Are we losing ground in our efforts to control sexually transmitted Chlamydia trachomatis infection?
Before we can answer this question, we must first consider recent trends in Chlamydia from around the world to establish a baseline for understanding the possible explanations underlying these data.
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Most developed countries base their surveillance of genital Chlamydia trachomatis infection on the tracking of case reports often after making Chlamydia a legally reportable disease. Fortunately, the definition of a Chlamydia case is relatively uniform across jurisdictions. In the province of British Columbia (BC), Canada, Chlamydia case reports have increased steadily from 1997 until the present after a steady decline beginning in 1991.1 The recent upward trend occurred despite enhanced Chlamydia control efforts that included making sexually transmitted Chlamydia a legally reportable disease in 1994, distributing free-of-charge azithromycin as single dose treatment for Chlamydia since 1996 and implementing a province-wide, centrally funded Chlamydia contact tracing programme in 1997. From 1985–2005, Sweden witnessed a very similar trend of decreasing cases followed by increasing cases in the face of enhanced awareness and control efforts (fig 1).2 3 This downward-upward pattern has also been reported from Norway and Finland4 whereas the USA, the UK and Australia witnessed steady increases throughout the last decade.5–7 For developing countries, the World Health Organization (WHO) has estimated that incident Chlamydia infections in adults increased from 1995 to 1999 in all regions with the exception of Latin America and the Caribbean.8
HYPOTHESES FOR INCREASING CHLAMYDIA RATES
Seven hypotheses can be conceptualised as explaining these recent increasing Chlamydia trends (fig 2). None of the hypotheses are mutually exclusive and several are likely to be simultaneously operative. The first four hypotheses are rooted in new testing technologies, primarily nucleic acid amplification testing (NAAT), which is highly sensitive and can be performed on urine, and female self-collected specimens, which are more acceptable to groups at increased risk such as youth. Hypotheses II–IV are based on improved case finding whereas hypotheses V–VII are based on increased prevalence and incidence. The hypotheses based on new testing technologies can be stated as follows:
III. NAAT testing of urine is more acceptable, especially for men, leading to higher testing rates;11 and
There is good evidence in the peer-reviewed literature to support a possible role for each one of these hypotheses.3 9–13 Higher testing volume with no significant increase in test per cent positivity could result in higher Chlamydia case rates; however, higher testing rates are sometimes associated with increasing positivity rates suggesting that other factors are at play.3 11 14 As well, many Chlamydia rate increases began before and continued after a switch to NAAT and female self-collection has not yet been implemented widely enough to affect population-based Chlamydia rates in most jurisdictions. Thus, new testing technologies cannot be the sole explanation for increasing Chlamydia case rates.
The next hypotheses are based on true increasing incidence and prevalence. Hypothesis V states that decreasing Chlamydia antimicrobial susceptibility is resulting in higher prevalence and higher incidence because of treatment failure. Although decreased antimicrobial susceptibility is indeed an important issue with gonorrhoea and syphilis, there have been no major reports of Chlamydia antibiotic resistance from the laboratory or of treatment failures from the field. In BC, apparent Chlamydia treatment failures occur about twice a year and are usually associated with azithromycin rather than doxycycline. Hypothesis VI states that increasing high risk sexual behaviour is resulting in an increase in incidence and prevalence. The evidence for this is mixed. Increasing Chlamydia cases in some jurisdictions have been recorded together with increases in high risk sexual behaviour and/or increases in HIV and/or other sexually transmitted infections (STIs) such as gonorrhoea and syphilis. Chlamydia increases in other jurisdictions have been reported independent of increases in risky sexual behaviour, HIV or other STIs.3 15
Hypothesis VII is termed the arrested immunity hypothesis and is based on increasing incidence and prevalence subsequent to declining immunity. This hypothesis specifically posits that :
“Early, expanded treatment interrupts the natural immune response enhancing population susceptibility to infection as susceptible patients re-enter the same sexual networks.”1
In other words, when we treat Chlamydia early we reduce the body’s ability to fully respond immunologically and this increases the likelihood of reinfection upon re-exposure. This is most important for patients who return to the same or similar sexual networks with the same or similar sexual risk patterns, as is often the case. There are five lines of evidence that support this intriguing proposition.
