HCV and Intravenous Immune Globulin
Journal of American Medical Association 1997;277:627-628
JAMA Letters - February 26, 1997
To the Editor.--The diagnosis of common variable
immunodeficiency (CVI) is made by demonstrating the lack of the
ability to generate new antibody responses or recall antibody
responses against protein antigens, such as tetanus and diphtheria,
coupled with low serum immunoglobulin levels and recurrent
infections. It is interesting that in the cohort described by Dr
Bresee and colleagues,[1] 26 of 29 immune-deficient patients (the
bulk of whom appear to have CVI) who were documented to be positive
for hepatitis C virus (HCV) nucleic acid were able to generate an
antibody response against HCV proteins. Is there some special
feature on the protein constituents of HCV that enables it to
overcome the profound immune dysfunction characteristic of CVI?
Eric Macy, MD; Kaiser Permanente Health Care Program; San Diego,
Calif
References
1. Bresee JS, Mast EE, Coleman PJ, et al. Hepatitis C virus
infection associated with administration of intravenous immune
globulin: a cohort study. JAMA. 1996;276:1563-1567.
(JAMA. 1997;277:627)
To the Editor.--Dr Bresee et al[ 1] reported an epidemic of HCV
infection among immunodeficient persons treated with Gammagard
intravenous immune globulin (IGIV). The aggregate of 23 cases in 1
clinic was convincingly attributed to 9 or more lots. Related cases
are known elsewhere in the United States, as well as in the United
Kingdom, Sweden, and Spain. Investigators of the Boston, Mass,
aspect of the epidemic concluded that the introduction of more
sensitive donor screening for the antibody to HCV (anti-HCV)
resulted in increased amounts of uncomplexed virus entering the
IGIV fraction.[2] However, other factors may have been equally or
more important for this product.
The HCV cases in 1983 associated with Gammagard from a pilot
plant[ 3] provoked only a brief postmarketing surveillance study,
interpreted as showing safety. The subsequent absence of reported
cases until 1994 associated with any US Gammagard IGIV preparation
does not mean that none occurred. For the Boston lots, Gammagard
had an infection rate of just 11%. At that level in more typically
sized immunology clinics, no more than a single case might occur
and be dismissed as community acquired. Suspicion about Gammagard
IGIV would be low because of the usual safety of all immunoglobulin
preparations. Only routine monitoring of aminotransferase levels
demonstrated the Gammagard-spread cases in the United
Kingdom.[4]
The investigators suggest differences in manufacture may have
contributed to Gammagard transmission, but they believe that no
single manufacturing error would persist over several months. The
latter statement, however, deserves scrutiny. The investigators
similarly mention but fail to discuss any coinciding changes in
paid plasmapheresis donor sources that could have increased the HCV
load in plasma pools. In addition, the manufacturer's Polygam IGIV,
made for the American Red Cross from voluntary donations, did not
transmit to the study population. The Food and Drug Administration
(FDA) stated that the same manufacturing process was used for both
Gammagard and Polygam.[ 5] In Boston, Polygam was given to 129
persons without implication in HCV transmission.
The lack of HCV cases from other IGIV brands, particularly
Polygam, must mean epidemiologically that there were other factors
that placed Gammagard beyond the margin of safety compared with
other brands. The present use of viral inactivation steps in all
products should not end the inquiry into manufacture and viral
burden, because all contributions to virus transmission must be
identified to minimize them in the future.
James W. Mosley, MD; University of Southern California; Los
Angeles
References
1. Bresee JS, Mast SE, Coleman PJ, et al. Hepatitis C virus
infection associated with administration of intravenous immune
globulin: a cohort study. JAMA. 1996;276:1563-1567.
2. Yei S, Yu MW, Tankersley DL. Partitioning of hepatitis C virus
during Cohn-Oncley fractionation of plasma. Transfusion.
1992;32:824-828.
3. Ochs HD, Fischer SH, Virant FS, et al. Non-A, non-B hepatitis
and intravenous immune globulin. Lancet. 1985;1:404-405.
4. Healey CJ, Sabharwal NK, Daub J, et al. Outbreak of acute
hepatitis C following the use of anti-hepatitis C virus screened
intravenous immunoglobulin therapy. Gastroenterology.
1996;110:1120-1126.
5. Yu MW, Finlayson JS, Tankersley DL. Hepatitis C virus
transmission by intravenous immunoglobulin. Lancet.
