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Hepatology, January 1999, p. 299-300, Vol. 29, No. 1

Correspondence

To the Editor:

In their interesting review, Heintges and Wands1 wrote: "... HCV-RNA was detectable in more than one-half of the intramuscular preparations of immunoglobulins. Thus, patients with immunoglobulin deficiency and who received such prophylactic antibody preparations frequently developed chronic HCV infection."

However, Heintges and Wands cited a study by Bjøro et al.,2 who reported that patients with primary hypogammaglobulinemia who received intramuscular immunoglobulins for long periods of time never acquired hepatitis C virus (HCV) infection. Only a group of patients who received a batch of intravenous immunoglobulin contaminated with non A, non B hepatitis virus acquired the infection.

Clearly, there is a need to clarify the topic of immunoglobulin administration and HCV transmission also in view of the medical, scientific, and legal aspects.

IMMUNOGLOBULIN PREPARATIONS

Standard or "polyvalent" immunoglobulin is prepared from blood pooled from at least 1,000 donors. Immunoglobulin preparations contain a wide range of antibodies resulting from infections widely spread in the population or from vaccinations. Hyperimmune globulin is prepared from the blood of a smaller number of donors appropriately vaccinated or convalescent from a given disease; hence hyperimmune globulin contains the same range of antibodies as standard immunoglobulin, but one antibody is much more concentrated than the others (at least 5-fold). After injection, the antibodies are present in the bloodstream and in interstitial fluids where they bind specifically to the various infectious agents (antigens) to form immune complexes that then are eliminated via the reticular-endothelium cell system. Antibodies do not enter the cells, and they have a half-life of 21 to 25 days. Thus, their protective effect can last 2 to 3 months.

Since 1971, hepatitis B surface antigen-positive blood units have not been included in immunoglobulin starting material. Since 1985 and 1992, also anti-human immunodeficiency virus-1- and anti-human immunodeficiency virus-2-positive units, respectively, have been discarded. In the early 1990s, most developed countries forbade the use of anti-HCV-positive blood for immunoglobulin products (e.g., 1990 in France, 1991 in the United States, and 1993 in Italy).

INTRAMUSCULAR IMMUNOGLOBULIN

Intramuscular immunoglobulin preparations are prepared according to the Cohn fractionation process, which separates the fraction containing antibodies that neutralize various infectious agents. The resulting preparations are highly concentrated (16% in solution and containing 160 mg of protein/mL). Other manufacturing procedures do not ensure the same safety.3

Over the last 50 years, many millions of individuals worldwide have received intramuscular immunoglobulin without contracting infections. Intramuscular immunoglobulin prepared according to the Cohn process has been proclaimed safe by the Centers for Disease Control4,5 and by the World Health Organization.6

Recently, concern was aroused when 50% of batches of unscreened intramuscular immunoglobulin, both standard7 and hyperimmune,7,8 tested positive for HCV-RNA. This led to the suggestion that patients with chronic hepatitis C infection could have been infected by a previous inoculation of intramuscular immunoglobulin. We were able to provide the first direct evidence that HCV infection is not transmitted by intramuscular immunoglobulin containing HCV-RNA. In fact, in a randomized controlled trial 450 at-risk sexual partners (mean age: 43.8 years) of HCV-infected individuals received 4 mL of unscreened intramuscular immunoglobulin every 2 months for a mean of 13.5 months. A total of 3,260 doses of immunoglobulin were administered, about 50% of which were HCV-RNA positive, and none of the immunoglobulin recipients monitored at 4-month intervals became HCV infected.9,10

Similarly, in an uncontrolled trial that started at the end of 1989,11 we treated 78 at-risk sexual partners (mean age: 29 years) of HCV-infected subjects for about 6 years according to the same protocol.9 The partners received unscreened intramuscular immunoglobulin (about 50% were HCV-RNA positive) until March 1993, when testing of blood units for anti-HCV became mandatory in Italy. Thenceforth, the sexual partners received screened immunoglobulin preparations. The study was stopped in July 1995, when it was first demonstrated that the "new" screened commercial intramuscular immunoglobulin lacked anti-gpE1/E2 neutralizing antibodies, whereas the "old" unscreened commercial intramuscular immunoglobulin contained high titers of these antibodies.9,12 No sexual partner of this study became HCV-RNA positive.

