Over time, particularly in high-income countries, discussions about CT control have come to focus more on widescale testing for asymptomatic CT [
10], and routine urogenital CT testing is advocated in young women and in most guidelines for MSM [
6‐
9]. This prevailing view is primarily based on the arguments that (1.1) ‘in women, urogenital CT is prevalent, easily transmitted, and may cause complications’; and (1.2) ‘with resources available, CT is simple to test and treat in women and MSM’. In 2017, Unemo et al. [
10] set the stage for rethinking the testing of asymptomatic persons. With regard to the CT control cascade, challenges were identified, including setting realistic targets for the achievable benefits of test-and-treat strategies, and pleas were made to focus more on monitoring health outcomes and preventing complications, such as PID in women (rather than preventing infections), with a focus on improving case management for the patient and his/her sex partners (CT control activity level ii). In line with these ideas, a narrative review [
11] expressed concerns on the widescale testing of asymptomatic women and MSM based on the arguments that (1.3) ‘test implementation in “real-life” does not achieve the desired benefits’ and (1.4) ‘testing may also bring harm’.
In women, urogenital CT is prevalent, easily transmitted, and may cause complications.
Prevalence in women The prevalence of urogenital CT in women worldwide was estimated to be approximately 3% in two meta-analyses [
12,
13]. Prevalence estimates (range: 0.2–12.2%) vary substantially by geography on both the large-spatial scale and the smaller local scale [
12,
13], reflecting the relatively high impacts of several social determinants of health such as socioeconomics, demographic characteristics, social vulnerability, and access to care. Chlamydia testing positivity is higher at venues such as STI clinics, emergency departments, youth homeless shelters, and among populations historically disadvantaged by structural and persistent racism. It should be noted that positivity in tested populations does not directly reflect population prevalence [
14].
Bacterial load The CT bacterial load may differ between tested populations, possibly reflecting different periods of having an infection before being tested [
15,
16]. In Dutch CT-infected women, primary care patients had a higher mean urogenital CT load than STI clinic patients, while hospital (e.g. gynaecology) or community-based tested patients had lower mean load [
15,
16]. Data in women in a US study [
17] and laboratory registry data in men and women in a Dutch study [
18] and in Australian women [
19] showed that urogenital CT load was lower in repeat infections than in initial CT infections. Proposed hypotheses for this phenomenon [
20] include that past infection may confer some protective immunity and impacts on organism replication (but not chlamydial entry), or that initial CT infection in tested populations may represent a biased sample of higher load infections that have not cleared (as lower load infections clear more quickly). Large-scale epidemiological evaluations of CT load have become feasible by using the cycle quantification value of the NAAT test as a proxy as a practical method aiding in CT epidemiology. Various other, more laborious methods have been used, and a review revealed 14 different methods in 28 studies, severely hampering comparison, and calling for the standardization of load measurement and reporting [
21]. It is of interest to learn about associated factors for CT load, but only a few factors (e.g. young age) were observed in men and women [
16,
17,
20,
21].
Spontaneous clearance in women Most asymptomatic CT infections will resolve spontaneously if not treated, and the median time to natural clearance for urogenital CT is approximately one year [
22,
23]. The spontaneous clearance of urogenital CT between diagnosis and treatment (9–10 days) was 6–9% in large-scale evaluations of urine samples and vaginal swabs, and was faster with a lower baseline bacterial load [
24,
25]. In women, spontaneous clearance was high (i.e. 32%) when vaginal CT was a single anatomic site infection, possibly indicating low load detections. Between diagnosis and treatment, vaginal CT rarely cleared (2%) when rectal CT was initially diagnosed [
25].
Viability in women A limitation of NAAT is that it cannot distinguish between viable bacteria and non-viable molecular remnants. New assays were recently developed to measure CT viability in clinical samples; that is, via the detection of messenger RNA by digital PCR [
26], and the use of V-PCR by Australian and Dutch laboratories [
27]. These assays are highly sensitive in contrast to cultures, but also laborious and thus applied in research contexts only. The presence of viable organisms does not prove—yet strongly indicates—that the NAAT-detected CT is a ‘true infection’. In nearly all digital PCR/V-PCR tested vaginal samples, viable CT was detected Of CT-DNA-positive vaginal samples, 83% (24/29) had mRNA detected [
26], and 94% (469/499) showed viable CT by V-PCR in a prospective cohort study [
28]. Women had lower viability of vaginal CT (with lower viable load) when they did not have a rectal CT at the same time. Vaginal CT viability was 48% in single-site vaginal CT [
25]. The vaginal viable load (by V-PCR [
27]) was slightly higher with symptoms of altered vaginal discharge, although almost half of the women in the highest viable load quartile did not have symptoms in a prospective cohort study [
28].
