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Little is known about the extent of Clostridium difficile infection in Europe. Our aim was to obtain a more complete overview of C difficile infection in Europe and build capacity for diagnosis and surveillance. We set up a network of 106 laboratories in 34 European countries. In November, 2008, one to six hospitals per country, relative to population size, tested stool samples of patients with suspected C difficile infection or diarrhoea that developed 3 or more days after hospital admission. A case was defined when, subsequently, toxins were identified in stool samples. Detailed clinical data and stool isolates were collected for the first ten cases per hospital. After 3 months, clinical data were followed up. The incidence of C difficile infection varied across hospitals (weighted mean 4·1 per 10 000 patient-days per hospital, range 0·0–36·3). Detailed information was obtained for 509 patients. For 389 of these patients, isolates were available for characterisation. 65 different PCR ribotypes were identified, of which 014/020 (61 patients [16%]), 001 (37 [9%]), and 078 (31 [8%]) were the most prevalent. The prevalence of PCR-ribotype 027 was 5%. Most patients had a previously identified risk profile of old age, comorbidity, and recent antibiotic use. At follow up, 101 (22%) of 455 patients had died, and C difficile infection played a part in 40 (40%) of deaths. After adjustment for potential confounders, an age of 65 years or older (adjusted odds ratio 3·26, 95% CI 1·08–9·78; p=0·026), and infection by PCR-ribotypes 018 (6·19, 1·28–29·81; p=0·023) and 056 (13·01; 1·14–148·26; p=0·039) were significantly associated with complicated disease outcome. PCR ribotypes other than 027 are prevalent in European hospitals. The data emphasise the importance of multicountry surveillance to detect and control C difficile infection in Europe. European Centre for Disease Prevention and Control.

Background In 2014 the World Health Organisation (WHO) established validation criteria for elimination of mother-to-child transmission (EMTCT) of HIV and syphilis. Additionally, the WHO set targets to eliminate hepatitis, including hepatitis B (HBV). We evaluated to what extent the Netherlands has achieved the combined WHO criteria for EMTCT of HIV, syphilis and HBV. Methods Data of HIV, syphilis and HBV infections among pregnant women and children (born in the Netherlands with congenital infection) for 2009–2015, and data required to validate the WHO criteria were collected from multiple sources: the antenatal screening registry, the HIV monitoring foundation database, the Perinatal Registry of the Netherlands, the national reference laboratory for congenital syphilis, and national HBV notification data. Results Screening coverage among pregnant women was > 99% for all years, and prevalence of HIV, syphilis and HBV was very low. In 2015, prevalence of HIV, syphilis and HBV was 0.06, 0.06 and 0.29%, respectively. No infections among children born in the Netherlands were reported in 2015 for all three diseases, and in previous years only sporadic cases were observed In 2015, treatment of HIV positive pregnant women was 100% and HBV vaccination of children from HBV positive mothers was > 99%. For syphilis, comprehensive data was lacking to validate WHO criteria. Conclusions In the Netherlands, prevalence of maternal HIV, syphilis and HBV is low and congenital infections are extremely rare. All minimum WHO criteria for validation of EMTCT are met for HIV and HBV, but for syphilis more data are needed to prove elimination.

Background The impact of human papillomavirus (HPV) vaccination programs depends on the degree of indirect protection against new infections achieved among unvaccinated women. We estimated the indirect effect of bivalent HPV vaccination by comparing the HPV-type incidence in unvaccinated female participants between a cohort offered vaccination in 2009/2010 and a cohort of similar-aged women offered vaccination in 2014. Methods We compared the incidence rates of HPV types in the HAVANA cohort (follow-up from 2010/2011 until 2015/2016) with those from the HAVANA-2 cohort (2017–2022) using two regression approaches to estimate the indirect effect of HPV vaccination. First, we calculated the incidence ratio (IRR) for a vaccine or cross-protective type in HAVANA-2 versus HAVANA by Poisson regression and compared it to the IRR for a non-cross-protective type. The indirect vaccine effect is defined as 1-ratio of the IRRs. Second, we performed Cox regression with infection by vaccine or cross-protective type as the endpoint and calculated the hazard ratio (HR) for HAVANA-2 versus HAVANA after adjusting for time-varying sociodemographic variables. The indirect effect is defined as 1-HR. Results We included 661 unvaccinated participants in HAVANA and 927 in HAVANA-2. We observed a significant reduction in incident HPV16 infections of 70.9% (95% CI 48.3–83.7%) with Poisson regression and of 73.1% (95% CI 53.3–84.5%) with Cox regression. For HPV45, significant decreases of 67.3% (95% CI 8.8–88.3%) and 69.8% (95% CI 15.2–89.3%) were observed. For HPV18, HPV31, and HPV33, the indirect effect was not statistically significant. Conclusions Large indirect effects of the bivalent HPV vaccination program were observed for HPV16 and HPV45 infections.

