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This study aims to assess the potential association of MBL2 gene single nucleotide polymorphisms (SNPs) to Chlamydia trachomatis infection. We analysed a selected sample of 492 DNA and serum specimens from Dutch Caucasian women. Women were categorized into four groups of infection status based on the results of DNA and antibody tests for C. trachomatis: Ct-DNA+/IgG+, Ct-DNA+/IgG−, Ct-DNA−/IgG+, and Ct-DNA−/IgG−. We compared six MBL2 SNPs (−619G > C (H/L), −290G > C (Y/X), −66C > T (P/Q), +154C > T (A/D), +161A > G (A/B), and +170A > G (A/C)) and their respective haplotypes in relation to these different subgroups. The −619C (L) allele was less present within the Ct-DNA−/IgG+ group compared with the Ct-DNA−/IgG− group (OR = 0.49; 95% CI: 0.28−0.83), while the +170G (C) allele was observed more in the Ct-DNA+/IgG+ group as compared with the Ct-DNA−/IgG− group (OR = 2.4; 95% CI: 1.1−5.4). The HYA/HYA haplotype was more often present in the Ct-DNA−/IgG− group compared with the Ct-DNA+/IgG+ group (OR = 0.37; 95% CI: 0.16−0.87). The +170G (C) allele was associated with increased IgG production (p = 0.048) in C. trachomatis PCR-positive women. This study shows associations for MBL in immune reactions to C. trachomatis. We showed clear associations between MBL2 genotypes, haplotypes, and individuals’ stages of C. trachomatis DNA and IgG positivity.

Background: Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can manifest with varying disease severity and mortality. Genetic predisposition influences the clinical course of infectious diseases. We investigated whether genetic polymorphisms in candidate genes ACE2, TIRAP, and factor X are associated with clinical outcomes in COVID-19., Methods: We conducted a single-centre retrospective cohort study. All patients who visited the emergency department with SARS-CoV-2 infection proven by polymerase chain reaction were included. Single nucleotide polymorphisms in ACE2 (rs2285666), TIRAP (rs8177374) and factor X (rs3211783) were assessed. The outcomes were mortality, respiratory failure and venous thromboembolism. Respiratory failure was defined as the necessity of >5 litres/minute oxygen, high flow nasal oxygen suppletion or mechanical ventilation., Results: Between March and April 2020, 116 patients (35% female, median age 65 [inter quartile range 55-75] years) were included and treated according to the then applicable guidelines. Sixteen patients (14%) died, 44 patients (38%) had respiratory failure of whom 23 required endotracheal intubation for mechanical ventilation, and 20 patients (17%) developed venous thromboembolism. The percentage of TIRAP polymorphism carriers in the survivor group was 28% as compared to 0% in the non-survivor group (p = 0.01, Bonferroni corrected p = 0.02). Genotype distribution of ACE2 and factor X did not differ between survivors and non-survivors., Conclusion: This study shows that carriage of TIRAP polymorphism rs8177374 could be associated with a significantly lower mortality in COVID-19. This TIRAP polymorphism may be an important predictor in the outcome of COVID-19., Competing Interests: The authors have declared that no competing interests exist.

