MINUTES OF THE SEVENTY-FIRST MEETING OF THE SICKLE CELL DISEASE ADVISORY COMMITTEE Bethesda, Maryland November 18, 1996 COMMITTEE MEMBERS PRESENT Dr. Kenneth Bridges Dr. Iris Buchanan Dr. James Eckman Dr. Joseph DeSimone Dr. James Eckman Dr. Mary Fabry Dr. Cage Johnson Dr. William Mentzer Ms. June Vavasseur COMMITTEE MEMBERS ABSENT Dr. Jessica Davis EX-OFFICIO MEMBERS PRESENT Dr. Martin Steinberg Dr. Scott Wegner EX-OFFICIO MEMBERS ABSENT Dr. Jane Lin-Fu Dr. William Hannon PROGRAM STAFF AND AFFILIATED ORGANIZATION REPRESENTATIVES: Dr. Clarice D. Reid, DBDR; Duane Bonds,SCRG; Dr. Junius Adams, SCRG; Dr. Carol H. Letendre, DBDR; Ms. Susan Pucie; Dr. Oswaldo Castro, Howard University, Dr. William P. Winter, Howard University, Sonia I. Ross, Maryland, DHMH, Office of Hereditary Diseases ; Ms. Patricia Penn, Maryland, DHMH, Office of Hereditary Diseases. Executive Secretary - Dr. Clarice D. Reid Secretary - Ms. Petronella A. Barrow I. INTRODUCTORY REMARKS Dr. Cage Johnson, Chairman, called the 71st meeting of the Sickle Cell Disease Advisory Committee to order at 9:00 am. He welcomed the new members, Dr. Kenneth Bridges and Dr. Joseph DeSimone. II. ANNOUNCEMENTS Dr. Clarice Reid, Executive Secretary, read the mandatory conflict of interest statement and reminded members to sign and return their forms to Ms. Barrow. She noted that Dr. Jessica Davis and Dr. Jane Lin-Fu would not be attending due to a conflict with the meeting of the American Public Health Association (APHA) in New York. Members were requested to note the time of the next meeting date, June 10, 1997. Dr. Reid stated that the membership roster should be completed before the next meeting with the likely addition of Dr. Vipul Mankad to the committee. III. CONSIDERATION OF MINUTES The minutes of the last meeting were unanimously approved without modification. IV. CHAIRMAN'S REPORT Dr. Johnson briefly highlighted the previous reports to the committee from Dr. Harold Davis, FDA medical epidemiologist. Of specific interest was the documentation of continued improvement of overall mortality from sickle cell disease from 1968-1992; geographic differences in mortality in young children; the apparent tendency for the use of prophylactic penicillin in children to decline after the first two years based on Medicaid prescription data; and the annual health care costs for sickle cell disease patients at approximately $450 million. Dr.Johnson also referred to the potential increase in medical care litigation issues as presented to the committee by Dr. Lubin. He pointed out that the Academy of Pediatrics had recently published guidelines on health supervision for children with sickle cell disease and their families. This document should be very useful as more children will be referred for care to Health Maintenance Organizations. Copies of the guidelines were distributed to the committee. V. DIRECTOR'S REPORT Dr. Reid highlighted the budget status of the NIH and NHLBI for 1997. For the first time in several years, NIH had a spending bill prior to the end of the fiscal year rather than the usual continuing resolution. The NIH fared very well, as did some of the other PHS and health-related agencies in comparison with other federal agencies. The NIH received an increase of 6.9% from the previous year. Included in this increase is $90 million for reconstruction of the Clinical Center. The Clinical Center will be named after Senator Mark Hatfield who has been a strong supporter of biomedical research. The NHLBI received an increase of 5.9% over FY 96 which is one of the smallest increases of the ICD's and Centers at NIH. Dr. Reid pointed out that the budget did not include any increase in the administrative costs category which has a significant impact on how the mission of the Institute is carried out. In the Division, the budget of $223 million for FY 96 was primarily to investigator-initiated research; a smaller amount to RFA's, contracts and centers; and even less to the career development and training programs. There needs to be more aggressive attention to training programs. Dr. Reid further pointed out that while this distribution reflects the total Division's funding, there are significant differences in distribution between the mechanisms in each program. For example, the largest component in the sickle cell scientific group is the sickle cell centers (47%) and unfortunately there has been a decline in the investigator-initiated grants. The largest component of our investigator research (66%) is in the Thrombosis and Hemostasis program where there are a few SCORs and no contracts. Although this gap is closed somewhat through RFA's, the investigator-initiated research is the area that maintains the overall progress in the field. Dr. Reid reviewed with the committee the program areas of special attention presented to Council for FY97. Included were a number