Summary and Assessment

The belief that infectious agents may cause certain chronic diseases can be traced to the mid-19th century, when cancer was studied as a possible infectious disease. This effort met with little success. In the 1950s and 1960s, much more biomedical research was directed, again unsuccessfully, at the identification of microorganisms purported to cause a variety of chronic diseases. In recent years, however, the picture has begun to change. A number of chronic diseases have now been linked, in some cases definitively, to an infectious etiology: peptic ulcer disease with Helicobacter pylori, cervical cancer with several human papillomaviruses, Whipple’s disease with Tropheryma whipplei, Lyme arthritis and neuroborreliosis with Borrelia burgdorferi, AIDS with the human immunodeficiency virus, liver cancer and cirrhosis with hepatitis B and C viruses, to name a few. Indeed, evidence continues to mount implicating microorganisms as etiologic agents of chronic diseases that have substantial morbidity and mortality, including atherosclerosis and cardiovascular disease, type 1 diabetes, inflammatory bowel disease, and a variety of neurological diseases. The proven and suspected roles of microbes does not stop with physical ailments; infections are increasingly being examined as associated causes of or possible contributors to a variety of serious, chronic neuropsychiatric disorders and to developmental problems, especially in children.

It also has become apparent that multiple pathogens sometimes interact in causing chronic diseases or rendering them more virulent. For example, people who have concomitant infection with hepatitis C virus and the organism that causes schistosomiasis—as many individuals do in some developing countries—often develop schistosomiasis much more rapidly than do people who are not



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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary Summary and Assessment The belief that infectious agents may cause certain chronic diseases can be traced to the mid-19th century, when cancer was studied as a possible infectious disease. This effort met with little success. In the 1950s and 1960s, much more biomedical research was directed, again unsuccessfully, at the identification of microorganisms purported to cause a variety of chronic diseases. In recent years, however, the picture has begun to change. A number of chronic diseases have now been linked, in some cases definitively, to an infectious etiology: peptic ulcer disease with Helicobacter pylori, cervical cancer with several human papillomaviruses, Whipple’s disease with Tropheryma whipplei, Lyme arthritis and neuroborreliosis with Borrelia burgdorferi, AIDS with the human immunodeficiency virus, liver cancer and cirrhosis with hepatitis B and C viruses, to name a few. Indeed, evidence continues to mount implicating microorganisms as etiologic agents of chronic diseases that have substantial morbidity and mortality, including atherosclerosis and cardiovascular disease, type 1 diabetes, inflammatory bowel disease, and a variety of neurological diseases. The proven and suspected roles of microbes does not stop with physical ailments; infections are increasingly being examined as associated causes of or possible contributors to a variety of serious, chronic neuropsychiatric disorders and to developmental problems, especially in children. It also has become apparent that multiple pathogens sometimes interact in causing chronic diseases or rendering them more virulent. For example, people who have concomitant infection with hepatitis C virus and the organism that causes schistosomiasis—as many individuals do in some developing countries—often develop schistosomiasis much more rapidly than do people who are not

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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary coinfected. Exploring such pathogen interactions and their effects on the immune system represent rapidly burgeoning areas of scientific interest.1 This report summarizes a two-day workshop held by the Institute of Medicine’s Forum on Microbial Threats on October 21–22, 2002, to address this rapidly evolving field. Invited experts presented research findings on a range of recognized and potential chronic sequelae of infections, as well as on diverse pathogenic mechanisms leading from exposure to chronic disease outcomes. Cancers, cardiovascular disease, demyelinating syndromes, neuropsychiatric diseases, hepatitis, and type 1 diabetes were among the conditions addressed. Participants explored factors driving infectious etiologies of chronic diseases of prominence, identified difficulties in linking infectious agents with chronic outcomes, and discussed broad-based strategies and research programs to advance the field. Table S-1 lists the infectious agents and associated diseases discussed in this report. Emerging infectious diseases are conceptualized either as newly identified or appreciated infectious illnesses and conditions, or as previously recognized syndromes that are newly attributed to infection. Some scientists now believe that a substantial portion of chronic diseases may be causally linked to infectious agents. Just as the germ theory opened the way for numerous discoveries about the sources of acute infections, changing ideas about the nature of both infectious diseases and chronic diseases, coupled with the advent of powerful new laboratory techniques, are leading to novel claims concerning the infectious origins of chronic diseases. DEFINING THE RELATIONSHIP The traditional standards for establishing a microbial or bacterial cause of disease are those that were developed for acute infections. Known as “Koch’s postulates,” they state that the causal organism must be: present in diseased tissue; isolated and grown in pure culture outside the animal host; shown to induce the same disease when injected into a healthy animal; and isolated from the experimentally inoculated animal in pure culture and shown to be the same as the original agent. 1   It should be clearly noted throughout this summary report that the nature of the evidence for causality of a chronic disease from an infectious agent varies considerably. Each of the cases reviewed here represents a wide spectrum of the nature of the relationship between the infectious agent and the chronic disease. In some cases, the links are definitive (e.g., human papillomavirus and cervical cancer). In other cases, the relationship has only recently been investigated with little more than suspected associations from preliminary data (e.g., enteroviruses and Type I diabetes).

