Journal of Clinical Apheresis 7:171-172 (1992)
Editorial Toxicity of the Staphylococcal Protein A Immunoadsorption Column In the spring of 1992, a letter from the manufacturer of a staphylococcal protein A (SPA) immunoadsorption column provided new reports on the efficacy of the column (Prosorbam,ImrC Corporation, Seattle, WA). This letter described successes in the resolution of chronic immunologic thrombocytopenic purpura (ITP), refractoriness to platelet transfusion, and chemotherapyassociated thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS). Three of the four accompanying abstracts were manufacturer-sponsored studies. The letter included a caution that, except for ITP, the column is limited by federal law to investigational use. There was also mention of “minimal toxicity” during SPA immunoadsorption, including a flu-like syndrome that was “transient and manageable. It further stated that premedication usually prevented or moderated symptoms and that there were no long-term treatment-related side effects. Last year in this journal, a study sponsored by the same manufacturer discussed minimal toxicity during protein A immunoadsorption in malignant disease and described the procedure as an outpatient therapy [ 11. An earlier study included some discussion of toxicity and stated that “none occurred which had not been observed in routine dialysis and therapeutic apheresis procedures” [2]. A reader could reasonably infer that the use of the SPA column is at least as safe as plasmapheresis itself. The type of reactions described were indeed similar to some seen in hemodialysis, but quite unlike those encountered in hemapheresis [ 3 ] . How safe is plasmapheresis? In a review of many studies and reports, one of us reported approximately three deaths worldwide per 10,000 therapeutic apheresis procedures [4]. That may well have been a low estimate, as many plasma exchanges were then being done with donor plasma as the replacement medium. More recently, Rock reported the Canadian experience of 29 moderate-to-severe reactions per thousand plasmapheresis procedures, including three associated deaths [5]. Schmitt et a1 reported this year on a three year experience with a National Registry in Germany. There were four fatalities in 1,945 procedures which they felt resulted from the plasmapheresis therapy [6]. So, even without ”
0 1992 Wiley-Liss, Inc.
the addition of plasma perfusion, plasmapheresis itself is not a totally benign procedure. As for the use of SPA columns, Garley and coworkers warned of serious side effects [ 71. They reported the death of one patient as possibly due to the immunoadsorption procedure. Four other patients had severe pulmonary reactions. Other very serious toxic reactions have occurred [8-131, some of which took place in patient populations reported in the manufacturer-sponsored studies. A list of known severe reactions is given in Table I. The clinical trial reports have tended to belittle the reactions as “transient and manageable,” while the claimed benefits are presented in detail. The result is an unbalanced picture of the clinical effects of SPA columns. Lists of complications provided by the manufacturer, like those in the reported studies, show a wide range in the percentages of patients experiencing reactions. This is understandable, in that the studies cover column use in different clinical conditions. Reactions encountered in treating chronic ITP may well differ from those in malignant disease or chemotherapy-associated TTP/ HUS, or conditions other than those that are the subject of current trials. Perfusing plasma through SPA-silica columns produces profound effects on the immune system, including the binding of immune complexes, complement activation, freeing of complexed antibodies, and increase in helper T lymphocyte activity. These alterations evidently exert a beneficial effect on some immune-mediated diseases. The same mechanisms clearly have other effects on the organism, which may be deleterious. Removal of immune complexes may indiscriminately free undesired antibody [9]. Complement activation that helps bind immune complexes has well-known side effects, some of which seem to have occurred in the clinical trials. One ~~~
~~~
Received for publication December 28, 1992; accepted January 6, 1993. Address reprint requests to Francis S . Morrison, Department of Medicine, University of Mississippi Medical Center, 2500 North State Street, Jackson, MI 39216.
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thing is clear: many if not most patients treated with SPA columns have adverse reactions. Most of them may well be transitory, easily controlled, and minor in the context of the disease under treatment. But not all have been so benign. Lumping together mild and moderate reactions because they are “manageable,” while failing to mention more serious occurrences, can be misleading. Also some of the definitions are suspect. For example, many studies report a few “respiratory” reactions. The uneasy reader is left without details. Clinicians need to be alert to adverse reactions if they are to assess risks and benefits and obtain meaningful informed consent for these largely experimental procedures. Furthermore, the more severe reactions may give clues to immune perturbations or other pathophysiologic processes involved in both beneficial and harmful effects of SPA columns. Understandably, manufacturers want to see beneficial results of therapy with a new procedure. But those who carry out clinical trials have an equal professional obligation to see that adverse effects are thoroughly studied and given adequate prominence. Closer focus on adverse effects will not necessarily impede utilization of new treatments since it has long been held that “For extreme illnesses extreme treatments are most fitting” [14].
