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Immunoglobulin Transmits Hepatitis C. True or False?

Immune serums (immune globulin) provide passive immunity to infectious disease. The protection will be of rapid onset, but of short duration (1-3 months). Immune sera are obtained from pooled human plasma of either general population donors or hyperimmunized donors. It may be administered either by intravenous (IV) or intramuscular (IM) injection.

  1. Intramuscular immune globulin is available in broad-spectrum form, or disease-specific hyperimmune serum.

     
    1. Immune serum globulin intramuscular (IM) (IG, Gamma Globulin, ISG, Gamastan, Gammar) (HCPCS/CPT codes J1460-J1560) is indicated for the following conditions:
      1. Hepatitis A exposure (ICD-9: V01.7).
      2. Measles (Rubeola) : for a susceptible patient (has not been vaccinated and has not had measles and is at high risk for complication) who has been exposed less than three days prior to treatment (ICD-9 V04.2 ).
      3. Rubella: for a woman in early pregnancy, who is exposed to the virus and does not have immunity. (ICD-9 V22.2 and V01.4; or 647.50; or 647.53)
      4. Varicella: for passive immunization in immunosuppressed patients when varicella zoster immunoglobulin is not available (ICD-9: V05.4).
      5. Immunoglobulin deficiency: for prevention of serious infection when circulating IgG levels are low. Prophylactic therapy, especially against infections due to encapsulated bacteria, is often effective in Bruton-type, sex-linked congenital agammaglobulinemia, agammaglobulinemia associated with thymoma and acquired agammaglobulinemia (ICD-9: 042, 279.00-279.06, 279.2, 279.3). Therapy may not prevent chronic infections of external secretory tissues such as the respiratory or GI tracts.


       

    2. Specific hyperimmune serum globulin includes several different disease-specific drugs.
      1. Hepatitis B serum (CPT 90371) is indicated post-exposure for transient prevention of hepatitis B infection. (ICD-9 V15.85)
      2. Rabies serum (CPT 90375, 90376) is indicated post-exposure for transient prevention of rabies infection when the patient has not been completely immunized with the vaccination. (ICD-9 V01.5)
      3. Vaccinia serum (CPT 90393) is indicated for transient prevention of or modification of aberrant infections induced by vaccinia (smallpox) vaccine, the vaccinia virus, such as eczema vaccinatum, some cases of progressive vaccinia, and possibly ocular vaccinia. (ICD-9 V01.4)
      4. Varicella-zoster serum (CPT 90396) is indicated for transient prevention of varicella-zoster infection in exposed, susceptible individuals who have a greater risk of complications from varicella (ICD-9 V01.7). Documentation in the progress notes must indicate one of the following complicating conditions to verify medical necessity: - a personal history of leukemia or lymphoma - HIV infection - current immunosuppressive therapy - a newborn with exposure to chickenpox (the documentation must indicate why the newborn is at increased risk; e.g., if the mother was exposed within 5 days of delivery).
      5. Tetanus serum (J1670) is indicated for transient protection against tetanus post-exposure to tetanus (ICD-9 code V03.7). Documentation in the progress notes must identify the following: - The wound is other than a clean minor wound, and the date of the injury; - The active immunization with tetanus toxoid is unknown or uncertain; or - The patient has received either less than 2 prior doses of tetanus toxoid; or two prior doses of tetanus toxoid, but there has been a delay of 24 hours or more between the time of injury and the initiation of tetanus prophylaxis.

 

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.

More Studies on the transmission of Hepatitis C by ISG.
Atrah HI, Ala FA, Gough D. Blood exchanged in ritual ceremonies as a possible route for infection with hepatitis C virus. J Clin Pathol 1994 Jan;47(1):87.

Bjorkander J, Fasth A, Widell A. Intravenous immunoglobulin and hepatitis C virus: the Scandinavian experience. Clin Ther 1996;18 Suppl B:73-82.

Bjoro 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 Dec 15;331(24):1607-11; N Engl J Med 1994 Dec 15;331(24):1649-50; N Engl J Med 1995 May 4;332(18):1235; discussion 1236-7; N Engl J Med 1995 May 4;332(18):1235-6.

