Diagnosis and Prevention of Pneumococcal Community-Acquired Pneumonia

The first part of this thesis mainly focuses on the diagnosis of pneumococcal Community-Acquired Pneumonia (CAP). It describes the results of a prospective, observational study, conducted in 23 hospitals across the Netherlands to validate a novel serotype specific urinary antigen detection assay (UAD). This test had a sensitivity 98%, compared to vaccine-type blood cultures, and a specificity of 100%, compared to CAP of other aetiology. In addition to conventional diagnostic methods the serotype specific UAD increased the diagnostic yield for S. pneumoniae by 39%. And it describes the development of a prediction model with clinical parameters to predict pneumococcal aetiology, defined by culture results, serotype specific UAD or conventional urinary antigen test, but this model was not useful in daily clinical practice. In the second part of this thesis the results of the Community-Acquired Pneumonia immunization Trial in Adults (CAPiTA) are described. The CAPiTA study was a randomized, placebo-controlled trial in 84,496 immunocompetent adults of 65 years and older investigating the efficacy of the 13-valent pneumococcal conjugate vaccine (PCV13) vaccination in prevention of a first episode of vaccine serotype pneumococcal (VT) CAP, non-bacteremic/ non-invasive (NB/NI) VT-CAP and VT-Invasive Pneumococcal Disease (IPD). In total there were 139 first episode of VT-CAP in the per protocol population: 49 in the PCV13 and 90 in the placebo group, demonstrating a vaccine efficacy (VE) of 45.6%. The VE in prevention of a first episode of NB/NI VT-CAP was 45.0% and for the first episode of VT-IPD it was 75.0%. To evaluate cost-effectiveness of adult PCV13 vaccination in the Netherlands the base-case scenario of PCV13 vaccination of individuals aged 65-74 years was compared to no vaccination, resulting in an Incremental Cost-Effectiveness Ratio (ICER) of €8,650/Quality-adjusted life year. Comparing different vaccination strategies for risk- and age-groups demonstrated that PCV13 vaccination of ‘high-risk‘ individuals aged 65-74 years was most cost-effective (i.e. cost-saving). Vaccine efficacy (VE) of PCV13 was evaluated for patients with diabetes mellitus (DM), heart disease and respiratory disease and there was significant effect modification of DM on the VE (p-value 0.002), with a higher VE for those with than for those without DM. Effect modification of respiratory disease was not significant (p-value 0.056), but VE tended to be lower in subjects with than in those without respiratory disease. VE stratified by heart disease was comparable for both groups. Effect modification of DM was confirmed in 40,427 subjects with comorbidity status of their general practioner available (p-value 0.020). PCV13 vaccination was not associated with a reduction in influenza-associated (VE 34.4%, p=0.117) or viral-associated CAP (VE 3.6%, p=0.737) and not associated with any impact on disease severity, defined by radiographic characteristics, PSI, physical, laboratory or outcome parameters. Of all CAPiTA participants referred to the hospital with a suspected pneumonia (detected in records of general practioners) 63% - 74% was identified as CAP cases by the research nurse in the hospital. After adjustment for these missed episodes, the ‘number needed to vaccinate’ for prevention of VT-CAP reduced from 1007 to 634