Francis S. Morrison, M.D. Departments of Medicine and Pathology University of Mississippi Medical Center Jackson, Mississippi Douglas W. Huestis, M.D. Department of Pathology University of Arizona College of Medicine Tucson, Arizona REFERENCES I. Snyder H W , Jr., Henry DH, Messerschmidt GL, Mittelman A, Bertram J, Ambinder E, Kiprov D, B a h t JP, Jr., MacKintosh
FR, Hamburger M, Viola MV, Fiore J , Louie J, Higby DJ. O’Brien P, Ainsworth S, Fisher LD, Perkins W , Jones FR: Minimal toxicity during protein A immunoadsorption treatment of malignant disease: An outpatient therapy. J Clin Apheresis 6:l-10, 1991. 2. Jones FR, B a h t JP, Jr., Snyder HW, Jr., The Prosorba Column Clinical Trial Group: Selective extracorporeal removal of immunoglobulin-G and circulating immune complexes: A review. Plasma Ther Transfus Techno1 71333-349, 1986.
TABLE I. Reported Severe Reactions to SPA Columns Reaction Exacerbation of disease, generalized pain, fever, rigors. sweating, leukocytosis Profound hypotension. nausea, severe abdominal pain Profound hypotension, nausea, dyspnea, cyanosis, disorientation, obtundation Delayed chills. fever, hypotension, arthralgia, painful lymphadenopathy, generalized skin rash, vasculitis Vasculitic purpura (2 cases) Thrombosis, major vessels (4 cases) Renal failure, urticaria, arthralgia, edema, depressed sensorium Exacerbation of basic disease” Severe skin rash, chest pain, flashing lights in one eyea
Reference
8 II II
10
9 7 I2 II II
‘These patients had their plasma adsorbed with an SPA column other than that of the Imr6 Corporation.
3. Huestis DW: Risks and safety practices in hemapheresis procedures. Arch Pathol Lab Med 113:273-278, 1989. 4. Huestis DW: Mortality in therapeutic haelnapheresis, Lancet 1:1043, 1983. 5. Rock GA, Herbert C A . Canadian Apheresis Study Group: Therapeutic apheresis in Canada. J Clin Apheresis 7:47-48, 1992. 6. Schmitt E, Gunter K , Klinkmann H: Three years with a national apheresis registry. J Clin Apheresis 7:58-62. 1992. 7. Garley DC, Hagen G , Chopek M: Increased frequency of pulmonary reactions with the use of Staph protein A column. J Clin Apheresis 5:39 (Abstract), 1989. 8. Wuest D, Ciavarella D, McCroskey A, Mittelman A: Thrombosis associated with protein A immunoadsorption. J Clin Apheresis 5:165 (Abstract), 1990. 9 . Huestis DW. Rifkin RM, Durie BGM, Sibley WA, lrani M: An unexpected complication following immunoadsorption with a staphylococcal protein A column. .I Clin Apheresis 7:75-77, 1992. 10. Ainsworth SK, Pilia PA, Pepkowitz S H , O’Brien P: Toxicity following protein A treatment of metastatic breast adenocarcinoma. Cancer 61:1495-1500, 1988. 11. Smith RE, Gottschall JL, Pisciotta AV: Life-threatening reaction to staphylococcal protein A immunomodulation. J Clin Apheresis 7:4-5, 1992. 12. Morrison FS, Schwartz KA: Severe toxic reactions associated with the use of protein A columns. J Clin Apheresis 7:34 (Abstract). 1992. 3. Friedman KD, Saddler M C , Tarnower AC, Yang G. Harford AM: Transient renal failure in a patient with idiopathic thrombocytopenic purpura after treatment with concomitant protein A immunosorption and intravenous immune globulin. Blood 80, Supplement, p. 483a (Abstract 1923). 1992. 4. Hippocrates: Aphorisms, Sec. 1,6. Translation from Bartlctt J , “Familiar Quotations,” 14th ed, Boston: Little Brown, 1968.