of proposed workshops and Special Emphasis Panels. One of these will address bone marrow transplantation for sickle cell disease. She indicated changes in the previously structured planning process and the interest of more involvement of Council in this process. In closing, attention was called to a series of handouts, including a summary of Congressional report language and the Dear Colleague letter from Dr. Lenfant. VI. "Emerging Concepts in Iron Metabolism"...Dr. Kenneth Bridges, Brigham and Women's Hospital. Dr. Bridges reviewed the current and emerging concepts of sideroblastic anemia and how these concepts related to iron metabolism in general. Sideroblastic anemia most often presents as a normochromic normocytic anemia, with ring sideroblasts in the bone marrow being the cardinal feature. Although there are many syndromes that give rise to sideroblastic anemia, the unifying feature of these disorders is that most of them are mitochondrial cytopathies. Pearson's syndrome results from a 4 kilobase deletion in the circular mitochondrial genome. Diamond-Blackfan syndrome is also the result of a deletion, but in another region of the mitochondrial genome. The interesting feature of mitochondrial cytopathies is that the genetics of mitochondrial mutations is non-nuclear. Mitochondrial genes are inherited separately from nuclear genes and are inherited from the mother. When somatic cells divide, the mitochondria are stochastically separated, and cells may contain both normal and abnormal mitochondria. Wolfram syndrome is particularly interesting in that it appears to result from mutations in the mitochondrial genome, but these mutations appear to be secondary to a mutation in the nuclear genome. The classic X-linked form of sideroblastic anemia described by Cooley in 1946 is due a mutation in the coding region of delta-aminolevulinic acid synthase, which causes oxidative insult to the mitochondria. External agents, such as alcohol and chloramphenicol, may also act to insult the mitochondria. Thus, the mitochondrion is at the center of the plethora of causes that lead to siceroblastic anemia. VII. Stroke Prevention Trial .....Dr. Robert Adams, Medical College of Georgia Dr. Adams, Principal Investigator of the STOP trial, reviewed the neurologic complications in sickle cell disease with a series of angiograms indicating the rationale for pursuing a noninvasive technique for identifying children at risk for stroke. He described the Doppler ultrasound measuring blood flow comparing the velocity in normal children, in children with anemia and in children with sickle cell disease. From pilot studies, the threshold for transcranial Doppler (TCD) stroke velocity was established at 200 centimeters/sec. The STOP trial is a randomized clinical trial involving 14 clinical centers with patients randomized to chronic transfusion therapy and standard care. The hypothesis is that in children who have a TCD velocity exceeding 200 cms. and no prior history of stroke, can be prevented from having a first stroke if the sickle hemoglobin is reduced to 30% or less. The end point is stroke and STOP is the first primary prevention trial in sickle cell disease. Patient entry and randomization has been completed. VIII. COMMITTEE REPORT....Sickle Cell Trait Results Dr. James Eckman reviewed the history of this project with the committee pointing out the long unresolved controversory regarding the follow up of sickle cell trait carriers identified through the newborn screening program. For a number of years, the subcommittee entitled "Sickle Cell, Thalassemia and Other Hemoglobin Variants" of the Council of Regional Networks (CORN) has been examining this issue in an attempt to develop guidelines and has drafted a document. . In 1995, Dr. Wethers convened a symposium on this topic and at its conclusion, it was suggested by Dr. Reid to bring this matter to the attention of the Sickle Cell Disease Advisory Committee. After presentations to this committee by Drs. Eckman, Pas and Wethers, a Working group was established to explore the issues further and drafted a set of principles that were presented at the last meeting. Dr. Eckman pointed out differences in various other documents on this subject that related to the issue of qualifications of counselors and educators. This information is important especially for states to assure that the interpretation of information provided to famililies is accurate and meets minimal standards. Considerable discussion ensued regarding the need for quality control. It was pointed out that most states are looking for guidance in the area of quality control, especially in the absence of any additional resources to do follow-up of trait carriers. . The committee voted to endorse the CORN guidelines and for Dr. Eckman and Ms. Vavasseur to continue to work on this project as liaisons with the Sickle Cell