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Gammagard® and reported hepatitis C virus episodes
CLINICAL THERAPEUTICS®/VOL. 18, SUPPL. B, 1996
Gammagard® and Reported Hepatitis C Virus Episodes Edward D. Gomperts, MD Baxter Healthcare Corporation, Hyland Division, Glendale, California
ABSTRACT Since first licensed in the United States in 1986, Gammagard ®, an intravenous immunoglobulin produced by the Hyland Division of Baxter Healthcare Corporation, had been considered an effective and safe form of immunoglobulin. Its safety had been proved in patients with immunoglobulin A (IgA) deficiency, including those with the complication of antiIgA antibodies. However, in early 1994, there were reported episodes of hepatitis C virus transmission associated with administration of Gammagard manufactured during April 1993 and thereafter. The investigations into the mechanisms to account for these events, including the manufacturing processes, are reviewed. The results of studies and analyses by both Baxter and the US Food and Drug Administration, including first- and secondgeneration enzyme-linked immunosorbent assays, polymerase chain reaction 0149-2918/96/$3.50
analyses, and the solvent-detergent viralinactivation manufacturing step, are discussed. Evaluations of donor histories identified a group of donors who contributed to three target lots of the agent and who were subsequently excluded from donor pools. The classification scheme and criteria for all patient reports of hepatitis associated with administration of Gammagard, as well as the classification of all hepatitis C virus episodes, are presented. GAMMAGARD ® AND HEPATITIS C VIRUS Gammagard®, * an intravenous immunoglobulin, has been manufactured and marketed by the Hyland Division of Baxter Healthcare Corporation, Glendale, Call-
"Trademark: Baxter Healthcare Corporation, Hyland Division, Glendale, California.
3
CLINICAL THERAPEUTICS®
fornia, since its first licensure in the United States in 1986. This sterile, dried, and highly purified preparation of immunoglobulin G is manufactured in a process specifically designed to ensure that the immunoglobulin has no denaturation or enzyme degradation and has minimal contamination with immunoglobulin A (IgA) or immunoglobulin M, both of which may be associated with serious adverse reactions. This process involves the Cohn-Oncley series of alcohol-precipitation steps and collection of fraction II paste (cold ethanol fractionation) and ion-exchange chromatography for purification. Gammagard has demonstrated excellent efficacy 1-4 and safety, including the absence of transmission of hepatitis 5,6 and has been used safely in patients with IgA deficiency complicated by the presence of anti-IgA antibodies. 7 However, there have been isolated reports of non-A, non-B hepatitis (NANB) or hepatitis C virus (HCV) transmission associated with the use of intravenous immunoglobulin from a number of sources. 8-12 One of the main results of the identification of HCV as the principal causative agent of NANB was the identification of an HCV antibody as a marker of infection; another consequence was the development of a procedure to detect this antibody as evidence of potential infection with HCV. Initially, this screening procedure, enzyme-linked immunosorbent assay (ELISA I), was developed by using a single viral antigen. This assay was introduced worldwide to identify and exclude HCV-infected blood donors, resulting in an improved level of safety of transfused blood and blood components. However, controversy surrounded the applicability of the assay for removing antibody-positive donations from plasma pools. Re-
searchers hypothesized that the presence of anti-HCV antibodies accounted for the lack of infectivity of plasma pool-derived intravenous immunoglobulin 13 and that exclusion of antibody-positive donors would make the products less safe--rather than safer--from HCV transmission. Subsequently, the screening test was improved by using multiantigen systems, resulting in improved sensitivity and specificity (ELISA II). Because of isolated reports in the medical literature of NANB and HCV associated with intravenous immunoglobulin therapy, Baxter conducted experiments to include a viral-inactivation procedure in the manufacturing process for intravenous immunoglobulin. In November 1989, this research focused on the use of a solventdetergent (SD) viral-inactivation step in manufacturing Gammagard. Having incorporated this step into the manufacturing process, Baxter submitted applications in the third quarter of 1992 for licensure to manufacture and market Gammagard SD in the United States and Europe. Approval was granted in Sweden in November 1993, in Germany in April 1994, and in the United States in May 1994. Each of the periodic and sporadic reports of adverse reactions to various manufactured products, including Gammagard, is evaluated and reported to regulatory authorities. Reports of viral transmission claims are unusual, and any such claims are thoroughly investigated. Until late 1993, investigations showed that when Gammagard was involved, the report either was inaccurate or other reasons were identified to account for the claimed adverse event. However, in November 1993 and January 1994, two unsubstantiated claims of hepatitis associated with Gammagard were received and investigated.