First, there are clear indications that the normal host immune response to Chlamydia stimulates protective immunity over time. Strong evidence that the host can clear Chlamydia on its own can be found in an interesting nested, case-controlled study from Colombia, which was originally designed to delineate the natural history of human papillomavirus (HPV) infection in females. The authors retrospectively identified 82 women who (1) had a positive Chlamydia test by PCR on cervical scraping at enrolment, (2) had normal cervical cytology, (3) returned for follow-up testing and questioning every 6–8 months for 4 years; and (4) had not taken antibiotics.16 Within this nested cohort, 90% of women cleared their Chlamydia infection within 3 years.
Additionally, young age is the most consistent risk factor in the peer-reviewed literature for acquisition of sexually transmitted Chlamydia,17 18 suggesting an acquired, protective, immune response. This is illustrated in a study from Hawaii where free and confidential Chlamydia screening and treatment are available at multiple public and private sites for anyone 14 years of age or older without parental consent or notification. In 2001, the results of 20 222 Chlamydia screening tests showed a highly significant association between test positivity and young age (p<0.0001 for linear trend).19 In that same year, the US Youth Risk Behavioral Survey results for Hawaii showed an increasing trend of sexual activity with age from 20% of ninth graders to 50% of high school seniors.19 Such studies when considered together demonstrate increasing age to be associated with increasing sexual activity but decreasing Chlamydia infection rates. This strongly implies that host immunity is at work.
Further support for the interpretation that declining Chlamydia rates with increasing age is due to acquisition of immunity rather than changes in sexual risk behaviour comes from a recently published, randomised controlled trial involving Madagascar sex workers where sexual risk behaviours are similar across different age classes. Chlamydia prevalence at baseline and Chlamydia incidence at 6, 12 and 18 months were significantly higher in 16–19 versus 20–64 year old sex workers.20 The risk ratio of incident Chlamydia infection at 6 months, adjusted for sexual behaviour, was 1.72 (95% confidence interval (CI) 1.35, 2.19) for the younger cohort. However, this analysis did not control for the fact that the younger cohort was more likely to have been beaten or raped and the older cohort may have been more expert at proper condom usage. The evidence for immunity is strengthened by the finding that increasing years of sex work is protective against Chlamydia infection.21 If natural immunity plays an important role, one would expect immune compromise (for instance, HIV infection) to increase susceptibility to Chlamydia acquisition and, indeed, this has been demonstrated among Nairobi sex workers,21 although the increased Chlamydia risk with HIV infection was not related to the absolute CD4 lymphocyte count. This finding together with an enhanced risk during the sero-converting phase of HIV infection (before absolute CD4 counts are affected) suggests that the defect in host defences may relate to a defect in memory CD4 lymphocyte function. Finally, youth is an independent predictor of the bacterial load for Chlamydia shedding from the cervix.22
A second line of evidence supporting arrested immunity lays in the correlation between increasing Chlamydia rates overall and increasing Chlamydia reinfection rates. In BC, an in-depth examination of annual Chlamydia reinfection cases versus single infection cases demonstrated that the risk of reinfection increased by 4.64% per year (95% CI 3.27%, 6.03%) from 1996 to 2003.1 This relative risk was maintained across a variety of definitions of reinfection and there was no change in follow-up testing recommendations or practices for those diagnosed with Chlamydia over this same period. Third, there is evidence that arrested immunity may be operative in trachoma—a chronic follicular kerato-conjunctivitis caused by the non-genital C trachomatis serotypes A, B, Ba and C. Trachoma causes 15% of all cases of blindness in the world. A study published in 2006 compared the trachoma reinfection rates in three Vietnamese communes that employed differing trachoma control strategies. The commune that used surgery alone had a significantly lower reinfection rate at 36 months than either the commune that used surgery and antibiotics (azithromycin) (odds ratio (OR) 4.2, 95% CI 1.1 to 17.3) or the commune that used the full WHO recommended SAFE regimen (surgery, antibiotics, facial cleanliness and environmental improvement) (OR 4.1, 95% CI 1.5 to 9.8).23
