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Problem: Tubal factor infertility (TFI) is a severe complication of genital Chlamydia trachomatis infections. In fertility workup, chlamydia antibody test (CAT) is used to predict TFI. The predictive value for TFI of most commonly used CAT is moderate., Method of Study: A total of 183 infertile Dutch Caucasian women were included in this study. All underwent tubal patency testing (hysterosalpingography [HSG] or laparoscopy). Cases had TFI, and controls had no TFI (ie normal findings during HSG or laparoscopy). TFI was categorized based on severity (TFI 1-TFI 4). This study investigated the predictive values of major outer membrane protein (MOMP), translocated actin-recruiting phosphoprotein (TARP), chlamydial protease-like activity factor (CPAF), heat shock protein-60 (HSP60) and outer membrane protein 2 (OMP2) for TFI. A predictive algorithm is developed to detect TFI with a high certainty based on combinations of antibody titres. Serum was tested with the Mikrogen recomLine immunoblot and quantified with the recomScan. A greedy algorithm that explores all possible antibody combinations was developed., Results: Significant differences in the distributions of antigen titres between cases and controls were observed for CPAF (P = 0.0021), HSP60 (P = 0.0061), MOMP (P = 0.0497) and OMP2 (P = 0.0016). Single antibodies could not discriminate between TFI and controls by themselves. The greedy algorithm performs better in specificity, positive predictive value (PPV), accuracy and clinical utility index than the original Mikrogen algorithm. CPAF combined with HSP60 identified 18.2% of TFI cases with 100% certainty. Most of the TFI 4 cases were identified with cut-offs of CPAF > 10.7 or OMP2 > 3.9., Conclusion: This proof-of-principle study shows that combinations of antibodies in serum are predictive for TFI. A commercially available test can be adapted to predict TFI with a 100% specificity., (© 2019 The Authors. American Journal of Reproductive Immunology Published by John Wiley & Sons Ltd.)

Objectives: Chlamydia trachomatis (CT) IgG serology is used in many fertility clinics in order to estimate the risk for tubal factor infertility (TFI) in the fertility work-up. The predictive value for TFI of the currently used mono-target CT serology test should be improved. This study compares the performance of the new multi-target Mikrogen recomWell CT IgG ELISA with the Mikrogen recomLine CT immunoblot and visualizes distribution of individual antibodies in serum with the immunoblot in order to potentially improve the current CT IgG serology test that is clinically used., Methods: Study population consisted of 183 Dutch Caucasian infertile women who underwent laparoscopy and/or hysterosalpingography. 48 women had TFI, 135 were controls. Serum was tested with Mikrogen CT IgG ELISA, which detects 3 CT IgG antibodies in one well, and Mikrogen CT immunoblot, which can individually detect 5 CT IgG antibodies. Tests were compared based on the results in general and in the case and control group also taking the individual antibodies into account. Sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), Kappa value and distribution of individual antibodies in positive samples were calculated., Results: In 183 patients 51% tested positive in the ELISA versus 35% in the immunoblot. 32% versus 65% tested negative. Difference between PPV was not statistically significant (33% and 39% respectively) and NPV in both tests was 81%. Difference in sensitivity and specificity was statistically significant, respectively 65% vs. 52% and 54% vs. 71%. Kappa was only 45%. 64.5% of samples that tested positive with ELISA were positive for at least 4 individual CT antibodies with the immunoblot., Conclusion: The concordance between CT ELISA and CT immunoblot is moderate. Due to separate criteria for positivity of both tests there is a significant difference in sensitivity and specificity. PPV and NPV, the most relevant characteristics for clinicians, of both tests did not differ significantly. The distribution of individual antibodies and the adjustment of the immunoblot algorithm will be further explored in the future in order to develop a potentially better prediction method for TFI with a higher clinical accuracy., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