E.D. GOMPERTS
Early in February 1994, 1 report of hepatitis in the United States was followed by 4 reported cases in Sweden and 8 cases in Spain (5 from Madrid and 3 from Seville). All of these episodes were promptly investigated. The investigation included onsite visits to the two cities in Spain, polymerase chain reaction (PCR) analysis of relevant samples from the Swedish patients, and inquiries into the manufacturing process of relevant lot numbers. It became apparent that HCV accounted for at least some of the episodes of hepatitis and that a number of Gammagard lots were possible sources. Baxter became concerned that the safety of this product could not be ensured and, as a result, voluntarily withdrew the product from the worldwide market on February 21, 1994. After the withdrawal, formal investigations were conducted by Baxter personnel, US Food and Drug Administration officials, and the Belgian reg-
ulatory authority, and an emergency therapeutic protocol with the viral-inactivated Gammagard SD was put into effect. No manufacturing irregularities or variances were identified. The first lot of Gammagard that used only the second-generation anti-HCV screening (ELISA II) procedure for all plasma was released in February 1993, and most lots released after April 1993 used plasma from ELISA II-screened (multiantigen) sources. As of March 1995, there were 247 claims of hepatitis associated with the use of Gammagard in 10 different countries (Table I); 223 of these had sufficient data to be reported. Approximately 40% of these 247 reports, however, did not have Gammagard lot number associations and approximately 13% and 26% of the 247 reports had an "unlikely" (n = 31) or only "possible" (n = 65) association, respectively (Tables II and III).
Table I. Summary of 247 reports of patients with hepatitis who received Gammagard ®* as of March 30, 1995. Patient Reports Reviewed and Classified
New Patient Reports Currently Unclassifiable Because of Inadequate Information
Country
Number
Country
Number
A B C D E F G
99 12 34 30 16 2 27
A
20
F G
1 1
H I
2 1
H
1
J
Totfl
223
*Trademark:BaxterHealthcareCorporation,HylandDivision,Glendale,California.
1
24
CLINICAL THERAPEUTICS®
Table II. Classification scheme and criteria for all patient reports of hepatitis associated with administration of Gammagard ®* within 3 months of the episode. Classification Very likely
Criteria Patients with hepatitis (ALT >2.5 times normal) Patients previously documented (within past 12-18 months) to have normal ALT Patients previously documented (within past 12-18 months) to be anti-HCV-negative Patients who are ELISA-determined anti-HCV-positive or l~R-detennined HCV-positive
Likely
Patients with hepatitis (ALT >2.5 times normal) Patients previously documented (within past 12-18 months) to have normal ALT Patients with no previous serologic documentation Patients who are anfi-HCV-positive in association with elevated ALT levels with no PCR data, or ELISA-determined anti-HCV-negative but PCR-determined HCV-positive
Probable
Patients with hepatitis (ALT >2.5 times normal) Patients with no previous ALT or serologic documentation Patients who are ELISA-determined anti-HCV-positive Patients with no PCR data
Possible
Patients with hepatitis (ALT >2.5 times normal) Patients with no serologic documentation or PCR data
Unlikely
Patients with hepatitis (ALT <2.5 times normal) Patients with hepatitis (ALT >2.5 times normal) but previous evidence of hepatitis, blood transfusions, or other causes of hepatitis
ALT = alanine aminotransferase; HCV = hepatitis C virus; ELISA = enzyme-linked immunosorbant assay; PCR = polymerase chain reaction; anti-HCV = anti-HCV antibody. *Trademark: Baxter Healthcare Corporation, Hyland Division, Glendale, California.
The incidence of infectivity of the product appears to vary widely. Of the patients evaluated in the United Kingdom, 36 received one lot of the drug, and 29 (80.5%) of these were shown to be PCR positive for HCV. In the New England area of the United States, only 16 (7%) of 245 recipients of multiple lots of the product had documented evidence of infection. 14 Preliminary data from 300 patients who received Gammagard in Sweden also showed a low incidence rate, with only 10
(8%) of 120 patients who were tested for H C V confirmed by PCR analysis to be HCV-positive.
