Sander Ouburg

2015 European guideline on the management of Chlamydia trachomatis infections

Chlamydia trachomatis infections, which most frequently are asymptomatic, are major public health concerns globally. The 2015 European C. trachomatis guideline provides: up-to-date guidance regarding broader indications for testing and treatment of C. trachomatis infections; a clearer recommendation of using exclusively-validated nucleic acid amplification tests for diagnosis; advice on (repeated) C. trachomatis testing; the recommendation of increased testing to reduce the incidence of pelvic inflammatory disease and prevent exposure to infection; and recommendations to identify, verify and report C. trachomatis variants. Improvement of access to testing, test performance, diagnostics, antimicrobial treatment and follow-up of C. trachomatis patients are crucial to control its spread. For detailed background, evidence base and discussions, see the background review for the present 2015 European guideline on the management of Chlamydia trachomatis infections (Lanjouw E, et al. Int J STD AIDS. 2015).

Alarmingly poor performance in Chlamydia trachomatis point-of-care testing

Background Infection by Chlamydia trachomatis (CT) is the most prevalent sexually transmitted infection (STI) world wide. The most frequently used diagnostic test for CT is a nucleic acid amplification test (NAAT), which is highly sensitive and specific. To further shorten time delay until diagnosis has been made, in order to prevent CT spread, the use of point-of-care (POC) tests may be the way forward. Objectives The diagnostic performance of three POC tests, Handilab-C, Biorapid CHLAMYDIA Ag test and QuickVue Chlamydia test, was evaluated and compared with NAAT. Methods All women, above the age of 16 years, attending for a consultation at an STI clinic between September 2007 and April 2008, were asked to participate. Women were asked to complete a short questionnaire and to collect six self-taken vaginal swabs (SVS). SVS 2 was used for NAAT and SVS 3 to 5 were randomised for the different POC tests. SVS 1 and 6 were used for determining quantitative CT load to validate the use of successive SVS. All POC tests were performed without knowledge of NAAT results. NAAT was used as the ‘gold standard’. Results 772 women were included. CT prevalence was 11% in our population. Sensitivities of the Biorapid CHLAMYDIA Ag test, QuickVue Chlamydia and Handilab-C test were 17%, 27% and 12%, respectively. Conclusions The evaluated POC tests, owing to their very low sensitivities, are not ready for widespread use. These results underline the need for good-quality assurance of POC tests, especially in view of the increased availability of these tests on the internet.

Do host genetic traits in the bacterial sensing system play a role in the development of Chlamydia trachomatis-associated tubal pathology in subfertile women?

BackgroundIn 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.MethodsOf 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.ResultsFollowing 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.ConclusionCarrying 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.

Cross-Sectional Study of Genital, Rectal, and Pharyngeal Chlamydia and Gonorrhea in Women in Rural South Africa

Background Epidemiological data of genital chlamydia and gonorrhea, required to inform design and implementation of control programs, are limited for rural Africa. There are no data on the prevalence of rectal or pharyngeal infections among African women. Methods A cross-sectional study of 604 adult women visiting 25 primary health care facilities in rural South Africa was conducted. Vaginal, anorectal, and oropharyngeal swabs were tested for Chlamydia trachomatis and Neisseria gonorrhoeae. Results Prevalence of genital chlamydia was 16% and that of gonorrhea was 10%; rectal chlamydial infection was diagnosed in 7.1% and gonococcal in 2.5% of women. One woman had pharyngeal chlamydia. Most women with genital chlamydia (61%) and gonorrhea (57%) were asymptomatic. Independent risk factors for genital chlamydia were younger age (adjusted odds ratio [aOR], 0.96 per year; 95% confidence interval [CI], 0.93–0.98), hormonal contraceptive use (aOR, 2.2; 95% CI, 1.3–3.7), pregnancy (aOR, 2.4; 95% CI, 1.3–4.4), and intravaginal cleansing (aOR, 1.7; 95% CI, 1.04–2.8). Intravaginal cleansing was associated with genital gonorrhea (aOR, 1.9; 95% CI, 1.1–3.3). Conclusions Genital and rectal, but not pharyngeal, chlamydia and gonorrhea are highly prevalent and frequently asymptomatic in women in rural South Africa. Young women attending health care facilities for antenatal care or family planning should be prioritized in control efforts.

Evaluation of sexual history-based screening of anatomic sites for chlamydia trachomatis and neisseria gonorrhoeae infection in men having sex with men in routine practice

BackgroundSexually 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.MethodsAll 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.ResultsA 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.ConclusionsThe 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.