There is a need for more accurate Chlamydia trachomatis (CT) IgG antibody tests for tubal factor infertility (TFI) diagnostics. We evaluated the predictive value for TFI of Medac ELISA plus (MOMP) and multitarget Mikrogen ELISA (MOMP-CPAF-TARP). Based on Medac ELISA plus results, 183 subfertile women underwent either hysterosalpingography or laparoscopy to diagnose TFI. TFI was defined as extensive adhesions and/or distal occlusion of at least one tube. Women not fulfilling the definition of TFI served as controls. Serum was subsequently tested with Mikrogen ELISA and results were compared. 48 patients had TFI, 135 were controls. Mikrogen ELISA tested 125 patients positive/borderline of which 32% had TFI. Medac ELISA plus tested 77 patients positive/borderline of which 29.9% had TFI. Mikrogen tested 40 out of 48 TFI patients positive/borderline, Medac 23 out of 48. Kappa value was 0.34. PPV of Mikrogen ELISA and Medac ELISA plus were respectively 32% (95% CI 26%-39%) and 30% (95% CI 24%-37%), and NPV 86% (95% CI 81%-91%) and 76% (95% CI 70%-82%). Both tests were comparable in the prediction of TFI. However, Mikrogen ELISA had a higher NPV and might be more reliable in identifying patients without TFI. Kappa-value showed limited concordance between both tests., (© FEMS 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: This study aims to identify elements perceived by Dutch fertility specialists as barriers and facilitators for the introduction of genetic testing, and their attitudes towards the use of genetic information. The genetic test would be implemented in routine screening for tubal pathology and identifies SNPs relevant for the immune response causing tubal pathology., Methods: Experienced reproductive specialists working in Dutch Academic Hospitals were interviewed. Based on the results of four interviews a questionnaire was developed and used to survey medical doctors in six out of eight Dutch Academic hospitals., Results: 60.4% (n=91) stated that the addition of genetic markers to the Chlamydia trachomatis antibody test (CAT) in screening for tubal pathology would increase screening accuracy. 68.2% (n=90) agreed they would require additional training on clinical genetics. Clinical utility (91.2%, n=91) and cost-effectiveness (95.6%, n=91) were recognized by the respondents as important factors in gaining support for the new screening strategy., Conclusion: In summary, respondents showed a positive attitude towards the implementation of a genetic test combined with CAT for tubal factor infertility (TFI) screening. To gain their support the majority of respondents agreed that clinical utility, specifically cost-effectiveness, is an important factor. Comprehensive research about economic implications and utility regarding the introduction of genomic markers should be the next step in the implementation strategy. Furthermore, education and training would need to be developed and offered to fertility care professionals about genetic markers, their interpretation, and implications for clinical decision-making., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Since Waddlia chondrophila is closely related to Chlamydia trachomatis, we hypothesise that W. chondrophila may also be associated with tubal factor infertility (TFI) in women, a major complication of chronic C. trachomatis infection. Five hundred twenty serum samples were tested for anti-Waddlia antibodies by ELISA. Among the 520 investigated women, a total number of 142 (27.3%) has had laparoscopic diagnosis performed, and were either classified TFI positive or negative. Presence of high titres of W. chondrophila antibodies was linked to TFI (p < 0.0001; OR: 7.5; 95% CI: 3.3-17). Moreover, antibody positivity to both W. chondrophila and C. trachomatis-MOMP was strongly associated with TFI (p < 0.0001; OR: 21; 95% CI: 3.8-12E1). This association was much stronger than the statistical association of C. trachomatis-MOMP antibodies only (p < 0.0001; OR: 7.1; 95% CI: 3.7-14), suggesting that co-infection with W. chondrophila and C. trachomatis may lead to more severe reproductive sequelae and immune responses than single infection with either Chlamydiales members., (Copyright © 2015 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.)

Chlamydia trachomatis (CT) infections in women can result in tubal pathology (TP). Worldwide 10-15% of all couples are subfertile, meaning they did not get pregnant after 1 year. Part of the routine subfertility diagnostics is the Chlamydia Antibody Test (CAT) to decide for laparoscopy or not in order to diagnose TP. The CAT positive and negative predictive value is such that many unneeded laparoscopies are done and many TP cases are missed. Addition of host genetic markers related to infection susceptibility and severity could potentially improve the clinical management of couples who suffer from subfertility. In the present study, the potential translational and clinical value of adding diagnostic host genetic marker profiles on the basis of infection and inflammation to the current clinical management of subfertility was investigated. This review provides an overview of the current state of the art of host genetic markers in relation to CT infection, proposes a new clinical diagnostic approach, and investigates how the Learning-Adapting-Leveling model (LAL, a public health genomic (PHG) model) can be of value and provide insight to see whether these host genetic markers can be translated into public health. This review shows that the preliminary basis of adding host genetic marker profiles to the current diagnostic procedures of subfertility is present but has to be further developed before implementation into health care can be achieved. CT infection is an example in the field of PHG with potential diagnostic to be taken up in the future in the field of subfertility diagnosis with a time line for integration to be dependent on enhanced participation of many stakeholders in the field of PHG which could be advanced through the LAL model., (Copyright © 2013 S. Karger AG, Basel.)