Transmission between women and their male sex partners Chlamydia transmits easily. Transmission probabilities were estimated by modelling at 2–15% per sex act in heterosexual, 32–35% per partnership from men to women, and 5–21% from women to men in a UK modelling study [
29]. It is posited that the transmission between partners increases with high organism load, although prospective data are lacking. A US cross-sectional study of heterosexual couples showed that CT-infected women with a CT-positive male partner had a higher median load than women with a CT-negative partner, although causality is unknown [
30].
Transmission between anatomic sites within a woman Transmission occurs between persons and possibly also between the vaginal and rectal sites in women. Evidence for autoinoculation has been provided in a mathematical model in women attending STI clinics, with a daily probability of 0.5–1% that a urogenital infection leads to a rectal infection, or vice versa [
31]. This was also supported by prospective observational data (15–40 two-week follow-up periods) showing that urogenital CT, especially with high load, was strongly predictive of rectal CT acquisition two weeks later without sexual exposure [
32].
Complications in women In women, CT infections can initiate inflammatory and immunological processes leading to several reproductive complications, such as PID, which can lead to chronic abdominal pain, EP, and TFI [
33,
34]. Repeat infection increases the risk of PID [
34]. In a statistical evidence synthesis, the authors estimated that every 1000 CT infections led to 171 episodes of PID, 73 cases of salpingitis, 2 EP, and 5 TFI [
35]. Prospective Dutch data showed a slight delay in time to pregnancy [
36]. Other complications include adverse pregnancy outcomes such as preterm birth, low birthweight, and postpartum infections [
37]. Two meta-analyses confirmed associations with a range of adverse pregnancy outcomes, but also noted the uncertainty of estimated risks due to bias in the design and conduct of studies [
38,
39]. Risks of spontaneous abortion, infertility, and ectopic pregnancy appeared higher in low- and middle-income countries than in high-income countries, with unknown reasons [
38]. Due to bias in study designs, there is uncertainty in causality inferences and uncertainty in estimated risks, also due to different assessments of confounders and outcome definitions [
40]. This makes it very difficult to know the actual risks and preventable fractions.
Urogenital CT in MSM The arguments for testing urogenital CT in clinical and public health practice are mainly based on the epidemiology in women. MSM, in whom urogenital CT testing also is routinely recommended in international guidelines, generally show a lower urogenital CT positivity than women, in studies in tested clinic populations [
41,
42], although prevalence estimates are scarce. Urogenital CT was estimated to be 0.4% in the general MSM population by respondent-driven sampling in Canada [
43]. In tested populations in STI clinics, urogenital CT positivity varies but it is generally lower than that established for rectal CT in MSM (see below). Bacterial load in urine samples was found lower than in vaginal samples but comparisons are hampered due to different sample materials [
16]. Spontaneous clearance data on urogenital CT in men are scarce [
24], though in most mathematical models it was assumed comparable to that of women. Viability data by digital-PCR or V-PCR have not been reported for urogenital CT in MSM. Symptoms of urogenital CT in MSM are uncommon but include urethritis and epididymitis; however, they may also include rare sexually acquired reactive arthritis or perihepatitis.
Test implementation in ‘real-life’ does not achieve the desired benefits
Women Mathematical models confirm that widescale testing of asymptomatic women should be effective to reduce the duration of infectiousness [
55] and CT prevalence [
56‐
58]. However, pragmatic studies indicate that it might be difficult to achieve a reduction in prevalence and in complications. Low test uptake hampered community-based testing in young people in the Dutch Chlamydia Screening Implementation trial and a cluster RCT in Australia [
59,
60]. Sustained uptake of widespread testing was deemed not feasible and unlikely to achieve a sizeable reduction in prevalence. In England, there is an absence of evidence that chlamydia screening has impacted population prevalence [
61], even though the National Chlamydia Screening Programme has resulted in a significant increase in STI testing capacity in England [
61].
