Date: Fri, 19 Jan 1996 09:22:55 +0500 From: gharaghs{CONTRACTOR/ASPEN/gharaghs}%NAC-GATEWAY.ASPEN@ace.aspensys.com Subject: Morbidity and Mortality Weekly Report 01 MORBIDITY AND MORTALITY WEEKLY REPORT ****************************************** Centers for Disease Control and Prevention January 19, 1996 Vol. 45, No. 2 Articles included: * Hepatitis A Among Persons with Hemophilia Who Received Clotting Factor Concentrate --- United States, 1995 * Surveillance of Tuberculosis and AIDS Co-Morbidity --- Florida, 1981--1993 Hepatitis A Among Persons with Hemophilia Who Received Clotting Factor Concentrate -- United States, September-December 1995 Hepatitis A outbreaks associated with receipt of clotting factor concentrate previously have been recognized in Europe but not in the United States (1-5). During September-November 1995, three cases of hepatitis A in recipients of AlphanateTM* factor VIII concentrate (Alpha Therapeutic Corporation, Los Angeles, California) from lot number AP5014A were reported to CDC. On December 8, the manufacturer voluntarily withdrew AlphanateTM lot number AP5014A from the market. In addition, one case of hepatitis A in a recipient of AlphaNine S-DTM factor IX concentrate (Alpha Therapeutic Corporation) has been reported and is under investigation. On January 11, 1996, the manufacturer voluntarily withheld four lots of AlphaNine S-DTM from further distribution as a precautionary measure. This report describes these four cases, summarizes the status of the investigation of the cases, and provides guidelines for testing and reporting of patients who received these products. Hepatitis A in Factor VIII Recipients Case 1. On September 5, 1995, a 13-year-old boy with mild hemophilia A (factor VIII deficiency) became acutely ill with nausea and vomiting after a 2-week period of fatigue, poor appetite, and low-grade fever. Blood tests revealed elevated liver enzymes and a positive test for immunoglobulin M antibody to hepatitis A virus (IgM anti-HAV). No sources of infection (e.g., close contact with a person with hepatitis A, household contact with a person working in or attending a day-care center, or international travel) were reported. During the 6 weeks preceding illness, the patient had used 68 vials (approximately 34,000 units) from the implicated lot (i.e., lot number AP5014A) of AlphanateTM and nine vials from four lots of another brand of factor VIII concentrate. Case 2. On October 20, during a hospital visit to evaluate vaginal bleeding 1 month postpartum, a 28-year-old woman with type 2 von Willebrand disease was found to have elevated liver enzymes and was IgM anti-HAV positive. She reported that, during September, she had had dinner on two occasions with an international visitor who had appeared jaundiced but not ill. No other potential sources of infection were identified. During 1995, her only exposure to factor concentrate was use of 48 vials (approximately 24,000 units) of AlphanateTM from the implicated lot on September 19. Case 3. On November 10, the National Hemophilia Foundation faxed a medical bulletin nationwide to 140 hemophilia treatment centers describing the first two cases of hepatitis A and their possible association with AlphanateTM lot number AP5014A. In response to this bulletin, two brothers with hemophilia A (aged 6 and 7 years) who had received this clotting factor concentrate were identified and tested for anti-HAV on November 17. The younger boy was IgM anti-HAV positive; the older boy was anti-HAV positive and IgM anti-HAV negative. Three weeks before testing for IgM anti-HAV, the younger brother had had a 5-day illness with nausea, vomiting, and abdominal pain. During the 3 months preceding testing, both boys had received approximately equal amounts of a total of 31 vials (approximately 15,500 units) of AlphanateTM from the implicated lot. No other factor products had been used during this interval, and no other sources of infection were identified. Laboratory studies. One sample each from the implicated lot of AlphanateTM, acute-phase serum from patient 2, and stool from patient 1 were positive for HAV RNA after amplification by polymerase chain reaction of the amino terminal region of that portion of the HAV genome coding for VP1. Genetic sequencing indicated that the viral nucleic acid isolated from each source was of HAV genotype 1a. Sequence analysis indicated that these isolates were identical and unique from other previously sequenced strains (6). Hepatitis A in a Factor IX Recipient On December 7, 1995, a 15-year-old boy with severe hemophilia B (factor IX deficiency) presented to his physician with symptoms of acute hepatitis; diagnostic studies indicated elevated liver enzymes and a positive test for IgM anti-HAV. No sources of infection were identified, and his family members were negative for anti-HAV and IgM anti-HAV. During the 3 months preceding testing, the boy had received 40 vials (approximately 40,000 units) of AlphaNine S-DTM; most of the vials had come from four different product