Editorial Toxicity of the Staphylococcal Protein A Immunoadsorption Column In the spring of 1992, a letter from the manufacturer of a staphylococcal protein A (SPA) immunoadsorption column provided new reports on the efficacy of the column (Prosorbam,ImrC Corporation, Seattle, WA). This letter described successes in the resolution of chronic immunologic thrombocytopenic purpura (ITP), refractoriness to platelet transfusion, and chemotherapyassociated thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS). Three of the four accompanying abstracts were manufacturer-sponsored studies. The letter included a caution that, except for ITP, the column is limited by federal law to investigational use. There was also mention of “minimal toxicity” during SPA immunoadsorption, including a flu-like syndrome that was “transient and manageable. It further stated that premedication usually prevented or moderated symptoms and that there were no long-term treatment-related side effects. Last year in this journal, a study sponsored by the same manufacturer discussed minimal toxicity during protein A immunoadsorption in malignant disease and described the procedure as an outpatient therapy [ 11. An earlier study included some discussion of toxicity and stated that “none occurred which had not been observed in routine dialysis and therapeutic apheresis procedures” [2]. A reader could reasonably infer that the use of the SPA column is at least as safe as plasmapheresis itself. The type of reactions described were indeed similar to some seen in hemodialysis, but quite unlike those encountered in hemapheresis [ 3 ] . How safe is plasmapheresis? In a review of many studies and reports, one of us reported approximately three deaths worldwide per 10,000 therapeutic apheresis procedures [4]. That may well have been a low estimate, as many plasma exchanges were then being done with donor plasma as the replacement medium. More recently, Rock reported the Canadian experience of 29 moderate-to-severe reactions per thousand plasmapheresis procedures, including three associated deaths [5]. Schmitt et a1 reported this year on a three year experience with a National Registry in Germany. There were four fatalities in 1,945 procedures which they felt resulted from the plasmapheresis therapy [6]. So, even without ”
0 1992 Wiley-Liss, Inc.
the addition of plasma perfusion, plasmapheresis itself is not a totally benign procedure. As for the use of SPA columns, Garley and coworkers warned of serious side effects [ 71. They reported the death of one patient as possibly due to the immunoadsorption procedure. Four other patients had severe pulmonary reactions. Other very serious toxic reactions have occurred [8-131, some of which took place in patient populations reported in the manufacturer-sponsored studies. A list of known severe reactions is given in Table I. The clinical trial reports have tended to belittle the reactions as “transient and manageable,” while the claimed benefits are presented in detail. The result is an unbalanced picture of the clinical effects of SPA columns. Lists of complications provided by the manufacturer, like those in the reported studies, show a wide range in the percentages of patients experiencing reactions. This is understandable, in that the studies cover column use in different clinical conditions. Reactions encountered in treating chronic ITP may well differ from those in malignant disease or chemotherapy-associated TTP/ HUS, or conditions other than those that are the subject of current trials. Perfusing plasma through SPA-silica columns produces profound effects on the immune system, including the binding of immune complexes, complement activation, freeing of complexed antibodies, and increase in helper T lymphocyte activity. These alterations evidently exert a beneficial effect on some immune-mediated diseases. The same mechanisms clearly have other effects on the organism, which may be deleterious. Removal of immune complexes may indiscriminately free undesired antibody [9]. Complement activation that helps bind immune complexes has well-known side effects, some of which seem to have occurred in the clinical trials. One ~~~
~~~
Received for publication December 28, 1992; accepted January 6, 1993. Address reprint requests to Francis S . Morrison, Department of Medicine, University of Mississippi Medical Center, 2500 North State Street, Jackson, MI 39216.
172
Morrison and Huestis
thing is clear: many if not most patients treated with SPA columns have adverse reactions. Most of them may well be transitory, easily controlled, and minor in the context of the disease under treatment. But not all have been so benign. Lumping together mild and moderate reactions because they are “manageable,” while failing to mention more serious occurrences, can be misleading. Also some of the definitions are suspect. For example, many studies report a few “respiratory” reactions. The uneasy reader is left without details. Clinicians need to be alert to adverse reactions if they are to assess risks and benefits and obtain meaningful informed consent for these largely experimental procedures. Furthermore, the more severe reactions may give clues to immune perturbations or other pathophysiologic processes involved in both beneficial and harmful effects of SPA columns. Understandably, manufacturers want to see beneficial results of therapy with a new procedure. But those who carry out clinical trials have an equal professional obligation to see that adverse effects are thoroughly studied and given adequate prominence. Closer focus on adverse effects will not necessarily impede utilization of new treatments since it has long been held that “For extreme illnesses extreme treatments are most fitting” [14].
