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Methadone and immune function
I
ICORRESPONDENCE
OLYAGGLUTINATION:A RARE hemolytic reactions. Bird [6] recMECHANISM FOR ommends the transfusion of INTRAVASCULARHEMOLYSIS washed RBCs to patients with
To the Editor:
We read with great interest the clinicopathologic conference (CPC) in the June 1990 issue of the Journal [l]. We would like to point out that there is another rare mechanism for intravascular hemolysis, polyagglutination. Polyagglutinable red blood cells (RBCs) have exposed cryptantigens either due to the action of microbial enzymes, or as the result of somatic mutation or inheritance of uncommon genes. These altered RBCs are agglutinated by a large percentage of compatible sera from healthy individuals but not usually by their own serum or from cord blood. They can be detected by the use of specific lectins. Very few case reports of patients with massive intravascular hemolysis due to polyagglutination have been described [2,3]. One of these was associated with disseminated intravascular coagulation (DIC) and renal failure [Z]. The enzyme neuraminidase, such as that produced by Clostridium perfringens, can modify the membrane of RBCs both in vivo and in vitro and expose the T cryptantigen. Neuraminidase cleaves sialic acid and exposes terminal fl Gal residue that is recognized by specific anti-T present in adult human sera and extracts of the peanut lectin Arathis hypogaea [4]. Exposure of cryptantigens on RBCs has been described in patients with malignancies [5]. In such patients, it is important to examine RBCs for polyagglutination with the use of lectins, especially if they require blood transfusion or the transfusion of fresh plasma products. In these cases, the presence of the naturally occurring polyagglutinins in donor plasma may induce or exacerbate severe, even fatal
In vivo hemolysis is not an invariable accompaniment of polyagglutinability; this controverpolyagglutinable RBCs. sial topic has recently been reIn the CPC reported, there was viewed by Mollison et al [I]. The no mention of polyagglutination, role of transfused plasma as a but the severe intravascular he- possible cause of in vivo hemolymolysis with DIC suggests that it sis in patients whose RBCs are may have been exacerbated in polyagglutinable has been part by this phenomenon. strongly suggested in a number of ERICA SIGLER,M.D. published reports, as reviewed in NAOMI A. LEVENE, M.D. reference 6 in the above letter Kaplan Hospital Rehovot, Israel and in Mollison’s [l] article. The CYRIL LEVENE, M.D. admonition to avoid transfusion Reference Laboratory of Blood of plasma-containing blood prodGroups ucts is well taken and should be Ministry of Health Jerusalem, Israel seriously considered whenever MORDECHAISHTALRID polyagglutinability has been Kaplan Hospital demonstrated. Unfortunately, Rehovot, Israel patients such as ours frequently 1. Clinrcopathologic Conference. Abdominal pain, demonstrate severe DIC with total intravascular hemolysis, and death in a 53year-old woman. Am J Med 1990; 88: 667-74. complicating hemorrhage, and 2. Levene C, Sela R, BlatY, Friedlander M, Manny N. transfusion of fresh frozen plasIntravascular hemolysis and renal failure in a patient ma may be unavoidable (as was with T-polyagglutination. Transfusion 1986; 26: the case in our patient). 243-5. 3. Levene NA, Levene C, Gekker E, Sigler E. Merhav H. Berrebi A. Th polyagglutination with fatal outcome rn a patient with massive intravascular hemolysis and perforated tumor of colon. Am J Hematol 1990; 35: 127-8. 4. Bird GWG. Anti-T in peanuts. VOX Sang 1964; 9: 748-50. 5. Buskila D, Levene C, Biran H, Levene NA. Exposure of crypatantigens in a patient with breast cancer. Cancer 1988; 61: 2455-9. 6. Bird GWG. In: Beck ML, Judd WJ, editors. Lectins and red cell polyagglutinability: history, comments and recent developments. Polyagglutination, a technical workshop. Washington, DC: AABB, 1980: 71-90. Submitted
March 29, 1991. and accepted
June 12, 1991
The Reply:
I appreciate the very interesting letter by Sigler et al regarding the possibility that polyagglutinability of the patient’s RBCs secondary to exposed cryptantigens may have contributed to the severity of intravascular hemolysis in our patient. There was no opportunity to observe polyagglutinability, since there were essentially no intact RBCs in the patient’s admission blood sample as submitted to the blood bank. She had received no transfusions at that time. January
1992
The American
HUGH
CHAPLIN,
M.D.
