Emerging Infectious Determinants of Chronic Diseases

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

Disclosures

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

In This Article

Breadth of the Field

A broad spectrum of infectious agents and their chronic outcomes compose this evolving field. Every organ system or tissue has been a target. Bacteria, fungi, parasites, viruses, and the recently discovered prions are all implicated, and as yet unidentified etiologic agents will likely be described over the coming years (Figure 2).

Figure 2.

Infectious determinants of chronic diseases.

Already established causal associations prove that certain infectious agents evoke only 1 type of chronic pathology (e.g., poliovirus-induced persistent flaccid paralysis). Yet single agents can also produce multiple distinct syndromes in different organ systems. HBV-associated CLD, HCC, and polyarteritis nodosa, as well as HCV-associated CLD, HCC, mixed cryoglobulinemia, and arthropathy demonstrate this phenomenon (http://www.cdc.gov/ncidod/diseases/hepatitis).[13,23,25,26] So do 3 very different outcomes of human T-cell lymphotropic virus type 1 (HTLV-1) infection: acute T-leukemia/lymphoma, tropical spastic paraparesis/HTLV-1—associated myelopathy, and chronic arthropathy.[27,28] On the other hand, disparate infections sometimes lead to 1 common chronic clinical syndrome, likely through converging pathogenic mechanisms (e.g., chronic HBV and HCV-related CLD or HCC; reactive arthritis following Salmonella, Shigella, Klebsiella, or Chlamydia trachomatis infections).[21,23,25,26,29]

A person's age at the time of infection—from intrauterine or perinatal, through childhood and adolescence, to adulthood and the elder years—may further influence the risk for chronic outcome. For example, perinatal HBV infection dramatically increases the risk of developing adult or pediatric CLD with or without HCC[11,12,13,30] (http://www.cdc.gov/ncidod/diseases/hepatitis). Recurrent infections or perhaps serial infections with certain agents might also determine a person's risk for chronic outcome.

Currently, the strength of causal evidence ranges from confirmed to speculative. Reproducible epidemiologic and laboratory data unambiguously establish that certain infectious agents directly lead to 1 or more distinct chronic outcome, globally or in unique populations. Animal models often illustrate the plausibility of human pathogenesis. Sometimes clinical trials and surveillance further demonstrate that preventing or treating the culprit infection(s) avoids or eliminates the long-term sequelae. Consider HBV-associated CLD. Sound scientific evidence now confirms that immunization and behavioral interventions prevent CLD and HCC by preventing infection and transmission (http://www.cdc.gov/ncidod/diseases/hepatitis).[11,12,13] Similarly, appropriate antimicrobial drug therapy can eliminate group A Streptococcus infections before rheumatic valvular disease develops and cure H. pylori—associated chronic gastritis and peptic ulcer disease.[7,9,10] Unfortunately, the translation of infectious disease knowledge into programs that minimize pathology and the human suffering produced by chronic disease often lags, even when all evidence supports causality.

At the opposite end of the evidence spectrum, only preliminary or inconclusive findings, conflicting or inconsistent data, case series or small studies, anecdotal reports, or unreproduced single-source data support certain hypotheses. A lack of sensitive or specific detection assays, analyses that target the wrong tissue, or investigations that seek infectious agents too long after the initial infection might explain such observations. Suboptimal study designs also hamper the ability to reproduce or compare research results and to correctly infer causality. For example, if investigations examine only persons at low risk, only those at high risk, too few exposed or at-risk persons, or too many people not even at risk for the chronic outcome, then positive or negative findings can produce faulty conclusions. Studies lacking appropriate controls also convey uninterpretable results. On the other hand, evidence for or against an infectious etiology of chronic disease can change over time, influenced by new and sometimes contradictory findings, improved detection tools, and data interpretation. Onchocerciasis is an intriguing example of this fluidity. Infection with the filarial parasite Onchocerca volvulus is the long-established cause of river blindness. Recent evidence, however, suggests that the Onchocerca endosymbiont bacterium, Wolbachia wuchereria, may stimulate the pathogenic inflammation responsible for this tragic, preventable lifelong disability.[31] If so, could Wolbachia also influence in whom W. bancrofti—associated lymphatic filariasis develops, potentially opening new therapeutic avenues to prevent this major cause of global disability?[32]

Despite the challenges, researchers continue to pursue elusive but plausible infectious agent origins of chronic syndromes such as systemic lupus erythematosus, rheumatoid arthritis and other inflammatory arthritides, Crohn disease, type 1 diabetes, multiple sclerosis, neuropsychiatric and developmental disorders, leukemias and lymphomas, and other malignancies.[33,34,35,36,37,38,39,40,41,42,43,44] In concert, previously unrecognized long-term effects of known infectious agents continue to emerge.

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