Congressional Briefing on Chronic Fatigue and Immune Dysfunction Syndrome (CFIDS) (also known as chronic fatigue syndrom, or CFS) May 16, 1997 Sponsored by: Senator Slade Gorton (R-WA), Senator Harry Reid (D-NV), Rep. John E. Porter (R-IL), and Rep Vic Fazio (D-CA) Hosted by: The CFIDS Association of America, Charlotte, NC (800) 442-3437; ---------------------------------------------------------------- Testimony of Robert J. Suhadolnik, Ph.D., Professor of Biochemistry, Temple University School of Medicine My name is Robert J. Suhadolnik. I am Professor of Biochemistry at Temple University School of Medicine in Philadelphia. Thank you for the opportunity to speak with you today and to share with you the results of our studies on CFIDS. I participated in the 1995 Congressional briefings. It is a pleasure to be here again and to tell you that we have made progress. The results I will describe to you today have been made possible by research support from The CFIDS Association of America and the hard work of graduate students and staff in my laboratory. Today, I will describe CFIDS to you as we see it in the laboratory. As you know, CFIDS is a complex illness. I will talk about biochemical changes we have observed in white blood cells of people with CFIDS compared to healthy people. The defects we have observed in CFIDS are in the immune system. These defects could also have application to other human diseases. In the laboratory, we have a saying, "Research is like a baby -- you don't know what it is going to be until it grows up." This certainly applies to our research efforts in CFIDS. My laboratory has been involved in studies of virus-associated diseases and cancers for the past 15 years. In addition to the CFIDS research grant awarded to me by the National Institutes of Health, I currently hold an NIH research grant directed to the study of AIDS. Our research in CFIDS began in 1988 when a package of frozen white blood cell (lymphocyte) pellets arrived in Philadelphia from Dr. Dan Peterson in Incline Village, Nevada. These pellets were from Dr. Peterson's CFIDS patients. I would like to desdribe what we learned in studying these lymphocyte pellets and in two subsequent studies -- a pilot study and a placebo-controlled, multi-center double-blind trial in CFIDS. I will also describe our most recent results. The research in my biochemistry laboratory is directed to the understanding of the atural antiviral defense pathways in humans. This pathway is called the 2-5A synthetase/RNaseL pathway. When all components of this antiviral pathway are functioning correctly, the human body can effectively control virus infections. Our research has demonstrated that several components of the antiviral pathway are not functioning properly in people with CFIDS. Specifically, the antiviral pathway is upregulated (or overactive) in people with CFIDS. The name of the molecule that drives this pathway is 2',5'-oligoadenylate trimer 5'-triphosphate. With a name like that, you can understand why the molecule has been nicknamed 2-5A. What does 2-5A do in the human body? 2-5A is the molecule that activates RNaseL, the enzyme that degrades viral RNA. With RNaseL that works properly, we can overcome virus infections. However, if RNaseL is defective, we have a problem. We can specifically measure RNaseL activity in biochemical assays of lymphocytes that we isolate from whole blood. From one tube of blood, we isolate a lymphocyte pellet. When we measure the RNaseL in people with CFIDS, we observed something we had never seen before. RNaseL in people with CFIDS is overactive. In the first study we did with Dr. Peterson, 13 of 15 people with CFIDS had this overactive RNaseL. Let me share with you the information we obtained about RNaseL in expanded studies in CFIDS. W have tested samples from more than a hundred people with CFIDS from across the country. What have we learned about CFIDS from all this testing? We've learned that there is an enzyme defect in people with CFIDS -- a defect in RNaseL. SOMETHING NEW IS GOING ON IN CFIDS. RNaseL WAS OVERACTIVE, UNLIKE ANYTHING WE HAD EVER SEEN BEFORE, and we have studied RNaseL activity in people with AIDS, Multiple sclerosis, lupus, human T-cell leukemia, and kidney cancer. When we observed this, we were intrigued and wanted to know more. We needed to find a biochemical explanation for why this RNaseL in CFIDS patients was so overactive. Where do we go from here? I tell my students that it takes more tme to discuss and design an experiment than to do it. This planning is the MENTAL GYMNASTICS involved in research. In a lymphocyte extract, there are thousands of proteins. We wanted to look at just one -- RNaseL. How can we do that? In order to determine why the RNaseL in people in CFIDS is overactive, it was necessary to develop a new two-part technology in the laboratory to advance our studies. We were able to develop this technology using ultraviolet light and an antibody to human RNaseL. So, with these new technologies, what have we learned about CFIDS? >From the blood samples we obtain, we can detect the presence and measure the activity of RNaseL. We have had another surprise in CFIDS - we have seen A NEW FORM OF RNaseL, a smaller form of RNaseL, in all people with CFIDS. These studies have been accepted for publication and will appear in the Journal of Inerferon and Cytokine Research in a few months. On the basis of what we know now, it is tempting to speculate that the presence and activity of the new form of RNasL correlates with the severity of clinical symptoms in people with CFIDS. I am pleased to be able to report to you today that our results have been confirmed. Using CFIDS patients selected by an independent physician and biochemical techniques similar to ours, the presence of the small form of RNaseL in CFIDS has been reported from an independent research group. As with our original obserbation on the overactive RNaseL in CFIDS, we must ask where to go from here? Time is money. We are continuing to analyze lymphocyte samples from