Background: Bacterial meningitis (BM) is a serious, life-threatening infectious disease of the central nervous system that often occurs in young children. The most common severe to moderate sequelae following BM are sensorineural hearing loss, neuromotor disabilities and mental retardation, while subtle sequelae include academic and behavioral disabilities. It is largely unknown whether these more subtle sequelae persist into adolescence and adulthood. Therefore, this study will investigate the very long-term effects of childhood BM in later life. Better understanding of long-term effects and early identification of adverse outcomes after BM are essential for more timely interventions. Additionally, certain single nucleotide polymorphisms (SNPs) are associated with disease severity and might predict adverse sequelae. These include SNPs in genes encoding for pathogen recognition and immune response upon infection. Accordingly, a secondary objective of this study is to investigate the role of genetic variation in BM and use any insights to predict short- and long-term outcomes., Methods: In the Dutch 20|30 Postmeningitis study, adolescents and young adults (n = 947) from two historical cohorts with a prior episode of BM during childhood will be enrolled into a cross-sectional follow-up investigation using mainly questionnaires that examine executive and behavioral functioning, health-related quality of life, subjective hearing, mood and sleeping disorders, academic performance, and economic self-sufficiency. The results will be compared to normative data by one-sample t-tests. Multivariable regression analysis will be used to assess for any associations with causative pathogens and severity of BM. Participants that complete the questionnaires will be approached to provide a swab for buccal DNA and subsequent sequencing analyses. Logistic regression models will be used to predict sequelae., Discussion: The unique follow-up duration of this cohort will enable us to gain insights into the possible very long-term adverse effects of childhood BM and how these might impact on quality of life. The investigation of host genetic factors will contribute to the development of prediction models which will serve as prognostic tools to identify children who are at high risk of adverse outcome after BM., Trial Registration: Dutch Trial Register NTR-6891. Retrospectively registered 28 December 2017.

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.)

Chlamydia trachomatis infections demonstrate remarkable differences in clinical course that are approximately 40% based on host genetic variation. Here, we study the single nucleotide polymorphisms (SNPs) and their haplotypes in TLR2, TLR4 and TLR9 (TLR2 +2477G>A; TLR2 -16934T>A; TLR4+896A>G; TLR9 -1237T>C and TLR9 +2848G>A) in relation to the susceptibility to, and severity of C. trachomatis infections. We analysed the five SNPs in a cohort of 770 Dutch Caucasian women either attending a sexually transmitted diseases outpatient clinic (n = 731) or having complaints of subfertility (n = 39). Haplotype analyses showed a trend for TLR2 haplotype I (-16934T/+2477G) to protect against the development of symptoms and tubal pathology (Ptrend = 0.03) after Chlamydia infection. In the susceptibility cohort, TLR9 haplotype III (-1237C/+2848A) showed a significant decreasing trend in the development of symptoms after C. trachomatis infection (P = 0.02, OR: 0.55, 95%CI: 0.33-0.91). Logistic regression of the TLR2 haplotypes, TLR4+896A>G, and TLR9 haplotypes showed that the TLR2 haplotype combinations AG-TA and AG-TG confer risk (OR 3.4 (P = 0.01) and 1.6 (P = 0.03)), while the TLR9 haplotype combination TG-TA protects against C. trachomatis infections (OR: 0.4, P = 0.004). Our study shows that both TLR2 and TLR9 genes and SNP combinations do influence the clinical course of Chlamydia infections., (© FEMS 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Intracellular pattern-recognition receptors NOD1 and NOD2 are capable of sensing common structural units of bacterial walls. Recognition triggers specific immune signalling pathways and leads to pro-inflammatory cytokine upregulation and adequate immune response. We investigated whether two functional polymorphisms in NOD1 and NOD2 exert an effect on susceptibility to (STD patients) and severity of (female patients visiting the fertility clinic) Chlamydia trachomatis infection in 807 Dutch Caucasian women. A significant association of the NOD1 +32656 GG insertion variant with protection against infection with C. trachomatis has been detected [p: 0.0057; OR: 0.52]. When comparing C. trachomatis-positive women without symptoms to C. trachomatis-positive women with symptoms, and to C. trachomatis-positive women with TFI, we observed an increasing trend in carriage of the GG allele [Ptrend: 0.0003]. NOD2 1007fs failed to reveal an association. We hypothesize that the underlying mechanism might be a functional effect of the GG insertion on IFN-beta-dependent regulation of immune response in the genital tract. The research is part of an ongoing effort of identifying key polymorphisms that determine the risk of TFI and effectively translating them into the clinical setting for the purpose of optimizing diagnostic management of women at risk for developing TFI., (© The Author 2015. Published by Oxford University Press on behalf of FEMS. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The prevalence of Chlamydia trachomatis varies between ethnic groups in The Netherlands. It is, however, unknown whether this is associated with specific serogroups. The objective of this study was to determine whether serogroup distribution is associated with ethnic origin in the region of The Hague, The Netherlands. Serogroups of 370 microbiologically confirmed C. trachomatis-positive samples were analysed. The samples were obtained from 247 women and 123 men between January and October 2008, of self-reported Dutch Caucasian, Dutch Antillean, Surinamese, N. African/Turkish or other descent. We observed a difference in serogroup distribution comparing Dutch Caucasian women to Dutch Antillean women (χ2 for distribution P = 0·035). Serogroup C was more common in Dutch Antillean women, whereas serogroup B was less common (P = 0·03). This difference was not observed for Dutch Antillean men. The observed difference in distribution of C. trachomatis serogroups between ethnic groups is relevant for further transmission studies.

