Hepatitis C Transmission Associated with ImmunoglobulinQuote: "Since the 1940s, immune globulin products licensed in the United States have
been
safely administered; these products previously have not been known to be
associated
with the transmission of bloodborne agents, including HIV. Cases of non-A, non-B
hepatitis (of which HCV is the primary etiologic agent) have been previously
associated
with an unlicensed IGIV product used in a clinical trial in the United States
and
with IGIV products manufactured and distributed abroad; however, reasons for
these
episodes of transmission ( 2 ) and the episodes described in this report have
not been
determined. Since mid-May 1994, the approved manufacturing process for both Gammagard
® and Polygam® includes a solvent-detergent treatment designed to inactivate
contaminating viruses. Products manufactured with this treatment should not pose
a
risk for HCV transmission to recipients."
Outbreak of Hepatitis C Associated with Intravenous
Immunoglobulin Administration
United States, October 1993–June 1994
MMWR 43(28);505-509
Publication date: 07/22/1994
On February 21, 1994, the Food and Drug Administration (FDA) was notified of
14 possible cases from three different countries of acute hepatitis C among
persons
who had received Gammagard®*, an intravenous immunoglobulin (IGIV) product
manufactured by Baxter Healthcare Corporation (Glendale, California). The
company
removed Gammagard® from the worldwide market on February 23, 1994. The American
Red Cross removed Polygam® (IGIV manufactured by Baxter Healthcare from
American Red Cross plasma) from the market on the same date. This report
presents
preliminary findings of an evaluation of transmission of hepatitis C virus (HCV)
infection
from these products and guidelines for monitoring patients who may have
received them.†
As of July 19, 1994, CDC had received 112 reports from 24 states and Puerto Rico
of
possible cases of acute HCV infection in recipients of IGIV; 111 were in persons
who
received Gammagard®, and one was in a person who received Polygam®. Medical
and epidemiologic information and serum samples for HCV serologic testing are
being
collected from each person. The dates of onset (defined by occurrence of
symptoms or first abnormal alanine aminotransferase [ALT] value) for suspected
cases were from October 1993 through June 1994 (Figure 1). Of 74 reported
persons
with possible HCV infection for whom risk factor data (e.g., blood transfusion
or
injecting-drug use) were available, 68 (92%) had receipt of IGIV as the only
risk factor
for infection.
The median age of persons with reported cases was 37 years (range: 2–84 years);
52% were female, and 63% received IGIV for treatment of a primary immuno-deficiency disorder (e.g., hypogammaglobulinemia). Of 62 persons tested at CDC
for
serologic markers of viral hepatitis, 42 (68%) were positive for antibody to HCV
(anti-HCV), and none were positive for serologic markers of acute hepatitis A or
hepatitis B
virus infection. Anti-HCV was detected in 20 (53%) of 38 patients with a
diagnosis of
primary immunodeficiency and in 21 (95%) of 22 patients with other diagnoses. In
blinded testing of serum specimens from 36 persons with suspected cases, none
were
positive for antibody to human immunodeficiency virus (HIV)-1 or HIV-2.
To assess the risk for HCV infection among persons who received IGIV and to
identify
risk factors for infection, a cohort study among persons exposed to different
IGIV
products at one hospital and a case-control study of persons from throughout the
United States have been initiated. Lot-specific denominator data needed to
complete
these analyses are not yet available from the manufacturer. Preliminary analysis
of the
cohort study found 16 (7%) cases of HCV infection among 245 recipients of
Gammagard
® (three persons with HCV infection had also received other IGIV products within
6 months of onset). However, no cases of HCV infection were found among 55
recipients
who had received only other IGIV products (p<0.05, two-tailed Fisher exact
test).
Additional laboratory testing for HCV will be performed on serum samples from
infected
persons and on samples of implicated and nonimplicated lots of IGIV. Other
cohort studies will examine any association between HCV infection and receipt of
other IGIV products or intramuscular immune globulin (IGIM). In one of these
studies
involving persons who received IGIM in 1993, no anti-HCV seroconversions were
found among 513 persons tested at least 6 months after IGIM administration (95%
confidence interval=0–0.7%).
*Of 112 reported possible cases, the date of illness onset or
date of first abnormal alanine
aminotransferase level was available for 81 cases.
FIGURE
1. Possible cases* of hepatitis C virus infection reported among persons
receiving GammagardÒ or PolygamÒ — United States, October 1993–June 1994
506 MMWR July 22, 1994
Reported by: L Schneider, R Geha, Harvard Medical School, Boston. Walter Reed
Army Institute
of Research, Washington, DC. Div of Transfusion Transmitted Diseases and Div of
Hematology,
Office of Blood Research and Review, Center for Biologics Evaluation and
Research, Food and
Drug Administration. Div of Digestive Diseases and Nutrition, National Institute
of Diabetes and
Digestive and Kidney Diseases; Dept of Transfusion Medicine, Warren G. Magnuson
Clinical
Center, National Heart, Lung, and Blood Institute, National Institutes of
Health. Hepatitis Br and
Epidemiology Activity, Div of Viral and Rickettsial Diseases, National Center
for Infectious
Diseases, CDC.
