The belief that many long-recognized chronic diseases are infectious in origin dates
to the mid-nineteenth century, when cancer was studied as a possible infectious disease.
In the 1950s and 1960s, much biomedical research was unsuccessful in confirming microbial
causes of various chronic syndromes. Recent years, however, are marked by successful
identification of several causal infectious agents of chronic disease such as Human
papillomavirus in cervical cancer, but challenges and controversies remain.
The Institute of Medicine’s Forum on Emerging Infections recently sought to address
this rapidly evolving field. To identify cross-disciplinary contributions and challenges
in determining infectious causes of chronic diseases, the forum hosted a 2-day workshop
on October 21–22, 2002, Linking Infectious Agents and Chronic Diseases: Defining the
Relationship, Enhancing the Research, and Mitigating the Effects. In response to invited
presentations, participants explored factors driving infectious causes of chronic
diseases to prominence, identified difficulties in linking infectious agents with
chronic conditions, and discussed broad-based strategies and research programs that
might advance the field.
Invited experts provided research findings on a diverse range of recognized and potential
chronic sequelae of infection as well as diverse pathogenic mechanisms from exposure
to chronic outcome. Cancers, demyelinating syndromes, cardiovascular disease, neuropsychiatric
diseases, hepatitis, and diabetes mellitus were among the chronic conditions addressed.
Ensuing discussions noted gaps in knowledge and in the translation of research data
to health-care interventions for both accepted and speculative causal associations.
Workshop participants remarked on the likely widespread clinical and public health
implications of linking infectious agents with chronic diseases that dominate health
care in economically established countries, including the United States. The potential
benefits of detecting and preventing causal infections, and the risks of interventions
against unproven causal agents, are substantial. Workshop participants advocated careful
research to produce and appropriately translate validated, reproducible data into
clinical management to alleviate the impactof chronic diseases.
Participants also recognized the potential impact of infectious disease control on
chronic diseases in economically developing countries. Within 20 years, chronic diseases
are expected to represent a substantial proportion of their health burden. Presentations
on human T-cell lymphotropic virus type 1 infection and hepatitis C–schistosomiasis
coinfection demonstrated the impact of progressive chronic infections that disproportionately
affect developing regions. These presentations emphasized the importance of considering
coinfections in chronic disease pathology. Data on chronic outcomes of malaria in
infected persons and in unborn children and of other coinfections emphasized these
points. Presentations also examined causal associations between enteric or parasitic
infections and long-term developmental disabilities, as well as links between infectious
agents and epilepsy. Coinfections and common acute infections may represent an under-recognized
source of chronic pathology. In regions with limited health-care resources, newly
identified infectious causes of chronic diseases, including tuberculosis and malaria,
may require increased attention.
Against the backdrop of multiple microbes and multiple chronic outcomes, participants
attempted to identify research opportunities, challenges, and barriers to understanding
linkages between infections and chronic syndromes, and ultimately efforts to mitigate
the impact of chronic diseases on human health. Recent developments in technology,
methodology, and collaborative research have clearly advanced the ability to determine
causal relationships. However, the workshop highlighted numerous factors that complicate
identification and confirmation of one or more infectious roots of a chronic disease—factors
that current and future research must address. These challenges include possible multifactorial
pathogenesis such as interactions between environmental and genetic (host and microbe)
influences; how the timing of infection determines final chronic outcome; and the
“hit-and-run” nature of certain microbes that may be eliminated before chronic disease
becomes apparent. Additional challenges include differentiating the roles of acute,
persistently active, latent, and recurrent infection in pathogenesis; the possible
singular role of certain species or strains in producing chronic sequelae; the influence
of coinfections in defining final pathology; difficulty detecting latent infection
before or when chronic disease is diagnosed; differences in the sensitivity and specificity
of detection assays in different tissues; difficulty culturing certain microbes; and
the lack of adequate methods to identify novel or rare microbes, viruses, and other
pathogens. Equally complex is balancing investment in potential infectious causes
of multifactorial, high burden diseases with that for rarer conditions that may have
one primary cause, infection.
Participants noted that recently developed molecular and immunologic techniques (e.g.,
representational difference analysis, gene-chip profiling of host and microbe, immune
response profiling, proteomics) offer new ways to overcome several obstacles to identifying
potential etiologic agents. However, continued investment in new technologies or improving
existing methods remains key to overcoming challenges. Defining the temporal relationship
between infection and chronic disease with appropriate technology is critical to translating
science into effective clinical strategies that intervene against infection to prevent
or minimize chronic disease.
Discussion further emphasized that scientifically sound, new technologies must be
applied to and guided by a foundation of epidemiologic clues from well-designed studies
and surveillance systems. A multipronged approach will be critical. Research and public
health activities need to facilitate appropriate linkage of existing and newly designed
databases, ensuring quality surveillance and epidemiology that better characterize
infectious and chronic diseases with their distributions and potential associations.
Many settings demand longitudinal investigations to complement case-control or cross-sectional
studies, requiring longer term investment. Detecting and confirming causal associations
will require study of both larger cohorts and at-risk subpopulations.
Improved coordination between basic and clinical scientists, pathologists, and epidemiologists
is critical to these goals. Networks and collaborative teams are needed to develop
and demand the necessary standardized case definitions (for the infection and the
chronic outcome), new and adequate specimen collections with pedigree databases, and
comparable methods of analysis. Overall discussions emphasized two major themes of
the workshop: 1) the need to define the nature and scope of future research that balances
global efforts among the various chronic syndromes and 2) development of a coordinated
and systematic strategy to maximize resource use and overcome the inherent technologic,
epidemiologic, and organizational challenges in this field.
A published summary of the workshop that includes individually authored papers by
workshop presenters will be available in early 2003 from the National Academy Press
(available from: URL: www.nap.edu or 800-624-6242). Additional information about the
activities of the Forum on Emerging Infections can be found at URL: http://www.iom.edu
under the Board on Global on Health or by contacting 202-334-3992.