Background: Sensorineural hearing loss is the most common sequela in survivors of bacterial meningitis (BM). In the past we developed a validated prediction model to identify children at risk for post-meningitis hearing loss. It is known that host genetic variations, besides clinical factors, contribute to severity and outcome of BM. In this study it was determined whether host genetic risk factors improve the predictive abilities of an existing model regarding hearing loss after childhood BM., Methods: Four hundred and seventy-one Dutch Caucasian childhood BM were genotyped for 11 single nucleotide polymorphisms (SNPs) in seven different genes involved in pathogen recognition. Genetic data were added to the original clinical prediction model and performance of new models was compared to the original model by likelihood ratio tests and the area under the curve (AUC) of the receiver operating characteristic curves., Results: Addition of TLR9-1237 SNPs and the combination of TLR2 + 2477 and TLR4 + 896 SNPs improved the clinical prediction model, but not significantly (increase of AUC's from 0.856 to 0.861 and from 0.856 to 0.875 (p = 0.570 and 0.335, respectively). Other SNPs analysed were not linked to hearing loss., Conclusions: Although addition of genetic risk factors did not significantly improve the clinical prediction model for post-meningitis hearing loss, AUC's of the pre-existing model remain high after addition of genetic factors. Future studies should evaluate whether more combinations of SNPs in larger cohorts has an additional value to the existing prediction model for post meningitis hearing loss.

Since 2003, a lymphogranuloma venereum epidemic has been reported in The Netherlands and other European countries. This epidemic is caused by Chlamydia trachomatis serovariant L2b and has only been seen in men having sex with men. The authors investigated a woman presenting with a bubo in her right groin. The authors showed by real-time PCR that the woman was infected with C trachomatis, serovariant L2b. This is the first reported case study of a female patient with bubonic lymphogranuloma venereum caused by serovariant L2b, which was probably contracted via her bisexual male partner.

Objectives: The aims of this study were: to determine the incidence of concurrent infections on a serovar level; to determine the incidence of multiple anatomical infected sites on a detection and genotyping level and analyse site-specific serovar distribution; to identify tissue tropism in urogenital versus rectal specimens., Methods: Chlamydia trachomatis-infected patients in two populations were analysed: 75 visiting the outpatient department of obstetrics and gynaecology of the MC Haaglanden, and 358 visiting the outpatient sexually transmitted disease clinic, The Hague, The Netherlands. The PACE 2 assay (Gen-Probe) was used to detect C trachomatis from urethral, cervical, vaginal, oropharyngeal and anorectal swabs. C trachomatis genotyping was performed on all C trachomatis positive samples, using the CT-DT genotyping assay., Results: Samples from 433 patients (256 female and 177 male) with confirmed C trachomatis infection were analysed. In 11 patients (2.6%), concurrent serovars in one anatomical sample site were present. In 62 (34.1%) female and four (9.3%) male patients, multiple sample site infections were found. A substantial percentage of women tested at the cervical/vaginal and rectal site were found to be positive at both sites (36.1%, 22/61). In men, D/Da and G/Ga serovars were more prevalent in rectal than urogenital specimens (p=0.0081 and p=0.0033, respectively), while serovar E was more prevalent in urogenital specimens (p=0.0012)., Conclusions: The prevalence of multiple serovar infections is relatively low. Significant differences in serovar distribution are found in rectal specimens from men, with serovar G/Ga being the most prominent, suggesting tissue tropism.