Background. Mortality among patients with Clostridium difficile infection (CDI) is high. Because of high age and multiple underlying diseases, CDI-related mortality is difficult to estimate. We estimated CDI-related mortality in an endemic situation, not influenced by outbreaks and consequently certain patients and C. difficile strains. Methods. Between 2006 and 2009, 13 Dutch hospitals included all hospitalized CDI patients. Nine hospitals individually matched each CDI patient to 2 control patients, based on ward and time of CDI hospitalization. Survival status was obtained via the Dutch Civil Registration System. Kaplan-Meier and Cox regression were used for survival analysis. Results. We identified 1366 patients with CDI (1.33 per 1000 admissions). All-cause mortality risk was 13% after 30 days and 37% after 1 year. The highest mortality was seen among elderly patients and patients with polymerase chain reaction ribotype 027. Three hundred seventeen CDI patients were matched to 317 patients without diarrhea and 232 patients with diarrhea, with a 30-day mortality risk of 5.4% and 8.6%, respectively. CDI patients had a 2.5-fold increased 30-day mortality rate compared to controls without diarrhea (hazard ratio 2.5 [95% confidence interval, 1.4–4.3]) when adjusted for age, sex, and underlying diseases. CDI-related death occurred mainly within 30 days after diagnosis. Conclusions. Mortality among CDI patients is high, even in an endemic situation. Our results show that CDI is associated with to a 2.5-fold increase in 30-day mortality. This highlights the considerable disease burden and clinical impact of CDI, even in absence of an outbreak.

Background The Netherlands is one of few countries worldwide which has used the bivalent HPV vaccine for girls-only for over a decade. This allows assessment of vaccine effectiveness (VE) against female genital HPV DNA-positivity of this vaccine in an observational post-licencing real-world setting. Additionally, it is unclear whether catch-up vaccination campaigns result in similar VE as routine vaccination. Therefore, type-specific and grouped VE were assessed and compared for women who had been eligible for catch-up vaccination at 13–16 years with those who had been eligible for routine vaccination at 12 years. Methods PASSYON is a Dutch biennial repeated cross-sectional (2011–2021) study among sexual health clinic clients aged 16–24 years old. Women provided self-collected vaginal samples, questionnaires on demographics and sexual behaviour were administered, and women self-reported HPV vaccination status. Samples were analysed using a PCR-based assay (SPF 10 -LiPA 25 ). Type-specific and grouped VE estimates, adjusted with propensity score stratification, were assessed against genital positivity for 14 HPV types. VE for targeted and non-targeted genotypes were compared between women who had been eligible for the catch-up and those who had been eligible for routine vaccination. Results The study included 4488 female participants who had been eligible for HPV vaccination and provided genital swabs (1561 eligible for catch-up, 2927 for routine vaccination). Very high VE against genital HPV-16 and HPV-18 was observed (resp. 93.5% and 89.5%) and significant cross-protection against six other genotypes (HPV-31/33/35/45/52/58), varying from 18.0% (HPV-52) to 79.6% (HPV-45). VE estimates were comparable between women who had been eligible for the catch-up campaign and those eligible for routine vaccination: VE HPV-16/HPV-18: 92.2% (95%CI: 87.9–94.9) vs. 91.8% (95%CI: 86.0–95.2). Conclusions In real-world settings, the VE of bivalent vaccine is high against targeted genotypes, with cross-protection against 6 other genotypes. Catch-up campaigns up to age 16 years can be as effective as routine vaccination at age 12, although it is recommendable to provide HPV vaccination at an age at which most are likely not sexually active yet. This may inform countries considering catch-up campaigns when introducing or extending the use of HPV vaccination within their national immunisation programmes.

