Invasive pneumococcal disease among adults with hematological and solid organ malignancies: A population-based cohort study.

OBJECTIVES: To determine the risk of invasive pneumococcal disease (IPD) in adult cancer patients stratified by type of underlying malignancy, age, and capsular serotype and to assess herd effects of childhood pneumococcal vaccination. METHODS: All adult IPD cases reported to the Dutch pneumococcal surveillance system between 2004 and 2016 were included in this study. IPD incidence rates (IR) stratified by subtype of malignancy were calculated per 100 000 patient-years of follow-up. Incidence rate ratios (IRR) were calculated to compare IRs between groups. RESULTS: A total of 7167 IPD cases were included, of which 1453 were in patients with malignancies. For patients with hematological malignancies (HM) and solid organ malignancies (SOM), IRs were 482/100 000 and 79/100 000, respectively, compared with 15/100 000 in controls. The highest incidence was observed among patients with multiple myeloma, non-Hodgkin lymphoma, chronic lymphocytic leukemia, pancreatic cancer, and lung cancer (3299/100 000, 2717/100 000, 538/100 000, 559/100 000, and 393/100 000, respectively), and in patients ≥50 years old. Among HM patients, the incidence of IPD declined significantly after the implementation of infant pneumococcal vaccination (IRR 0.65, 95% confidence interval 0.51-0.84); among SOM patients, the decline was not statistically significant (IRR 0.88, 95% confidence interval 0.72-1.07). CONCLUSIONS: The IPD disease burden in cancer patients remains high. Large differences in IPD incidence between the different types of cancer demand tailored guidance regarding pneumococcal vaccination.

Persisting Antibody Response 9 Years After Bivalent Human Papillomavirus (HPV) Vaccination in a Cohort of Dutch Women: Immune Response and the Relation to Genital HPV Infections.

The bivalent human papillomavirus (HPV) vaccine is highly effective and induces robust serological responses. Using a Dutch prospective cohort initiated in 2009, including 744 vaccinated and 294 unvaccinated girls (1993-1994) who provide a vaginal self-swab sample, serum sample, and questionnaire yearly, we report a high, persisting antibody response up to 9 years after vaccination for vaccine types HPV-16 or HPV-18. Antibodies against nonvaccine HPV types 31, 33, 45, 52, and 58 were lower but still significantly higher than in unvaccinated individuals. This was also reflected in the seroprevalence. We compared participant characteristics and antibody levels between vaccinated women with and those without HPV infections 1 year before infection (204 incident and 64 persistent infections), but we observed no consistent difference in type-specific antibody levels. Having a high-risk HPV infection was associated with sexual risk behavior and smoking 1 year before infection. Although high antibody levels are necessary for protection, our study suggests that on the individual level other factors such as HPV exposure or antibody avidity could be important.

Incidence and Risk Factors for Invasive Pneumococcal Disease and Community-acquired Pneumonia in Human Immunodeficiency Virus-Infected Individuals in a High-income Setting.

BACKGROUND: Although people living with human immunodeficiency virus (PLWH) are at increased risk of invasive pneumococcal disease (IPD) and community-acquired pneumonia (CAP), it is unclear whether this remains the case in the setting of early initiation of combination antiretroviral therapy (cART), at high CD4 cell counts. This is important, as pneumococcal vaccination coverage in PLWH is low in Europe and the United States, despite longstanding international recommendations. METHODS: We identified all CAP and IPD cases between 2008 and 2017 in a cohort of PLWH in a Dutch HIV referral center. We calculated incidence rates stratified by CD4 count and cART status and conducted a case-control study to identify risk factors for CAP in PLWH receiving cART. RESULTS: Incidence rates of IPD and CAP in PLWH were 111 and 1529 per 100 000 patient-years of follow-up (PYFU). Although IPD and CAP occurred more frequently in patients with CD4 counts <500 cells/µL (incidence rate ratio [IRR], 6.1 [95% confidence interval, 2.2-17] and IRR, 2.4 [95% confidence interval, 1.9-3.0]), the incidence rate in patients with CD4 counts >500 cells/µL remained higher compared with the general population (946 vs 188 per 100 000 PYFU). All IPD isolates were vaccine serotypes. Risk factors for CAP were older age, CD4 counts <500 cells/µL, smoking, drug use, and chronic obstructive pulmonary disease. CONCLUSIONS: The incidence of IPD and CAP among PLWH remains higher compared with the general population, even in those who are virally suppressed and have high CD4 counts. With all serotyped IPD isolates covered by pneumococcal vaccines, our study provides additional argumentation against the poor current adherence to international recommendations to vaccinate PLWH.