Washington University School of Medicine St. Louis, Missouri 1. Mollison PL, Engelfriet CD, Contreras M. Hemolytic syndrome due to T activation? In: Blood transfusion in clinical medicine. 8th ed. Boston: Blackwell Scientific Publications, 1987: 445-6.
METHADONEAND IMMUNE FUNCTION To the Editor:
The study by Klimas et al [l] on immune function in intravenous drug users receiving methadone relates to a subject of great clinical and public health interest. However, their suggestion that methadone is the most likely cause of the immunologic abnormalities they observed is not supported by their own data or the literature. Numerous studies of parenteral drug users performed before and after the onset of the epidemic of human immunodeficiency virus type 1 (HIV-l) have shown immunologic abnormalities indeJournal
of Medicine
Volume
92
113
CORRESPONDENCE
pendent of HIV-l infection. These include generalized lymphadenopathy, elevated serum immunoglobulin levels, lymphocytosis, elevated absolute numbers of T-lymphocyte subsets, impaired lymphocyte proliferative response to mitogens, and reduced natural killer (NK) cell activity [2-51. Klimas et a2 emphasize retroviruses and opiates as potential causes of these alterations but ignore the many other effects of parenteral drug abuse such as numerous infectious diseases of all types, effects of adulterants of narcotics, stress, poor nutrition, altered sleep-wake cycles, and chronic liver disease [3]. The immunologic abnormalities induced by the combination of these factors in parenteral drug users have been shown to persist during the first several years of methadone maintenance treatment [6-81, although they subside and even resolve during continued treatment [5]; thus, parenteral drug use per se is a much more likely explanation for the findings of Klimas et al than is the use of methadone. To determine whether methadone directly causes immunologic abnormalities, the authors would have to compare stable methadone maintenance patients with parenteral heroin users not receiving methadone or, if possible, with drugfree former parenteral heroin users. Data contained within the report by Klimas et al suggest that confounding variables for immunologic abnormalities exist in their patients. Although the authors do not indicate the duration of parenteral drug abuse or the range of elapsed times since the last injection, it is noteworthy that 58% of their patients reported at least some injections in the year preceding the study. Unspecified numbers of patients also used nonparenteral drugs, including alcohol.
It is likely that opiates, including methadone, do possess some immunomodulatory effects [3]. The key point, however, is that any such effect during successful methadone maintenance treatment will be biologically and clinically insignificant in relation to the normalization of immune function that occurs as a result of the sustained remission of parenteral heroin use. Methadone maintenance treatment is the most successful treatment for hard-core heroin addicts and can prevent HIV-l infection in such patients by eliminating parenteral drug use [lo]. Increased availability of this treatment is urgently needed. To suggest otherwise without proper data, as does the report by Klimas et al, is dangerous to patients and society.
114
of Medicine
January
1992
The American
Journal
We have published a report, curiously omitted by Klimas et al, in which NK cell activity and lymphocyte subsets were determined in methadone maintenance patients, parenteral heroin users, and apparently healthy subjects [5]. The methadone maintenance patients in our study had no parenteral drug use in the preceding 10 years and no alcohol or other drug use; their median dose of methadone was 40 mg, their median duration of treatment was 16 years (range: 11 to 21 years), and all were seronegative for antibody to HIV-l. We found no difference in NK cell activity or lymphocyte subsets between these very-long-term methadone maintenance patients and the apparently healthy subjects. Active parenteral heroin users, also HIV-l-seronegative, had, in contrast, markedly lower NK cell activities and higher absolute numbers of CD2-, CD3-, CD4-, and CDS-positive cells [5]. In a subsequent study, methadone concentrations above those achieved in any clinical use had no effect on NK cell activity in vitro
[9].
Volume
92
DAVID M. NOVICK, M.D. MAR Y JEANNE KREEK, M.D.
