Correspondence
Hepatitis C and Immune Globulin
N Engl J Med 1995; 332:1235-1237May 4, 1995
- Article
To the Editor:
The article by Bjøro et al.1 and the accompanying editorial by Schiff (Dec. 15 issue)2 focus on the potential risks of transmission of hepatitis C by intravenous immune globulin. In this follow-up study of Norwegian patients who received contaminated lots of intravenous immune globulin between 1982 and 1986, the patients with hypogammaglobulinemia had a high risk of hepatitis C infection and a severe and rapidly progressive course, with poor responses to recombinant interferon alfa-2b. Bjøro et al.1 present an unbalanced viewpoint that is likely to alarm physicians and patients with other disorders who may benefit from this therapy. Schiff's editorial2 also failed to put in perspective the risks of transmission of hepatitis C by intravenous immune globulin.3
Treating physicians must carefully weigh the risk–benefit ratio of using immune globulin. Patients with hypogammaglobulinemia and immunodeficiency have a higher risk of contracting disease from potentially infectious contaminants of immune globulin. The reasons most likely include difficulty in neutralizing the virus, impaired cellular immunologic responses, and perhaps hepatic disease in patients with common variable immune deficiency. Still, the risk–benefit ratio strongly favors the appropriate use of intravenous immune globulin. We strongly urge the monitoring of these patients, as recommended by the algorithm devised by the Centers for Disease Control and Prevention4; immunodeficient patients should be tested for viral antigen, since serologic testing usually provides no information.
The manufacturers of immune globulin and regulatory agencies should aggressively pursue ways to eliminate the widest possible range of infectious agents that may be transmitted by these products. Incubation of these products at room temperature, as proposed by Schiff,2 is an insufficient means of eradicating viruses in the absence of harsh chemical conditions.
The reported observations of hepatitis C infection after treatment with intravenous immune globulin1,2 should increase our level of vigilance and awareness of the potential risks of this product. Tests for viral detection should be improved. Although the development of serologic tests for hepatitis B core antibody and hepatitis C antibody has markedly reduced the risk of transmission of these viruses in recipients of blood transfusions, the effect of removing anti–hepatitis C virus antibodies, which have potential neutralizing activity, from the plasma pool has not yet been determined. The development of more sensitive tests for both antigen and antibody should make it possible to resolve this question. Other unresolved issues are the potential risk posed by nonenveloped viruses, such as parvoviruses, and as yet undetected viruses. The long incubation periods of some viruses may continue to pose incalculable risks.
4 ReferencesSteven D. Douglas, M.D.
Children's Hospital of Philadelphia, Philadelphia, PA 19104Herbert B. Slade, M.D.
3M Pharmaceuticals, St. Paul, MN 551441
Bjoro K ,Froland SG ,Yun Z ,Samdal HH ,Haaland T . Hepatitis C infection in patients with primary hypogammaglobulinemia after treatment with contaminated immune globulin. N Engl J Med 1994;331:1607-1611
Full Text | Web of Science | Medline2
Schiff RI . Transmission of viral infections through intravenous immune globulin. N Engl J Med 1994;331:1649-1650
Full Text | Web of Science | Medline3
Slade HB . Human immunoglobulins for intravenous use and hepatitis C viral transmission. Clin Diagn Lab Immunol 1994;1:613-619
Medline4
Outbreak of hepatitis C associated with intravenous immunoglobulin administration -- United States, October 1993-June 1994
Medline
To the Editor:
Bjøro et al. believe that the immune globulins “currently available for intravenous use . . . have a high degree of safety with respect to HCV [hepatitis C virus] contamination” because “manufacturers use only anti-HCV–negative plasma donors, and virus-inactivating procedures are [performed] in the manufacturing process.”
In our randomized study of marrow-transplant recipients 10 of 11 recipients treated with immune globulin seroconverted after the first dose of immune globulin. Although HCV RNA was not found in any patient, anti-HCV antibodies persisted for a median of 9 months (range, 4 to 14), with consequent diagnostic problems. None of the control patients seroconverted. All patients received anti-HCV–negative blood products tested with a second-generation enzyme-linked immunosorbent assay (ELISA).1 The immune globulin used (Polyglobin, Bayer, Berkeley, Calif.) was not obtained from anti-HCV–negative donors.