Targeted testing involves offering tests to key populations such as high-risk young women, sex workers, or MSM; for example, in general practice or ‘high-risk settings’ such as emergency departments, homeless shelters, and STI or HIV clinics. A meta-analysis reported that community-based testing in general populations may make little-to-no difference for CT transmission and a woman’s risk of PID or EP; evidence on infertility was very uncertain, and no evidence was found for cervicitis or chronic pelvic pain [
4]. Previous studies suggest that screening can reduce PID risk at the individual level [
40,
62]. The meta-analysis concluded that benefits might potentially be achieved for reducing CT transmission and PID by targeted and intense (repeat) testing of high-prevalence key female populations [
4]. Postulated reasons why test-and-treat strategies might not reduce prevalence in 'real-life' include—alongside low test uptake—that treated patients have lower protective immunity [
63], but reasons for the gap between models and practice remain largely unclear.
MSM The available data on the impact of testing on CT prevalence reduction in MSM are sparse. An ecological study among MSM in 23 EU countries showed no evidence that testing diminished prevalence based on 2010 data [
64]. Large online surveys for MSM (EMIS- ‘10/’17) showed a positive association of country-level testing rates and proportions of symptomatic CT [
65]. A review of observational studies in MSM (including 3-month universal testing) did not demonstrate reduced prevalence by test-and-treat strategies [
66]. Postulated reasons in MSM include the influx of new infections by untested/untreated male partners.
Testing may also bring harm
Harm in women and MSM A narrative review stressed that testing may introduce harm that should be carefully weighed against the benefits [
11]. Similar concerns have been raised for pharyngeal and rectal CT testing in an editorial [
67]. Testing may bring about adverse psychological effects. A meta-analysis reported that undergoing testing or having a diagnosis of CT may cause a small-to-moderate number of people to experience some degree of harm (feelings of stigmatization, anxiety about future infertility, intimate partner violence), with most studies in women [
4,
68,
69]. How patients weigh the potential benefits versus the harm of screening was found to be uncertain in this meta-analysis, yet risks to reproductive health (infertility, chronic pelvic pain) and transmission appear to be more important than the (often transient) psychosocial harm involved [
4]. However, it is unknown to what extent women over- (or under-) estimated the actual CT complication risks. Furthermore, harms that were not evaluated in this study were those induced by treatment as compromised microbiome, described in a systematic review and metataxonomic analysis [
70,
71], antimicrobial resistance (AMR) in
Neisseria gonorrhoea (NG),
Mycoplasma genitalium (MG), syphilis, and other pathogenic microorganisms [
72‐
75], as well as a possible arrested immune response [
76]. Further ‘harm’ includes economic individual and health care costs (‘value for money’) and issues related to inequity in health care access.
Benefits versus harms in women and MSM Recognizing potential harm and the need to balance risks and benefits boosts the rethinking about chlamydia control. Such as what realistic and achievable goals one should strive for, with what types of strategies, and how the focus can be shifted more towards disease control (preventing complications), rather than infection control (preventing infections), as historically championed [
10]. Some countries, including low- and middle-income states, are calling for enhanced large-scale CT control, such as targeting socio-spatial high-risk clusters [
77]. Some high-income countries are newly starting to recommend large-scale screening in key populations of women under 30 years of age in primary care [
78]. However, scientists and physicians are increasingly calling to stop attempting to reduce CT population prevalence through the extensive testing and treatment of asymptomatic women and MSM, and to move the paradigm from infection-control (i.e., test-and-treat to reduce the duration of infectiousness to prevent the infection from spreading) to disease-control (i.e., using strategies specifically to prevent complications) [
11,
61], thereby mitigating the harm of test-and-treat strategies.
In line with this thinking, there are attempts to design novel methods for preventing late complications in women by targeting high-risk pathogen and host profiles. In current care, this is complicated because diagnostic tools other than NAAT are unavailable to identify the most ‘infectious’ and ‘pathogenic’ CT, but viability diagnostics may help in the future. To identify those at highest risk of CT, a clear set of risk factors should be used, including PID biomarkers or host immunogenetic factors, which are explored as new avenues for updating existing prediction models for CT-related TFI, as described in narrative reviews [
79,
80]. However, these methods still require testing first.
In current practice, the focus is shifting back toward the patient and their partner (CT control activity levels i and ii), rather than remain on asymptomatic communities/key populations (activity levels iii and iv), as called for in a commissioned review paper [
10] and evidenced in guidelines (e.g. in Australia) to strengthen primary prevention, and to move toward better case management to reduce the risk of reinfection and of PID through partner management, patient delivered partner therapy, and re-testing at 3 months to detect reinfections early [
81]. Case management for women and MSM entails comprehensive sexual health management, history taking, counselling, appropriate diagnostics, clinical examination, clinical care, partner notification, health promotion advice, and follow-ups, and is in combination with primary prevention and surveillance in key populations.