Bresee JS, Mast EE, Coleman PJ, Baron MJ, Schonberger LB, Alter MJ, Jonas MM, Yu MY, Renzi PM, Schneider LC. Hepatitis C virus infection associated with administration of intravenous immune globulin. A cohort study. JAMA 1996 Nov 20;276(19):1563-7.

Couzigou P, Richard L, Dumas F, Schouler L, Fleury H. Detection of HCV-RNA in saliva of patients with chronic hepatitis C. Gut 1993;34(2 Suppl):S59-60.

Crowe J, Doyle C, Fielding JH, Holloway H, Keegan M, Kellcher D, Kelly P, Leader M, Little M, McDonald G, McCarthy CF, McWeeney J, O'Keane C, Rajan E/Walsh JK, Kenny Walsh L, Weir DG, Whelton M. Presentation of hepatitis C in a unique uniform cohort 17 years from inoculation [abstract]. Gastroenterology 1995 Apr;108(4 Suppl):A1054.

Echevarria JM, Leon P, Domingo CJ, Lopez JA, Elola C, Madurga M, Salmeron F, Yap PL, Daub J, Simmonds P. Laboratory diagnosis and molecular epidemiology of an outbreak of hepatitis C virus infection among recipients of human intravenous immunoglobulin in Spain. Transfusion 1996 Aug;36(8):725-30.

Feucht HH, Zollner B, Schroter M, Altrogge H, Laufs R. Tear fluid of hepatitis C virus carriers could be infectious. J Clin Microbiol 1995 Aug;33(8):2202-3.

Flora K, Schiele M, Benner K, Montanaro A, Johnston W, Whitham R, Press R. An outbreak of acute hepatitis C among recipients of intravenous immunoglobulin. Ann Allergy Asthma Immunol 1996 Feb;76(2):160-2.

From the Centers for Disease Control and Prevention. Outbreak of hepatitis C associated with intravenous immunoglobulin administration--United States, October 1993-June 1994. JAMA 1994 Aug 10;272(6):424-5.

Gomperts ED. Gammagard and reported hepatitis C virus episodes. Clin Ther 1996;18 Suppl B:3-8.

Healey C, Chapel H. Intravenous immunoglobulin and hepatitis C virus: the British episode. Clin Ther 1996;18 Suppl B:93-5.

Healey CJ, Sabharwal NK, Daub J, Davidson F, Yap PL, Fleming KA, Chapman RW, Simmonds P, Chapel H. Outbreak of acute hepatitis C following the use of anti-hepatitis C virus--screened intravenous immunoglobulin therapy. Gastroenterology 1996 Apr;110(4):1120-6. Comment in: Gastroenterology 1996 Apr;110(4):1307-10.

Higashi H, Matsumata T, Hayashi J, Yanaga K, Shimada M, Shirabe K, Taketomi A, Kashiwagi S, Sugimachi K. Detection of hepatitis C virus RNA in the ultrasonic dissector irrigating solution used in liver surgery. Br J Surg 1994 Sep;81(9):1346-7.

Jonas MM, Baron MJ, Bresee JS, Schneider LC. Clinical and virologic features of hepatitis C virus infection associated with intravenous immunoglobulin. Pediatrics 1996 Aug;98(2 Pt 1):211-5.

Karna P, Murray DL, Valduss D, Mattarella N, Dyke JW, Maier GA. Passive transfer of hepatitis antibodies during intravenous administration of immune globulin. J Pediatr 1994 Sep;125(3):463-5. Comment in: J Pediatr 1995 Feb;126(2):321-2.

Lefrere JJ, Loiseau P, Martinot-Peignoux M, Mariotti M, Ravera N, Thauvin M, Marcellin P, Janot C. Infection by hepatitis C virus through contaminated intravenous immune globulin: results of a prospective national inquiry in France. Transfusion 1996 May;36(5):394-7.

McKee TA, Avery S, Majid A, Brinsden PR. Risks for transmission of hepatitis C virus during artificial insemination. Fertil Steril 1996 Jul;66(1):161-3.

