Susanne M. Huijts

Validation of an immunodiagnostic assay for detection of 13 Streptococcus pneumoniae serotype-specific polysaccharides in human urine.

ABSTRACT To improve the clinical diagnosis of pneumococcal infection in bacteremic and nonbacteremic community-acquired pneumonia (CAP), a Luminex technology-based multiplex urinary antigen detection (UAD) diagnostic assay was developed and validated. The UAD assay can simultaneously detect 13 different serotypes of Streptococcus pneumoniae by capturing serotype-specific S. pneumoniae polysaccharides (PnPSs) secreted in human urine. Assay specificity is achieved by capturing the polysaccharides with serotype-specific monoclonal antibodies (MAbs) on spectrally unique microspheres. Positivity for each serotype was based on positivity cutoff values calculated from a standard curve run on each assay plate together with positive- and negative-control urine samples. The assay is highly specific, since significant signals are detected only when each PnPS was paired with its homologous MAb-coated microspheres. Validation experiments demonstrated excellent accuracy and precision. The UAD assay and corresponding positivity cutoff values were clinically validated by assessing 776 urine specimens obtained from patients with X-ray-confirmed CAP. The UAD assay demonstrated 97% sensitivity and 100% specificity using samples obtained from patients with bacteremic, blood culture-positive CAP. Importantly, the UAD assay identified Streptococcus pneumoniae (13 serotypes) in a proportion of individuals with nonbacteremic CAP, a patient population for which the pneumococcal etiology of CAP was previously difficult to assess. Therefore, the UAD assay provides a specific, noninvasive, sensitive, and reproducible tool to support vaccine efficacy as well as epidemiological evaluation of pneumococcal disease, including CAP, in adults.

Diagnostic accuracy of a serotype specific antigen test in community-acquired pneumonia

Our aim was to evaluate the diagnostic accuracy and clinical utility of a serotype-specific urinary antigen detection multiplex assay for identification of 13 pneumococcal serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F) in urine of patients with community-acquired pneumonia. Adult patients with clinical suspicion of community-acquired pneumonia were included. In addition to standard diagnostic procedures, a urine sample was collected to perform the urinary antigen detection test. Demographic, clinical, radiological and microbiological data were collected. Among 1095 community-acquired pneumonia patients Streptococcus pneumoniae was identified as causative pathogen in 257 (23%), when using conventional diagnostic methods and in 357 (33%) when urinary antigen detection was added. Of the 49 bacteraemic episodes caused by one of the 13 serotypes covered by the urinary antigen detection, 48 were detected by the urinary antigen detection, indicating a sensitivity of 98%. Of the 77 community-acquired pneumonia episodes with a “non-urinary antigen detection” causative pathogen, none had a positive urinary antigen detection result, indicating a specificity of 100%. Addition of the urinary antigen detection test to conventional diagnostic methods increased the prevalence of S. pneumoniae community-acquired pneumonia by 39%. Using bacteraemic episodes as reference sensitivity and specificity of the urinary antigen detection was 98% and 100%, respectively. Addition of urinary antigen detection test to conventional diagnostic methods increases prevalence of S. pneumoniae CAP http://ow.ly/nSA1l

Cost-effectiveness of adult pneumococcal conjugate vaccination in the Netherlands.

The Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) demonstrated the efficacy of 13-valent pneumococcal conjugate vaccine (PCV13) in preventing vaccine-type community-acquired pneumonia and vaccine-type invasive pneumococcal disease in elderly subjects. We examined the cost-effectiveness of PCV13 vaccination in the Netherlands. Using a Markov-type model, incremental cost-effectiveness ratios (ICER) of PCV13 vaccination in different age- and risk-groups for pneumococcal disease were evaluated using a societal perspective. Estimates of quality-adjusted life-years (QALYs), costs, vaccine efficacy and epidemiological data were based on the CAPiTA study and other prospective studies. The base-case was PCV13 vaccination of adults aged 65–74 years compared to no vaccination, assuming no net indirect effects in base-case due to paediatric 10-valent pneumococcal conjugate vaccine use. Analyses for age- and risk-group specific vaccination strategies and for different levels of hypothetical herd effects from a paediatric PCV programme were also conducted. The ICER for base-case was €8650 per QALY (95% CI 5750–17 100). Vaccination of high-risk individuals aged 65–74 years was cost-saving and extension to medium-risk individuals aged 65–74 years yielded an ICER of €2900. Further extension to include medium- and high-risk individuals aged ≥18 years yielded an ICER of €3100. PCV13 vaccination is highly cost-effective in the Netherlands. The transferability of our results to other countries depends upon vaccination strategies already implemented in those countries. Vaccinating the elderly with 13-valent pneumococcal conjugate vaccine is highly cost-effective http://ow.ly/NVeui

Incidence, direct costs and duration of hospitalization of patients hospitalized with community acquired pneumonia: A nationwide retrospective claims database analysis.