1995;346:374-375.
(JAMA. 1997;277:627)
In Reply.--We, like Dr Macy, did not expect the high rate of
detection of anti-HCV in this cohort of immunodeficient patients.
In prior reports of HCV transmission to patients with primary
hypogammaglobulinemia following IGIV administration, 2% to 27% of
patients with HCV RNA detected by reverse transcriptase-polymerase
chain reaction had detectable anti-HCV.[1,2] Variability in the
proportion of immunodeficient patients with detectable anti-HCV may
reflect differences in the patient population, differences in the
timing of anti-HCV testing, or both. We are not aware of any unique
features of HCV or the recombinant HCV antigens in the antibody
test that would account for immunodeficient patients responding at
a higher rate to these antigens than to other viral antigens.
We agree with Dr Mosley that further laboratory studies are
needed to determine the exact reasons for the infectivity of
Gammagard. However, there was no evidence that changes in either
plasma donor sources or manufacturing practices played a
significant role.[3] At least 2 factors may be related to
transmission being associated with Gammagard, but not with Polygam,
which was produced using an identical manufacturing process.
Although the first lot of Gammagard derived exclusively from
second-generation anti-HCV enzyme immunoassay (EIA) (HCV EIA 2.0,
Abbott Laboratories, North Chicago, Ill)-screened plasma was
manufactured in February 1993, the first lot of Polygam made only
from EIA-screened plasma was manufactured in August 1993 and was
not available for distribution until October 1993.[3] Thus, few
lots of Polygam derived entirely from EIA-screened plasma were used
before the products were withdrawn in February 1994. In addition,
Gammagard was produced using plasma from paid donors, which
probably had higher HCV titers compared with the recovered plasma
from volunteer donors that was used to produce Polygam.
Although sporadic HCV cases associated with IGIV administration
could be missed by passive surveillance, this outbreak was detected
because of reports by observant physicians who cared for only a few
patients receiving IGIV. Based on epidemiologic evidence from our
investigation, we believe the period of risk for HCV transmission
from Gammagard was confined to a relatively short period that began
coincident with changes in plasma-screening policies. All
symptomatic cases among Gammagard recipients reported in the United
States and from other countries had onset of illness after the
distribution of Gammagard lots produced with EIA-screened plasma.
Infection was also strongly associated with receipt of Gammagard
produced from EIA-screened plasma and not with Gammagard produced
from unscreened or first-generation screened plasma. In addition,
although detection of HCV RNA by reverse transcriptase-polymerase
chain reaction does not necessarily indicate the presence of
infectious virus, HCV RNA was detected in a substantially larger
proportion of Gammagard lots manufactured using EIA-screened
plasma, and in greater titers, compared with lots produced from
unscreened or first-generation-screened plasma.[ 4,5] Moreover, the
HCV RNA in Gammagard made from EIA-screened plasma had a buoyant
density of free (not complexed) hepatitis C virions.[5]
Currently, all US-licensed IGIV products have a viral
inactivation step(s) included in the manufacturing process, and no
hepatitis C cases have been documented in patients who have
received such products.
Joseph S. Bresee, MD; Eric E. Mast, MD, MPH; Mei-ying W. Yu,
PhD; Lynda C. Schneider, MD; Miriam J. Alter, PhD; Centers for
Disease Control and Prevention, Atlanta, Ga
References
1. 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;331:1607-1611.
2. Healey CJ, Sabharwal NK, Daub J, et al. Outbreak of acute
hepatitis C following the use of anti-hepatitis C virus-screened
intravenous immunoglobulin therapy. Gastroenterology.
1996;110:1120-1126.
3. Yu MW, Finlayson JS, Tankersley DL. Hepatitis C virus
transmission by intravenous immune globulin. Lancet.
1995;346:374-375.
4. Yu MW, Mason BL, Guo ZP, et al. Hepatitis C transmission
associated with intravenous immunoglobulin. Lancet.
1995;345:1173-1174.
5. Yu MW, Mason BL, Guo ZP, Renzi PM, Tankersley DL. Detection and
characterization of HCV RNA in an intravenous immune globulin
preparation associated with hepatitis C transmission. In: Rizetto
M, ed. Proceedings of the 1996 International Symposium on Viral
Hepatitis and Liver Disease. Rome, Italy. In press.
(JAMA. 1997;277:627-628)
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