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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary TABLE S-1 Possible Infectious Etiologies for Chronic Diseases Discussed at the Workshop Infectious Agent Chronic Disease/Condition Chapter Human papillomavirus Cervical cancer 1 Hepatitis B virus Liver cancer Cirrhosis 1 Chlamydia pneumoniae Atherosclerosis 1 Vaccinia virus Postinfectious encephalomyelitis or acute disseminated encephalomyelitis (ADEM) 1 JC virus Progressive multifocal leucoencephalopathy (PML) 1 Various viruses Multiple sclerosis 1 Enteroviruses Type I diabetes mellitus 1 Toxoplasma gondii Schizophrenia 1 Herpes Simplex virus Type 2 Schizophrenia 1 Jaagsiekte sheep retrovirus (JSRV) Ovine pulmonary adenocarcinoma 1 Propionibacterium acnes Chronic inflammatory acne Other chronic diseases 1 Cryptosporidiosis and intestinal helminthic infections Disability consequences including growth shortfalls, fitness and cognitive impairment 2 Helminthic infections Epilepsy 2 Plasmodium falciparum Epilepsy 2 Treponema pallidum Congenital syphilis 2 Toxoplasma gondii Congenital toxoplasmosis 2 Maternal rubella virus Congenital rubella 2 Perinatal HIV Developmental disabilities 2 Perinatal herpes viruses Neurodevelopmental disabilities 2 Plasmodium falciparum Cognitive development Childhood anemia 2 Haemophilus influenzae Type B meningitis Nervous system impairment 2 Japanese encephalitis virus Neuropsychiatric sequelae 2 Measles virus Developmental disabilities 2 Poliovirus Paralysis Chlamydia trachomatis Trachoma Human T-cell lymphotropic virus Type 1 Adult T-cell leukemia/lymphoma Autoimmune disorders Infections associated with immunosuppression 2 Human herpes virus Type 8 Kaposi’s sarcoma 3 Borna disease virus Neurodevelopmental disorders 3 Hepatitis C virus and Schistosoma mansoni interaction 2 HIV and Plasmodium falciparum interaction 2