Francis S. Morrison, M.D. Departments of Medicine and Pathology University of Mississippi Medical Center Jackson, Mississippi Douglas W. Huestis, M.D. Department of Pathology University of Arizona College of Medicine Tucson, Arizona REFERENCES I. Snyder H W , Jr., Henry DH, Messerschmidt GL, Mittelman A, Bertram J, Ambinder E, Kiprov D, B a h t JP, Jr., MacKintosh
FR, Hamburger M, Viola MV, Fiore J , Louie J, Higby DJ. O’Brien P, Ainsworth S, Fisher LD, Perkins W , Jones FR: Minimal toxicity during protein A immunoadsorption treatment of malignant disease: An outpatient therapy. J Clin Apheresis 6:l-10, 1991. 2. Jones FR, B a h t JP, Jr., Snyder HW, Jr., The Prosorba Column Clinical Trial Group: Selective extracorporeal removal of immunoglobulin-G and circulating immune complexes: A review. Plasma Ther Transfus Techno1 71333-349, 1986.
TABLE I. Reported Severe Reactions to SPA Columns Reaction Exacerbation of disease, generalized pain, fever, rigors. sweating, leukocytosis Profound hypotension. nausea, severe abdominal pain Profound hypotension, nausea, dyspnea, cyanosis, disorientation, obtundation Delayed chills. fever, hypotension, arthralgia, painful lymphadenopathy, generalized skin rash, vasculitis Vasculitic purpura (2 cases) Thrombosis, major vessels (4 cases) Renal failure, urticaria, arthralgia, edema, depressed sensorium Exacerbation of basic disease” Severe skin rash, chest pain, flashing lights in one eyea
Reference
8 II II
10
9 7 I2 II II
‘These patients had their plasma adsorbed with an SPA column other than that of the Imr6 Corporation.
3. Huestis DW: Risks and safety practices in hemapheresis procedures. Arch Pathol Lab Med 113:273-278, 1989. 4. Huestis DW: Mortality in therapeutic haelnapheresis, Lancet 1:1043, 1983. 5. Rock GA, Herbert C A . Canadian Apheresis Study Group: Therapeutic apheresis in Canada. J Clin Apheresis 7:47-48, 1992. 6. Schmitt E, Gunter K , Klinkmann H: Three years with a national apheresis registry. J Clin Apheresis 7:58-62. 1992. 7. Garley DC, Hagen G , Chopek M: Increased frequency of pulmonary reactions with the use of Staph protein A column. J Clin Apheresis 5:39 (Abstract), 1989. 8. Wuest D, Ciavarella D, McCroskey A, Mittelman A: Thrombosis associated with protein A immunoadsorption. J Clin Apheresis 5:165 (Abstract), 1990. 9 . Huestis DW. Rifkin RM, Durie BGM, Sibley WA, lrani M: An unexpected complication following immunoadsorption with a staphylococcal protein A column. .I Clin Apheresis 7:75-77, 1992. 10. Ainsworth SK, Pilia PA, Pepkowitz S H , O’Brien P: Toxicity following protein A treatment of metastatic breast adenocarcinoma. Cancer 61:1495-1500, 1988. 11. Smith RE, Gottschall JL, Pisciotta AV: Life-threatening reaction to staphylococcal protein A immunomodulation. J Clin Apheresis 7:4-5, 1992. 12. Morrison FS, Schwartz KA: Severe toxic reactions associated with the use of protein A columns. J Clin Apheresis 7:34 (Abstract). 1992. 3. Friedman KD, Saddler M C , Tarnower AC, Yang G. Harford AM: Transient renal failure in a patient with idiopathic thrombocytopenic purpura after treatment with concomitant protein A immunosorption and intravenous immune globulin. Blood 80, Supplement, p. 483a (Abstract 1923). 1992. 4. Hippocrates: Aphorisms, Sec. 1,6. Translation from Bartlctt J , “Familiar Quotations,” 14th ed, Boston: Little Brown, 1968.