In 2008, a bundle of care to prevent Surgical Site Infections (SSIs) was introduced in the Netherlands. The bundle consisted of four elements: antibiotic prophylaxis according to local guidelines, no hair removal, normothermia and 'hygiene discipline' in the operating room (i.e. number of door movements). Dutch hospitals were advised to implement the bundle and to measure the outcome. This study's goal was to assess how effective the bundle was in reducing SSI risk. Hospitals assessed whether their staff complied with each of the bundle elements and voluntary reported compliance data to the national SSI surveillance network (PREZIES). From PREZIES data, we selected data from 2009 to 2014 relating to 13 types of surgical procedures. We excluded surgeries with missing (non)compliance data, and calculated for each remaining surgery with reported (non)compliance data the level of compliance with the bundle (that is, being compliant with 0, 1, 2, 3, or 4 of the elements). Subsequently, we used this level of compliance to assess the effect of bundle compliance on the SSI risk, using multilevel logistic regression techniques. 217 489 surgeries were included, of which 62 486 surgeries (29%) had complete bundle reporting. Within this group, the SSI risk was significantly lower for surgeries with complete bundle compliance compared to surgeries with lower compliance levels. Odds ratios ranged from 0.63 to 0.86 (risk reduction of 14% to 37%), while a 13% risk reduction was demonstrated for each point increase in compliance-level. Sensitivity analysis indicated that due to analysing reported bundles only, we probably underestimated the total effect of implementing the bundle. This study demonstrated that adhering to a surgical care bundle significantly reduced the risk of SSIs. Reporting of and compliance with the bundle compliance can, however, still be improved. Therefore an even greater effect might be achieved.

To substantiate cross-protection reported across AS04-adjuvanted bivalent human papillomavirus (HPV) vaccine (2vHPV) studies, we reevaluated vaccine effectiveness against type-specific HPV positivity as a function of phylogenetic distance to vaccine target types HPV-16 and -18. We provide evidence of sustained cross-protection up to 8 years postvaccination in a high-risk population in the Netherlands. Moreover, our findings suggest that genomic distance better explains cross-protection than distance measures based on capsid antigens only. Taken together, 2vHPV is predicted to provide partial cross-protection against HPV-31, -33, -35, -45, -52, and possibly -58, that is, acknowledged oncogenic types with close phylogenetic relationships to HPV-16 or -18.

Background Genital herpes results in considerable morbidity, including risk of neonatal herpes, and is increasingly being caused by Herpes Simplex Virus (HSV) type 1. Possibly children are less often HSV-1 infected, leaving them susceptible until sexual debut. We assessed changes in the Dutch HSV-1 and HSV-2 seroprevalence over time and determinants associated with HSV seropositivity. Methods We used data from two population-based seroepidemiological studies conducted in 1995–6 and 2006–7 with a similar study design. Serum samples of 6 months to 44-year-old participants were tested for type-specific HSV antibodies using HerpesSelect® with a cut-off level of >1.10 for seropositivity. Age and sex-specific HSV-1 and HSV-2 seroprevalence was weighted for the Dutch population. Logistic regression was performed to investigate determinants associated with HSV seropositivity. Results Overall, weighted HSV-1 seroprevalence was significantly lower in 2006–7 [42.7 % 95 % confidence interval (CI) 39.9-45.4] than in 1995–6 (47.7 % 95 % CI 44.8-50.7), especially among 10- to 14-year-olds. Overall, weighted HSV-2 seroprevalence remained stable: 6.8 % in 1995–6 and 6.0 % in 2006–7. Adults who ever had sexual intercourse were more often seropositive for HSV-1 [adjusted Odds Ratio (aOR) 1.69 95 % CI 1.33-2.16] and HSV-2 (aOR 2.35 95 % CI 1.23-4.52). Age at sexual debut was the only sexual risk determinant associated with HSV-1 seropositivity. Conclusions Because of the lower HSV-1 seroprevalence in 2006–7 compared to 1995–6, more adults are susceptible to genital HSV-1, including women of reproductive age. Given the higher risk of neonatal herpes when HSV is acquired during pregnancy, prevention and control measures during pregnancy also targeting HSV-1, are important.