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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary In almost all cases, identifying and confirming an infectious cause of a chronic disease using Koch’s postulates is complicated by several factors, including: Disease etiology may be multifactorial, including environmental, host genetic, and microbial genomic factors. Michael Dunne (Chapter 1) surveys a number of pathogens proposed to contribute to atherosclerosis and cardiovascular disease. Chlamydia pneumoniae, cytomegalovirus, and herpes simplex virus are among the suggested bacterial and viral pathogens, with the greatest body of evidence surrounding C. pneumoniae. Yet in all of these cases, when these agents are considered in the context of well-established risk factors for cardiovascular disease—family history, high-fat diet, inactivity—it is less clear how much infection would truly contribute to the condition and the outcome. Eduardo Franco (Chapter 1) describes the association that has been found between human papillomavirus and cervical cancer. Even years after discovery of this link, however, questions remain about the roles of cofactors, as only some of the many people infected develop malignancy. Microorganisms may act in a hit-and-run fashion, striking and then disappearing from the host by the time the disease process becomes apparent. This form of attack appears to be the case in Reiter’s syndrome, Guillain-Barré syndrome, and rheumatic heart disease. As another example, Robert Yolken and Fuller Torrey (Chapter 1) report that a retrospective study of schizophrenics found that their mothers’ blood at the time of birth exhibited elevated IgG, IgM, and certain cytokines, suggesting that an ongoing inflammatory process may possibly be associated with Toxoplasma infection. Antibodies directed against endogenous retroviruses, including Herv-W, have also been found at elevated levels. Infection in the perinatal period may have set the stage for later neurological disease, although there may be little or no evidence of active infection at the time of diagnosis. Acute, chronic, latent, or recurrent infections may be involved in pathogenesis, and coinfections may play a critical role in disease manifestation. Richard Johnson (Chapter 1) describes postinfectious encephalomyelitis in which patients develop fever, become obtunded, and develop multifocal neurological signs several days after resolution of an acute rash caused by a virus. This is an example of an acute systemic disease with a postinfectious immune response leading to demyelination within the central nervous system. In other cases, a long period of active viral replication may precede the onset of disease. William Mason (Chapter 1) reports that the risk of developing chronic hepatitis B virus infection is greater than 90 percent when a person is infected at birth or in early childhood, but drops to less than 10 percent when a person is infected as an adult. In such chronic infections, the risk of fatal liver disease (cirrhosis or liver cancer) rises to approximately 25 percent, with a 30 year to 50 year interval between the onset of the infection and the consequent pathological outcome. A similar picture

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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary occurs with hepatitis C virus infection, although in this case there is virus persistence when the infection occurs in adulthood. Viral infections may also be latent at the time of diagnosis. For example, there are several viruses for which patients with multiple sclerosis (MS) exhibit higher antibody levels than control patients. Johnson reports on one study which revealed that 23 percent of MS patients had antibodies to two or more viruses present within their central nervous systems, with one patient presenting with 11 viruses. It is not yet clear whether infection(s) triggers MS or whether elevated markers of infection are secondary to the underlying inflammatory processes of the disease. Such findings emphasize the complexity of directly attributing chronic disease to one or more specific infectious agents. Detecting and/or isolating microbes that are present in a variety of tissues may pose significant technical difficulties. Current methods to identify novel or rare microorganisms may be inadequate. During the workshop, David Persing reported on the deficiencies and weaknesses of conventional methods for identifying and subtyping microorganisms. However, newer molecular technology, such as broad-range amplification of ribosomal targets directly from tissue or culture, can complement conventional systems, and these tools have helped in identifying several new species and pathogenic subtypes. For example, the infectious agent strongly suspected of causing Whipple’s disease remained elusive for years. Applying broad-range polynuclear chain reaction techniques enabled scientists to amplify and categorize the etiologic Tropheryma whipplei bacterium. Patrick Moore (Chapter 3) recounts the development of a technique called representational difference analysis to identify Kaposi’s sarcoma-associated herpesvirus as a cause of AIDS-associated Kaposi’s sarcoma. These discoveries exemplify the diligent effort required to move from identification of a new DNA sequence to confirming causality in a specific disease. During the workshop, Persing also described the potential for gene expression arrays (microarrays), proteomics, and other technologies to identify patterns of host response to an infection(s) that might explain the pathogenic processes from exposure to chronic disease and lead to the development of diagnostic tools for these entities. Phylogenetic analysis can relate new pathogens for which there are no effective diagnostic assays to known agents through conserved epitopes and other properties, facilitating the evaluation of new infectious causes of disease. Given the various reasons why it may often prove difficult to satisfy Koch’s postulates in linking a particular infectious agent to a particular chronic disease, alternative sets of criteria may need to be developed for determining causation. Such criteria must take into account the more complex relationships that are being observed between microbial agents and chronic disease, and they likely will require collection of more challenging types of experimental data, especially molecular data, that can help clarify discrete causal links. Toward this goal, several promising avenues of research are being pursued, including extending vari-

