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Institute of Medicine (US) Forum on Microbial Threats; Knobler SL, O'Connor S, Lemon SM, et al., editors. The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects: Workshop Summary. Washington (DC): National Academies Press (US); 2004.

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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects: Workshop Summary.

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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 ascertain 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 populations. 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 immunologic 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.

Copyright © 2004, National Academy of Sciences.
Bookshelf ID: NBK83704

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