BACKGROUND Community-acquired pneumonia (CAP) is one of the most common acute infections associated with a substantial clinical and economic burden. There have been few studies assessing incidence rate, duration of hospitalization, and costs of hospitalized CAP by age and care-setting. METHODS A retrospective study was conducted using a nationwide Dutch database containing healthcare claims data of 16.7 million inhabitants. Patients with at least one claim with a discharge diagnosis of CAP between January 2008 and December 2011 were selected. The main outcome measures considered were the incidence rate, duration of hospitalization, and the direct costs of hospitalized CAP stratified by age and care-setting. RESULTS In total, 195,372 CAP cases were included in the analysis resulting in an average incidence of 295 per 100,000 population per year. Sixty-three percent (123,357) of the included patients were hospitalized for 1 or more nights, of which 5.9% (n=7241) spent at least one night in the Intensive Care Unit (ICU). Overall, these 123,357 patients spent 824,985 days in the hospital of which 48,324 were spent on the ICU. The mean duration of hospitalization of ICU patients and general ward patients was 15.2 days and 6.2 days, respectively. The total costs related to all 195,372 CAP episodes during these 4 years were €711 million, with the majority (76%) occurring among those aged 50 years and older. Median (and mean) costs were dependent on age and type of care with costs ranging from €344 (€482) per episode for 0-9 year olds treated in the outpatient hospital setting up to €10,284 (€16,374) per episode for 50-64 year olds admitted to the ICU. CONCLUSION There is a large variation in terms of incidence, disease burden and costs across different age groups and the treatment setting. Effective interventions, targeted at older adults, to prevent pneumonia could reduce the (financial) burden due to pneumonia.

Vaccine against Pneumococcal Pneumonia in Adults

n engl j med 373;1 nejm.org july 2, 2015 91 1. Hulten E, Bittencourt MS, Singh A, et al. Coronary artery disease detected by coronary computed tomographic angiography is associated with intensification of preventive medical therapy and lower low-density lipoprotein cholesterol. Circ Cardiovasc Imaging 2014;7:629-38. 2. Hachamovitch R, Nutter B, Hlatky MA, et al. Patient management after noninvasive cardiac imaging results from SPARC (Study of myocardial perfusion and coronary anatomy imaging roles in coronary artery disease). J Am Coll Cardiol 2012;59:462-74.

The impact of age on the efficacy of 13-valent pneumococcal conjugate vaccine in elderly

In a post hoc analysis of the Community-Acquired Pneumonia (CAP) immunization Trial in Adults the model-predicted 13-valent pneumococcal conjugate vaccine efficacy for preventing vaccine-type specific CAP and Invasive Pneumococcal Disease declined from 65% to 40% for subjects being 65 and 75 year olds at the time of vaccination, respectively.

Pneumococcal conjugate vaccine herd effects on non-invasive pneumococcal pneumonia in elderly

BACKGROUND Herd protection from infant pneumococcal conjugate vaccination is well established for invasive pneumococcal disease (IPD) but not for non-IPD pneumococcal community-acquired pneumonia (PCAP). We assessed the contribution of vaccine-serotypes in non-IPD PCAP in adults 65 years and older in the period 2008-2013. METHODS This is a post hoc analysis of two prospective studies from the Netherlands. Serotype specific urinary antigen detection and routine microbiological testing were used to categorize episodes as IPD or non-IPD PCAP caused by 7-valent pneumococcal conjugate vaccine (PCV7), PCV10-7 (three additional PCV10 serotypes), PCV13-10 (three additional PCV13 serotypes), and non-PCV13 serotypes. Proportions per vaccine-serotype group were assessed per year from June 1st to May 31st. Time trends were compared to national IPD data. RESULTS Of 270 non-IPD PCAP episodes with known serotype, PCV7 serotypes decreased from 28% in 2008/2009 to 7% in 2012/2013 (p-value for trend <0.001). No change in PCV10-7 (19% overall) and PCV13-10 (29% overall) serotypes was observed. Non-PCV13 serotypes increased from 30% in 2008/2009 to 37% in 2012/2013 (p-value for trend 0.048). Trends corresponded with national IPD data. CONCLUSION PCV7 serotypes declined in non-IPD PCAP among elderly between 2008 and 2013, comparable to IPD data. No reduction in the additional PCV10 serotypes could be demonstrated within the first two years after PCV10 introduction.