Background: Sexually transmitted infection (STI) screening programmes are implemented in many countries to decrease burden of STI and to improve sexual health. Screening for Chlamydia trachomatis and Neisseria gonorrhoeae has a prominent role in these protocols. Most of the screening programmes concerning men having sex with men (MSM) are based on opportunistic urethral testing. In The Netherlands, a history-based approach is used. The aim of this study is to evaluate the protocol of screening anatomic sites for C. trachomatis and N. gonorrhoeae infection based on sexual history in MSM in routine practice in The Netherlands., Methods: All MSM visiting the clinic for STI in The Hague are routinely asked about their sexual practice during consulting. As per protocol, tests for urogenital, oropharyngeal and anorectal infection are obtained based on reported site(s) of sexual contact. All consultations are entered into a database as part of the national STI monitoring system. Data of an 18 months period were retrieved from this database and analysed., Results: A total of 1455 consultations in MSM were registered during the study period. The prevalence of C. trachomatis and N. gonorrhoeae per anatomic site was: urethral infection 4.0% respectively and 2.8%, oropharynx 1.5% and 4.2%, and anorectum 8.2% and 6.0%. The majority of chlamydia cases (72%) involved a single anatomic site, which was especially manifest for anorectal infections (79%), while 42% of gonorrhoea cases were single site. Twenty-six percent of MSM with anorectal chlamydia and 17% with anorectal gonorrhoea reported symptoms of proctitis; none of the oropharyngeal infections were symptomatic. Most cases of anorectal infection (83%) and oropharyngeal infection (100%) would have remained undiagnosed with a symptom-based protocol., Conclusions: The current strategy of sexual-history based screening of multiple anatomic sites for chlamydia and gonorrhoea in MSM is a useful and valid guideline which is to be preferred over a symptom-based screening protocol.

The data on serovar distributions of Chlamydia trachomatis - the most diagnosed sexually transmitted infection (STI) worldwide - are important for epidemiologic purposes and transmission studies but are completely lacking in Russia. The aim of the current study is to determine the serogroup and serovar distributions in Russian men and women and compare these data with Dutch serogroup and serovar distributions. In Russian men and women, serogroup B was the most prevalent (46%), followed by the intermediate serogroup (I group; 33%) and serogroup C (21%). The distribution was comparable between men and women. The serogroup distribution was similar to the previously published distribution in Dutch cohorts. However, on a serovar level statistically very significant differences were observed, reaching up to P < 0.0001. The serovars B and G/Ga had higher prevalences compared with the reported Dutch prevalences, while serovars F, H, I/Ia, J and K had lower prevalences compared with the Dutch studies. In conclusion, this is the first report of Russian C. trachomatis serovar/serogroup distributions. Serogroup B is the most prevalent, followed by serogroup I and serogroup C with no statistical differences on the serogroup level. However, significant differences between Russia and the Netherlands were observed in the distribution of C. trachomatis serovars., (Copyright 2009 Prous Science, S.A.U. or its licensors. All rights reserved.)