Changes in (risk) behavior and HPV knowledge among Dutch girls eligible for HPV vaccination: an observational cohort study.

BACKGROUND: Implementation of human papillomavirus (HPV) vaccination raised concerns that vaccination could lead to riskier sexual behavior. This study explored how possible differences in sexual behavior and HPV knowledge developed over time between HPV-vaccinated and unvaccinated girls. METHODS: A random sample of 19,939 girls (16-17 year olds) eligible for the catch-up HPV vaccination campaign in the Netherlands was invited for a longitudinal study with questionnaires every 6 months over a two-year follow-up period. Possible differences over time between vaccinated and unvaccinated participants were studied using generalized equations estimation (GEE). RESULTS: A total of 2989 girls participated in round one, of which 1574 participated (52.7%) in the final 5th round. Vaccinated girls were more likely to live in more urban areas (OR 1.28, 95%CI 1.10-1.47) and to use alcohol (OR 1.46, 95%CI 1.24-1.70) and contraceptives (OR 1.69, 95%CI 1.45-1.97). Vaccinated and unvaccinated girls showed comparable knowledge on HPV, HPV vaccination, and transmission. Vaccinated girls were more likely to be sexually active (OR 1.19, 95%CI 1.02-1.39), and this difference increased over time (OR for interaction 1.06, 95%CI 1.00-1.12). However, they had a slightly lower number of lifetime sexual partners (mean difference - 0.20, 95%CI -0.41-0.00). Vaccinated girls were less likely to use a condom with a steady partner (aOR 0.71, 95%CI 0.56-0.89). However, the difference between vaccinated and unvaccinated girls with regard to condom use with casual or steady partner(s) did not significantly change over time. CONCLUSION: Overall, we did not find indications that vaccination influenced sexual behavior in girls during 2 years of follow-up. The few differences found may be related to existing disparities in the socio-demographic characteristics of the young population pointing to the importance and improvement of education with regard to safe sex practices. Our findings do not suggest that vaccination status is associated with changes in sexual risk behavior and thus it is unlikely that this might influence the effectiveness of the vaccination program.

Long-term mortality after IPD and bacteremic versus non-bacteremic pneumococcal pneumonia.

BACKGROUND: Short-term mortality after invasive pneumococcal disease (IPD) and pneumococcal pneumonia is high but data on long-term mortality (including the comparison between bacteremic and non-invasive/non-bacteremic pneumococcal pneumonia) within the first years after diagnosis are scarce. METHODS: Adult patients with 'non-pneumonia' IPD and 'invasive pneumonia' (from 2004 to 2012) and with 'bacteremic' vs 'non-invasive/non-bacteremic (NI/NB)' pneumococcal pneumonia (from 2008 to 2012) diagnosed by negative blood culture but a positive urinary antigen test (UAT) were identified in a Dutch hospital. Mortality of patients up to 10years after diagnosis was compared with age- and sex-matched life-expectancy data of the general population. Multivariable Cox regression analysis was used to study predictors for mortality in invasive pneumonia patients and to adjust for confounders comparing mortality between bacteremic and NI/NB/UAT-positive pneumonia patients. RESULTS: Of 228 invasive pneumonia patients 17% died within 30days and in 30-day survivors cumulative long-term mortality at 1 and 5years were 16% and 39% as compared with 3% and 15% in age- and sex-matched persons. High mortality was largely dependent on pre-existent comorbidities. In invasive pneumonia patients who survived the first 30days, age, male gender, chronic cardiovascular disease, malignancy and PCV7 serotype disease were independent predictors for higher long-term mortality. For bacteremic pneumonia patients (n=128) 30-day mortality was 16% and almost similar to 14% in NI/NB/UAT-positive pneumococcal pneumonia patients (n=170). In 30-day survivors of bacteremic pneumonia (n=108, median age 66years), cumulative mortality at 1 and 3years were 13% and 29% as compared with 18% and 40% in NI/NB/UAT-positive pneumococcal pneumonia patients (n=146, median age 67years) without a significant difference in mortality. CONCLUSIONS: Approximately 40% of all patients, who survived the first 30days after presentation with non-pneumonia IPD and pneumococcal pneumonia died within the following 5years. High long-term mortality was largely dependent on pre-existent comorbidity.