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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary ous genetic technologies and modifying animal and cell culture models of human disease to make them more immediately relevant to microbial disease causation. Ensuing discussions highlighted gaps in scientific knowledge and in the translation of research data to health care interventions for both well-accepted and more speculative causal associations. Participants noted the complexity of these issues, as well as the importance of strengthening the critical linkages among clinicians, researchers, epidemiologists, and public health officials. IMPLICATIONS FOR DEVELOPING COUNTRIES Chronic diseases are a leading health issue in economically established countries, and they take a significant toll in developing countries as well. Human T-cell lymphotropic virus type 1 infection and hepatitis C-schistosomiasis coinfection demonstrate the impact of progressive chronic infections that already disproportionately affect developing regions. During the next 20 years, chronic diseases are expected to become even more important in economically developing regions, as the types of chronic conditions currently found primarily in industrialized nations spread to other regions. Not only will changing economics, demographic shifts with lower childhood mortality, and changing lifestyles drive this trend, but migration from rural to urban areas and into previously uninhabited ecosystems may expose populations to new infectious agents that underlie chronic disease. Both newly identified and well-recognized infectious etiologies of chronic disease, including infections known to enter a chronic state, such as tuberculosis and malaria, will acquire increasing importance to domestic and global health. These associations also will create serious burdens in addition to the chronic infection. Richard Guerrant (Chapter 2) relates that enteric and parasitic infections, often marked by diarrhea and contributing to malnutrition, can have long-term consequences, impairing development and cognitive abilities as well as general health. Once again, coinfections and common acute infections are likely to loom large and may represent an under-recognized source of chronic pathology. Attending to the challenges imposed by chronic diseases will be difficult in strained healthcare systems that have limited research capacity and that already are overwhelmed by the myriad of acute health problems in developing regions. OBSTACLES AND OPPORTUNITIES FOR FRAMING THE RESEARCH: PRIORITIES FOR THE FUTURE Human disease is a function of the environment in which people live and of their genetic susceptibility to infection or its outcome. People live in concert with a variety of microbial agents that may or may not cause disease, depending on an individual’s exposure and surrounding environment and the genetic background on which these are superimposed. When chronic disease stems from infectious disease, the situation is even more complex, because it may be difficult to ascer-

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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary tain the precise timing of infection (which may have happened well in the past) or the exact nature of the pathogen. Scientifically sound data on the infectious etiologies of chronic diseases must derive from new technologies and the optimization of existing assays. The research must be guided by epidemiologic insights gained from well-designed studies of disease in human populations and from the application of sophisticated surveillance systems to detect and monitor diseases and pathogens. Standardization and reproducibility will be essential. Selection of appropriate cases and controls is imperative, with the use of systematic case studies or experimental designs when this is not possible. Prospective cohort studies should incorporate appropriate surveillance and be capable of detecting outbreaks of infection as well as identifying recently infected individuals. Throughout all, researchers will need to employ comparable definitions of infection and of the chronic disease being explored. To develop enough human capital for these endeavors, it will be necessary to attract more scientists to the relevant fields and provide more training in attendant epidemiological and scientific areas. Overcoming these obstacles will require the concentrated efforts of researchers from a variety of disciplines, including epidemiology, clinical medicine, molecular biology, and pathology, among others. It also will require harnessing new analytical tools and approaches that have emerged recently, and continue to emerge, from molecular biology, genomics, and biotechnology. One of the most fruitful technologies centers on the ability to detect and manipulate nucleic acid molecules in microorganisms, thus creating a powerful means for identifying previously unknown microbial pathogens and for studying the host-pathogen relationship. Other new tools being employed include broad-range polymerase chain reaction and representational difference analysis, both of which have played key roles in linking numerous pathogens with chronic diseases. Equipped with these and other advanced tools, researchers are becoming better able to move beyond the limitations of Koch’s postulates and to link infectious agents with chronic diseases more precisely and with greater confidence than ever before. In addition, researchers are developing sophisticated approaches for exploring the interplay of genetic and environmental factors in the causation of a number of important developmental behavioral disorders. Participants also identified a number of general characteristics of a comprehensive and coordinated effort that would enhance efforts both to identify links between infectious microorganisms and chronic diseases and to develop and implement interventions to minimize their health consequences. For example, they noted need to develop prototypes and standards to guide this work. Standardized case definitions are needed to facilitate research as well as the clinical diagnosis of infection (active, persistent, or latent) and the chronic syndromes or outcomes that result from it. Laboratory assays need to be adopted that are uniform in terms of sensitivity, specificity, and reproducibility. High-throughput assays meeting similar standards will be key to the study of large cohorts and popu-