Single Nucleotide Polymorphisms in TLR9 Are Highly Associated with Susceptibility to Bacterial Meningitis in Children

BACKGROUND Bacterial meningitis (BM) is a severe infection mainly caused by Streptococcus pneumoniae and Neisseria meningitidis (NM). However, genetically determined susceptibility to develop severe infections by these microorganisms is variable between individuals. Toll-like receptor 9 (TLR9) recognizes bacterial DNA leading to intracellular inflammatory signaling. Single nucleotide polymorphisms (SNPs) within the TLR9 gene are associated with susceptibility to several diseases, no such association with meningitis has been described. METHODS We studied the role of TLR9 SNPs in host defense against BM. Two TLR9 SNPs and 4 TLR9 haplotypes were determined in 472 survivors of BM and compared to 392 healthy controls. RESULTS Carriage of the TLR9+2848-A mutant was significantly decreased in meningococcal meningitis (MM) patients compared with controls (p: .0098, odds ratio [OR]: .6, 95% confidence interval [CI]: .4-.9). TLR9 haplotype I was associated with an increased susceptibility to MM (p: .0237, OR 1.3, 95% CI: 1.0-1.5). In silico analysis shows a very strong immunoinhibitory potential for DNA of NM upon recognition by TLR9 (CpG index of -106.8). CONCLUSIONS We report an association of TLR9 SNPs with susceptibility to BM, specifically MM indicating a protective effect for the TLR9+2848-A allele. We hypothesize that the TLR9+2848-A mutant results in an up-regulation of TLR9 induced immune response compensating the strong inhibitory potential of NM CpG DNA.

Analyses of multiple-site and concurrent Chlamydia trachomatis serovar infections, and serovar tissue tropism for urogenital versus rectal specimens in male and female patients

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.

Anal Lymphogranuloma Venereum Infection Screening With IgA Anti-Chlamydia trachomatis-Specific Major Outer Membrane Protein Serology

Background: Anal lymphogranuloma venereum (LGV) infections, caused by Chlamydia trachomatis biovar L (Ct+/LGV+), are endemic among men who have sex with men (MSM). Anal non-LGV biovar Ct infections (Ct+/LGV−) can be eradicated with 1 week doxycycline, whereas Ct+/LGV+ infections require 3-week doxycycline. To differentiate Ct+/LGV+ from Ct+/LGV− infections, biovar-specific Nucleic Acid Amplification Test (NAAT) are standard, but also expensive and laborious. A chlamydia-specific serological assay could serve as an alternative test. Methods: MSM were screened for anal Ct+/LGV+ and Ct+/LGV− infections with a commercial nonspecific NAAT and an in house biovar L-specific NAAT. Serum samples were evaluated with chlamydia-specific anti-Major Outer Membrane Protein (MOMP) and antilipopolysaccharide assays of IgA and IgG classes. Asymptomatic patients were identified as: (1) no anal complaints or (2) no microscopic inflammation (i.e., <10 leucocytes per high power field in anal smears). The best differentiating assay was subsequently evaluated in 100 Ct+/LGV+ and 100 Ct+/LGV− MSM using different cut-off points. Results: The anti-MOMP IgA assay was the most accurate to differentiate Ct+/LGV+ (n = 42) from Ct+/LGV− (n = 19) with 85.7% sensitivity (95% confidence interval [CI], 72.2–93.3) and 84.2% specificity (95% CI, 62.4–94.5), even among asymptomatic patients. In a population comprising 98 Ct+/LGV+ and 105 Ct+/LGV− patients, the anti-MOMP IgA assay scored most accurate when the cut-off point was set to 2.0 with 75.5% (95% CI, 65.8–83.6) sensitivity and 74.3% (95% CI, 64.8–82.3) specificity. Conclusions: The IgA anti-MOMP assay can identify a considerable proportion of the (asymptomatic) anal LGV infections correctly. Yet, biovar L-specific NAAT are still the preferred diagnostic tests in clinical settings.

The first case record of a female patient with bubonic lymphogranuloma venereum (LGV), serovariant L2b

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.

Toll-like receptor 9 polymorphisms are associated with severity variables in a cohort of meningococcal meningitis survivors

BackgroundGenetic variation in immune response genes is associated with susceptibility and severity of infectious diseases. Toll-like receptor (TLR) 9 polymorphisms are associated with susceptibility to develop meningococcal meningitis (MM). The aim of this study is to compare genotype distributions of two TLR9 polymorphisms between clinical severity variables in MM survivors.MethodsWe used DNA samples of a cohort of 390 children who survived MM. Next, we determined the genotype frequencies of TLR9 -1237 and TLR9 +2848 polymorphisms and compared these between thirteen clinical variables associated with prognostic factors predicting adverse outcome of bacterial meningitis in children.ResultsThe TLR9 -1237 TC and CC genotypes were associated with a decreased incidence of a positive blood culture for Neisseria (N.) meningitidis (p = 0.014, odds ratio (OR) 0.5. 95% confidence interval (CI) 0.3 – 0.9). The TLR9 +2848 AA mutant was associated with a decreased incidence of a positive blood culture for N. meningitidis (p = 0.017, OR 0.6, 95% CI 0.3 – 0.9). Cerebrospinal fluid (CSF) leukocytes per μL were higher in patients carrying the TLR9 -1237 TC or CC genotypes compared to carriers of the TT wild type (WT) (p = 0.024, medians: 2117, interquartile range (IQR) 4987 versus 955, IQR 3938). CSF blood/glucose ratios were lower in TLR9 -1237 TC or CC carriers than in carriers of the TT WT (p = 0.017, medians: 0.20, IQR 0.4 versus 0.35, IQR 0.5). CSF leukocytes/μL were higher in patients carrying the TLR9 +2848 AA mutant compared to carriers of GG or GA (p = 0.0067, medians: 1907, IQR 5221 versus 891, IQR 3952).ConclusionsWe identified TLR9 genotypes associated with protection against meningococcemia and enhanced local inflammatory responses inside the central nervous system, important steps in MM pathogenesis and defense.