The safety of HCV-RNA-positive intramuscular immunoglobulin preparations can be attributed to several factors: (1) partitioning of viruses away from immunoglobulin, (2) inactivation of viruses by the fractionation process, and (3) a high concentration of neutralizing antibodies.7,9,12

Since 1995, it has been recommended to perform HCV-RNA testing on the final product13,14 or on the starting plasma pools15 with respect to intramuscular immunoglobulins that have not undergone any HCV inactivation process following Cohn fractionation process.

INTRAVENOUS IMMUNOGLOBULIN

Intravenous immunoglobulin is 5% solution of normal or specific immunoglobulin (the concentration of the latter can be even higher) that undergoes an additional preparation process to be administered by the intravenous route.

Although intramuscular immunoglobulin has never been associated with HCV transmission, from 1983 to 1994 at least 8 outbreaks of non A, non B/HCV infections occurred, 7 outside the United States and 1 inside the United States, in subjects who received intravenous immunoglobulin. During each outbreak, the number of HCV-infected patients varied from 1 to 28.16 In 1994 an outbreak of HCV infection was associated with intravenous immunoglobulin (Gammagard) produced by Baxter Healthcare Corporation (BHC), Deerfield, IL.13 The first cases occurred in the United Kingdom, Spain, and Sweden. Successively, 110 cases were reported in the United States.17 It is noteworthy that, at that time, Gammagard was produced without any of the additional HCV-inactivation processes that later came into use.13,18 To explain this outbreak, it was suggested that, after the introduction of blood screening for anti-HCV and consequently the exclusion of anti-HCV-positive blood units, the starting blood pool could have contained blood from donors in an early stage of disease, i.e., before the patients became anti-HCV positive. It was also speculated that a hypothetical neutralizing antibody could have been removed with the anti-HCV-positive blood units.19,20

In this context, it is interesting to recall a recent study in which plasma containing infectious HCV incubated with experimental intravenous immunoglobulin prepared from about 200 anti-HCV-positive blood donors did not cause infection in the chimpanzee, whereas the same infectious plasma incubated with commercial intravenous immunoglobulin prepared from over 1,000 anti-HCV-negative donors caused infection in the animal.21 These results are consistent with the presence of neutralizing antibodies in the intravenous immunoglobulin from anti-HCV-positive blood and their absence from intravenous immunoglobulin from anti-HCV-negative blood.

Since 1994, most intravenous immunoglobulin products---in addition to the Cohn method---undergo stringent procedures to inactivate HCV and other infectious agents.18,22

Although many millions of grams of intravenous immunoglobulin are used each year, and their use is continuously increasing, no cases of HCV infection have been reported in treated subjects after the advent of new viral-inactivation procedures.14

There are several possibilities to explain why pre-1994 intravenous immunoglobulin resulted in some cases of HCV infection, whereas intramuscular immunoglobulin did not. (1) Intramuscular immunoglobulin is more concentrated than intravenous immunoglobulin, so that immune complexes form more easily in the former; when these complexes enter the bloodstream they are eliminated by the reticular-endothelium cells system. (2) Intramuscular immunoglobulin is adsorbed more slowly; in fact, the highest antibody titer in the blood is reached about 48 hours after injection. (3) A higher amount of immunoglobulin is injected intravenously than intramuscularly. (4) Although both types of immunoglobulin were produced with the Cohn method, the subsequent production steps differ.

In conclusion, (1) intramuscular immunoglobulin has never transmitted HCV infection; and (2) some intravenous immunoglobulin products used before 1994 caused a few cases of HCV infection, whereas intravenous immunoglobulin prepared after 1994 is totally safe.

Marcello Piazza, M.D.
Istituto di Malattie Infettive
Secondo Policlinico
Università "Federico II" Napoli
Napoli, Italy

 

REFERENCES

1.

Heintges T, Wands JR. Hepatitis C virus: epidemiology and transmission. HEPATOLOGY 1997;26:521-526[Medline].

2.

Bjøro K, Froland SS, 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[Medline].

3.