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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary lations. Without such tools, it will be difficult to interpret the significance of clinical studies and to relate the results of one study to those of another. Research coupled with appropriate public health activities will facilitate the linkage of existing and newly designed databases, and ensure the quality surveillance and epidemiologic studies needed to better characterize infectious and chronic diseases by their population distribution and potential associations. Many settings will demand expensive longitudinal investigations or the study of new, prospective cohorts to complement case-control or cross-sectional investigations. Additional observations can be made by conducting follow-up and look-back studies using infectious disease and chronic disease surveillance systems and by following outbreak cohorts or recently infected individuals. Longitudinal studies may prove particularly valuable given that rapid advances in the field may dictate that we might not know today which pieces of evidence will be needed in the future. Detecting and confirming causal associations will require study of both larger cohorts and better-defined at-risk populations. A number of specific populations should receive particular attention, including people who move from rural areas into cities, both in the developing and the developed world. Studies are needed to see whether such movements redefine an individual’s risk for a chronic outcome based on infections that they bring with them or susceptibility to new infections that they previously had not encountered. To provide effective clinical interventions, continued studies are needed to define temporal relationships between infections and disease—that is, what stage of infection determines outcome. Studies also are needed to clarify at which stage infection must be prevented or treated in order to minimize or eliminate chronic sequelae. It will be important to determine the expected benefit of actions, to ensure that the benefits will outweigh any possible risks. The improvement of both prevention and treatment for chronic diseases will require a better understanding of their natural history, especially the earliest stages. To generate such knowledge, clinicians should be encouraged to identify patients who have recently developed or who seem to be developing a suspect chronic disease, to systematically collect a range of clinical specimens, to follow the course of the disease, and to identify telltale clinical features early. Better animal models are also needed to explore and understand the potential infectious causes of chronic illness. Diseases occurring in animals should be explored to better understand the potential paradigms of causal relationships. Animal models do not necessarily mimic human pathogenic processes, but examination of the similarities and differences between various models and human diseases can be extremely informative. Additionally, more effort should be devoted to teaching health professionals about their value and their limitations. Psychiatric modeling with animals may present an especially ripe area for probing a variety of important questions, yet many practitioners in the field are not accustomed to working with such models. Basic tools, such as species-specific immu-

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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary nologic reagents and diagnostics, must be developed to take advantage of this potentially valuable approach. Similarly, the sensitivity and specificity of reagents for human specimens must be verified when translating animal research to people. Issues related to informed consent and human specimen collections and repositories take on new dimensions given these demands. The potential for developing new and improved diagnostic and analytical technologies that identify new targets for chronic disease prevention strategies is very real. However, it is impossible to know how specimens collected today may be used in the future. There is widespread concern that current regulations and guidelines are too complex, too uncertain, or too restrictive for the meaningful sharing of data. Parties from government, academia, and private funding agencies must collaborate to develop a standard method of gaining patients’ consent, gathering identifying information, and being able to use such information in the future. Current consent strategies typically do not allow specimens and data to be used for unforeseen purposes. Further complicating this issue are new state and federal laws regarding the safeguarding and transfer of health-related information among professionals and institutions, and stricter interpretation of long-standing regulations related to informed consent. The complexity of this field calls for an examination of whether the scientific community is optimally organized to address these issues and whether its various components communicate effectively. The community also should mount a concerted effort to identify gaps in current knowledge about the etiology of chronic diseases, pinpoint what needs to be done to close those gaps, chart the obstacles that stand in the way, and then identify and provide the necessary financial resources (monetary and human) to drive progress. Cross-disciplinary and multidisciplinary approaches will be of critical importance, and the problems created by specialization and programmatic stove-piping should be addressed explicitly. Veterinary researchers, clinical researchers, basic scientists, and epidemiologists need to work together as teams. An increasingly large share of future research will likely involve either groups of investigators from a variety of disciplines or groups of institutions working collaboratively. In many cases, these large projects will include a multinational component to ensure that sufficient attention is paid to multiracial, multiethnic, and multicultural differences. There are many precedents for developing investigator collaborations, interdisciplinary consortia, and partnerships among academics and public health officials, but such endeavors are not necessarily easy and may not come naturally. Both top-down and bottom-up strategies are appropriate for engaging the various scientific disciplines required for this work. By setting appropriate guidelines, funding agencies can play a major role in driving the formation of such interdisciplinary research teams. Steps have been taken toward this end, but these promising efforts need to be nurtured to ensure continued cooperation.