Disease Association of America (SCDAA) and to explore their interest as a certifying body for counselors. The issue of counselor qualifications, a trait curriculum and on-site training in a genetic clinical setting were considered important for this purpose. There will be ongoing reports back to the SCDAC from the liaisons on progress in this area. IX. AGENCY REPORTS Veteran's Administration(VA) Dr.Martin Steinberg reported that the VA had completed its reorganization and that it is having a major impact on clinical services. The research components have also been reorganized with designated areas of research emphasis. Sickle cell disease is not a primary area of focus, however, meritorious sickle cell disease research will continue to be supported. There continues to be a decline in the overall VA sickle cell program. The interest and visibility depend on the hematologist. Dr. DeSimone commented that the two Chicago medical centers have been reorganized administratively and that the West Side inpatient facility may be closed. There appears to be similar activities occurring in other VA facilities across the country with a lot of uncertainty about the future of jobs and research. Department of Defense (DoD) Dr. Wegner reported on the status of sickle cell trait screening in the military. The purpose of screening is the possibility of increased risk of death during military training and aviation. The basis for this concern was the 12 unexplained deaths in the early eighties reported by DoD out of 2 million recruits and more recently by a report of 2 unexplained deaths in the Air Force. The current screening policy is an initial test with sickledex for all recruits on the second day of training. This is followed up by a hemoglobin electrophoresis on all positives. If the hemoglobin A is less than 50%, the recruit is discharged. There are no restrictions or other guidelines for individuals with sickle cell trait. The trainers are instructed to encourage all trainees to maintain adequate hydration during physical exertion. The committee members discussed the need to really emphasize hydration and referred to data showing that with measures to prevent dehydration during training, deaths could be eliminated. There is no formal counseling of sickle cell trait carriers. X. PROGRAM ACTIVITIES Dr. Junius Adams summarized the sickle cell disease grant activities during the past year. Seventeen center grants were submitted in September and will be reviewed in the spring of 1997. Ten center awards will be made in 1998. Dr. Adams commented on the success of a grant in the area of nutrition. He provided a synopsis of research areas recommended for further study from the therapy workshop including cellular adhesion, the role of non-globin genes or genetic elements, genetic modifiers, and transfusion therapy. There was extensive discussion regarding these research needs and opportunities along with the previously drafted initiative on vascular pathobiology. Several members agreed to assist with these projects. Dr. Duane Bonds reported on the following ongoing clinical studies:1) the Multi center Study of Hydroxyurea Follow-up (MSH ) patients will complete the first year physical:2) In the STOP Clinical Trial, the patient recruitment goal has been met and patients are in the follow-up stage; and the phase II pediatric hydroxyurea study is actively following 70 patients and will be completed in 1997. A proposed trial of the conjugated pneumococcal vaccine has been submitted to the Institute. Dr. Bonds summarized research recommendations from the Immune Function Workshop and solicited committee input on areas to explore for a basic research initiative.The committee inquired about studies to compare bone marrow transplantation vs. hydroxyurea vs. transfusions and the pediatric hydroxyurea study. Dr. Bonds indicated that the feasibility and planning for any further studies involving hydroxyurea would depend on the data from the Phase II study. Committee members re-emphasized the advantages of a clinical network to conduct small therapeutic interventions and obtain pilot data that could be used for a larger trial. Other clinical research areas that need to be pursued include the pathophysiology of lung and kidneys. The latter topic was considered timely for a workshop. FUTURE AGENDA ITEMS: It was suggested that Dr. Charles Greenburg, Duke University, be invited to make a scientific presentation. The meeting was adjourned at 2:35 pm.. FUTURE MEETING DATES June 10, 1997 November 14, 1997 I hereby certify that to the best our knowledge, the foregoing minutes are accurate and complete. ___________________________ _____________ Date Cage S. Johnson, M.D. Chairman Sickle Cell Disease Advisory Committee ___________________________ ______________ Date Clarice D. Reid, M.D. Executive Secretary Sickle Cell Disease Advisory Committee .