On the basis of this experience, we subsequently began to use exclusively immune globulin prepared from anti-HCV–negative plasma donors according to manufacturer's information (Polyglobin, Bayer; Gammagard, Baxter, Deerfield, Ill.). We have given anti-HCV–negative immune globulin to four patients (two patients with idiopathic thrombocytopenic purpura and two bone marrow–transplant recipients with cytomegalovirus pneumonia). Blood samples were obtained from the patients the day before and the day after the administration of the anti-HCV–negative immune globulin, and the immune globulin preparations used on these days were also tested. All four immune globulin preparations tested positive on an anti-HCV third-generation ELISA, and all four patients seroconverted. No liver-chemistry abnormalities were detected after immune globulin administration. HCV RNA was not detected either in the two patients in whom the test was performed or in the immune globulin preparations. The most likely cause of the discrepancy between our results and those of the manufacturers is that some donors who test negative for anti-HCV on the basis of first- and second-generation ELISAs are found to be positive when tested with the more sensitive third-generation ELISA.2
Most immune globulin preparations currently used come from plasma donors tested with first- and second-generation anti-HCV assays. Every test, as well as virus-inactivating procedures, must be performed to reduce the risks of immune globulin therapy. Anti-HCV screening has limited success.
2 ReferencesJavier López-Jiménez, M.D.
J. Odriozola, M.D.
J. Pérez-Oteyza, M.D.
J. García-Laraña, M.D.
Hospital Ramón y Cajal, 28034 Madrid, Spain1
Lopez-Jimenez J ,Villalon L ,Mateos ML ,Odriozola J . Hepatitis C virus antibody seroconversion in bone marrow transplant recipients treated with immune globulin: the impact of the problem. Blood 1994;84:665-666
Web of Science | Medline2
Janot C ,Courouce AM , Groupe de Travail "Hepatites Virales" de_la_Societe Francaise de Transfusion Sanguine. Etude analytique des trousses de dépistage et de confirmation des anticorps anti-VHC Abbot et Ortho. Rev Fr Transfus Hemobiol 1992;35:171-182
Medline
To the Editor:
In his editorial, Dr. Schiff casts doubt on the efficacy of the process involving a solvent and a detergent that is used to sterilize many plasma derivatives, including intravenous immune globulins, stating: “Detergent disrupts the membranes of the viral envelope but leaves potentially infectious nucleic acid intact.” This statement is misleading.
If the statement were true, the extraordinary safety record of all products treated with a solvent and a detergent would be inconceivable. These products, including factor VIII, factor IX, intravenous immune globulins, pooled fresh-frozen plasma, and fibrinogen, have not resulted in the transmission of hepatitis B virus, HCV, or human immunodeficiency virus (HIV) infections to the many thousands of patients who have received these products (more than 7 million doses) in the 10 years since this virus-sterilization process was introduced.1
The reason for this extraordinary safety record, at least in the case of viruses with RNA genomes and lipid envelopes, is that, through their combined action, solvents and detergents permeate the nucleocapsid of these viruses, permitting ubiquitous ribonucleases to digest the viral RNA. This fact can be readily demonstrated by labeling the viral RNA with [3H]uridine and then analyzing the sedimentation properties of the label in a sucrose gradient. When this was done with HIV, the untreated sample showed label banding at the density of the virion (1.16 g per cubic centimeter). By contrast, after solvent–detergent treatment, all the radiolabeled tracer was found on the top of the gradient, indicating that the viral RNA had been reduced to nucleotides or small oligonucleotides (unpublished data). Thus, intravenous immune globulins treated with a solvent and a detergent should pose no risk of transmission of hepatitis B virus, HCV, or HIV.
1 ReferencesAlfred M. Prince, M.D.
Bernard Horowitz, Ph.D.
