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

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

Executive Summary: Applying genetics and public health strategies to primary immunodeficiency diseases


On November 8-9, 2001, the Centers for Disease Control and Prevention (CDC), convened a panel of more than 50 experts in clinical immunology, public health, genetics, and communication from state and federal agencies, academic centers, public health laboratories, professional organizations, and advocacy foundations to identify genetic and public health strategies that can be applied to primary immunodeficiency (PI), a diverse group of more than 95 disorders, many of which result from single-gene defects. The defects may affect one or more components of the immune system and lead to a characteristic increased susceptibility to recurrent and persistent infections. Recent advances in molecular biology and genetics have led to the identification of the genetic defects for many of these diseases and prompted the development of promising new diagnostic tools and therapies.

During the meeting, experts outlined a framework for a public health approach to PI diseases, as a model for a public health approach to other single-gene disorders. Participants assessed the public health impact of PI and examined public health interventions to prevent morbidity, disability, and mortality and to improve health outcomes. They reviewed data available for a public health assessment of PI diseases; examined uses of laboratory tests-particularly genetic tests-and their role in clinical practice; and discussed potential public health interventions, including enhanced early clinical recognition, population-based screening, and education and outreach to increase awareness of these diseases.


The public health framework is based on a combined genetic-epidemiologic approach with four components: (1) public health assessment; (2) evaluation of genetic testing; (3) development, implementation, and evaluation of population interventions; and (4) communication and information dissemination. Each of these components requires (1) partnerships and coordination of genetic and public health activities; (2) attention to the ethical, legal, and social issues that can arise when applying genetics to health promotion and disease/disability prevention, and (3) education and training of providers and the public and provision of timely and accurate information.

I. Public Health Assessment

Public health assessment is the application of traditional public health methods-surveillance, epidemiology, and laboratory science-to assess the impact of discovered genes on community health. In order to translate genetic research into clinical and public health practice, ongoing population-based epidemiologic studies are needed to assess the impact of gene variants on the risk for disease, disability, and death; to identify modifiable risk factors; and to evaluate interventions.

At the meeting, presenters reviewed current efforts to assess the burden and impact of PI diseases, including estimates derived from national and regional disease registries and surveys of PI disease prevalence. They reported on data from U.S. disease-specific registries for chronic granulomatous disease and seven other PI diseases and from the PI disease registry of the European Society for Immunodeficiency Diseases (ESID). ESID has also established web-based immunodeficiency mutation databases. One such database, BTKbase, provides information about mutations in the BTK gene that cause X-linked agammaglobulinemia.

Presentations highlighted the potential for using existing population-based data (e.g., national mortality data, hospital-discharge data, state-based data, health maintenance organization [HMO] data) to assess PI disease prevalence and health outcomes. The goals and methods of ongoing public health surveillance were presented, using birth defects surveillance as an example. Efforts to collect epidemiologic and surveillance data on patients with other genetic diseases, including the Cystic Fibrosis Patient Registry and the Comprehensive Prevention Program for Persons with Bleeding Disorders, were presented as models that may help assess PI diseases.

II. Laboratory Issues/Evaluation of Genetic Testing

The Secretary’s Advisory Committee on Genetic Testing provides recommendations to enhance the oversight of genetic testing. Criteria to assess the benefits and risks of genetic tests include analytical validity, clinical validity, clinical utility, and ethical, legal, and social consequences.

Speakers discussed current diagnostic tests for PI diseases, including genetic tests; reviewed evaluation criteria for diagnostic and screening tests, including analytic validity, clinical validity, and clinical utility, with a focus on early clinical recognition and the potential role of
population-based screening; and reviewed the role of genetic tests in clinical practice (diagnosis, screening, management) and the availability and accessibility of genetic tests. Meeting participants emphasized the importance of continually developing and maintaining tests for rare genetic diseases and establishing a comprehensive system to collect data on rare diseases.

III. Developing, Implementing, and Evaluating Population Interventions

The intervention component of the public health framework involves developing intervention strategies for diseases with a genetic component; implementing pilot demonstration projects; and evaluating the impact of interventions on morbidity, disability, health care costs, and mortality. Timely and effective public health interventions can reduce complications from genetic diseases, including PI diseases. These strategies include enhanced early clinical recognition in early symptomatic populations or population-based screening in asymptomatic populations. Early diagnosis, combined with effective therapy such as bone marrow transplantation, intravenous immunoglobulin, and antibiotics, can reduce the burden of these diseases.