Editorial Note: The temporal association of acute hepatitis C with Gammagard®
administration
and the absence of other risk factors among these patients indicate that
HCV was most likely transmitted by administration of Gammagard®. The report of
one
possible case in a person who received only Polygam® and had no other risk
factors
suggests that Polygam® also may be associated with transmission of HCV.
Preliminary
analysis of data from epidemiologic studies suggests that HCV transmission is
not related to the administration of other IGIV products or IGIM, and there is
no need
for change in the use of these products.
Since the 1940s, immune globulin products licensed in the United States have
been
safely administered; these products previously have not been known to be
associated
with the transmission of bloodborne agents, including HIV. Cases of non-A, non-B
hepatitis (of which HCV is the primary etiologic agent) have been previously
associated
with an unlicensed IGIV product used in a clinical trial in the United States
and
with IGIV products manufactured and distributed abroad; however, reasons for
these
episodes of transmission ( 2 ) and the episodes described in this report have
not been
determined. Since mid-May 1994, the approved manufacturing process for both
Gammagard
® and Polygam® includes a solvent-detergent treatment designed to inactivate
contaminating viruses. Products manufactured with this treatment should not pose
a
risk for HCV transmission to recipients.
Chronic hepatitis develops in more than 60% of persons infected with HCV ( 3 ).
All
patients who received Gammagard® or Polygam® since April 1, 1993 (6 months
before
the first reported case), should be screened for evidence of HCV infection and
the
results interpreted according to the algorithm established by the Public Health
Service
(PHS) (Table 1). Initial screening of these patients should include a test for
ALT activity
and an FDA-licensed enzyme immunoassay (EIA) for anti-HCV. All specimens
repeatedly
(two or more times) reactive for anti-HCV should be tested using an FDA-licensed
supplemental anti-HCV assay to reduce the likelihood of false-positive EIA
results.
Because some patients will have a prolonged interval between exposure and
seroconversion
to anti-HCV, patients who are anti-HCV–negative but have abnormal ALT
levels should be retested for anti-HCV 3–6 months later. In most patients with
normal
immune status, seroconversion occurs within 6 months after infection ( 3,4 ).
However,
approximately 10% of HCV-infected patients with normal immune status will be
persistently
negative for anti-HCV, even after prolonged follow-up ( 3 ). Persons with
immunodeficiency disorders may be less likely to seroconvert or may have longer
intervals between infection and seroconversion than persons with normal immune
function.
For anti-HCV–negative persons with elevated ALT levels, the diagnosis of
hepatitis
C is possible with the use of polymerase chain reaction (PCR) for the detection
of
HCV RNA. However, PCR assays, which are difficult and expensive to perform,
should
be done only by experienced laboratories using specimens that have been properly
collected, stored, and handled. These assays are not licensed by FDA.
Patients aged ³18 years with chronic hepatitis C (abnormal ALT levels for more
than
6 months) should be evaluated for possible therapy with alpha interferon by a
physician
experienced in its use ( 5 ). Patients should be informed that the proportion of
adults with chronic hepatitis C who sustain a long-term response to alpha
interferon
is low (approximately 20%). Although FDA has not licensed alpha interferon for
patients
aged <18 years, they can be considered for therapy if entered into an approved
study protocol.
All patients with hepatitis C should be considered potentially infectious.
However,
because of limited data on the risk of household, sexual, and perinatal
transmission
and because testing cannot determine infectivity, PHS does not recommend
substantial
changes in behavior based on knowledge of infection status
( 1 ). PHS recommends
that household articles such as toothbrushes and razors that could become
contaminated with blood should not be shared, and cuts or skin lesions should be
covered to prevent the spread of infectious secretions or blood
( 2 ). HCV
transmission
by sexual contact appears to occur, but this route of transmission is much less
efficient than that for other bloodborne sexually transmitted diseases
( 3 ).
Although
anti-HCV–positive persons should be informed of the potential for sexual
transmission,-there are insufficient data to recommend changes in current sex practices for
persons with one steady sex partner. To prevent many sexually transmitted
diseases,
including hepatitis and HIV infection, persons with multiple partners should
follow
safer sexual practices, including reducing the number of sex partners and using
barriers
(e.g., latex condoms) to prevent contact with body fluids. No evidence supports
advising against pregnancy based on anti-HCV status or using any special
treatments
or precautions for pregnant women or their offspring.
References
1. CDC. Public Health Service inter-agency guidelines for screening donors of
blood, plasma,
organs, tissues, and semen for evidence of hepatitis B and hepatitis C. MMWR
1991;40(no.RR-4):6–17.
2. Lever AML, Webster ADB, Brown D, Thomas HC. Non-A, non-B hepatitis occurring
in agammaglobulinaemic
patients after intravenous immunoglobulin. Lancet 1984;2:1062–4.
3. Alter MJ. The detection, transmission, and outcome of hepatitis C virus
infection. Infectious
Agents and Disease 1993;2:155–66.
4. Vallari DS, Jett BW, Alter HJ, Mimms LT, Holzman R, Shih JW. Serological
markers of posttransfusion
hepatitis C viral infection. J Clin Microbiol 1992;30:552–6.
5. Hoofnagle JH. Therapy of acute and chronic viral hepatitis. Adv Intern Med
1994;39:241–75.
Vol. 43 / No. 28 MMWR 509
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