DISCUSSION AND CONCLUSION During the last few years, a number of episodes of HCV transmission have been associated with the administration of Gammagard processed during and after April 1993. The mechanism(s) accounting for these events are being investigated. To
E.D. GOMPERTS
Table III. Classification of 223 Gammagard ®* patient reports of hepatitis received as of March 30, 1995. Country A B C D E F G H I
Total
Unlikely
Possible
Probable
Likely
Very Likely
Total
11 4 1 3 2 0 10 0
42 1 7 4 3 0 6 2
24 2 9 1 9 1 7 0
18 3 13 4 2 0 2 0
4 2 4 18 0 1 2 0
99 12 34 30 16 2 27 2
0
0
0
1
0
1
31
65
53
43
31
223
*Trademark: Baxter Healthcare Corporation, Hyland Division, Glendale, California.
date, studies and analyses at the US Food and Drug Administration have documented PCR-identifiable HCV material in multiple lots of Gammagard, although such material usually was not observed in products manufactured with either unscreened or first-generation-screened (ELISA I) plasma. Evaluations of donor
histories have identified a group of donors who contributed to three target lots and who were thereafter excluded from donating plasma because of anti-HCV seroconversions. Additional information regarding the distribution of lots of Gammagard for classified patients reporting episodes of hepatitis is provided in Table IV.
Table IV. Distribution of Gammagard ®* lots for classified patients reporting episodes of hepatitis (N = 223). Percentage of reports in the United States providing lot information Percentage of reports outside the United States providing lot information Percentage of all reports (all countries) providing lot information (n = 134) Restriction criteria for lots (regardless of patient classification) No. of lots (after June 30, 1993) involved in reported cases No. of lots administered within 120 days of the episode and involved in reported cases Mean no. of recognized lots (after June 30, 1993) reported per patient Minimum no. of lots reported per patient Maximum no. of lots reported per patient *Trademark: Baxter Healthcare Corporation, Hyland Division, Glendale, California.
48 69 60 116 79 4.3 0 17
CLINICAL THERAPEUTICS*
REFERENCES 1. Cooperative Group for the Study of Immunoglobulin in Chronic Lymphocytic Leukemia. Intravenous immunoglobulin for the prevention of infection in chronic lymphocytic leukemia: A randomized controlled clinical trial. NEJM. 1988;319: 902-907. van der Meche FG, Schmitz PI, and the Dutch Guillain-Barr6 Study Group. A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain-Barr6 syndrome. NEJM. 1992; 326:1123-1129. 3. The Intravenous Immunoglobulin Collaborative Study Group. Prophylactic intravenous administration of standard immune globulin as compared with core-lipopolysaccharide immune globulin in patients at high risk of postsurgical infection. NEJM. 1992;327:234-240. 4. Baker CJ, Melish ME, Hall RT, et al. The Multicenter Group for the Study of Immune Globulin in Neonates. Intravenous immune globulin for the prevention of nosocomial infection in low-birth-weight neonates. NEJM. 1992;327:213-219. 5. Lee ML, Courter SG, Tait D, Kingdon HS. Long-term evaluation of intravenous immune globulin preparation with regard to non-A, non-B hepatitis safety. In: Zuckerman AJ, ed. Viral Hepatitis and Liver Disease. New York: Alan R. Liss; 1988: 596-599. 6. Oomes PG, van des Meahe FGA, Kleyweg RP. Liver function disturbances in Guillain-Barre syndrome: A prospective
longitudinal study in 100 patients. Neurology. 1996;46:96-100. 7. Cunningham-Rundles C, Zhou Z, Mankarious S, Courter S. Long-term use of IgAdepleted intravenous immunoglobulin in immunodeficient subjects with anti-IgA antibodies. J Clin lmmunol. 1993;13: 272-278. Murdoch A. Irish mothers called for hepatitis C virus screening. BMJ. 1994;308: 613-614. 9. Ochs HD, Fischer SH, Virant FS, et al. Non-A non-B hepatitis and intravenous immunoglobulin. Lancet. 1985;1:404-405. 10. Weiland O, Mattsson L, Glaumann H. Non-A non-B hepatitis after intravenous gamma globulin. Lancet. 1986; 1:976--977. Letter. 11. Lane RS. Non-A non-B hepatitis from intravenous immunoglobulin. Lancet. 1983; 2:974-975. Letter. 12. Lever AM, Webster AD, Brown D, Thomas HC. Non-A non-B hepatitis occurring in agammaglobulinaemic patients after intravenous immunoglobulin. Lancet. 1984;2:1062-1064. 13. Finlayson JS, Tankersley DL. Anti-HCV screening and plasma fractionation: The case against. Lancet. 1990;335:12741275. Letter. 14. Centers for Disease Control. Outbreak of hepatitis C associated with intravenous immunoglobulin administration: United States, October 1993-June 1994. MMWR. 1994;43:505-509.