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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary OPPORTUNITIES TO PREVENT AND MITIGATE THE IMPACT OF CHRONIC DISEASES CAUSED BY INFECTIOUS AGENTS Documentation of an association between a specific infectious agent and one or more of the high-morbidity, high-mortality chronic diseases that consume most health care resources in economically developed countries would have widespread clinical and public health implications. The significance also would be felt in developing countries, since chronic diseases already are consuming increasing proportions of their available health-related resources—and the threat they face from such diseases continues to grow apace. The benefits to be derived from detecting and preventing causal infections, and from discontinuing interventions against unproven causal agents, could be substantial. Workshop participants also noted the potentially high impact of addressing less common chronic conditions for which a preventable infection is the major cause. Achieving these potential gains will hinge on several issues. Importantly, it will be necessary to be able to identify causal links and their temporal relationships while minimizing the risks of interventions against unproven etiologies. With this scientifically sound information, new strategies can target the critical point along the path from infection to chronic disease at which interventions might avoid or mitigate illness and disability. Linking one or more highly prevalent chronic conditions to infection with a specific virus or bacteria might enable physicians to use vaccines and/or antibiotics to prevent or cure the condition, thus eliminating the need for health workers to rely on nonspecific therapies aimed at mitigating the symptoms of the condition. A classic example is immunization with hepatitis B vaccine. The introduction of this vaccine into universal childhood immunization programs has reduced the incidence of hepatocellular carcinoma in some regions of the world where this was previously one of the most common types of malignancy. There is a strong possibility that the new sciences of genomics and proteomics will help to detect the relevant antigens and to advance our understanding of both host immunity to these pathogens and the process of disease pathogenesis. Such knowledge will certainly open new strategies for therapy and prevention. Better approaches to optimizing vaccine antigens also are being developed, and advances in the field of vaccinology should promote such efforts. Improved coordination among basic and clinical scientists, pathologists, and epidemiologists will be critical to accomplishing these goals. Priorities for these networks and collaborative teams are the development and application of: standardized case definitions (to be used in defining both infection and disease outcomes); new and adequate specimen collections associated with pedigreed databases;

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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary appropriate epidemiologic design; and comparable methods of analysis that can be applied across a field of study. The Forum discussions emphasized two major themes: (1) the need to define the nature and scope of future research that will balance global efforts targeting various chronic disease syndromes, and (2) the need to develop a coordinated and systematic strategy to maximize resource use and overcome the inherent technologic and epidemiologic challenges, as well as the organizational barriers, that now impede progress in this field. CONCLUSION The substantial burden posed by chronic diseases of likely infectious etiology demands global attention and action. Evidence continues to mount implicating microorganisms as important etiologic agents of chronic diseases that contribute substantially to morbidity and mortality. However, the identification and confirmation of infectious causes of chronic diseases is complicated by several problems, including frequent multifactor causation for many of these diseases and differences in the environmental background and genetic composition of different populations. Recently developed molecular and immunological techniques offer new approaches to addressing the technical barriers. However, improved coordination among basic and clinical scientists, pathologists, and epidemiologists also will be critical to progress. Standardization of case definitions and analytical assays combined with sound epidemiologic design will help, as will the development of broad, new strategies for creating carefully pedigreed specimen collections and disease registries. Although the task is daunting, taking the practical and pragmatic pathways described above could clarify many of the uncertain relationships between infectious agents and chronic diseases.   Siobhán O’Connor, M.D., M.P.H. Assistant to the Director of the National Center for Infectious Diseases, Centers for Disease Control and Prevention Clinical Assistant Professor, Emory University School of Medicine   Stanley M. Lemon, M.D. Vice-Chair, Forum on Microbial Threats Dean, School of Medicine, University of Texas Medical Branch

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