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Epidemiologic Notes and Reports Outbreak of Hepatitis C Associated with Intravenous Immunoglobulin Administration -- United States, October 1993-June 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 {Registered} *, an intravenous immunoglobulin (IGIV) product manufactured by Baxter Healthcare Corporation (Glendale, California). The company removed Gammagard {Registered} from the worldwide market on February 23, 1994. The American Red Cross removed Polygam {Registered} (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 {Registered}, and one was in a person who received Polygam {Registered}. 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 immunodeficiency 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 {Registered} (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 less than 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%).

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

Editorial Note: The temporal association of acute hepatitis C with Gammagard {Registered} administration and the absence of other risk factors among these patients indicate that HCV was most likely transmitted by administration of Gammagard {Registered}. The report of one possible case in a person who received only Polygam {Registered} and had no other risk factors suggests that Polygam {Registered} 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 {Registered} and Polygam {Registered} 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 {Registered} or Polygam {Registered} 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 greater than or equal to 18 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 less than 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 (1). 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.


  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.

* Use of trade names and commercial sources is for identification only and does not imply endorsement by the Public Health Service or the U.S. Department of Health and Human Services. 

** Copies of this report and the Public Health Service recommendations for medical evaluation and counseling of patients with hepatitis C (1) are available from CDC's Hepatitis Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Mailstop G-37, 1600 Clifton Road, NE, Atlanta, GA 30333; or from CDC's Voice Information System, telephone (404) 332-2553.


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TABLE 1. Algorithm for screening and management of patients who received
Gammagard {R} * or Polygam {R} * since April 1, 1993
  Screening results
ALT +       Anti-HCV &      Interpretation      Patient management
Abnormal    Positive @      Hepatitis C         Serial ALTs -- if abnormal for >=6 months,
                                                refer for evaluation of chronic liver

Abnormal    Negative **     Possible            Consider other liver diagnoses; repeat
                            hepatitis C         anti-HCV in 3-6 months; serial ALTs -- if
                                                abnormal for >=6 months, refer for
                                                evaluation of chronic liver disease.

Normal      Positive @      Possible            Serial ALTs -- if becomes abnormal and
                            hepatitis C         remains abnormal for >= 6 months, refer
                                                for evaluation of chronic liver disease.

Normal      Negative **     No evidence of      No further testing.
                            hepatitis C
 * Use of trade names and commercial sources is for identification only and does not imply
   endorsement by the Public Health Service or the U.S. Department of Health and Human
 + Alanine aminotransferase.
 & Antibody to hepatitis C virus.
 @ Repeatedly (two or more times) reactive by enzyme immunoassay and positive by
   supplemental anti-HCV testing.
** Nonreactive by enzyme immunoassay or negative by supplemental anti-HCV testing.

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