Gammagard® and Reported Hepatitis C Virus Episodes Edward D. Gomperts, MD Baxter Healthcare Corporation, Hyland Division, Glendale, California
ABSTRACT Since first licensed in the United States in 1986, Gammagard ®, an intravenous immunoglobulin produced by the Hyland Division of Baxter Healthcare Corporation, had been considered an effective and safe form of immunoglobulin. Its safety had been proved in patients with immunoglobulin A (IgA) deficiency, including those with the complication of antiIgA antibodies. However, in early 1994, there were reported episodes of hepatitis C virus transmission associated with administration of Gammagard manufactured during April 1993 and thereafter. The investigations into the mechanisms to account for these events, including the manufacturing processes, are reviewed. The results of studies and analyses by both Baxter and the US Food and Drug Administration, including first- and secondgeneration enzyme-linked immunosorbent assays, polymerase chain reaction 0149-2918/96/$3.50
analyses, and the solvent-detergent viralinactivation manufacturing step, are discussed. Evaluations of donor histories identified a group of donors who contributed to three target lots of the agent and who were subsequently excluded from donor pools. The classification scheme and criteria for all patient reports of hepatitis associated with administration of Gammagard, as well as the classification of all hepatitis C virus episodes, are presented. GAMMAGARD ® AND HEPATITIS C VIRUS Gammagard®, * an intravenous immunoglobulin, has been manufactured and marketed by the Hyland Division of Baxter Healthcare Corporation, Glendale, Call-
"Trademark: Baxter Healthcare Corporation, Hyland Division, Glendale, California.
3
CLINICAL THERAPEUTICS®
fornia, since its first licensure in the United States in 1986. This sterile, dried, and highly purified preparation of immunoglobulin G is manufactured in a process specifically designed to ensure that the immunoglobulin has no denaturation or enzyme degradation and has minimal contamination with immunoglobulin A (IgA) or immunoglobulin M, both of which may be associated with serious adverse reactions. This process involves the Cohn-Oncley series of alcohol-precipitation steps and collection of fraction II paste (cold ethanol fractionation) and ion-exchange chromatography for purification. Gammagard has demonstrated excellent efficacy 1-4 and safety, including the absence of transmission of hepatitis 5,6 and has been used safely in patients with IgA deficiency complicated by the presence of anti-IgA antibodies. 7 However, there have been isolated reports of non-A, non-B hepatitis (NANB) or hepatitis C virus (HCV) transmission associated with the use of intravenous immunoglobulin from a number of sources. 8-12 One of the main results of the identification of HCV as the principal causative agent of NANB was the identification of an HCV antibody as a marker of infection; another consequence was the development of a procedure to detect this antibody as evidence of potential infection with HCV. Initially, this screening procedure, enzyme-linked immunosorbent assay (ELISA I), was developed by using a single viral antigen. This assay was introduced worldwide to identify and exclude HCV-infected blood donors, resulting in an improved level of safety of transfused blood and blood components. However, controversy surrounded the applicability of the assay for removing antibody-positive donations from plasma pools. Re-
searchers hypothesized that the presence of anti-HCV antibodies accounted for the lack of infectivity of plasma pool-derived intravenous immunoglobulin 13 and that exclusion of antibody-positive donors would make the products less safe--rather than safer--from HCV transmission. Subsequently, the screening test was improved by using multiantigen systems, resulting in improved sensitivity and specificity (ELISA II). Because of isolated reports in the medical literature of NANB and HCV associated with intravenous immunoglobulin therapy, Baxter conducted experiments to include a viral-inactivation procedure in the manufacturing process for intravenous immunoglobulin. In November 1989, this research focused on the use of a solventdetergent (SD) viral-inactivation step in manufacturing Gammagard. Having incorporated this step into the manufacturing process, Baxter submitted applications in the third quarter of 1992 for licensure to manufacture and market Gammagard SD in the United States and Europe. Approval was granted in Sweden in November 1993, in Germany in April 1994, and in the United States in May 1994. Each of the periodic and sporadic reports of adverse reactions to various manufactured products, including Gammagard, is evaluated and reported to regulatory authorities. Reports of viral transmission claims are unusual, and any such claims are thoroughly investigated. Until late 1993, investigations showed that when Gammagard was involved, the report either was inaccurate or other reasons were identified to account for the claimed adverse event. However, in November 1993 and January 1994, two unsubstantiated claims of hepatitis associated with Gammagard were received and investigated.