ObjectivesA better understanding of Chlamydia trachomatis infection (chlamydia)–related sequelae can provide a framework for effective chlamydia control strategies. The objective of this study was to estimate risks and risk factors of pelvic inflammatory disease (PID), ectopic pregnancy and tubal factor infertility (TFI) with a follow-up time of up until 8 years in women previously tested for chlamydia in the Chlamydia Screening Implementation study (CSI) and participating in the Netherlands Chlamydia Cohort Study (NECCST).MethodsWomen who participated in the CSI 2008–2011 (n=13 498) were invited in 2015–2016 for NECCST. Chlamydia positive was defined as a positive CSI-PCR test, positive chlamydia serology and/or self-reported infection (time dependent). Data on PID, ectopic pregnancy and TFI were collected by self-completed questionnaires. Incidence rates and HRs were compared between chlamydia-positive and chlamydia-negative women corrected for confounders.ResultsOf 5704 women included, 29.5% (95% CI 28.3 to 30.7) were chlamydia positive. The incidence rate of PID was 1.8 per 1000 person-years (py) (1.6 to 2.2) overall, 4.4 per 1000 py (3.3 to 5.7) among chlamydia positives compared with 1.4 per 1000 py (1.1 to 1.7) for chlamydia negatives. For TFI, this was 0.4 per 1000 py (0.3 to 0.5) overall, 1.3 per 1000 py (0.8 to 2.1) and 0.2 per 1000 py (0.1 to 0.4) among chlamydia positives and negatives, respectively. And for ectopic pregnancy, this was 0.6 per 1000 py (0.5 to 0.8) overall, 0.8 per 1000 py (0.4 to 1.5) and 0.6 per 1000 py (0.4 to 0.8) for chlamydia negatives. Among chlamydia-positive women, the strongest risk factor for PID was symptomatic versus asymptomatic infection (adjusted HR 2.88, 1.4 to 4.5) and for TFI age <20 versus >24 years at first infection (HR 4.35, 1.1 to 16.8).ConclusionWe found a considerably higher risk for PID and TFI in chlamydia-positive women, but the incidence for ectopic pregnancy was comparable between chlamydia-positive and chlamydia-negative women. Overall, the incidence rates of sequelae remained low.Trial registration NTR-5597.

Population-based Chlamydia trachomatis (CT) serology studies help evaluate the effectiveness of CT-control strategies. Determinants of CT seropersistence over time are largely unknown, but may include host genetic factors. This study aims to assess seropositivity, map antibody trajectories, and identify determinants of seropositivity and seropersistence. We analyzed anti-chlamydial immunoglobulin G levels in serum of women of reproductive age who participated in a prospective cohort and CT screening study. CT history was determined using screening results and self-reported diagnoses from sexual debut onward. We assessed seropersistence for n = 1,405 participants with samples at baseline and after six years, and seropositivity for n = 2,997 participants with baseline samples. Multivariable logistic regression identified demographic, behavioral, and host single nucleotide polymorphism (SNP) factors associated with seropersistence and seropositivity. Among seropositive women at baseline, 42.0% (n = 118/281) were seropositive at follow-up. Seropersistence was more often found in women who reported treated asymptomatic and symptomatic CT infections as compared to those who did not (aOR: 3.74, 95%CI: 1.75-8.15 and 4.79, 95%CI: 2.42-9.47, respectively). Other associated factors were higher baseline antibody titers, carrying SNPs in TLR2 (aOR: 3.06, 95%CI: 1.31-7.36) and TLR9 (2.09, 95%CI: 1.09-4.08) genes and practical education (aOR: 3.16, 95%CI: 1.56-6.64). Seropositivity (24.9%, n = 748/2,997) was associated with a CCR5 deletion (aOR: 0.65, 95%CI: 0.42-0.99). CT seropersistence was more often found in women who reported treated CT infections as compared to women who did not report having had a CT infection or receiving treatment for it. Genetic predisposition and behavioral factors are linked to diversity in seropersistence patterns.