Immune Responses After 2 Versus 3 Doses of HPV Vaccination up to 4½ Years After Vaccination: An Observational Study Among Dutch Routinely Vaccinated Girls.

BACKGROUND: In 2014 the Netherlands switched from 3 to 2 doses for routine vaccination with the prophylactic bivalent human papillomavirus (HPV) vaccine. The current study explored whether antibody responses are noninferior after 2 versus 3 doses in girls. METHODS: Girls vaccinated at 12 years of age with 2 (at 0 and 6 months) or 3 doses (at 0, 1, and 6 months) of the bivalent HPV vaccine were identified in the vaccination registration system. Type-specific antibody concentrations and avidity against HPV-16/18/31/33/45/52/58 were assessed. Analyses were stratified for time since the first dose (0-2, 2-3, 3-4, or 4-4½ years). Noninferiority (margin, 0.5) of the 2- versus the 3-dose schedule in girls was examined. RESULTS: Geometric mean concentrations (GMCs) for vaccine types were only noninferior for 2 versus 3 doses for HPV-18 (at 2-3 years after the first dose; GMC ratio, 0.89; 95% confidence interval, .57-1.38) For vaccine types and cross-protective types (HPV-16/18/31/33/45), the avidity index was noninferior for the 2-dose compared with the 3-dose schedule, except for HPV-31 at 4-4½ years after the first dose and HPV-33 at 3-4 and 4-4½ years. CONCLUSIONS: GMCs for HPV-16/18 were not noninferior for 2 versus 3 doses, except for HPV-18 (at 2-3 years after first dose). However, antibody avidity for these types showed noninferiority, independent of concentrations.

Effectiveness of human papillomavirus vaccine against incident and persistent infections among young girls: Results from a longitudinal Dutch cohort study.

INTRODUCTION: Because of the long interval between infection with high-risk human papillomavirus (hrHPV) and development of cervical cancer surrogate markers for cancer incidence are necessary to monitor vaccine effectiveness (VE). The aim of this study was to calculate VE of HPV16/18 vaccination by annually assessing incident and persistent infections among (un)vaccinated girls from the general Dutch population up to 3 years after vaccination. METHODS: In 2009, 1668 girls (54% vaccinated) aged 14-16 years were enrolled in a prospective cohort study. Annually, questionnaire data were obtained, and a vaginal swab was tested for type-specific HPV DNA with SPF10-LiPA. VE was estimated by a Poisson model comparing type-specific infection rates in (un)vaccinated girls. RESULTS: The adjusted VE (95% CI) was 73% (49-86%) against incident infections with HPV16/18 and 72% (52-84%) against HPV16/18/31/45. VE against persistent HPV16/18 was 100% and 76% (-17 to 95%) against HPV16/18/31/45. This number was lower (36%) when girls who were positive for HPV16 and 18 at baseline were included in the analysis. The overall VE for hrHPV types combined was small. Although 96% of girls were HPV-naïve at baseline, the cumulative 36-month incidence for any HPV was 20%, indicating high sexual activity. DISCUSSION: Vaccination is effective against incident and persistent infections with HPV16/18 and HPV16/18/31/45. Low VE against persistent HPV16/18 infection in girls positive at baseline indicates importance of vaccination before sexual debut.

Inconclusive evidence for non-inferior immunogenicity of two- compared with three-dose HPV immunization schedules in preadolescent girls: A systematic review and meta-analysis.