lots. Three of these lots originated from source plasma pools common to the implicated lot of AlphanateTM. Reported by: FB Ruymann, MD, Div of Pediatric Hematology/Oncology, Children's Hospital, Columbus; CE Krill, Jr, MD, Hemophilia Treatment Center, Children's Hospital Medical Center, Akron; TJ Halpin, MD, State Epidemiologist, Ohio Dept of Health. WH Churchill, Jr, MD, Blood Bank, B Ewenstein, MD, Comprehensive Hemophilia Treatment Center, Brigham and Women's Hospital, Boston; A DeMaria, Jr, MD, State Epidemiologist, Massachusetts Dept of Public Health. MJ Manco-Johnson, MD, Univ of Colorado Health Sciences Center, Denver; RE Hoffman, MD, State Epidemiologist, Colorado Dept of Public Health and Environment. National Hemophilia Foundation, New York. Office of Blood Research and Review, Center for Biologics and Evaluation Research, Food and Drug Administration. Hematologic Diseases Br, Div of AIDS, STD, and TB Laboratory Research, and Hepatitis Br, Div of Viral and Rickettsial Diseases, National Center for Infectious Diseases, CDC. Editorial Note: This report is the first to document transmission of HAV through clotting factor concentrates in the United States. Most cases of hepatitis A in the United States occur in community-wide outbreaks through person-to-person transmission by the fecal-oral route. However, because viremia occurs during the prodromal phase of the illness, asymptomatic blood donors, on rare occasions, have been the source of HAV infection transmitted by transfusion (7). Several key findings support the conclusion that clotting factor concentrate was the source of infection in the factor VIII case-patients. First, the cases occurred in geographically dispersed areas, none of which were having community-wide epidemics of hepatitis A, and no community source of infection was identified. Second, the patients received the same lot of factor VIII concentrate. Third, HAV RNA was identified in that product lot. Finally, the genetic sequence of the HAV RNA from the factor concentrate was identical to that obtained from two of the case-patients. In Europe, investigations of recent hepatitis A outbreaks among recipients of factor VIII concentrates implicated products prepared by a manufacturing method that included a solvent detergent (S-D) viral inactivation step (1-5). The largest outbreak occurred in Italy, involving 52 patients with hemophilia (5). The only risk factor for hepatitis A infection was receipt of factor VIII concentrate prepared using this method, and HAV RNA was detected in the factor concentrate (8). No hepatitis A outbreaks associated with receipt of factor IX concentrates have been reported previously. The factor concentrates used by the case-patients described in this report also were prepared using the S-D method of viral inactivation. Although this method inactivates enveloped viruses such as hepatitis B virus, hepatitis C virus, and human immuno- deficiency virus (9), nonenveloped viruses such as HAV are resistant to inactivation by this method. Other plasma-derived factor VIII and factor IX concentrates manufactured using similar or different viral-reducing steps also may contain HAV, although no documented cases of transmission have been reported. Clotting factor concentrates manufactured by recombinant technology, which are now available for the treatment of factor VIII deficiency, have not been shown to transmit infectious agents. No recombinant factor IX clotting products have been approved by the Food and Drug Administration. CDC is continuing to investigate these cases and requests assistance in identifying additional cases. Patients who received lot numbers CA5410A, CA5412A, CA5413A, or CA5421A of AlphaNine S-DTM since July 1, 1995, should be tested for IgM anti-HAV. Patients receiving any clotting factor who develop symptoms of acute hepatitis should have a complete diagnostic evaluation, including testing for IgM anti-HAV. A positive test for IgM anti-HAV is evidence of HAV infection during the previous 6 months. Persons who are anti-HAV positive and IgM anti-HAV negative had HAV infection greater than 6 months previously and are immune. Patients who are IgM anti-HAV positive should be reported to their local or state health department and directly to CDC's Hematologic Disease Branch, Div of AIDS, STD, and TB Laboratory Research, National Center for Infectious Diseases (NCID), telephone (404) 639-3925. Inactivated hepatitis A vaccine (HAVRIX[Registered], SmithKline Beecham, Inc., Pittsburgh, Pennsylvania) was licensed in 1995, and physicians should consider vaccinating susceptible patients who receive clotting factor. Because limited available data suggest a high seroprevalence of anti-HAV among persons with hemophilia, all such patients should undergo prevaccination testing. Persons who are anti-HAV (total) positive are immune to HAV and do not require vaccination. The vaccine provides active immunity against HAV, which is estimated to persist for at least 20 years in healthy adults (10). Information about the vaccine's