Mele A, Corona R, Tosti ME, Palumbo F, Moiraghi A, Novaco F, Galanti C, Bernacchia R, Ferraro P. Beauty treatments and risk of parenterally transmitted hepatitis: results from the hepatitis surveillance system in Italy. Scand J Infect Dis 1995;27(5):441-4.

Nelson SP, Jonas MM. Hepatitis C infection in children who received extracorporeal membrane oxygenation. J Pediatr Surg 1996 May;31(5):644-8.

Ollero M, Merino D, Pujol E, Marquez P, Gimeno A, Angulo C. Tattoos and hepatitis C virus infection [abstract]. Int Conf AIDS 1992 Jul 19-24;8(3):180 (abstract no. PuC 8163).

Outbreak of hepatitis C associated with intravenous immunoglobulin administration--United States, October 1993-June 1994. MMWR Morb Mortal Wkly Rep 1994 Jul 22;43(28):505-9.

Power JP, Lawlor E, Davidson F, Holmes EC, Yap PL, Simmonds P. Molecular epidemiology of an outbreak of infection with hepatitis C virus in recipients of anti-D immunoglobulin. Lancet 1995 May 13;345(8959):1211-3. Comment in: Lancet 1995 Aug 5;346(8971):372.

Power JP, Lawlor E, Davidson F, Yap PL, Kenny-Walsh E, Whelton MJ, Walsh TJ. Hepatitis C viraemia in recipients of Irish intravenous anti-D immunoglobulin [letter]. Lancet 1994 Oct 22;344(8930):1166-7.

Purcell RH. Enterically transmitted non-A, non-B hepatitis. Prog Liver Dis 1990;9:497-504.

Sartori M, La Terra G, Aglietta M, Manzin A, Navino C, Verzetti G. Transmission of hepatitis C via blood splash into conjunctiva [letter]. Scand J Infect Dis 1993;25(2):270-1.

Schneider LC, Jonas MM, Baron MJ, Mast EF, Alter MJ, Schonberger LB, Lambert S, Coleman P, Bresee JS. Intravenous immunoglobulin and hepatitis C virus: the Boston episode. Clin Ther 1996;18 Suppl B:108-9.

Slade HB. Human Immunoglobulins for intravenous use and hepatitis C viral transmission. Clin Diagn Lab Immunol 1994 Nov;1(6):613-9.

Webster AD, Brown D, Franz A, Dusheiko G. Prevalence of hepatitis C in patients with primary antibody deficiency. Clin Exp Immunol 1996 Jan;103(1):5-7.

Yap PL. Intravenous immunoglobulin and hepatitis C virus: an overview of transmission episodes with emphasis on manufacturing data. Clin Ther 1996;18 Suppl B:43-58.

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

Yap PL, McOmish F, Webster AD, Hammarstrom L, Smith CI, Bjorkander J, Ochs HD, Fischer SH, Quinti I, Simmonds P. Hepatitis C virus transmission by intravenous immunoglobulin. J Hepatol 1994 Sep;21(3):455-60.

Yu MW. Follow-up studies of hepatitis C association with an intravenous immunoglobulin. Dev Biol Stand 1996;88:215-6.

Yu MW, Mason BL, Guo ZP, Tankersley DL. Safety of intravenous immunoglobulin with regard to hepatitis C virus. Clin Ther 1996;18 Suppl B:71-2.

 
Information about ISG

Immune serums (immune globulin) provide passive immunity to infectious disease. The protection will be of rapid onset, but of short duration (1-3 months). Immune sera are obtained from pooled human plasma of either general population donors or hyperimmunized donors. It may be administered either by intravenous (IV) or intramuscular (IM) injection.

Immune Globulin (Human) (IG) is a solution of immunoglobulin G (IgG) indicated for prophylaxis of hepatitis A, prevention or modification of measles (Rubeola), and for immunoglobulin deficiency. It is administered intramuscularly.

Additional specific immune globulins for intramuscular administration are obtained from donors whose plasma contains selected high titer antibodies. Products are available for use in the passive prophylaxis of varicella-zoster, tetanus, hepatitis B, rabies, and other infections. Another product, Rho(D) Immune Globulin (Human), is for the prevention of sensitization to the Rho(D) antigen and hemolytic disease of the newborn. Some of the intramuscular immunoglobulin products have been subjected to heat- or solvent/detergent-treatment.