Foster PR, McIntosh RV, Welch AG. Hepatitis C infection from anti-D immunoglobulin. Lancet 1995;346:372-375.

4.

Centers for Disease Control. Recommendations of the Immunization Practices Advisory Committee (ACIP): Recommendations for protection against viral hepatitis. MMWR Morb Mortal Wkly Rep 1985;34:313-335[Medline].

5.

Centers for Disease Control. Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 1996;45:1-30.

6.

World Health Organization. Public health control of hepatitis A: memorandum from a WHO meeting. WHO Bulletin 1995;73:15-20[Medline].

7.

Yu MYW, Mason BL, Tankersley DL. Detection and characterization of hepatitis C virus RNA in immune globulins. Transfusion 1994;34:596-602[Abstract].

8.

Pisani T, Cristiano K, Wirz M, Pini C, Gentili G. Hepatitis C viral RNA in tetanus intramuscular immune globulin. Transfusion 1997;37:986-987[Medline].

9.

Piazza M, Sagliocca L, Tosone G, Guadagnino V, Stazi MA, Orlando R, Borgia G, et al. Sexual transmission of the hepatitis C virus and efficacy of prophylaxis with intramuscular immune serum globulin: a randomized controlled trial. Arch Intern Med 1997;157:1537-1544[Medline].

10.

Piazza M, Sagliocca L, Tosone G, Orlando R, Borgia G, Palumbo F, Guadagnino V, et al. More evidence on safety of intramuscular immune serum globulin produced from plasma unscreened for anti-hepatitis C virus antibodies. Arch Intern Med 1998;158:807-808[Medline].

11.

Piazza M. Periodic gammaglobulin to prevent hepatitis C in at-risk sexual partners. Lancet 1990;336:823-824.

12.

Piazza M, Chien D, Quan S, Houghton M. Lack of antibodies to the envelope glycoproteins of hepatitis C virus in immunoglobulin preparations from screened donors. J Biol Res Boll Soc It Biol Sper 1996;72:69-70[Medline].

13.

Bresee JS, Mast EE, Coleman PJ, Baron MJ, Schonberger LB, Alter MJ, Jonas MM, et al. Hepatitis C virus infection associated with administration of intravenous immune globulin. A cohort study. JAMA 1996;276:1563-1567[Medline].

14.

Bresee JS, Mast EE, Yu MW, Schneider LC, Alter MJ. Hepatitis C virus and intravenous immune globulin. JAMA 1997;277:627-628.

15.

Committee for Proprietary Medicinal Products. Intramuscular immunoglobulins: nucleic acid amplification tests for HCV-RNA detection. CPMP 117/95.

16.

Healey CJ, Sabharwal NK, Daub J, Davidson F, Yap PL, Fleming KA, Chapman RWG, et al. Outbreak of acute hepatitis C following the use of anti-hepatitis C virus---screened intravenous immunoglobulin therapy. Gastroenterology 1996;110:1120-1126[Abstract].

17.

Meeks EL, Beach MJ. Outbreak of hepatitis C associated with intravenous immunoglobulin administration---United States, October 1993-June 1994. MMWR Morb Mortal Wkly Rep 1994;43:505-509[Medline].

18.

Schiff RI. Transmission of viral infections through intravenous immune globulin. N Engl J Med 1994;331:1649-1650[Medline].

19.

James RC, Mosley JW. Hepatitis C virus transmission by intravenous immunoglobulin. Lancet 1995;346:374-375[Medline].

20.

Koretz RL. Less than an ounce of prevention. Gastroenterology 1998;115:234-236[Full Text].

21.

Yu MW, Guo ZP, Mason BL, Feinstone SM, Renzi PM, Jong JS. Presence of protective antibodies in an experimental intravenous immune globulin prepared from anti-HCV positive donor units. Proceedings of 5th International Meeting on Hepatitis C Virus and Related Viruses. Venice, June 25-28 1998; Abs n°H13 (p 223).

22.

Yap PL. The viral safety of intravenous immune globulin. Clin Exp Immunol 1996;104(Suppl 1):35-42.


 In the early 1990s, most developed countries forbade the use of anti-HCV-positive blood for immunoglobulin products