E.D. GOMPERTS
Early in February 1994, 1 report of hepatitis in the United States was followed by 4 reported cases in Sweden and 8 cases in Spain (5 from Madrid and 3 from Seville). All of these episodes were promptly investigated. The investigation included onsite visits to the two cities in Spain, polymerase chain reaction (PCR) analysis of relevant samples from the Swedish patients, and inquiries into the manufacturing process of relevant lot numbers. It became apparent that HCV accounted for at least some of the episodes of hepatitis and that a number of Gammagard lots were possible sources. Baxter became concerned that the safety of this product could not be ensured and, as a result, voluntarily withdrew the product from the worldwide market on February 21, 1994. After the withdrawal, formal investigations were conducted by Baxter personnel, US Food and Drug Administration officials, and the Belgian reg-
ulatory authority, and an emergency therapeutic protocol with the viral-inactivated Gammagard SD was put into effect. No manufacturing irregularities or variances were identified. The first lot of Gammagard that used only the second-generation anti-HCV screening (ELISA II) procedure for all plasma was released in February 1993, and most lots released after April 1993 used plasma from ELISA II-screened (multiantigen) sources. As of March 1995, there were 247 claims of hepatitis associated with the use of Gammagard in 10 different countries (Table I); 223 of these had sufficient data to be reported. Approximately 40% of these 247 reports, however, did not have Gammagard lot number associations and approximately 13% and 26% of the 247 reports had an "unlikely" (n = 31) or only "possible" (n = 65) association, respectively (Tables II and III).
Table I. Summary of 247 reports of patients with hepatitis who received Gammagard ®* as of March 30, 1995. Patient Reports Reviewed and Classified
New Patient Reports Currently Unclassifiable Because of Inadequate Information
Country
Number
Country
Number
A B C D E F G
99 12 34 30 16 2 27
A
20
F G
1 1
H I
2 1
H
1
J
Totfl
223
*Trademark:BaxterHealthcareCorporation,HylandDivision,Glendale,California.
1
24
CLINICAL THERAPEUTICS®
Table II. Classification scheme and criteria for all patient reports of hepatitis associated with administration of Gammagard ®* within 3 months of the episode. Classification Very likely
Criteria Patients with hepatitis (ALT >2.5 times normal) Patients previously documented (within past 12-18 months) to have normal ALT Patients previously documented (within past 12-18 months) to be anti-HCV-negative Patients who are ELISA-determined anti-HCV-positive or l~R-detennined HCV-positive
Likely
Patients with hepatitis (ALT >2.5 times normal) Patients previously documented (within past 12-18 months) to have normal ALT Patients with no previous serologic documentation Patients who are anfi-HCV-positive in association with elevated ALT levels with no PCR data, or ELISA-determined anti-HCV-negative but PCR-determined HCV-positive
Probable
Patients with hepatitis (ALT >2.5 times normal) Patients with no previous ALT or serologic documentation Patients who are ELISA-determined anti-HCV-positive Patients with no PCR data
Possible
Patients with hepatitis (ALT >2.5 times normal) Patients with no serologic documentation or PCR data
Unlikely
Patients with hepatitis (ALT <2.5 times normal) Patients with hepatitis (ALT >2.5 times normal) but previous evidence of hepatitis, blood transfusions, or other causes of hepatitis
ALT = alanine aminotransferase; HCV = hepatitis C virus; ELISA = enzyme-linked immunosorbant assay; PCR = polymerase chain reaction; anti-HCV = anti-HCV antibody. *Trademark: Baxter Healthcare Corporation, Hyland Division, Glendale, California.
The incidence of infectivity of the product appears to vary widely. Of the patients evaluated in the United Kingdom, 36 received one lot of the drug, and 29 (80.5%) of these were shown to be PCR positive for HCV. In the New England area of the United States, only 16 (7%) of 245 recipients of multiple lots of the product had documented evidence of infection. 14 Preliminary data from 300 patients who received Gammagard in Sweden also showed a low incidence rate, with only 10
(8%) of 120 patients who were tested for H C V confirmed by PCR analysis to be HCV-positive.