effectiveness in persons with hemophilia and immunocompromised persons is limited. The vaccine is licensed as a two-dose series of 1440 ELISA units (EL.U.) per dose for adults, with the second dose administered 6-12 months after the first dose, and in a 3-dose series of 360 EL.U. per dose for children aged 2-18 years, with the second dose administered 1 month after the first dose, and the third dose administered 6-12 months after the first dose. The vaccine is not licensed for use in children aged less than 2 years. The vaccine should be administered by intramuscular injection in the deltoid. A physician familiar with the patient's risk for bleeding should evaluate whether the vaccine can be given with reasonable safety by this route. No data are available regarding administration of the vaccine by the intradermal or subcutaneous route. If the patient receives clotting factor or other similar therapy, intramuscular vaccination can be scheduled shortly after receipt of such therapy. Patients should consult their physician or health-care provider for answers to any questions related to their current factor VIII or factor IX replacement product. Additional information about this investigation is available from the Hematologic Diseases Branch and additional information about the hepatitis A vaccine, including preventive measures for children aged less than 2 years, is available from CDC's Hepatitis Branch, Division of Viral and Rickettsial Diseases, NCID, telephone (404) 639-3048. References 1. Mannucci PM, Santagostino E, Di Bona E, et al. The outbreak of hepatitis A in Italian patients with hemophilia: facts and fancies. Vox Sang 1994;67(suppl 1):31-5. 2. Brackmann H-H, Oldenburg J, Eis-Hubinger AM, Gerritzen A, Hammerstein U, Hanfland P. Hepatitis A virus infection among the hemophilia population at the Bonn Hemophilia Center. Vox Sang 1994;67(suppl 1):3-8. 3. Lawlor E, Johnson Z, Thornton L, Temperley I. Investigation of an outbreak of hepatitis A in Irish haemophilia A patients. Vox Sang 1994;67(suppl 1):18-20. 4. Peerlinck K, Goubau P, Coppens G, Desmyter J, Vermylen J. Is the apparent outbreak of hepatitis A in Belgian hemophiliacs due to a loss of previous passive immunity? Vox Sang 1994;67(suppl 1):14-7. 5. Mannucci PM, Gdovin S, Gringeri A, et al. Transmission of hepatitis A to patients with hemophilia by factor VIII concentrates treated with organic solvent and detergent to inactivate viruses. Ann Intern Med 1994;120:1-7. 6. Robertson BH, Hkanna B, Nainan OV, Margolis HS. Epidemiologic patterns of wild-type hepatitis A virus determined by genetic variation. J Infect Dis 1991;163:286-92. 7. Lemon SM. The natural history of hepatitis A: the potential for transmission by transfusion of blood or blood products. Vox Sang 1994;67(suppl 4):19-23. 8. Normann A, Graff J, Gerritzen A, Brackmann H, Flehmig B. Detection of hepatitis A virus RNA in commercially available factor VIII preparation [Letter]. Lancet 1992;340:1232. 9. Schwinn H, Smith A, Wolter D. Progress in purification of virus-inactivated factor VIII concentrates. Drug Res 1989;39:1302. 10. Van Damme P, Thoelen S, Cramm M, De Groote K, Safary A, Meheus A. Inactivated hepatitis A vaccine: reactogenicity, immunogenicity, and long-term antibody persistence. J Med Virol 1994;44:446-51. * 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. Surveillance of Tuberculosis and AIDS Co-Morbidity -- Florida, 1981-1993 Because immunosuppression induced by human immunodeficiency virus (HIV) infection increases the likelihood that latent tuberculosis (TB) infection will become active in HIV-infected persons (1,2), in 1987, extrapulmonary or disseminated TB was added to the acquired immunodeficiency syndrome (AIDS) surveillance case definition (3), and in 1993, pulmonary TB in HIV-infected persons was added to the case definition (4). In Florida and other areas (5), AIDS surveillance activities include assessment of the completeness and validity of reported cases based on confidential record linkages with the TB registry and other disease registries. In December 1993, the Florida Department of Health and Rehabilitative Services (HRS) matched cases from the AIDS and TB registries to verify documented TB data, include more complete TB data on the AIDS registry, and identify cases from the AIDS registry with un- reported TB. This report summarizes an analysis of this match, which underscored the need for collaboration and crosstraining of surveillance staff in AIDS and TB reporting. HRS matched the records of all 16,559 cases of TB reported in Florida from 1984 (the earliest year for which computerized TB data were available) through December 22, 1993, with records of all 36,002 cases of AIDS reported in Florida from 1981 through December 22, 1993. Persons with atypical mycobacterioses and persons who did not reside in Florida at the time of TB diagnosis were excluded. Computer matching was based on combinations of the variables of name, date of birth, race, and sex and identified 5135 possible matches. Manual record reviews