and 10 of 17 (59%) patients without substance were censored. From the plot of survival function estimates, it is apparent that the two groups differ in survival time. The log rank test was significant with p = .0022.

[Figure 1 ILLUSTRATION OMITTED]

Cause of death is summarized as follows. Among the 15 patients with substance abuse who died, 5 succumbed to sepsis, 3 to veno-occlusive disease, 2 to graft versus host disease, and 1 each to respiratory disease, hemorrhage, liver failure, hemolytic uremic syndrome, and disease recurrence. Among the 7 comparison patients without substance abuse who died, 4 succumbed to respiratory disease, 2 to graft versus host disease, and 1 to hemorrhage.

Through survival analysis, trends in different survival times by type of transplant, with worst survival for matched unrelated transplants (p = .054), and by history of cigarette smoking, with worse survival among smokers (p = .07), are suggested. Finally, additional tests were consistent with reduced survival time for substance abusers in comparison to patients without substance abuse after controlling for BMT type, p = .0006, and after controlling for smoking history, p = .025.

DISCUSSION

The principal finding of this retrospective study is that patients with lifetime substance abuse or dependence have a diminished probability of survival in comparison to comparable patients without substance abuse or dependence after bone marrow transplantation. Data analyses also suggested trends in different survival times by type of bone marrow transplant and by history of cigarette smoking.

Potential limitations of this study may include the sample size, which precludes a full multivariate analysis and the retrospective design. It is unlikely, however, that with the thorough pretransplant assessment that other transplant patients with obvious substance abuse diagnoses were unrecognized and not included in the study.

The sample size of 34, which required five years to assemble, would have been further reduced if an attempt had been made to match cases and controls for cigarette smoking, in addition to type and stage of cancer, pretransplant conditioning regimen, type of transplant, and age, which were all known risk factors for transplant outcome at the inception of this study. The retrospective design was the most practical method of inquiry for this specialized population and now provides leads for future, definitive cohort studies (9).

Explanations as to how substance abuse and which substances in particular might have an adverse impact on bone marrow transplant outcome are necessarily speculative at present. Possible reasons include subclinical hepatic injury from current or remote alcohol or intravenous drug use, with alterations in hepatic drug-metabolizing enzymes, or pulmonary damage from cigarette smoking (10). A prospective study of 351 medical and surgical intensive care unit patients demonstrated that a prior history of chronic alcohol abuse significantly increases the risk of developing Acute Respiratory Distress Syndrome, which is associated with a 40 to 65% mortality rate (11). Substance users may have less healthful lifestyles or practices, such as cigarette smoking, that may put them at risk for increased mortality, or have less supportive environments which could jeopardize posttransplant care.

This retrospective study suggests that substance abuse or dependence has an adverse relationship with bone marrow transplant survival when other clinical factors are equal. Although patients with substance abuse diagnoses should not be denied the opportunity of transplant on the basis of this report, prospective studies of bone marrow transplant patients with systematic assessment of their substance use, including cigarette smoking, are indicated. Goals of future research include testing the generalizability of these findings and assessment of the impact of the magnitude and recency of specific substance use on transplant outcome.

ACKNOWLEDGMENTS

The authors wish to acknowledge Michele Hassler, RN, and Peter Sullivan, RN, who assisted in identification of patients with substance abuse.

REFERENCES

(1.) Armitage, J. O., Bone marrow transplantation, The N. E. J. Med 330(12):827-838 (1994).

(2.) McCullough, J., Rogers, G., Therkelsen, D., et al., Development and operation of a program to obtain volunteer bone marrow donors unrelated to the patient, Transfusion 26(4):315-323 (1986).

(3.) Lucey, M. R., Liver transplantation for the alcoholic patient, Advances in liver Transplantation 22(2):243-256 (1993).

(4.) Moss, A. H., and Siegler, M., Should alcoholics compete equally for liver transplantation, JAMA 265(10):1295-1298 (1991).

(5.) Cohen, C., Benjamin, P., and the Ethics and Social Impact Committee of the Transplant and Health Policy Center, Alcoholics and liver transplantation, JAMA 265(10):1299-1301 (1991).

(6.) Starzl, T. E., VanThiel, D., Tzakis, A. G., et al., Orthopic liver transplantation for alcoholic cirrhosis. JAMA 260(17):2542-2547 (1988).

(7.) American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Third Edition--Revised, American Psychiatric Association, Washington, D.C., 1987.

(8.) SAS Institute, The Lifetest Procedure in SAS Institute, SAS/STAT User's Guide, Volume 2, GLM-VARCOMP. SAS Institute, Cary, North Carolina, 1990, pp. 1027-1069.

(9.) Kelsey, J. L., Thompson, W. D., and Evans, A. S., Methods in Observational Epidemiology, Oxford University Press, 1986, New York, pp. 148-186.

(10.) Secretary of Health and Human Services, Eighth Special Report to the US Congress on Alcohol and Health, EEI, Alexandria, Virginia, 1993, pp. 165-185.

(11.) Moss, M., Bucher, B., Moore, F. A., et al., The role of chronic alcohol abuse in the development of acute respiratory distress syndrome in adults, JAMA 275(1):50-54 (1996).

Grace Chang, M.D., M.P.H., Joseph H. Antin, M.D., E. John Orav, Ph.D., Una Randall, R.N., Carol McGarigle, R.N., Heidi M. Behr, C.A.D.C., Brigham and Women's Hospital Boston, Massachusetts

Grace Chang, M.D., M.P.H., Department of Psychiatry Harvard Medical School Boston, Massachusetts

Joseph H. Antin, M.D., Division of Hematology-Oncology Department of Medicine, Harvard Medical School Boston, Massachusetts

E. John Orav, Ph.D., Department of Medicine (Biostatistics) Harvard Medical School Boston, Massachusetts 02115

Grace Chang, M.D., M.P.H., To whom correspondence should be addressed at the Division of Psychiatry, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115. Telephone: (617) 732-6775. Fax: (617) 738-8703. E-mail: GChang@Bics.BWH.Harvard.edu.

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