DISCUSSION AND CONCLUSION During the last few years, a number of episodes of HCV transmission have been associated with the administration of Gammagard processed during and after April 1993. The mechanism(s) accounting for these events are being investigated. To
E.D. GOMPERTS
Table III. Classification of 223 Gammagard ®* patient reports of hepatitis received as of March 30, 1995. Country A B C D E F G H I
Total
Unlikely
Possible
Probable
Likely
Very Likely
Total
11 4 1 3 2 0 10 0
42 1 7 4 3 0 6 2
24 2 9 1 9 1 7 0
18 3 13 4 2 0 2 0
4 2 4 18 0 1 2 0
99 12 34 30 16 2 27 2
0
0
0
1
0
1
31
65
53
43
31
223
*Trademark: Baxter Healthcare Corporation, Hyland Division, Glendale, California.
date, studies and analyses at the US Food and Drug Administration have documented PCR-identifiable HCV material in multiple lots of Gammagard, although such material usually was not observed in products manufactured with either unscreened or first-generation-screened (ELISA I) plasma. Evaluations of donor
histories have identified a group of donors who contributed to three target lots and who were thereafter excluded from donating plasma because of anti-HCV seroconversions. Additional information regarding the distribution of lots of Gammagard for classified patients reporting episodes of hepatitis is provided in Table IV.
Table IV. Distribution of Gammagard ®* lots for classified patients reporting episodes of hepatitis (N = 223). Percentage of reports in the United States providing lot information Percentage of reports outside the United States providing lot information Percentage of all reports (all countries) providing lot information (n = 134) Restriction criteria for lots (regardless of patient classification) No. of lots (after June 30, 1993) involved in reported cases No. of lots administered within 120 days of the episode and involved in reported cases Mean no. of recognized lots (after June 30, 1993) reported per patient Minimum no. of lots reported per patient Maximum no. of lots reported per patient *Trademark: Baxter Healthcare Corporation, Hyland Division, Glendale, California.
48 69 60 116 79 4.3 0 17
CLINICAL THERAPEUTICS*
REFERENCES 1. Cooperative Group for the Study of Immunoglobulin in Chronic Lymphocytic Leukemia. Intravenous immunoglobulin for the prevention of infection in chronic lymphocytic leukemia: A randomized controlled clinical trial. NEJM. 1988;319: 902-907. van der Meche FG, Schmitz PI, and the Dutch Guillain-Barr6 Study Group. A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain-Barr6 syndrome. NEJM. 1992; 326:1123-1129. 3. The Intravenous Immunoglobulin Collaborative Study Group. Prophylactic intravenous administration of standard immune globulin as compared with core-lipopolysaccharide immune globulin in patients at high risk of postsurgical infection. NEJM. 1992;327:234-240. 4. Baker CJ, Melish ME, Hall RT, et al. The Multicenter Group for the Study of Immune Globulin in Neonates. Intravenous immune globulin for the prevention of nosocomial infection in low-birth-weight neonates. NEJM. 1992;327:213-219. 5. Lee ML, Courter SG, Tait D, Kingdon HS. Long-term evaluation of intravenous immune globulin preparation with regard to non-A, non-B hepatitis safety. In: Zuckerman AJ, ed. Viral Hepatitis and Liver Disease. New York: Alan R. Liss; 1988: 596-599. 6. Oomes PG, van des Meahe FGA, Kleyweg RP. Liver function disturbances in Guillain-Barre syndrome: A prospective
longitudinal study in 100 patients. Neurology. 1996;46:96-100. 7. Cunningham-Rundles C, Zhou Z, Mankarious S, Courter S. Long-term use of IgAdepleted intravenous immunoglobulin in immunodeficient subjects with anti-IgA antibodies. J Clin lmmunol. 1993;13: 272-278. Murdoch A. Irish mothers called for hepatitis C virus screening. BMJ. 1994;308: 613-614. 9. Ochs HD, Fischer SH, Virant FS, et al. Non-A non-B hepatitis and intravenous immunoglobulin. Lancet. 1985;1:404-405. 10. Weiland O, Mattsson L, Glaumann H. Non-A non-B hepatitis after intravenous gamma globulin. Lancet. 1986; 1:976--977. Letter. 11. Lane RS. Non-A non-B hepatitis from intravenous immunoglobulin. Lancet. 1983; 2:974-975. Letter. 12. Lever AM, Webster AD, Brown D, Thomas HC. Non-A non-B hepatitis occurring in agammaglobulinaemic patients after intravenous immunoglobulin. Lancet. 1984;2:1062-1064. 13. Finlayson JS, Tankersley DL. Anti-HCV screening and plasma fractionation: The case against. Lancet. 1990;335:12741275. Letter. 14. Centers for Disease Control. Outbreak of hepatitis C associated with intravenous immunoglobulin administration: United States, October 1993-June 1994. MMWR. 1994;43:505-509.