Chlamydia trachomatis infections may cause several disease conditions ranging from asymptomatic infections to severe upper genital tract pathology, thereby causing significant morbidity worldwide. Remarkable interindividual differences in the clinical course of C. trachomatis infection have been observed, and are mainly based on variation in genes encoding immune-regulatory and bacteria-sensing proteins. Toll-like receptors (TLRs) are closely involved in pathogen recognition and host defense in C. trachomatis infections. The aim of this study is to assess the role of TLR2 single nucleotide polymorphisms and haplotypes in the susceptibility to, and severity of C. trachomatis infections. The study comprised a sexually transmitted disease cohort of 468 Dutch Caucasian women and a control group of 321 women. The subfertility cohort consisted of 56 women with clinically well-defined tubal pathology. The results showed no significant differences in individual TLR2 genotype frequencies in the susceptibility for C. trachomatis infections between the C. trachomatis-positive group and controls. However, haplotype 1 was statistically significant (P = 0.015) and was associated with protection against tubal pathology following C. trachomatis infection. The same haplotype was also significantly decreased (P = 0.021) in increasing severity of C. trachomatis infections (asymptomatic > symptomatic > tubal pathology) suggesting a protective effect of this haplotype against the development of late complications., (Copyright 2009 Prous Science, S.A.U. or its licensors. All rights reserved.)

Reliable analysis of single nucleotide polymorphisms (SNPs) in DNA derived from samples containing low numbers of cells or from suboptimal sources can be difficult. A new procedure to characterize multiple SNPs in traces of DNA from plasma and old dried blood samples was developed. Six SNPs in the Mannose Binding Lectin 2 (MBL2) gene were chosen as targets for analysis. DNA was extracted from plasma obtained from mothers (n=49) and their neonates (n=49) and from old dried blood samples (n=204). Multiple Real-Time SNP analyses in the MBL2 gene were carried out on all samples. Because of very low DNA concentrations in most of the samples, a pre-amplification step was utilized. It was possible to analyze all plasma samples (n=98), including those with very low cell numbers (n=21) and 93% of the old dried blood samples (n=189). Results obtained from pre-amplified samples were in full agreement with neat samples. All possible SNP alleles were present in our population. The frequencies of the different alleles from both plasma and dried blood samples (n=287) were in agreement with earlier studies of the Caucasian population. In conclusion, amplification prior to Real-Time PCR SNP analysis is a convenient, cost effective and useful method to significantly improve the reliable SNP detection in specimens containing very low concentrations or poor quality DNA from suboptimal sources.

Background: The functional polymorphism -260 C>T in the LPS sensing TLR4 co-receptor CD14 gene enhances the transcriptional activity and results in a higher CD14 receptor density. Individuals carrying the T/T genotype also have significantly higher serum levels of soluble CD14. The T allele of this polymorphism has recently been linked to Chlamydia pneumoniae infection. We investigated the role of the CD14 -260 C>T polymorphism in the susceptibility to and severity (defined as subfertility and/or tubal pathology) of C. trachomatis infection in Dutch Caucasian women., Methods: The different CD14 -260 C>T genotypes were assessed by PCR-based RFLP analysis in three cohorts: 1) A cohort (n = 576) of women attending a STD clinic, 2) a cohort (n = 253) of women with subfertility, and 3) an ethnically matched control cohort (n = 170). The following variables were used in the analysis: In cohort 1 the CT-DNA status, CT IgG serology status, self-reported symptoms and in cohort 2, the CT IgG serology status and the tubal status at laparoscopy., Results: In the control cohort the CC, CT and TT genotype distribution was: 28.2%, 48.2%, and 23.5% respectively. No differences were found in the overall prevalence of CD14 -260 genotypes (28.1%, 50.7%, and 21.2%) in cohort 1 when compared to the control cohort. Also no differences were observed in women with or without CT-DNA, with or without serological CT responses, with or without symptoms, or in combinations of these three variables. In subfertile women with tubal pathology (cohort 2, n = 50) the genotype distribution was 28.0%, 48.0%, and 24.0% and in subfertile women without tubal pathology (n = 203), 27.6%, 49.3% and 23.2%. The genotype distribution was unchanged when CT IgG status was introduced in the analyses., Conclusion: The CD14 -260 C>T genotype distributions were identical in all three cohorts, showing that this polymorphism is not involved in the susceptibility to or severity of sequelae of C. trachomatis infection.