Lindsley F. Kimball Research Institute of the New York Blood Center, New York, NY 100211
Horowitz B ,Prince AM ,Horowitz MS ,Watklevicz C . Viral safety of solvent-detergent treated blood products. Dev Biol Stand 1993;81:147-161
Medline
Author/Editor Response
The authors reply:
To the Editor: Douglas and Slade claim that we “present an unbalanced viewpoint that is likely to alarm physicians and patients with other disorders who may benefit from this therapy.” Their criticism is surprising, since the main message of our paper was that the risk of contracting chronic HCV infection from contaminated immune globulin products is particularly high among patients with primary hypogammaglobulinemia (as compared with HCV-infected patients with normal immune systems) and results in considerable morbidity and mortality. Douglas and Slade also state that these patients have a higher risk of contracting disease from potentially infectious contaminants and that our observations “should increase our level of vigilance and awareness of the potential risks of this product,” a view we wholeheartedly endorse. However, we do not totally agree with their claim that “the risk–benefit ratio strongly favors the appropriate use of intravenous immune globulin.” Together with three other Scandinavian centers, we have recently reported that subcutaneous immune globulin is a safe, cost-effective, and convenient method of immune globulin replacement in patients with primary hypogammaglobulinemia.1
López-Jiménez and colleagues emphasize that the use of first- and second-generation ELISAs to screen donors for anti-HCV is inadequate to prevent the transmission of HCV. We certainly agree. Even with the use of the various virus-inactivating methods available, the total absence of infectious virus in immune globulins for intravenous use cannot be guaranteed, as emphasized by Schiff in his editorial. To remind colleagues of this important fact is not being alarmist.
1 ReferencesKristian Bjøro, M.D., Ph.D.
Stig S. Frøland, M.D., Ph.D.
National Hospital, 0027 Oslo, Norway1
Gardulf A ,Andersen V ,Bjorkander J , et al. Subcutaneous immunoglobulin replacement in patients with primary antibody deficiencies: safety and costs. Lancet 1995;345:365-369
CrossRef | Web of Science | Medline
Author/Editor Response
Drs. Douglas and Slade express concern that the article by Bjøro et al. and my editorial might cause undue alarm about the risks of transmission of hepatitis. Indeed, the patients described in the Norwegian study, as well as previously described Swedish patients infused with the same brand of immune globulin (Gammonativ), did have a severe course. The patients infected after treatment with Gammagard appear to have had a less severe course, but until these patients have been followed for several years, we will not know the true risks.
Douglas and Slade point out that treating physicians must weigh the risk–benefit ratio, which was the main point of my editorial. The risk of transmitting viral infections with intravenous immune globulin, especially the newer preparations that have been treated with a solvent and a detergent, is very low. Therapy is easily justified as long as the indication for using the immune globulin is clear. It is only when patients are treated for marginal or unproved indications that even small risks are unjustifiable.
They also imply that I recommended that incubating the immune globulin at room temperature was sufficient to eradicate viruses. I merely suggested that incubation of Gamimune N at a low pH might have reduced the risk of transmission and might explain why hepatitis C was transmitted by Gammagard but not Gamimune N. Data from Miles Pharmaceuticals indicate that the incubation process inactivates a variety of viruses, but only more specific processes, such as treatment with a solvent and a detergent, will be an adequate standard for the future.
Drs. Prince and Horowitz, who developed the solvent–detergent process at the New York Blood Center, express concern about the statement that potentially infectious nucleic acid could remain after disruption of the lipid envelope of the hepatitis virus. Although their data are reassuring, few studies have inoculated animals with material infected with a multiplicity of viral particles to prove that the partially digested nucleic acids are no longer infectious. The excellent safety record of blood products treated with a solvent and a detergent is impressive, but one should remember that millions of grams of Gammagard were infused into patients before the transmission of hepatitis was identified. Whether that was due to the removal of potentially protective antibodies from the immune globulin may never be known, but it is clear that no product can be considered 100 percent safe. Variations in manufacturing processes, high levels of contamination, or the emergence of a new, resistant organism may present risks in the future. The solvent–detergent process provides us with a greater margin of safety, but we cannot be complacent.
Richard I. Schiff, M.D., Ph.D
Duke University Medical Center, Durham, NC 27710