Background: In women, Chlamydia (C.) trachomatis upper genital tract infection can cause distal tubal damage and occlusion, increasing the risk of tubal factor subfertility and ectopic pregnancy. Variations, like single nucleotide polymorphisms (SNPs), in immunologically important host genes are assumed to play a role in the course and outcome of a C. trachomatis infection. We studied whether genetic traits (carrying multiple SNPs in different genes) in the bacterial sensing system are associated with an aberrant immune response and subsequently with tubal pathology following a C. trachomatis infection. The genes studied all encode for pattern recognition receptors (PRRs) involved in sensing bacterial components., Methods: Of 227 subfertile women, serum was available for C. trachomatis IgG antibody testing and genotyping (common versus rare allele) of the PRR genes TLR9, TLR4, CD14 and CARD15/NOD2. In all women, a laparoscopy was performed to assess the grade of tubal pathology. Tubal pathology was defined as extensive peri-adnexal adhesions and/or distal occlusion of at least one tube., Results: Following a C. trachomatis infection (i.e. C. trachomatis IgG positive), subfertile women carrying two or more SNPs in C. trachomatis PRR genes were at increased risk of tubal pathology compared to women carrying less than two SNPs (73% vs 33% risk). The differences were not statistically significant (P = 0.15), but a trend was observed., Conclusion: Carrying multiple SNPs in C. trachomatis PRR genes tends to result in an aberrant immune response and a higher risk of tubal pathology following a C. trachomatis infection. Larger studies are needed to confirm our preliminary findings.

T cell immunity protects against diseases caused by the obligate intracellular bacterium Chlamydia trachomatis. Incidentally, host inflammatory response that includes T cells appears to also contribute to the pathogenesis of chlamydial diseases such as trachoma and tubal factor infertility (TFI). Therefore, designing effective prevention strategies requires a delineation of immune processes responsible for pathology and those mediating immunity, and identification of the immunogenetic factors predisposing to complication development. The chemokine receptor CCR5 is crucial for T cell activation and function since its deficiency causes suppression of T cell response. We investigated the hypothesis that the clearance of genital chlamydial infection in CCR5-deficient mice could be delayed in the short term; however, a beneficial effect could include protection against inflammation-related complications such as TFI. In a translational study in humans, we investigated the effect of a functional 32 bp deletion in the CCR5 gene on the risk of developing tubal pathology in Dutch Caucasian women with immunologic evidence [i.e., immunoglobulin G (IgG) responses] of chlamydial infection. When genitally-infected wild-type (WT) and CCR5 knockout (CCR5KO) mice were evaluated for microbiologic shedding of chlamydiae, there was a greater intensity of infection and delayed resolution in the knockout mice. However, compared to WT mice, the fertility of infected CCR5KO mice (measured by pregnancy rate) was only mildly affected in the short term and unaffected in the long term (70% vs 30% reduction in the short term, and 50 vs 0% in the long term, respectively). Immunobiologic analysis revealed that the diminished capacity of CCR5KO to control acute chlamydial infection correlated with the relatively low chemokine [interferon-inducible protein 10 (IP-10) and regulated upon activation normal cell expressed and secreted (RANTES)] and cytokine (mainly interferon-gamma and tumor necrosis factor-alpha) expression corresponding to a poor early T-helper I response. However, the reduced incidence of complications in the CCR5KO mice appears to correlate with the low activity of long term inflammatory mediators. Besides, the translational studies in humans revealed that among patients with positive anti-chlamydial IgG responses, tubal pathology correlated with a low incidence of CCR5delta32 deletion (7%), while women without tubal pathology had higher incidence of the CCR5delta32 deletion (31%) as compared to controls (19%). Thus, in mice and humans the inflammation associated with CCR5 function may predispose to development of complications of chlamydial infection, such as TFI.