A. Strategies to increase early clinical recognition
Meeting participants discussed the development and assessment of early recognition systems and initial laboratory tests; considered which PI diseases could benefit from and should be targeted for early recognition strategies; and discussed the essential components of early clinical recognition instruments, including their practicality and usefulness to primary care providers and the need for evaluation of any proposed screening instruments.

B. Potential role for population-based newborn screening
Population-based screening is the systematic application of a test to a population that has not sought medical attention for symptoms. Both population-based screening and clinical algorithms select high-risk persons for diagnostic testing and prompt intervention. Participants discussed the potential role of population-based newborn screening in enhanced early identification, using severe combined immune deficiency (SCID). SCID presents early in the first 6 months of life; and, without treatment, leads to death in the first year. Their deliberations centered on issues pertaining to the condition, characteristics of possible screening tests, interventions, infrastructure, and research needs.

IV. Communication and Information Dissemination
Effective communication will depend 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. Communication strategies to increase awareness build on the public health assessment of PI diseases and an improved understanding of the uses of new genetic tests, recognition of PI diseases with valid clinical tools, and the impact of early recognition on outcomes. Speakers from organizations and agencies that have developed educational and outreach efforts targeted to patients, providers, and the public discussed their activities; reviewed strategies and successes; identified lessons learned; and proposed recommendations for future education and communication efforts, including how to develop and evaluate activities to enhance early identification and awareness of PI diseases.

Summary of Recommendations for Future Public Health Research and Activities

Public Health Assessment
Recommendations include the collection of good epidemiologic data on incidence, prevalence, and the natural history of single-gene disorders, such as PI diseases; the relationship between genotype and phenotype; and the impact of early recognition and effective therapies on morbidity and mortality. Certain PI diseases were targeted as priorities for public health assessment which included profound T-cell defects, antibody deficiencies, and chronic granulomatous disease (CGD). Pilot activities to collect, use, and improve epidemiologic and surveillance data should be considered and included convening a working group to provide guidance on accurate case definitions and for registry and surveillance activities; developing collaborative efforts between public and private groups to expand current PI disease registries in terms of data collection, completeness, and analysis; examining existing population-based databases; and developing collaborative surveillance activities at the state level for genetic diseases, including PI diseases. In addition, the group promoted the development of a network of model centers, and encouraged the use of these centers for epidemiologic data collection and specimen repository.

Laboratory Issues
Recommendations included ensuring that referral centers and laboratory testing are accessible for the diagnosis of persons with rare genetic diseases, such as suspected PI diseases. Data should be collected on the analytic and clinical validity of molecular tests used for diagnosis of PI diseases or any proposed screening programs.

Public Health Interventions – Recommendations for practical and effective public health interventions to reduce morbidity and mortality from genetic diseases such as PI diseases focused on two areas: early clinical recognition and newborn screening.

For early clinical recognition, data should be collected on the effectiveness of early intervention for PI diseases. A working group should be established to create early clinical recognition tools for PI diseases for specific target audiences and to identify which PI diseases should be targeted for early recognition. Before widespread application, an evaluation of the usefulness and accuracy of early clinical recognition tools (e.g., clinical signs and symptoms, initial laboratory tests) for early recognition of PI diseases should be conducted as well as exploring existing databases to test proposed algorithms. The usefulness of obtaining a family history should also be evaluated.

SCID or profound T-cell deficiency were considered as potential candidates for pilot studies of population-based newborn screening. Partnerships among investigators and CDC laboratory personnel should be encouraged to develop and validate methods to measure T-cell lymphocytes from dried blood spots (DBS). Validation could include blinded comparisons of T-cell counts using an assay from DBS, with manual differential count from cord blood samples as the gold standard. Once an assay is developed and validated, pilot testing of the screening assay should be conducted in collaboration with states, CDC, Health Resources and Services Administration (HRSA), National Institutes of Health (NIH), and other partners.

