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Meeting Report:
Applying Genetics and Public Health Strategies to Primary Immunodeficiency Diseases

November 8-9, 2001 ~ Atlanta, Georgia
Prepared by: Office of Genomics and Disease Prevention, Centers for Disease Control and Prevention Department of Health and Human Services


Welcome and Introductions

Dr. Muin Khoury, Director, Office of Genetics and Disease Prevention, National Center for Environmental Health (NCEH), CDC, opened the meeting and welcomed the participants. He thanked the organizers, acknowledged the contributions and efforts of Fred and Vicki Modell, and introduced Dr. Richard Jackson, Director, NCEH, who represented CDC's Director, Dr. Jeffrey Koplan.

Dr. Richard Jackson, Director, NCEH, CDC, added his welcome and apologized for the absence of Dr. Koplan, who was preparing for a visit to CDC from President Bush. Dr. Jackson provided a brief background on the genesis of the meeting, which originated with a request to NCEH from Dr. Koplan to apply research findings from the genomic revolution to primary immunodeficiency (PI) diseases. NCEH is well positioned to address this need, given Dr. Khoury's leadership and vision, the availability of the Center's premiere public health/genetics laboratory, CDC's track record in the application of research findings to clinical action, and the presence of Dr. Mary Lou Lindegren, who recently joined NCEH to lead the PI initiative.

Integrating Genetics into Public Health
Dr. Muin Khoury, Director, Office of Genetics and Disease Prevention, NCEH, CDC

Only by the integration of genetics into a public health research agenda can gene discoveries be translated into meaningful, population-based information for use in improving health and preventing disease. With the progress of the Human Genome Project, an estimated 50,000 human genes have been mapped, and tests for more than 800 genes are available in clinical practice. However, gene discovery is only the beginning. For most diseases, a wide gap exists between sequencing and discovering genes and using genetic information safely and effectively to improve health outcomes. The focus of this meeting is to begin to fill in this gap for the 95 genes that cause PI diseases.

Advances in human genetics and the evolution of the Human Genome Project will play a central role in the practice of medicine and public health in the twenty-first century. CDC's Director, Dr. Koplan, and Deputy Director, Dr. David Fleming, have highlighted genetic breakthroughs among the top 10 public health priorities for the twenty-first century (JAMA 2000). However, only after researchers complete clinical and epidemiologic studies on thousands of genes and interacting factors will the data be available to translate gene discoveries into medical practice. Dr. Francis Collins and colleagues considered the implications of gene-based medicine in a hypothetical scenario of a 23-year-old man evaluated for elevated cholesterol levels in 2010 (N Engl J Med 1999). Through the use of genetic tests, the patient learns about his risks for various conditions based on his genetic profile and about interventions to modify these risks. What is not acknowledged, however, is the immense gap between the discovery of a gene and the use of genetic information to prevent disease. Public health research has a crucial role in closing that gap. Moving from gene discovery to clinical applications requires the full engagement of public health to quantify the impact of genetic discoveries, develop policies on the appropriate use of genetic tests and services, initiate and maintain behavior change among patients and health care providers, and address access to and quality of health services.

In 1997, CDC created the Office of Genetics and Disease Prevention to address the emerging role of genetics in the practice of public health in the United States. This action was recommended in a CDC-wide strategic plan that outlined a conceptual framework for a public health program in genetics. The framework identified four essential functions of a public health genetics program: public health assessment using surveillance and population-based epidemiologic studies; evaluation of genetic tests; development, implementation, and evaluation of intervention programs; and communication and information dissemination. Each of these functions will be addressed at this meeting. Affecting all of these are the cross-cutting issues of partnerships; ethical, legal, and social considerations; and education and training.

CDC already has embarked on several public health activities addressing single-gene disorders. When it was recognized that hereditary hemochromatosis met many of the criteria for population-based screening (i.e., a common disorder that can be detected during a long presymptomatic phase and that has a safe and effective treatment), CDC and NIH co-sponsored a workshop on the use of gene testing for population screening. The resulting recommendations are guiding clinical and public health research. CDC also convened a workshop to discuss the benefits and risks associated with newborn screening for cystic fibrosis and to develop public health policies.

CDC's ongoing genetics and public health agenda for the next 3 years address: (1) genetic information (evaluations of genes, tests, and diseases; publication of an annual report; development of a web-based information system), (2) surveillance and applied research (epidemiology, policy, communication, health services), and (3) public health capacity at state and local levels (development of genomics competencies and tools).

Goals and Objectives of the Meeting
Dr. Mary Lou Lindegren, Office of Genetics and Disease Prevention, NCEH, CDC

CDC's framework for a public health program in genetics applies essential public health functions to the prevention of disease, disability, and death and to the improvement of health outcomes among persons who inherit specific genotypes. The framework is based on a combined genetic-epidemiologic approach with four components: public health assessment; evaluation of genetic testing; development, implementation, and evaluation of population interventions; and communication and information dissemination. Each component requires partnerships and coordination of genetic and public health activities; attention to the ethical, legal, and social issues related to the application of genetics to health promotion and disease and disability prevention; and education and training of providers and the public and provision of timely and accurate information. The meeting agenda and objectives reflect the four components of the public health framework and the associated cross-cutting issues.