The Rockefeller University New York, New York 1. Klimas NG, Blaney NT, Morgan RO. eta/. Immune function and anti-HTLV-l/II status in anti-HIV-l-negative intravenous drug users receiving methadone. Am J Med 1991; 90: 163-70. 2. Kreek MJ. Immune function in heroin addicts and former heroin addicts in treatment: pre- and postAIDS epidemic. Natl lnst Drug Abuse Res Monogr Ser 1990; 96: 192-219. 3. Novick DM, Ochshorn M, Kreek MJ. In viva and in vitrostudies of opiates and cellular immunity in narcotic addicts. In: Friedman H. Specter S. Klein TW, editors. Drugs of abuse, immunity, and immunodeficiency. New York: Plenum Press, 1991: 159-70. 4.Zolla-Pawner S. Des Jarlais DC, Friedman SR, et al. Nonrandom development of immunologic abnormalities after infection with human immunodeficiency virus: implications for immunologic classification of the disease. Proc Nat1 Acad Sci U S A 1987: 84: 5405-a. 5. Novick DM, Ochshorn M, Ghali V, et al. Natural killer cell activity and lymphocyte subsets in parenteral heroin abusers and long-term methadone maintenance patients. J Pharmacol Exp Ther 1989; 250: 606-10. 6. Cushman P. Grieco MH. Hyperimmunoglobulinemia associated with narcotic addiction: effects of methadone treatment. Am J Med 1973; 54: 320-6. 7. Kreek MJ. Medical safety and side effects of methadone in tolerant individuals. JAMA 1973; 2’23: 665-8. 8. Cushman P, Gupta S, Grieco MH. Immunological studies in methadone maintained patients. Int J Addict 1977; 12: 241-53. 9. Ochshorn M, Novick DM, Kreek MJ. In vitrostudies of the effect of methadone on natural killer cell activity. Ix J Med Sci 1990; 26: 421-5. 10. Cooper JR. Methadone treatment and acquired immunodeficiency syndrome. JAMA 1989; 262: 1664-g. Submitted
March 29. 1991, and accepted
June 12, 1991
The Reply:
We are grateful to Novick and Kreek for bringing to our attention the citation for their recent study of 11 very-long-term methadone users [I]. They studied some immunologic markers in “successful, ” “stable” former addicts who remained clear of other drugs and on methadone maintenance for more than a decade. Novick et al found no differences between these subjects and controls for certain lymphocyte subsets and in NK cell cytotoxicity. Unfortunately, comparisons between their study and ours [Z] are difficult to make.
ICORRESPONDENCE
OLYAGGLUTINATION:A RARE hemolytic reactions. Bird [6] recMECHANISM FOR ommends the transfusion of INTRAVASCULARHEMOLYSIS washed RBCs to patients with
To the Editor:
We read with great interest the clinicopathologic conference (CPC) in the June 1990 issue of the Journal [l]. We would like to point out that there is another rare mechanism for intravascular hemolysis, polyagglutination. Polyagglutinable red blood cells (RBCs) have exposed cryptantigens either due to the action of microbial enzymes, or as the result of somatic mutation or inheritance of uncommon genes. These altered RBCs are agglutinated by a large percentage of compatible sera from healthy individuals but not usually by their own serum or from cord blood. They can be detected by the use of specific lectins. Very few case reports of patients with massive intravascular hemolysis due to polyagglutination have been described [2,3]. One of these was associated with disseminated intravascular coagulation (DIC) and renal failure [Z]. The enzyme neuraminidase, such as that produced by Clostridium perfringens, can modify the membrane of RBCs both in vivo and in vitro and expose the T cryptantigen. Neuraminidase cleaves sialic acid and exposes terminal fl Gal residue that is recognized by specific anti-T present in adult human sera and extracts of the peanut lectin Arathis hypogaea [4]. Exposure of cryptantigens on RBCs has been described in patients with malignancies [5]. In such patients, it is important to examine RBCs for polyagglutination with the use of lectins, especially if they require blood transfusion or the transfusion of fresh plasma products. In these cases, the presence of the naturally occurring polyagglutinins in donor plasma may induce or exacerbate severe, even fatal