 

Rh0(D) immune globulin is a plasma-derived product
comprised of anti-D immune globulin  Suppression of Rh isoimmunization related to transfusion or pregnancy: Intramuscular RhIg has been successfully used to prevent the development of Rho (D) antibodies for years. INTRAVENOUS (HUMAN) Rho(D) IMMUNE GLOBULIN A new preparation for the treatment of ITP and Rh isoimmunization  Katherine A. Anderegg, M.D., Fellow, The Institute For Transfusion Medicine Darrell J. Triulzi, M.D., Medical Director, The Institute For Transfusion Medicine

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

From August 1978 until March 1979, 14 batches of anti-D immune globulin contaminated with hepatitis C virus (HCV) genotype 1b (20,000-480,000 copies/dose) from a single erythrocyte donor had been administered for prophylaxis of rhesus isoimmunization throughout East Germany. All 2,867
Subcutaneous injections of a drug containing human immunoglobulins  1974 and early 1975, several cases of viral hepatitis were reported in Italy among subjects who had received subcutaneous injections of a drug containing human immunoglobulins that was prescribed for the treatment of allergies. The possibility that immunoglobulins can be responsible for the transmission of viral hepatitis raises a number of theoretical and practical problems concerning control and use of these blood products.
 

4.2.6 Intravenous anti-D immunoglobulin

Anti-D immunoglobulin is prepared from the plasma of donors with high concentrations of anti-rhesus D antibody. Intravenous anti-D immunoglobulin was first reported to be involved in the transmission of HCV in an outbreak of NANBH that occurred in East Germany between 1978 and 1979 (Dittmann et al 1991). A similar outbreak was also reported in Ireland where 12 women received anti-D immunoglobulin manufactured in 1977 that contained HCV-RNA sequences (Stevens et al 1984; Power et al 1994; Power et al 1995a). Both of these outbreaks were traced to index cases who donated HCV-antibody-positive blood.

Another intravenous preparation implicated in the transmission of HCV was an immunoglobulin product, Gammagard, used to treat primary immunodeficiency disorders such as hypogammaglobulinaemia. In the USA, 43 people with acute HCV infection were reported to the Centers for Disease Control and Prevention (CDC) between 1993 and mid 1994 where the only risk factor for HCV infection was receipt of the intravenous immunoglobulin, Gammagard (Anonymous 1994). Gammagard was subsequently removed worldwide in early 1994. Preliminary epidemiological investigations in the USA have indicated that no other intravenous immunoglobulin products or intramuscular immune globulin have been associated with HCV transmission (Anonymous 1994).

The recent introduction of anti-viral treatments used in the manufacture of immunoglobulin products has substantially reduced the risk of transmission of HCV to recipients of these products.

 

 

  1. Intramuscular immune globulin is available in broad-spectrum form, or disease-specific hyperimmune serum.

     
    1. Immune serum globulin intramuscular (IM) (IG, Gamma Globulin, ISG, Gamastan, Gammar) (HCPCS/CPT codes J1460-J1560) is indicated for the following conditions:
      1. Hepatitis A exposure (ICD-9: V01.7).
      2. Measles (Rubeola) : for a susceptible patient (has not been vaccinated and has not had measles and is at high risk for complication) who has been exposed less than three days prior to treatment (ICD-9 V04.2 ).
      3. Rubella: for a woman in early pregnancy, who is exposed to the virus and does not have immunity. (ICD-9 V22.2 and V01.4; or 647.50; or 647.53)
      4. Varicella: for passive immunization in immunosuppressed patients when varicella zoster immunoglobulin is not available (ICD-9: V05.4).
      5. Immunoglobulin deficiency: for prevention of serious infection when circulating IgG levels are low. Prophylactic therapy, especially against infections due to encapsulated bacteria, is often effective in Bruton-type, sex-linked congenital agammaglobulinemia, agammaglobulinemia associated with thymoma and acquired agammaglobulinemia (ICD-9: 042, 279.00-279.06, 279.2, 279.3). Therapy may not prevent chronic infections of external secretory tissues such as the respiratory or GI tracts.