BACKGROUND: The European Medicines Agency (EMA) recently approved two-dose immunization schedules for bivalent (HPV 16/18) and quadrivalent (HPV 6/11/16/18) human papillomavirus (HPV) vaccines in nine to fourteen and thirteen year-old-girls, respectively. Registration was based on trials comparing immunogenicity of two-dose schedules in girls 9-14 years to three-dose schedules in young women 15-26 years. We evaluate comparability of antibody levels between and within age groups and discuss potential implications for monitoring the effectiveness of HPV vaccination. METHODS: A systematic literature search was performed for studies comparing immunogenicity of two- to three-dose schedules of HPV vaccination. We compared geometric mean concentrations (GMCs) of vaccine-type antibodies between different dosing schedules across different age groups. Meta-analysis was used to estimate pooled GMC ratios (bivalent vaccine) of two- compared with three-dose schedules within girls. FINDINGS: For both vaccines, two-dose immunization of girls yielded non-inferior GMCs relative to a three-dose schedule in young women up to respectively 36 and 48 months follow-up. Pooled GMC ratios for the bivalent vaccine within girls showed the two-dose schedule becoming inferior to the three-dose schedule in girls for HPV 16 at approximately two years after the first dose. For the quadrivalent vaccine, antibody responses for HPV-18 became inferior from 18 months follow-up onwards when comparing the two-dose schedule with the three-dose schedule within girls. IMPLICATIONS: Two-dose immunization of girls has non-inferior immunogenicity compared to a three-dose schedule among young women. However, non-inferior immunogenicity of two- compared with three-dose schedules within girls has not been shown at all time points. Due to this inconclusive evidence, implementation of two-dose HPV vaccination needs to be monitored closely.

E-learning enables parents to assess an infantile hemangioma.

BACKGROUND: Infantile hemangiomas (IH) at risk for complications need to be recognized early. OBJECTIVE: We sought to determine if parents are able to assess, after e-learning, whether their child has an IH, is at risk for complications, and needs to be seen (urgently) by a specialist. METHODS: This was a prospective study of 158 parents participating in an IH e-learning module. Parents were asked to assess their child's skin abnormality. A dermatologist answered the same questions (by e-consult). The 2 assessments were compared. RESULTS: Parents showed a 96% concordance with the dermatologist for correct diagnosis after e-learning. Concordances were 79%, 75%, and 84% (P < .001), respectively, on assessing the risk of complications, the need to be seen by a specialist, and the urgency for specialized care. LIMITATIONS: Parents had a relatively high education level and were therefore not representative of the general population. CONCLUSION: Parents were able to correctly diagnose and evaluate an IH after completing an e-learning module. E-learning by parents could result in earlier presentation and treatment of high-risk IH.

Differences in interaction and subgroup-specific effects were observed between randomized and nonrandomized studies in three empirical examples.

OBJECTIVE: To determine the comparability of subgroup-specific and interaction effects (differences between subgroups) between different study designs. STUDY DESIGN AND SETTING: We compared effects of interventions based on observational studies, randomized clinical trials (RCTs), and individual patient data meta-analyses (IPDMAs) of RCTs (reference) on three clinical topics: (1) mammography screening and breast cancer mortality, (2) coronary artery bypass surgery (CABG) and all-cause mortality, and (3) statins and incidence of major coronary events. Main, subgroup-specific, and interaction effects were compared. RESULTS: Main and subgroup-specific effects were comparable with respect to the direction of the effects. Differences in the magnitude of subgroup-specific effects in observational studies yielded different interactions compared with those in IPDMA. In the mammography example, the ratio of risk ratios (RRR) (i.e., interaction effect) among observational studies was 1.46 [95% confidence interval (CI): 1.09, 1.96] compared with an IPDMA effect of 1.10 (95% CI: 0.89, 1.37). For the CABG studies, the observational RRR was 1.03 (95% CI: 0.84, 1.26), whereas in the IPDMA, this was 1.40 (95% CI: 1.08, 1.1.81). Finally, in the statin example, the RRR was 1.35 (95% CI: 1.13, 1.61) and 0.90 (95% CI: 0.84, 0.97) for observational studies and IPDMA, respectively. CONCLUSION: Main and subgroup-specific effects based on observational data were similar to main and subgroup-specific effects in IPDMAs based on RCTs, yet interactions differed.