Emerging Infectious Determinants of Chronic Diseases

Siobhán M. O'Connor; Christopher E. Taylor; James M. Hughes


Emerging Infectious Diseases. 2006;12(7):1051-1057. 

In This Article

Reasons for Emergence

Evolving ecology and changing human behavior, such as migration, recreation, work, and culture, influence human exposures to the infectious determinants of chronic as well as acute illnesses.[1,2] Microbial virulence factors, wildlife behavioral traits, zoonotic infections, and the environment all converge to determine both the infectious capacity of potential pathogens and the likelihood of human exposure. Superimposed on human genetics and biology, the milieu shapes individual and population risk profiles for the causal infections agents and their chronic sequelae.[7,14,21]

Over recent years, the powerful tools of molecular biology, particularly PCR, plus advances in immunologic and other techniques, have exposed new causal links by detecting difficult-to-culture and novel agents in chronic disease settings. Microbes can now be irrefutably linked to pathology without meeting Koch's postulates, Hill's epidemiologic criteria, or even the revised criteria of Hill and Evans.[22] For example, applying recombinant immunoscreening for the first time, investigators cloned the previously undescribed agent of most transfusion-associated (non-A, non-B) hepatitis and the cause of a major portion of chronic hepatitis, HCV.[23] Innovative sequence-based analysis (broad-range PCR) and phylogenetic relationships finally identified Tropheryma whipplei as the elusive microbial source of Whipple disease.[19,22] Improved culture techniques subsequently facilitated propagation of the bacterium. Now evidence confirms neurologic and ocular manifestations of this chronic gastrointestinal syndrome. Representational difference analysis identified the viral cause of Kaposi sarcoma (KS) in HIV-positive gay men.[24] Later, researchers also linked the KS-associated herpesvirus to endemic or classic KS in the absence of HIV infection.

Today, technical advances boost the armory of detection tools available to uncover new infectious etiologies of chronic diseases, including the following: broad-range amplification of bacterial ribosomal targets, gene expression arrays (microarrays) that detect microbes or characterize host response to specific agents, degenerate probe screens for families or groups of viruses, mass spectrometry, electron microscopy, enhanced antigen and antibody detection techniques, and growth-promoting factors that improve microbe cultivation.[1] The highly successful sensitivity of these tools, however, can be a double-edged sword. Detecting an infectious agent, its nucleic acid, or other biomarkers of infection in the setting of chronic disease does not prove it caused disease. Neither does the presence of antibodies to pathogens, for immunoglobulin G signifies previous infection but not necessarily causation.[22] This fact is particularly true for ubiquitous infections. For example, chronic Lyme disease, reactive arthritis, CLD or HCC, peptic ulcer disease, cervical cancer, and Chagas cardiomyopathy develop only in some of the many people infected with B. burgdorferi, Chlamydia trachomatis or Salmonella species, HBV or HCV, H. pylori, HPV, and Trypanosoma cruzi. In contrast, the inability to detect an agent in the setting of chronic disease does not rule out infectious etiology. Existing tools and methods may not be sensitive enough to link known agents with chronic disease, or they may be unable to detect as yet uncharacterized novel or emerging microbes. Diagnostic assays might not access intracellular, sequestered, or nonreplicating agents. Testing may occur too long after the exposure, particularly when years of pathology precede diagnosis of the chronic condition, or persistent immune response to an already cleared infectious agent accounts for chronic disease. Studies that focus on the wrong group of people or the wrong tissue cannot support or refute causality. In all these circumstances, a true infectious determinant might remain unidentified.


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