       

    2. Specific hyperimmune serum globulin includes several different disease-specific drugs.
      1. Hepatitis B serum (CPT 90371) is indicated post-exposure for transient prevention of hepatitis B infection. (ICD-9 V15.85)
      2. Rabies serum (CPT 90375, 90376) is indicated post-exposure for transient prevention of rabies infection when the patient has not been completely immunized with the vaccination. (ICD-9 V01.5)
      3. Vaccinia serum (CPT 90393) is indicated for transient prevention of or modification of aberrant infections induced by vaccinia (smallpox) vaccine, the vaccinia virus, such as eczema vaccinatum, some cases of progressive vaccinia, and possibly ocular vaccinia. (ICD-9 V01.4)
      4. Varicella-zoster serum (CPT 90396) is indicated for transient prevention of varicella-zoster infection in exposed, susceptible individuals who have a greater risk of complications from varicella (ICD-9 V01.7). Documentation in the progress notes must indicate one of the following complicating conditions to verify medical necessity: - a personal history of leukemia or lymphoma - HIV infection - current immunosuppressive therapy - a newborn with exposure to chickenpox (the documentation must indicate why the newborn is at increased risk; e.g., if the mother was exposed within 5 days of delivery).
      5. Tetanus serum (J1670) is indicated for transient protection against tetanus post-exposure to tetanus (ICD-9 code V03.7). Documentation in the progress notes must identify the following: - The wound is other than a clean minor wound, and the date of the injury; - The active immunization with tetanus toxoid is unknown or uncertain; or - The patient has received either less than 2 prior doses of tetanus toxoid; or two prior doses of tetanus toxoid, but there has been a delay of 24 hours or more between the time of injury and the initiation of tetanus prophylaxis.


     

  2. *Intravenous immune globulin (IGIV, Gamimune N, Gammagard, Gammar-IV, Iveegam, Sandoglobulin, Venogloblin-I) (CPT codes J1563, *J1564) provides immediate antibody levels. IVIG has been used as a therapy of last resort for some of the conditions and is indicated only if standard approaches have failed, become intolerable, or are contraindicated. IVIG may be indicated for the following conditions:

     
    1. Immunodeficiency Syndrome: to include congenital agammaglobulinemia such as x-linked aglobulinemia, common variable hypoglobulinemia, x-linked immunodeficiency with hyper IGM, combined immunodeficiency, and AIDS (ICD-9: 042, 279.00-279.06, 279.2)

       
    2. Idiopathic thrombocytopenic purpura (ICD-9: 446.6, 287.3).

       
    3. Alloimmune thrombocytopenia, refractoriness to platelet transfusions (ICD-9 287.4). Routine use is not indicated. IVIG may have a role in patients with severe thrombocytopenia of documented immune basis for whom other modalities are unsuccessful or contraindicated. IVIG may be used in neonates with severe immune thrombocytopenia if other interventions are unsuccessful or contraindicated. Maternal antenatal infusion may be considered.

       
    4. Post-transfusion purpura (ICD-9 287.4). IVIG may be considered as first-line therapy in severely affected patients.

       
    5. B-Cell Chronic Lymphocytic Leukemia (ICD-9: 204.10)

       
    6. Autoimmune hemolytic anemia (ICD-9: 283.0). Routine use is not indicated. IVIG may have a role in patients with warm-type AIHA that does not respond to corticosteroids.

       
    7. Immune-mediated neutropenia (ICD-9 288.0). Routine use is not indicated. IVIG may have a role in severe illness that does not respond to other modalities or when the latter are contraindicated.

       
    8. Multiple Myeloma (ICD-9 203.00-203.80). Routine use is not indicated. It may have a role in patients with stable (plateau phase) disease and high risk of recurrent infections.

       
    9. Pediatric intractable epilepsy (ICD-9 345.11, 345.3, 345.61). Routine use is not indicated. IVIG may have a role in certain syndromes as a last resort, especially in patients who may be candidates for surgical resection.