more individuals with CFIDS. We have just received a bridge grant from the NIH to continue and expand our studies on the fundamental biology of CFIDS. We are very excited about the POTENTIAL OF THESE RESULTS as a marker for CFIDS. CFIDS, as currently defined, may well represent a heterogeneous group of disorders. No unifying pathophysiology for CFS has been established. Expanded studies are underway to determine if our results are representative of all patients with CFIDS and if these findings can distinguish individuals with CFIDS from those with clinically similar illnesses. Longitudinal studies are also underway to establish if the RNaseL enzyme dysfunction observed in CFIDS is characteristic of a particular stage in the course of the illness or if the dysfunction fluctuates over time. A remarkable group of people have contributed to this research effort I have described today. First, I would like to acknowledge The CFIDS Association of America for the financial support we have received from this research. Second, the efforts of Drs. Peterson and Cheney were essential to this research project. They are truly pioneering physicians in the diagnosis of CFIDS. Third, the graduate students and staff in my laboratory are remarkably dedicated people. What a wonderful opportunity this CFIDS research has been to train promising young scientists. I would also like to thank the members of Congress for the funds that have been appropriated to NIH extramural programs for CFIDS research. I am confident that these funds will be put to good use. In closing, let me say that I have been fortunate to hold uninterrupted research support from the National Institutes of Health and the National Science Foundation since 1965. Without a doubt, this CFIDS research is the most challenging research effort of my scientific career. Why? Because it crosses a wide range of disciplines -- biochemistry, immunology, virology, and molecular biology. CFIDS is a complex illness that demands a multi-disciplinary research effort. What else is necessary? At the research level, continued and expanded research support of course. There is now a critical mass of scientists that is aware of CFIDS and interested in addressing its pathogenesis and treatment. At this point in the understanding of CFIDS, we don't know what we don't know. I would strongly encourage international collaborations in the investigation of CFIDS. This disease doesn't recognize borders. There are fundamental questions that remain to be answered -- as with any emerging disease. The call from AIDS researchers a few years ago was to go back to basic science. The same applies to CFIDS. Thank you for your attention. ---------------------------------------------------------------- Testimony of Karen Jordan, Ph.D., Project Director, CFS Epidemiology Project and Clinical Psychologist, DePaul University Congressman Porter, Congressman Fazio, Senator Gorton, Senator Reid and Members of Congress: Thank you for the opportunity today to discuss the issue of Chronic Fatigue Syndrome (CFS), also known as Chronic Fatigue and Immune Dysfunction Syndrome (CFIDS), with you. My name is Karen Jordan, and I am a clinical psychologist working at DePaul University in Chicago. I am currently the project director of a large, community-based grant that is examining the prevalence of CFS in adults. This grant was generously funded through the National Institute of Allergy and Infectious Diseases. We have also been awarded a small supplement to begin some preliminary work in the area of the epidemiology of pediatric CFS. As you may know, CFS is a complex illness characterized by severe, incapacitating fatigue as well as a host of physical complaints and neurological impairments. The symptoms are of a relapsing and remitting nature, often made worse by physical exertion of stress, and may persist for months or years. The majority of studies concerning CFS have concentrated on the adult population, with children and adolescents with CFS receiving decidedly less attention. However, the illness does strike children, presenting most commonly after puberty. Two basic building blocks for understanding this disorder in children are currently being assembled, although both continue to need attention. First, a definition for children must be determined in order to facilitate research and communication about CFS. Second, we must determine how many children are affected by the disorder in order to develop programs to assist them in all realms, including medical, academic, social, and developmental. At the present time, other than the adult criteria, there are no specific diagnostic criteria for children. The most common symptoms reported, besides fatigue, by pediatric CFS patients are headaches, sleep disturbance and cognitive impairment. The cognitive problems are often severe enough to interfere with school performance and other learning tasks. However, the typical pediatric CFS patient often presents appearing healthy, with only minor abnormalities present on laboratory testing and physical examination. This is in sharp contrast with the patient's reports of severely limited activity and numerous symptoms. Lacking a definitive diagnostic test, it is imperative that criteria specific to children and adolescents be adopted to be used as a standard in future research. This is a necessary priority for valid and reliable research as groups of children need to be accurately identified according to one case definition in order to facilitate standardization across studies. Much of the current literature is skewed by the lack of a definition, as studies have included children who do not meet the adult criteria or who have the symptom of chronic fatigue (as distinct from CFS). Once a case definition has been proposed, testing as to its reliability and validity must be conducted. Regarding the second basic building block of epidemiology, although to date no study has examined children and youth exclusively, prevalence estimates have been determined from larger population