In vivo hemolysis is not an invariable accompaniment of polyagglutinability; this controverpolyagglutinable RBCs. sial topic has recently been reIn the CPC reported, there was viewed by Mollison et al [I]. The no mention of polyagglutination, role of transfused plasma as a but the severe intravascular he- possible cause of in vivo hemolymolysis with DIC suggests that it sis in patients whose RBCs are may have been exacerbated in polyagglutinable has been part by this phenomenon. strongly suggested in a number of ERICA SIGLER,M.D. published reports, as reviewed in NAOMI A. LEVENE, M.D. reference 6 in the above letter Kaplan Hospital Rehovot, Israel and in Mollison’s [l] article. The CYRIL LEVENE, M.D. admonition to avoid transfusion Reference Laboratory of Blood of plasma-containing blood prodGroups ucts is well taken and should be Ministry of Health Jerusalem, Israel seriously considered whenever MORDECHAISHTALRID polyagglutinability has been Kaplan Hospital demonstrated. Unfortunately, Rehovot, Israel patients such as ours frequently 1. Clinrcopathologic Conference. Abdominal pain, demonstrate severe DIC with total intravascular hemolysis, and death in a 53year-old woman. Am J Med 1990; 88: 667-74. complicating hemorrhage, and 2. Levene C, Sela R, BlatY, Friedlander M, Manny N. transfusion of fresh frozen plasIntravascular hemolysis and renal failure in a patient ma may be unavoidable (as was with T-polyagglutination. Transfusion 1986; 26: the case in our patient). 243-5. 3. Levene NA, Levene C, Gekker E, Sigler E. Merhav H. Berrebi A. Th polyagglutination with fatal outcome rn a patient with massive intravascular hemolysis and perforated tumor of colon. Am J Hematol 1990; 35: 127-8. 4. Bird GWG. Anti-T in peanuts. VOX Sang 1964; 9: 748-50. 5. Buskila D, Levene C, Biran H, Levene NA. Exposure of crypatantigens in a patient with breast cancer. Cancer 1988; 61: 2455-9. 6. Bird GWG. In: Beck ML, Judd WJ, editors. Lectins and red cell polyagglutinability: history, comments and recent developments. Polyagglutination, a technical workshop. Washington, DC: AABB, 1980: 71-90. Submitted
March 29, 1991. and accepted
June 12, 1991
The Reply:
I appreciate the very interesting letter by Sigler et al regarding the possibility that polyagglutinability of the patient’s RBCs secondary to exposed cryptantigens may have contributed to the severity of intravascular hemolysis in our patient. There was no opportunity to observe polyagglutinability, since there were essentially no intact RBCs in the patient’s admission blood sample as submitted to the blood bank. She had received no transfusions at that time. January
1992
The American
HUGH
CHAPLIN,
M.D.
Washington University School of Medicine St. Louis, Missouri 1. Mollison PL, Engelfriet CD, Contreras M. Hemolytic syndrome due to T activation? In: Blood transfusion in clinical medicine. 8th ed. Boston: Blackwell Scientific Publications, 1987: 445-6.
METHADONEAND IMMUNE FUNCTION To the Editor:
The study by Klimas et al [l] on immune function in intravenous drug users receiving methadone relates to a subject of great clinical and public health interest. However, their suggestion that methadone is the most likely cause of the immunologic abnormalities they observed is not supported by their own data or the literature. Numerous studies of parenteral drug users performed before and after the onset of the epidemic of human immunodeficiency virus type 1 (HIV-l) have shown immunologic abnormalities indeJournal
of Medicine
Volume
92
113
CORRESPONDENCE
pendent of HIV-l infection. These include generalized lymphadenopathy, elevated serum immunoglobulin levels, lymphocytosis, elevated absolute numbers of T-lymphocyte subsets, impaired lymphocyte proliferative response to mitogens, and reduced natural killer (NK) cell activity [2-51. Klimas et a2 emphasize retroviruses and opiates as potential causes of these alterations but ignore the many other effects of parenteral drug abuse such as numerous infectious diseases of all types, effects of adulterants of narcotics, stress, poor nutrition, altered sleep-wake cycles, and chronic liver disease [3]. The immunologic abnormalities induced by the combination of these factors in parenteral drug users have been shown to persist during the first several years of methadone maintenance treatment [6-81, although they subside and even resolve during continued treatment [5]; thus, parenteral drug use per se is a much more likely explanation for the findings of Klimas et al than is the use of methadone. To determine whether methadone directly causes immunologic abnormalities, the authors would have to compare stable methadone maintenance patients with parenteral heroin users not receiving methadone or, if possible, with drugfree former parenteral heroin users. Data contained within the report by Klimas et al suggest that confounding variables for immunologic abnormalities exist in their patients. Although the authors do not indicate the duration of parenteral drug abuse or the range of elapsed times since the last injection, it is noteworthy that 58% of their patients reported at least some injections in the year preceding the study. Unspecified numbers of patients also used nonparenteral drugs, including alcohol.