Public health assessmentis the application of traditional public health methods to assess the impact of discovered genes on community health. These methods include surveillance (systematic collection, analysis, interpretation, dissemination, and evaluation of population-based data to monitor the magnitude of the disease burden in the population), epidemiology (study of the distribution and determinants of disease in populations and application to the control of health problems), and laboratory science.

For single-gene disorders, an understanding of the natural history of a disease elucidates opportunities for public health assessment and intervention. The natural history starts along a spectrum from birth through a variable asymptomatic period to early clinical presentation of disease, clinical morbidity, and late complications/clinical sequelae leading to disability and then death. Along this continuum, investigators can measure the disease impact in terms of both morbidity and mortality and incidence (number and proportion of new cases in a population over a specified time period) and prevalence (number and proportion of existing cases in a population). They can also measure the effectiveness of interventions applied along the continuum. Population-based data are needed on genotype-phenotype relationships and the natural history of disease and gene-gene and gene-environment interactions.

Meeting Objective 1 is to conduct a public health assessment of the impact of PI diseases. Participants are to:

  • Review available epidemiologic data and identify gaps;

  • Assess existing and potential population-based data sources;

  • Examine assessment models for other genetic disorders; and

  • Determine priorities among research questions, propose activities, and develop partnerships.

Genetic testingis the analysis of human DNA, RNA, chromosomes, proteins, and certain metabolites to detect a person's genotype for clinical purposes. Genetic tests are used to predict the risk for disease, identify carriers, and establish prenatal and clinical diagnosis or prognosis. The NIH Task Force on Genetic Testing has proposed that genetic tests be evaluated according to their analytic validity (ability of the test detect the underlying genotype), clinical validity (ability of the test to diagnose or predict the phenotype), and clinical utility (benefits and risks associated with the test and ensuing interventions). Such rigorous evaluation will provide data to allow researchers to determine whether genetic tests are safe and effective as they move from the research setting to clinical applications.

Meeting Objective 2 is to evaluate diagnostic testing, including genetic tests for PI diseases. Participants will:

  • Review the analytic validity of current diagnostic tests, including genetic tests;

  • Review the clinical validity of current tests;

  • Consider the utility of tests in clinical practice; and

  • Evaluate the availability and accessibility of diagnostic and genetic tests.

Public health interventionscan reduce complications from genetic diseases, including PI diseases. About one in 20 live-born infants is expected to have a single-gene disorder or a condition with an important genetic component by age 25. These persons will account for a disproportionate fraction of premature deaths, pediatric hospitalizations, and health care costs. Many of these conditions or their complications can be reduced by timely and effective intervention strategies. The intervention component of the public health framework involves developing intervention strategies for PI diseases; implementing pilot demonstration projects; and evaluating the impact on morbidity, disability, health care costs, and mortality. Intervention strategies include enhanced clinical recognition of persons with early symptoms or population-based screening in asymptomatic populations. Early diagnosis, with institution of effective therapy such as bone marrow transplantation, intravenous immunoglobulin, and antibiotics, can be expected to reduce the burden of PI diseases.

Enhanced early clinical recognitionis the first stage of a public health response when evidence suggests that early diagnosis and treatment will avert the late stage of disease and prevent morbidity, disability, and mortality. Enhanced clinical recognition requires information about disease prevalence, severity of late-stage complications, efficacy of treatment, analytic and clinical validity of early clinical signs and symptoms, and guidance on the use and interpretation of initial diagnostic laboratory testing.

Meeting Objective 3 is to develop strategies to increase early clinical recognition. Participants

  • Consider which PI diseases could benefit from early recognition;

  • Evaluate evidence that early recognition improves health outcomes, decreases morbidity and mortality, and is cost effective;

  • Identify essential components of early clinical recognition instruments; and

  • Consider needs of primary-care providers.

Population-based screeningis the systematic application of a test to identify persons who are at sufficient risk for a specified disorder to benefit from action, among a population of persons who have not sought medical attention for symptoms. Newborn screening for SCID has been proposed as a method to improve the outcomes of this otherwise fatal PI syndrome.

Meeting Objective 4 is to evaluate the potential for population-based newborn screening for SCID.
Meeting participants will:

  • Review what is known about the condition;

  • Identify tests proposed for screening and assess their analytic and clinical validity;

  • Assess the effectiveness and availability of early interventions; and

  • Evaluate the cost/benefit, ethical, legal, and social implications of newborn screening.

Communicationis key to the success of public health programs involving results from genetic research. Effectiveness depends on the coordination of communication strategies among various groups, targeting of appropriate audiences with messages that result in health promotion and disease prevention, and provision of messages that are accurate and technically and culturally appropriate. Strategies to reach primary-care physicians and other health care providers require special emphasis. Communication strategies to increase awareness of PI diseases build on the public health assessment and an improved understanding of the uses of genetic tests, disease recognition with valid clinical tools, and the impact of early recognition on outcomes.