studies. Prevalence estimates for children under 10 have ranged from 0.0 per 100,000 (Dobbins et al., 1996) to 5.5 per 100,000 (Lloyd et al., 1990) for children under age 10 or 11. However, for children over age 10, prevalence estimates range from 2.7 per 100,000 (Dobbins et al, 1996) to 47.9 per 100,000 (Lloyd et al, 1990). Translating these figures into absolute numbers, based on the current US Census Bureau's population estimates, there would be approximately 2,132 children under 10 with CFS and anywhere between 1,025 and 18,185 adolescents with CFS. Much more work needs to be done to improve the estimates of the true incidence of CFS in young children and in adolescents. A couple of notes should be made regarding these prevalence estimates. First, due to methodological problems, all stuies on pediatric and adolescent CFS probably underestimate the true prevalence of the disease. Thus, there may be many more unidentified cases in the population. Second, it should be noted that the prevalence estimate for the adolescent population cited by Lloyd is higher than their overall prevalence estimate of 37.1 cases per 100,000. Thus, adolescents may actually have a higher risk for developing CFS than some adult age groups. A third factor that is vitally important is to understand the limitations CFS places on children's growth and development, both physically and cognitively. A CFS student's school performance is often severely negatively impacted by repeated absences and difficulty concentrating while in school. School districts are often reluctant to construct home-based school programs to accommodate these children's needs. We know from studies regarding other populations of chronically ill children that it is often difficult for them to compensate for lost time in school and to remain on target with their same-age peers. Furthermore, their social developments is often hindered by months in bed, isolated from friends and social activities. With this information in mind, I would like to briefly describe the research that we have been conducting at DePaul University regarding the prevalence of CFS in children and adolescents. This research is ongoing, and thus the results presented are preliminary and many change as data continues to be collected. The first stage of the adult CFS epidemiology project involves telephone calls to 26,000 randomly-generated telephone numbers in the Chicago area. A short screening interview is administered to a randomly selected adult. If the adult reports 6 months or more of fatigue, a longer questionnaire regarding symptoms of CFS is administered. I then review all the extended questionnaires and select those who meet the current CDC definitional criteria based on their answers to the questions posed by the interviewers. These selected individuals are then administered a psychiatric interview and medical evaluation in order to determine if they do indeed have CFS. The final stage of the study involves the administration of psychosocial instruments to assess factors such as coping styles, social support, and illness management. Several months into data collection in the adult project, we added questions about children and adolescents in the household to the Stage I screening questionnaire. The following data is from this stage of data collection. We have completed interviews with the randomly selected individuals in 15,673 households to date. Of these, 11,803 ere asked the questions regarding children and adolescents. Thirty-one percent (3647) of these households reported having children under 18 currently living in the home, with a total of 8878 children living in these homes. Of the 8,878 children we've identified, 51 (0.57% or 570 per 100,000) met the current CDC definition of CDC according to the answers provided by the adult interviewed. Although we have a small supplemental grant to conduct follow-up telephone interviews with these children to gain a more complete understanding of their symptomatology, we cannot at this time definitely diagnose these children with CFS, as a medical evaluation is necessary for diagnosis. Thus, we can only say that these children have CFS symptoms. This is higher than the 0.0 per 100,000 found in the 2 to 11-year-old group and the 116.4 per 100,000 in the 12 to 17-year-old group found by the CDC to have CFS-like illness in their recent San Francisco study (Dobbins et al., 1996). Another interesting finding is the race distribution of our sample of children with CFS symptoms. The children identified as having CFS symptoms are 49% Hispanic, 18% African-American, 18% European American, 4% multi-racial, 2% Asian American, and 2% Native American. For comparison, the overall adult sample is 17% Hispanic, 20% African-American, and 55% European-American. Although we cannot say that all these Hispanic children do, in fact, have CFS, these data point to a problem that is definitely in need of further exploration and study. Moreover, these data remind us that this disease does not afflict only middle-age, upper-class, Caucasian individuals. Let me conclude by emphasizing the need for further research on CFS as it manifests in children and adolescents. It is heartening that the NIH and CDC have begun to recognize the unique concerns and issues of children and adolescents with CFS. Research has begun to answer the questions about this disease. Unfortunately, we are still far from understanding the mechanisms and manifestations of the illness, particularly in young people. Thanks to support from Congress and the public, research funds are being allocated so that we may continue to unravel these mysteries. Thank you for your continuing support. References: Dobbins JG, Randall B, Reyes M, et al. The prevalence of chronic fatigue illness among adolescents. Paper presented at the AACFS Chronic Fatigue Syndrome Research and Clinical Conference, San Francisco, Oct 1996. Lloyd AR, Hicki I, Boughton CR, et al. Prevalence of chronic fatigue syndrome in an Australian population. Medical Journal of Australia 1990; 153:322-528.