It is likely that opiates, including methadone, do possess some immunomodulatory effects [3]. The key point, however, is that any such effect during successful methadone maintenance treatment will be biologically and clinically insignificant in relation to the normalization of immune function that occurs as a result of the sustained remission of parenteral heroin use. Methadone maintenance treatment is the most successful treatment for hard-core heroin addicts and can prevent HIV-l infection in such patients by eliminating parenteral drug use [lo]. Increased availability of this treatment is urgently needed. To suggest otherwise without proper data, as does the report by Klimas et al, is dangerous to patients and society.
114
of Medicine
January
1992
The American
Journal
We have published a report, curiously omitted by Klimas et al, in which NK cell activity and lymphocyte subsets were determined in methadone maintenance patients, parenteral heroin users, and apparently healthy subjects [5]. The methadone maintenance patients in our study had no parenteral drug use in the preceding 10 years and no alcohol or other drug use; their median dose of methadone was 40 mg, their median duration of treatment was 16 years (range: 11 to 21 years), and all were seronegative for antibody to HIV-l. We found no difference in NK cell activity or lymphocyte subsets between these very-long-term methadone maintenance patients and the apparently healthy subjects. Active parenteral heroin users, also HIV-l-seronegative, had, in contrast, markedly lower NK cell activities and higher absolute numbers of CD2-, CD3-, CD4-, and CDS-positive cells [5]. In a subsequent study, methadone concentrations above those achieved in any clinical use had no effect on NK cell activity in vitro
[9].
Volume
92
DAVID M. NOVICK, M.D. MAR Y JEANNE KREEK, M.D.
The Rockefeller University New York, New York 1. Klimas NG, Blaney NT, Morgan RO. eta/. Immune function and anti-HTLV-l/II status in anti-HIV-l-negative intravenous drug users receiving methadone. Am J Med 1991; 90: 163-70. 2. Kreek MJ. Immune function in heroin addicts and former heroin addicts in treatment: pre- and postAIDS epidemic. Natl lnst Drug Abuse Res Monogr Ser 1990; 96: 192-219. 3. Novick DM, Ochshorn M, Kreek MJ. In viva and in vitrostudies of opiates and cellular immunity in narcotic addicts. In: Friedman H. Specter S. Klein TW, editors. Drugs of abuse, immunity, and immunodeficiency. New York: Plenum Press, 1991: 159-70. 4.Zolla-Pawner S. Des Jarlais DC, Friedman SR, et al. Nonrandom development of immunologic abnormalities after infection with human immunodeficiency virus: implications for immunologic classification of the disease. Proc Nat1 Acad Sci U S A 1987: 84: 5405-a. 5. Novick DM, Ochshorn M, Ghali V, et al. Natural killer cell activity and lymphocyte subsets in parenteral heroin abusers and long-term methadone maintenance patients. J Pharmacol Exp Ther 1989; 250: 606-10. 6. Cushman P. Grieco MH. Hyperimmunoglobulinemia associated with narcotic addiction: effects of methadone treatment. Am J Med 1973; 54: 320-6. 7. Kreek MJ. Medical safety and side effects of methadone in tolerant individuals. JAMA 1973; 2’23: 665-8. 8. Cushman P, Gupta S, Grieco MH. Immunological studies in methadone maintained patients. Int J Addict 1977; 12: 241-53. 9. Ochshorn M, Novick DM, Kreek MJ. In vitrostudies of the effect of methadone on natural killer cell activity. Ix J Med Sci 1990; 26: 421-5. 10. Cooper JR. Methadone treatment and acquired immunodeficiency syndrome. JAMA 1989; 262: 1664-g. Submitted
March 29. 1991, and accepted
June 12, 1991
The Reply:
We are grateful to Novick and Kreek for bringing to our attention the citation for their recent study of 11 very-long-term methadone users [I]. They studied some immunologic markers in “successful, ” “stable” former addicts who remained clear of other drugs and on methadone maintenance for more than a decade. Novick et al found no differences between these subjects and controls for certain lymphocyte subsets and in NK cell cytotoxicity. Unfortunately, comparisons between their study and ours [Z] are difficult to make.