Meeting Objective 5 is to propose and coordinate communication and information dissemination approaches. Participants will:

  • Review current education and outreach efforts for PI diseases;

  • Identify lessons learned from these and efforts related to other diseases;

  • Propose recommendations for future efforts; and

  • Identify collaborations and partnerships.

Meeting Objective 6 is to develop recommendations for future public health research and activities.
Meeting participants will:

  • Initiate partnerships and collaborations;
  • Identify public health research priorities for assessment and intervention;
  • Recommend activities and needed resources; and
  • Propose next steps.

Dr. Lindegren closed by acknowledging and thanking the members of CDC's Primary Immunodeficiency Working Group, which is composed of representatives from four Centers at CDC.

Overview of Primary Immunodeficiency Diseases
Dr. Lisa Kobrynski, Emory University

Primary immunodeficiency comprises 95 disorders caused by intrinsic dysfunctions in the cells of the immune system, often brought about by inherited genetic defects. Approximately 15 of these diseases account for more than 90 percent of cases. Most PI diseases are due to
single-gene defects. The most notable exception is common variable immune deficiency, which may be a combination of multiple gene factors or gene and environmental factors. The clinical hallmark of PI diseases is an increased susceptibility to infections, the severity of which varies by defect.

Classification of PI diseases as a group is complicated by different timing in the onset of disease; symptoms or signs may become manifest in the first few months of life or not until adulthood. Despite these disparities, however, the disorders share some features: unusual rate or severity of infection, infections with unusual or opportunistic organisms, and infections that are associated with specific syndromes. Without prompt diagnosis and intervention, most PI diseases are fatal.

Primary immunodeficiency diseases can be classified according to the affected components of the immune system. The relative distribution is as follows:

Antibody deficiencies(50 percent)--Antibody deficiencies occur in persons who have either too few antibody-producing B cells or B cells that do not function properly, leaving them susceptible to infections. Examples are X-linked agammaglobulinemia (XLA), common variable immunodeficiency (CVID), and selective IgA deficiency.

Combined immunodeficiencies(20 percent)--Combined immunodeficiencies occur in persons with impairments of both the antibody and cell-based defenses. Examples are SCID, Wiskott-Aldrich syndrome (WAS), and ataxia-telangiectasia.

Phagocytic deficiencies(18 percent)--Phagocytic cell deficiencies result in the inability of cells that engulf and kill antibody-coated invaders to act efficiently to remove pathogens or infected cells from the body. Examples are chronic granulomatous disease (CGD), leukocyte adhesion deficiency (LAD), and Chediak-Higashi syndrome.

Cellular immune deficiencies(10 percent)--T-cell deficiencies result in too few T cells or T cells that do not function properly. An example is DiGeorge syndrome.

Complement deficiencies(2 percent)--These usually involve an absence of one or several of the proteins that contribute to the complement system's ability to attach to antibody-coated foreign invaders. An example is C2 deficiency.

Other disorders--Disorders of unknown cause include hyper-IgE syndrome and chronic mucocutaneous candidiasis.

The range of incidence and prevalence varies from 1:500 (Caucasians) for selective IgA deficiency to ~1:1 million for hyper-IgM syndrome. In aggregate, the incidence of PI diseases is estimated at 1:5,000 to 1:10,000. These estimates can be compared with those for cystic fibrosis (1:2,500, Caucasians) and phenylketonuria (PKU, 1:15,000). However, data are lacking on the true incidence and prevalence of PI diseases.

PI diseases also can be stratified by natural history characteristics. Some diseases present very early in life, with only a short asymptomatic period after birth; without an effective early intervention, most result in death at a young age. Newborn screening may be the most effective method to improve the outcomes of diseases with such a narrow window for detection and intervention. For diseases with longer asymptomatic periods, a more feasible approach might be early symptomatic screening. Data on the benefits of early recognition of PI diseases are, however, limited. The impact may vary by age at diagnosis, presence of prior infections, history of vaccinations and blood transfusions, and genotype.

Interventions for PI diseases are aimed at preventing infection, prolonging life, and promoting improved quality of life. Curative interventions (e.g., bone marrow transplantation) are available for some PI diseases, and other interventions (e.g., gene therapy) hold promise for potential cures for other PI disorders.

Several characteristics of PI diseases make them good candidates for public health intervention: (1) the disorders are due to single-gene defects; (2) they share the common feature of susceptibility to infection; (3) they result in significant morbidity and mortality; and (4) effective treatments are available. A successful public health intervention to address PI diseases will require: (1) accurate knowledge of incidence and prevalence and natural history; (2) good case definitions, with accurate and accessible diagnostic testing; and (3) education of the public and health care providers to improve the timely recognition of affected persons. The remainder of the meeting agenda addresses these issues.