The fourth line of evidence comes from the murine model of Chlamydia genital infection. When mice are infected with C muridarum, the resultant titres of Chlamydia-specific IgG are highest in untreated mice and lowest in mice treated early.24 When similarly antibiotic treated or control mice are re-challenged later, the untreated mice shed the least number of infectious Chlamydia organisms cervico-vaginally whereas the mice treated early shed the most.24
The fifth and final argument in support of arrested immunity involves Chlamydia complications—pelvic inflammatory disease (PID), ectopic pregnancy and tubal factor infertility. Despite rising measured rates of Chlamydia cases, these complications of Chlamydia have been declining in many jurisdictions, including British Columbia, San Francisco County25 and Norway.26 To reconcile this apparent paradoxical situation, one needs to recall the two principal hypotheses of the pathophysiology of Chlamydia disease pathogenesis. The first hypothesis asserts that a host response to Chlamydia PID that involves a progression from an initial Th1 immune response (inflammation, cytokine release and fibrosis) through resolution of the infection to repeated infection ultimately generates damaging tissue fibrosis leading finally to tubal occlusion.27 28 Tubal occlusion can occur after one episode of PID as well. An alternate hypothesis of disease pathogenesis predicts that an immune response to Chlamydia PID is host-determined, sometimes following the path already described but at other times leading to a persistent infection, which causes an ongoing, cyclic immune response and ultimately tissue damage and fibrosis. The early, expanded treatment inherent in the arrested immunity hypothesis has the potential to interrupt this latter causal pathway involving persistent infection thereby leading to an overall reduction in complications. In this way, declining Chlamydia complications in the face of increasing Chlamydia case rates lends support to arrested immunity. However, if Chlamydia complications reflect a balance between those related to reinfections and those related to persistent infections, then the tendency of arrested immunity to increase reinfections could eventually lead to a nadir in complications perhaps followed by a reversal in trends.
The determination of Chlamydia case rates can be visualised on a continuum of susceptibility, infection, detection and immunity (fig 3). Each of the seven hypotheses we have described has a place in this cycle. The likelihood of persons moving from the susceptible state to the infected state is greater with higher risk sexual behaviour (hypothesis VI). The rate of detection of Chlamydia infection is affected by testing strategies and technologies (hypotheses I–IV). Once detected, the effectiveness and the timing of treatment may influence prevalence and the immune state (hypothesis V). And finally, the strength and completeness of the immune response determine susceptibility to reinfection (hypothesis VII).
Likewise, when public health officials are faced with evaluating the possible reasons for changing Chlamydia trends, especially increasing trends, all of the hypotheses discussed here need to be considered. Clearly, the Chlamydia testing technology can affect positive test and detection rates. When switching from culture to NAAT testing, false positive tests can be a problem, especially in low risk populations (that is, hypothesis I). This compromises the predictive value of a positive NAAT test and provides a rationale for confirmatory testing if the prevalence in the testing population is much below 3%, especially for individual clients whose history and/or clinical picture is not consistent with Chlamydia. Switching to NAAT from any non-NAAT test can result in a jump in test per cent positivity as high as 15–20% (that is, hypothesis II). These additional positive tests are true infections. Changes in specificity and sensitivity occur only at the point in time when the test changeover takes place within the laboratory. A recent report elegantly illustrates this one-time only phenomenon. On 2 September 1998, the Lothian Health Board (LHB) Laboratory, which performs all Chlamydia testing for the only LHB Genitourinary Medicine (GUM) Clinic, switched completely from Chlamydia culture to NAAT testing. There was a statistically significant, one-time increase in test positivity of 59% (95% CI 52%, 76%).11 However, all laboratories within the same jurisdiction do not usually switch at exactly the same time.
