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 methodundergo
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 virusscreened
intravenous immunoglobulin therapy. Gastroenterology
1996;110:1120-1126[Abstract].
|
|
17.
|
Meeks EL, Beach MJ. Outbreak
of hepatitis C associated with intravenous immunoglobulin
administrationUnited
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