Communication and Information Dissemination
The goal of a comprehensive communication strategy must consider and integrate the principles of effective communication within every phase of the PI campaign process from research to education and outreach. The first step should include convening a working group of PI experts to develop consensus regarding the case definition and clinician recommendations that will form the basis of the communication messages. The second step would be to convene a working group of health communication specialists and other appropriate PI partners to establish a comprehensive communication strategy that accomplishes the formative research, process, and outcome evaluation based on the findings from the first working group. The third step includes conducting the formative evaluation research to test pre-existing knowledge, determine target audiences, and define concepts to include in the communication messages, in addition to considering these aspects of materials already developed and disseminated. Another component is to establish and encourage partnerships with health care provider organizations, public and private advocacy groups, and academic centers. The next component includes developing or revising existing educational materials, using messages consistent with formative research findings; pre-test messages with target audiences and revise messages based on outcomes of
pre-testing. Then disseminate messages that are consistent with proposed pretest recommendations. Subsequently, perform process evaluation to track communication activities, assess reach with target audiences, and improve program accordingly. Finally, conduct outcome evaluation to demonstrate and build upon campaign results.

Table of Contents
Executive Summary
Summaries of Workshop Presentations
Session I…Overview and Objectives of the Conference
Welcome and Introductions…Muin Khoury, Richard Jackson, CDC
Integrating Genetics into Public Health…Muin Khoury, CDC
Goals and Objectives of the Meeting…Mary Lou Lindegren, CDC
Overview of Primary Immunodeficiency Diseases…Lisa Kobrynski, Emory University
Session II …Public Health Assessment of PI Diseases

Session IIA
…Public Health Assessment Efforts: Current and Past
Primary Immunodeficiencies: Prevalence and Distribution…E. Richard Stiehm, UCLA
National Registry of U.S. Residents with PI Diseases…Jerry Winkelstein, Johns Hopkins
ESID Registry and Immunodeficiency Mutation Databases…C.I. Edvard Smith, Karolinska Institutet

Session IIB
…Public Health Assessment Efforts: What Could Be Done
Use of Existing Databases to Study the Impact of Genetic Disease…Sonja Rasmussen, CDC
Surveillance for Birth Defects…Larry Edmonds, CDC
Cystic Fibrosis Patient Registry…Preston Campbell, CFF
Surveillance for Bleeding Disorders…Sally Crudder, CDC
Session III…Laboratory Issues
Evaluation of Genetic Testing…James Haddow – Foundation for Blood Research
Primary Immunodeficiencies: Diagnostic Tests…Hans Ochs – University of Washington
Uses of Genetic Testing for Primary Immunodeficiency…Jennifer Puck, NIH
Session IV…Strategies to Increase Early Clinical Recognition
Prevention Effectiveness Framework for Evaluating Strategies for Earlier Identification of PI Disorders…Scott Grosse, CDC
PI Diseases: Primary Care Perspective…Tracy Trotter, AAP
Timely Diagnosis of Immunodeficiency…Mary Ellen Conley, St. Jude Children’s Research Hospital
Targeting Primary Immunodeficiency: Development of a Hospital-Based Scoring System to Expand Recognition…Charlotte Cunningham-Rundles, Mount Sinai Medical Hospital
Shrinking the Haystack: Approaches to PI Disease for Clinicians…Richard Hong, University of Vermont
Session V…Potential for Population-Based Screening
Human Severe Combined Immunodeficiency (SCID) and Potential for Newborn Screening…Rebecca Buckley Duke University
Population-Based Newborn Screening: Current and Emerging Screening Criteria…Nancy Green, March of Dimes
Screening for PI Diseases: Potential Laboratory Strategies…Harvey Levy, Children’s Hospital of Boston
Overview of CDC’s Newborn Screening Quality Assurance Programs…Harry Hannon, CDC
Research Projects Using Dried Blood Spots…Robert Vogt, CDC
Session VI …PI Educational Programs and Outreach Efforts
NIH Educational Outreach Efforts…Allan Lock, NIH
Mount Sinai’s STRIDE Project…Barbara Brenner, Mount Sinai Medical Hospital
Jeffrey Modell Foundation Physician Education Programs and Outreach Efforts…Fred Modell, JMF
Immune Deficiency Foundation Physician Education Programs…Jonathan Goldsmith, IDF
Discussion: Lessons Learned, Recommendations, and Next Steps for Future PI Education and Communication Efforts
Session VII…Development of Recommendations for Public Health Activities and Research
Public Health Assessment: Improvement of Existing Studies and Priorities for Additional Studies
Public Health Intervention: Enhanced Early Clinical Recognition, Clinical Algorithms and Evaluation Strategies, Diagnostic Tests,Education for Patients, Providers, and the Public
Potential Role for Population-Based Screening
Closing Remarks…José Cordero, CDC
Summary of Recommendations for Future Public Health Research and Activities
Appendix I – List of Attendees
Page last reviewed: June 15, 2009