Changes to the uptake of Chlamydia testing and to the testing strategy can also affect rates. The implementation of NAAT testing for Chlamydia consistently leads to increases in testing volumes, for both males and females, because of the ease of urine collection compared to urethral and cervical sampling (that is, hypothesis III). If test per cent positivity increases, remains the same or decreases only slightly, the higher numbers of Chlamydia tests performed will generate higher numbers of Chlamydia diagnoses and more case reports. This effect may continue over an extended period. NAAT urine testing and female self-collected specimens can facilitate case finding and targeted screening among persons at high risk (that is, hypothesis IV). This effect is only beginning and the potential impact may be seen in two recent reports. In the first study, women entering jails in Chicago, Illinois, Birmingham, Alabama, and Baltimore, Maryland, were offered urine screening for Chlamydia and gonorrhoea. Over 90% (n = 5480) agreed to submit a urine specimen, 665 new Chlamydia or gonorrhoea diagnoses were made and 74% received documented treatment. The period covered was less than 1 year and no testing had been offered in prior years.13 In the second study, high school girls attending a school health clinic in Pittsburgh, Pennsylvania, were offered self-collected vaginal specimen testing for C trachomatis, Neisseria gonorrhoeae and Trichomonas vaginalis. Overall, 75% (n = 228) agreed and 18% had one or more positive tests: trichomonas 10%, Chlamydia 8% and gonorrhoea 2%. Of these youth, 13% had never had a gynaecological examination and 51% said they would not have pursued testing by traditional gynaecological examination if self-collection was not offered.12
Although there is currently no evidence of increasing antibiotic resistance for C trachomatis (that is, hypothesis V), this statement needs to be tempered by the fact that very few laboratories monitor Chlamydia antimicrobial susceptibility and by the caution that Chlamydia treatment failures may be asymptomatic and go unnoticed since routine post-treatment testing is not recommended. In fact, C suis, a porcine pathogen, was recently identified as tetracycline resistant due to the chromosomal insertion of the tet(C) resistance gene apparently acquired through horizontal gene transfer.29 This observation sets precedence for its possible occurrence in C trachomatis. Because sexual behaviour is difficult to monitor on a continuous basis and usually relies on self-report, delineating the influence of changes in sexual behaviour on Chlamydia case rates (that is, hypothesis VI) will often be problematic. Surrogate markers such as HIV, gonorrhoea, syphilis and herpes can be helpful in this regard but these conditions have their own distinct epidemiological, diagnostic and management characteristics. Some have argued that the decline in Chlamydia cases in the early 1990s was because of HIV awareness and prevention campaigns and that the climbing rates after that represent a return to a more “normal” pattern of sexual behaviour;2 but because the decline phase has not occurred uniformly across all jurisdictions that have rolled out Chlamydia control programmes, this seems unlikely to be the case in all instances.
The concept of arrested immunity (that is, hypothesis VII) remains unproven and its possible impact on Chlamydia rates remains undefined. However, a recent report from Finland has shown a significant decline in Chlamydia-specific IgG titres in a stratified random cohort of 8000 women with a minimum of two serum samples from consecutive pregnancies from 1983 through 2003.30 This 50% decline in Chlamydia sero-prevalence occurred in the face of a 60% increase in Chlamydia cases in Finland from 1995 to 2005. The authors state that “… early detection and treatment might lead to poor humoural antibody responses …”. Cell-mediated immunity (CMI) plays an important role in the host response to Chlamydia but the affect of early, expanded, treatment on CMI has not been delineated. Efforts to contain outbreaks of infectious syphilis, which is known to stimulate effective immunity,31 provide indirect support for hypothesis VII. Early, expanded, treatment for syphilis in the form of azithromycin mass treatment of 4384 persons at risk in BC resulted in a rebound in syphilis cases,32 which, by mathematical modelling, was consistent with an altered immune response.33 As well, the decade-long syphilis outbreak in BC has involved an increasing proportion of reinfections.34 There are good reasons to continue to diagnose and treat incident Chlamydia infections even if it does interrupt the host immune response. These include reducing Chlamydia and gonorrhoea morbidity and complications, reducing HIV spread by eliminating the enhanced risk of HIV transmission in the presence of Chlamydia and gonorrhoea, and preventing Chlamydia secondary transmission at the individual level.
In conclusion, let us return to the original debate question: are we losing ground in our efforts to control sexually transmitted C trachomatis infection? The authors come down clearly on the No side of this debate question. We are not losing ground because we are achieving the primary objective of Chlamydia control: to improve reproductive health. The authors also assert that the long term goal of prevention of Chlamydia will require the development of a vaccine and that C trachomatis immuno-epidemiology has emerged as an urgent research priority.35
Chlamydia case reports are increasing globally despite higher levels of awareness and improved prevention and control efforts.
Within the two general categories of changes in testing technologies and increasing incidence/prevalence, there are seven plausible hypotheses for higher Chlamydia case rates. Jurisdictions need to examine the possible role of each of these to understand their local situation.
The arrested immunity hypothesis posits that early expanded treatment interrupts the natural immune response enhancing population susceptibility to infection as susceptible patients re-enter the same sexual networks.
We are not losing ground in the epidemiology of Chlamydial infection because we are achieving the primary objective of Chlamydia control to improve reproductive health. The long term goal of prevention of Chlamydia will require the development of a vaccine and C trachomatis immuno-epidemiology has emerged as an urgent research priority.
Competing interests: None.
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