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

Infectious Disease-Chronic Disease Connections

For centuries, physicians and scientists hypothesized that infection might explain some chronic syndromes. Proof, however, lagged behind speculation. A paucity of tools to detect many agents and the challenges of linking past infection—sometimes decades in the past—with present chronic illness perpetuated the idea that most infectious diseases are acute illnesses, and that chronic diseases have noninfectious causes. By the latter third of the 20th century, however, exceptions to this dogma began to emerge. For example, hepatitis B virus (HBV) infection came to explain a large proportion of chronic liver disease (CLD) and hepatocellular carcinoma (HCC) in areas of endemic infection[8] (http://www.cdc.gov/ncidod/diseases/hepatitis). However, it was the discovery that Helicobacter pylori can induce gastric inflammation that truly transformed conventional thinking about the noncommunicable nature of many chronic conditions;[9] in recognition of this groundbreaking achievement, Marshall and Warren were awarded the Nobel Prize in Physiology or Medicine 2005. Researchers have subsequently demonstrated that eradication of H. pylori can cure most cases of peptic ulcer disease, a chronic condition long attributed to noninfectious factors such as stress, diet, smoking, and family history.[7,9,10] Today, scientists and physicians widely recognize the plausibility of infectious agent origins for chronic diseases.

The causal relationships fall into 3 basic categories.  First, an infectious agent produces chronic illness or long-term disability through progressive tissue pathology or organ decompensation (e.g., HBV-associated CLD and HCC), attributable to direct effects of persistent infection (e.g., transformation of host cells, tissue invasion); or) immune response to the persistent infectious agent; or ongoing immune response after the infectious agent(s) is cleared. Second, the initial stages of infection cause permanent, lifelong deficits or disability (e.g., poliovirus-induced permanent paralysis). Third, infection indirectly predisposes a person to chronic sequelae (e.g., maternal infection during pregnancy leads to preterm delivery that, with or without infection of the infant, increases the child's risk for chronic neurologic and pulmonary deficits). Together, these diverse relationships create a cascade of opportunities to reduce the impact of chronic disease by interrupting infection before the outcome is irreversible.

Stimulated by changing scientific perceptions, the advent of polymerase chain reaction (PCR) and other molecular techniques, and advances in immunology and culture methods, a succession of discoveries from 1975 to 1995 greatly expanded the number of recognized infectious determinants of chronic diseases (Figure 1). We now know that HBV and hepatitis C virus (HCV) infections account for most CLD and HCC cases worldwide.[8] In fact, HCC was the first recognized vaccine-preventable cancer (through HBV immunization). Blood donor screening, along with programs to prevent HBV and HCV transmission, now further reduces the risk for CLD and HCC (http://www.cdc.gov/ncidod/diseases/hepatitis).[11,12,13]

Figure 1.

Emergence timeline for infectious determinants of chronic diseases. For references to support this figure, see online version (available from http://www.cdc.gov/ncidod/EID/vol12no07/06-0037-G1.htm)

Today, immunization against human papillomavirus (HPV) promises to make cervical cancer—the second leading cause of cancer mortality in women worldwide—the next vaccine-preventable malignancy.[3] Until now, cervical cancer prevention has hinged on early detection and ablation of precancerous and malignant lesions through lifelong Papanicolaou cervical smear screening of all women. While successful where economically feasible, this strategy does not address the infectious etiology of cervical cancer; studies associate HPV with 90% to 99.7% of malignant lesions (high-risk viral subtypes HPV-16 and HPV-18 with 65% to 70% of lesions), and HPV-induced oncoproteins are implicated in the pathway from infection to malignancy.[14,15]

Microbes also cause nonmalignant chronic diseases. For example, Borrelia burgdorferi infections can result in chronic Lyme arthritis. In the absence of that discovery, an infectious portion of chronic inflammatory arthritis might still be categorized as a noninfectious autoimmune syndrome; B. burgdorferi and B. garinii infections also induce the chronic central nervous system manifestations of neuroborreliosis.[16,17] These examples illustrate only a few of the numerous causal associations identified over the past 50 years; yet even they forecast the possibility that many other chronic conditions await the identification of infectious determinants.

Although the pace of discoveries has slowed over the past decade, at least 13 of the ≈39 most recently described infectious agents induce at least 1 distinct chronic syndrome.[1,13,16,18,19,20] Most recently, a poliomyelitislike paralysis following West Nile virus infection expanded the list.[20] With ample precedent, researchers, clinicians, and veterinarians can anticipate that infectious determinants of chronic diseases will continue to emerge.

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