       
    10. Guillian-Baré syndrome (ICD-9 357.0). IVIG is recommended as an equivalent alternative to plasma exchange in children and adults.

       
    11. Myasthenia gravis (MG) (ICD-9 358.0). Routine use is not indicated. IVIG may be considered in patients with severe MG to treat acute severe decompensation when other treatments have been unsuccessful or are contraindicated.

       
    12. Polyneuropathy, chronic inflammatory demyelinating (ICD-9 357.8). IVIG is recommended as an equivalent alternative to plasma exchange in children and adults.

       
    13. Dermatomyositis (ICD-9 710.3). Routine use is not indicated. IVIG may be used in patients with severe active illness for whom other interventions have been unsuccessful or intolerable.

       
    14. Polymyositis (ICD-9 710.4). Routine use is not indicated. IVIG may be used in patients with severe active illness for whom other interventions have been unsuccessful or intolerable.

       
    15. Systemic lupus erythematosus (SLE) (ICD-9 710.0). Routine use is not indicated. IVIG may be used in patients with severe active SLE for whom other interventions have been unsuccessful or intolerable.

       
    16. Kawasaki disease (ICD-9 446.1).

       
    17. Severe Vasculitic Syndromes, systemic (polyartaritis nodosa) (ICD-9 446.0). Evidence does not suppport routine use of IVIG. IVIG may be used in patients with severe active illness for whom other interventions have been unsuccessful. or intolerable.

     

  3. Intravenous immune globulin for the treatment of autoimmune mucocutaneous blistering diseases is a National Coverage Decision (NCD). It is binding on all Medicare carriers, intermediaries, peer review organizations, health maintenance organizations, competitive medical plans, and health care prepayment plans. Under 42 CFR 422.256(b), an NCD that expands coverage is also binding on a Medicare+Choice Organization. In addition, an administrative law judge may not review an NCD. (See §1869(f)(1)(A)(i) of the Social Security Act.)

    Intravenous immune globulin (IVIg) (J1563) is a blood product prepared from the pooled plasma of donors. It has been used to treat a variety of autoimmune diseases, including mucocutaneous blistering diseases. It has fewer side effects than steroids or immunosuppressive agents.

 

To make immune serum globulin ( ISG) products, plasma is treated with a variety of substances to separate the desired proteins from others, in a process called fractionation. Fractionation  process used today is the Cohn-Oncley method. This process relies on precipitation of plasma proteins by a combination of cold alcohol (usually ethanol)-water mixtures and adjustments of pH, ionic strength, temperature, and protein concentration.

The fractionation process leading to immune globulin resulted in overall reduction in HCV RNA by a factor of 4.7 x 10(4). Although the presence of HCV RNA in the final product does not necessarily imply the presence of infectious virus, this work suggests that the safety of immune globulins with respect to HCV transmission is not due solely to the partitioning of HCV away from the immunoglobulin fraction.

Alternatively, some manufacturers separate plasma derivatives by column chromatography using ion exchange, gel filtration, or affinity methods, without alcohol. In all cases, fractions of plasma are separated sequentially, with the product from one step, such as the precipitate and/or supernatant, becoming the starting material for the next step in the fractionation process. If each step is not done properly, subsequent fractions can be adversely affected. Thus, the integrity of each final product is dependent on all of the preceding steps in the process.

After fractionation, derivatives undergo further processing to purify and concentrate proteins and to inactivate or remove (clearance) any bacterial or viral contaminants. While early steps in the manufacturing process are not performed aseptically, all final products must be  sterile. Types of viral clearance include those steps that are part of the fractionation process itself, e.g., pH4/pepsin or polyethylene glycol (PEG) fractionation, or those steps that are deliberately added, e.g., solvent/detergent treatment or viral filtration. In some instances more than one viral clearance step is used for a given product. Plasma derivatives are similar to other biological products in that they are protein-based and subject to denaturization at high temperatures. These products are usually filled by using aseptic processing techniques, and cannot be terminally sterilized, although in some instances they can be heat-treated in the final container to effect viral or bacterial inactivation.

 

  

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