DEPARTMENT OF HEALTH AND HUMAN SERVICES NATIONAL INSTITUTES OF HEALTH NATIONAL HEART, LUNG, AND BLOOD INSTITUTE MINUTES OF THE SPECIAL EMPHASIS PANEL ON CREUTZFELDT-JAKOB DISEASE (CJD) AND BLOOD TRANSFUSION The meeting sponsored by the NHLBI and the FDA took place on September 24-25, 1997. The first day was open and experts in various aspects of Transmissible Spongiform Encephalopathies presented recent data regarding the possible transmissibility of CJD by transfusion of blood or blood products. The second day was a closed meeting in which manufacturers of plasma protein derivatives updated FDA staff and other Government officials on steps being taken by industry to prevent contamination of their products with the CJD agent. PANEL MEMBERS (See attached Panel roster) Dr. Paul McCurdy (Chair), Dr. Jay Epstein, Mr. Jason Bablak, Dr. Paul Brown, Dr. Bob Rohwer, Dr. Laura Manuelidis, Dr. Jiri Safar, Dr. Larry Schonberger, and Ms. Marian Sullivan. MEMBERS OF THE PUBLIC PRESENT Michael Hansen, Consumers Union Miriam O'Day, Immune Deficiency Foundation Kim Berstein, OHS Access Program Larry Helseth, Baxter-Travenol Marc Salit, Baxter-Travenol Diana Giorgio, Novartis Robert Slinger, LCDC, Canada Mary Beth Chamberlain, Chandler Chicco Diane Gioragnoli, Abbott Elton Homan, Hercules, Inc. Henry Baron, Rhone-Poulenc Rorer Stephen Nighthingale, MMS Regina Kascsak, NY State Inst. of Basic Research Nanci Wappler, Immuno-US Eileen Church, AABB Edward Compester, Baxter-Travenol Arlene Vidor, Baxter-Travenol Don Baker, Baxter-Travenol FEDERAL EMPLOYEES PRESENT Fifty Federal Employees were present. OPEN MEETING Dr. Paul McCurdy called the meeting to order with a statement of purpose of the meeting. Scientific presentations on the open session indicated that progress in understanding the transmission and pathogenesis of CJD has been slow due to a lack of rapid and specific assay systems. The "gold standard" assay continues to be animal inoculation with infectious material followed by years of observation looking for development of neurological disease with typical brain pathology. Adaptation of TSE agents to mice or hamsters, including some transgenic strains, has reduced the incubation time to months rather than years. However, these animal models usually require months to achieve infectivity endpoints. A specific marker for CJD and related TSE is a protease-resistant protein (PRP). Whether this PRP is the cause of the disease or a consequence of it is still unclear. Some of the researchers favor the "prion" theory , one that holds the PRP itself is infectious. Others have circumstantial evidence derived from fractionation of CJD brain suggesting that infectivity resides in fractions rich in nucleic acids but lacking PRP, thus suggesting a viral etiology. Regardless, the PRP provides an excellent marker for the development of serological assays. This material arises when a normal cell membrane protein undergoes a slight reduction in size and a change in conformation. The abnormal protein enters the cell from the membrane and forms aggregates, some of which can be seen as "plaques." Several monoclonal antibodies (Mabs) recognizing different sequences within the PRP have been produced by research groups in the U.S. and Europe. However, none of these MAbs can distinguish the two conformations of the protein. A surrogate test using western blot can be done with the brain material before and after protease digestion to demonstrate PRP. Other tissue specimens such as tonsil, spleen, and lymph nodes have also been used to detect PRP. Thus far, however, sensitivity is limited. Infectivity has been demonstrated in several tissues from man and animals with TSE, most notably brain, lymph nodes (peripharyngeal and intestinal) and spleen. In animal-adapted strains, the blood and some blood products can be infectious by intracerebral inoculation, but transfusion of whole blood does not seem to transmit the disease so far. It is, however, very difficult to correlate the animal data with the situation with humans. CJD surveillance done by the CDC involving case report, case-control studies, special studies, and routine surveillance, has failed to identify a single transfusion-transmitted case. Since surveillance started in 1971, 3,905 cases of CJD have been reported, none of the patients having sickle cell disease, hemophilia, or thalassemia, conditions in which the patients have a lot of transfusion exposures. The 1 CJD death/1,000,000 population has remained constant. The CDC data indicates that the "risk of transmission via blood is extremely small and, at present, entirely theoretical." Additionally, a look back study involving 180 recipients of donations linked to CJD donors has yet to identify a transfusion-associated case of the disease. This study, conducted by the Red Cross, the New York Blood Center and the CDC involves 281 donations between 1959 and 1996 including blood from 10 confirmed and 4 probable cases of CJD. It appears to be a tenable hypothesis that small amounts of PRP is present in lymph nodes and hence in circulating lymphocytes. Accordingly, an immune assay that is both sensitive and specific to the abnormally conformed PRP may be possible. Such an assay, if developed, could help demonstrate if CJD truly is transmitted by blood and blood products (current concerns are based upon theoretical possibilities from animal models and, as noted above, are not supported by epidemiological studies). If need be, it could form the basis of a blood screening test. It also could provide a diagnostic test for use by neurologists. Although the end-stage clinical picture is characteristic, there is no way of detecting developing disease in the preclinical state. Meeting participants agreed that an unqualified and irreducible risk of exposure to CJD through blood and blood products does exist and, therefore, recommended that the NHLBI, possibly in conjunction with the NINDS, support studies that could lead to the development of specific Mabs to detect the PRP of CJD in animals and man. ADJOURNMENT The meeting was adjourned at 4:00 P.M. on September 24, 1997. CERTIFICATION We hereby certify that the foregoing minutes are accurate and complete. Paul McCurdy, M.D. Luiz H. Barbosa, D.V.M. Chairman Executive Secretary Special Emphasis Panel on CJD Special Emphasis Panel on CJD and Blood Transfusion and Blood Transfusion .