by HRS staff confirmed that 2567 (7.1%) patients reported with AIDS on the AIDS registry also were reported with TB on the TB registry. Of the 2567 identified registry matches, 2137 (83.2%) were previously reported with TB on the AIDS registry; the remaining 430 cases had been reported to the AIDS registry without documentation of TB (Figure 1). AIDS cases matched with the TB registry were updated with more complete TB data, including date of diagnosis and whether the TB was pulmonary, extrapulmonary, or both. Of the 36,002 cumulative AIDS cases, reports for 2816 (7.8%) cases indicated that the patient also had TB. For 679 AIDS cases with TB that were listed on the AIDS registry but that had not been reported to the TB registry as having TB, medical records were reviewed by HRS AIDS and TB surveillance staff, and cases were classified into mutually exclusive categories (Table 1). Reviews confirmed 78 (11.5%) as newly identified TB cases for the TB registry. Of the 516 AIDS cases that lacked validated TB diagnoses, for 298 (43.9%) investigators could not identify data to substantiate the CDC TB case definition, and for 90 (13.3%), cultures indicated infection with other species of mycobacteria (most frequently Mycobacterium avium). In addition, some cases originally diagnosed by physicians as TB were later revised, based on subsequent documentation, to a diagnosis of pneumonia from other causes. Because most (99%) of the 516 records without validated TB had other documented AIDS case criteria, they remained in the AIDS registry after correction of their TB status. Following the addition of updated TB data to some AIDS cases and the removal from the AIDS registry of some initially TB-defined AIDS cases with nonvalidated TB information, the number of reported AIDS cases with TB decreased 4.5% (from 2816 to 2690). Reported by: L Conti, DVM, S Lieb, MPH, T Liberti, R White, MBA, L Crockett, MD, R Hopkins, MD, State Epidemiologist, Florida Dept of Health and Rehabilitative Svcs. Surveillance Br, Div of HIV/AIDS Prevention, National Center for Prevention Svcs, CDC. Editorial Note: The AIDS and TB registry match conducted by Florida HRS evaluated the quality of AIDS and TB surveillance data, and enhanced completeness of reporting for both surveillance systems. For example, 11.5% of the TB cases in persons reported with AIDS had not been reported previously to the TB registry. However, 13.3% of the reported cases of AIDS with TB that had not been reported previously to the TB registry were identified as mycobacterial infections other than M. tuberculosis, underscoring the need for collaboration between TB and AIDS surveillance personnel to verify the TB data. Medical record reviews of most (76.0%) of the 679 unmatched cases of AIDS with TB could not validate a TB diagnosis, reflecting, in part, insufficient documentation of TB case-criteria by health-care providers when specific positive-culture results were absent. The increased incidence of TB as a result of the HIV epidemic (6-8) requires that health departments assist health-care providers in increasing their familiarity with the CDC TB case definition (9) to improve diagnostic accuracy and patient follow-up. In addition, state and local health departments should facilitate access by persons with TB to HIV testing and counseling services and provide tuberculin skin testing to persons with HIV infection (10). TB and AIDS registries should be matched at least annually to assist in characterizing the extent of co-morbidity and planning for necessary services. In Florida, AIDS and TB surveillance personnel have received additional training to improve their knowledge about both conditions. These training efforts have improved collaborative activities to ensure the accuracy and completeness of TB and AIDS surveillance data. References 1. Selwyn PA, Hartel DH, Lewis VA, et al. A prospective study of the risk of tuberculosis among intravenous drug users with human immunodeficiency virus infection. N Engl J Med 1989;320:545-50. 2. Buehler JW, Ward JW. A new definition for AIDS surveillance. Ann Intern Med 1995;118:390-2. 3. CDC. Revision of the CDC surveillance case definition for AIDS. MMWR 1987;36(no. 1-S):3S-15S. 4. CDC. 1993 Revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR 1992;41(no. RR-17):6-7. 5. CDC. Co-incidence of HIV/AIDS and tuberculosis--Chicago, 1982-1993. MMWR 1994;44:227-31. 6. Braun MM, Cote TR, Rabkin CS. Trends in death with tuberculosis during the AIDS era. JAMA 1993;269:2865-8. 7. Reider HL, Cauthen GM, Bloch AB, et al. Tuberculosis and acquired immunodeficiency syndrome--Florida. Arch Intern Med 1989;149:1268-73. 8. Burwen DR, Bloch AB, Griffin LD, Ciesielski CA, Stern HA, Onorato IM. National trends in the concurrence of tuberculosis and acquired immunodeficiency syndrome. Arch Intern Med 1995;155:1281-6. 9. CDC. Case definitions for public health surveillance. MMWR 1990:39(no. RR-13):39-40. 10. CDC. USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus: a summary. MMWR 1995;44(no. RR-8).