The arrested immunity hypothesis and the epidemiology of chlamydia control.

Case detection, antimicrobial treatment, and contact tracing are at the heart of control strategies for many important communicable bacterial diseases. Together with behavioral messages regarding safe sexuality, these have been the approaches taken in several countries to control sexually transmitted Chlamydia trachomatis.1 Advances in nucleic acid amplification tests (NAATs) and singledose azithromycin treatment make chlamydia an imminently feasible target for control. Chlamydia infection impacts reproductive health primarily for women, and control using these tools significantly reduced the reproductive impact of untreated infection in a prospective trial.2 The goal of chlamydia control has been to improve the reproductive health of women by interrupting transmission through shortening the duration of infection.3 Thus several national and regional chlamydia control programs were launched in the late 1980s and throughout the 1990s. We are now approaching 20 years of experience with chlamydia control programs, and at least 5 trends in chlamydia epidemiology are emerging. The first of these trends includes the development of 2 distinct epidemiologic profiles of reported case rates (as a measure of population based annual incidence) following the introduction of control programs. In Sweden, Norway, Finland, and Canada, case rates declined for a decade following program introduction but then have steadily increased from the midto late 1990s. In Australia, the United States, and the United Kingdom, case rates steadily increased following program rollout without an initial decline phase.4–6 It is not established what caused these 2 distinct epidemiologic response profiles, but it could reflect differences in populationwide versus incremental introduction of control activities. Second, increase in reinfection rates has paralleled increases in case rates. In British Columbia, Canada, reinfections now account for 14% of annual reported cases, with most reinfections ( 90%) occurring within the first year after initial infection.7 Third, reproductive sequelae rates (ectopic pregnancy and tubal infertility) have declined in jurisdictions where they have been measured. Again, in British Columbia, 40–60% declines in ectopic pregnancy and tubal infertility rates have been recorded during the era of chlamydia control.8 Fourth, in Sweden, case detection based on NAATs has been sufficiently intense to select for the emergence of a single novel genetic variant of C. trachomatis. This clone emerged in as little as 2–4 years and is able to escape conventional NAAT detection in such a manner that it now accounts for 20– 65% of all chlamydia strains identified in selected Swedish counties.9 The usual evolutionary response of a pathogen to “test and treat” public health programs has been to acquire antimicrobial resistance, often though lateral gene transfer. Thus it may be of fundamental biologic interest that the evolutionary response of chlamydia has been to acquire genetic escape not from the drug treatment but from the detection method itself. And fifth, A.M. Jolly and colleagues sampled the case-contact network structure at 3 distinct time intervals during the era of chlamydia control in Manitoba and demonstrated a remarkable reduction in the size of the largest sexual networks during the control era (A.M. Jolly, personal communication). Shrinkage in size of the giant component of sexual networks might have been expected to result in increased control, but this has not been the experience in Manitoba where case rates continue to rise.10 In British Columbia, Canada, where the epidemiology of chlamydia control has been analyzed in greatest detail, we have suggested that raising case rates are due to early treatment interfering with the development of protective immune responses.7 We have termed this the arrested immunity hypothesis. Because both the development of protective immune responses and the tissue damaging effects of infection appear to depend on the duration of infection, and because early detection and treatment would be expected to reduce infection duration, this hypothesis can explain both the raising case rates and the declining sequelae rates. A prediction of the arrested immunity hypothesis was that one would expect chlamydia antibody seroprevalence rates to fall while chlamydia case rates rise in the face of control efforts. Remarkably, this is precisely what has been observed in Finland and recently reported at the International Society for STD Research by Jorma Correspondence: Robert C. Brunham, MD, Department of Medicine, The University of British Columbia, Vancouver BC, Canada. E-mail: robert.brunham@bccdc.ca. Received for publication September 19, 2007, and accepted October 12, 2007. From *British Columbia Centre for Disease Control; and †Department of Medicine, The University of British Columbia, Vancouver BC, Canada Sexually Transmitted Diseases, January 2008, Vol. 35, No. 1, p.53–54 DOI: 10.1097/OLQ.0b013e31815e41a3 Copyright © 2007, American Sexually Transmitted Diseases Association All rights reserved.