Post-hoc analysis of a randomized controlled trial: Diabetes mellitus modifies the efficacy of the 13-valent pneumococcal conjugate vaccine in elderly

BACKGROUND The 13-valent pneumococcal conjugate-vaccine (PCV13) was effective in preventing vaccine-type Community-Acquired Pneumonia (VT-CAP) and Invasive Pneumococcal Disease (VT-IPD) in elderly subjects, but vaccine efficacy (VE) in patients with comorbidities at time of vaccination is unknown. METHODS This is a post hoc analysis of the CAPiTA study, a double blind, randomized controlled trial with 84,496 immunocompetent participants aged ⩾65years, receiving PCV13 or placebo vaccination. Presence of diabetes mellitus (DM), heart disease, respiratory disease, liver disease, asplenia, and smoking at the time of immunization was verified on medical records in 139 subjects developing the primary endpoint of VT-CAP. Presence of DM and respiratory disease based on International Classification of Primary Care (ICPC) coding was also determined in 40,427 subjects. FINDINGS In the 139 subjects developing VT-CAP, DM caused significant effect modification (p-value 0.002), yielding VE of 89.5% (95%CI, 65.5-96.8) and 24.7% (95%CI, -10.4 to 48.7) for those with and without DM, respectively. Comparable effect modification (p-value 0.020) was found in the 40,427 subjects with and without ICPC-based classification of DM with VE of 85.6% (95%CI, 36.7-96.7) and of 7.0% (95%CI, -58.5 to 45.5) respectively. Effect modification through respiratory disease was not statistically significant, although the point estimate of VE was lower for those with respiratory disease in both analyses. There was no evidence of effect modification in subjects stratified by heart disease, smoking, and presence of any comorbidity. CONCLUSIONS Among immunocompetent elderly, VE of PCV13 was modified by DM with higher VE among subjects with DM. Significant effect modification was not observed for subjects with heart disease, respiratory disease, smoking, or presence of any comorbidity. CAPiTA trial registration number: www.ClinicalTrials.gov; trial number NCT00744263.

The scrutiny of identifying community-acquired pneumonia episodes quantified bias in absolute effect estimation in a population-based pneumococcal vaccination trial

OBJECTIVES To determine the accurateness of detecting community-acquired pneumonia (CAP) in the Community-Acquired Pneumonia immunization Trial in Adults (CAPiTA), a community-based, double-blind, randomized placebo-controlled trial in which the needed to treat (NNT) for prevention of vaccine-type pneumococcal CAP was 1,007 [95% confidence interval (CI): 613, 2,646]. STUDY DESIGN AND SETTING Study participants developing pneumonia were identified in 58 participating hospitals by research nurses (RNs) using local-adapted protocols. In addition, general practitioner (GP) records were screened for hospital referrals for suspected pneumonia. Two independent reviewers determined reasons for not identifying pneumonia episodes, and the NNT adjusted for missed episodes was estimated. RESULTS Of 2,183 hospital referrals with suspected pneumonia detected in GP records, 232 (11%) were admitted outside established screening routes and 102 (5%) were not suspected of pneumonia on admission. Of the remaining 1,849 episodes, 1,374 (63% of all episodes and 74% of identifiable episodes) were identified by RNs. Several causes of missing episodes were identified. After adjustment for missed episodes, the NNT reduced to 634 (95% CI: 386, 1,675). CONCLUSION With the screening procedure, 63% of suspected pneumonia episodes were identified, and the estimated NNT reduced from 1,007 to 634. Root cause analysis of unidentified episodes provides guidance for improving pneumonia detection in future trials.

Predictors of bacteraemia in patients with suspected community-acquired pneumonia

Introduction The diagnostic yield of blood cultures is limited in patients with community-acquired pneumonia (CAP). Yet, positive blood culture results provide important information for antibiotic treatment and for monitoring epidemiologic trends. We investigated the potential of clinical predictors to improve the cost-benefit ratio of obtaining blood cultures. Methods Data from two prospective cohort studies of adults with suspected CAP, admitted to non-ICU wards, were combined. Two models were created, one using readily available parameters and one additionally including laboratory parameters. Results 3,786 patients were included (2,626 (69%) with X-ray confirmed CAP). Blood cultures were obtained from 2,977 (79%) patients (and from 2,107 (80%) with X-ray confirmed CAP). 266 (8.9%) of the patients with a blood culture had bacteraemia. Clinical predictors of bacteraemia were absence of pre-admission antibiotic treatment, pleuritic pain, gastro-intestinal symptoms, tachycardia, tachypnea, hypotension and absence of hypoxia. After including laboratory results in the model, younger age, C-reactive protein, leukocytosis or leukopenia, low thrombocyte count, low sodium level, elevated urea and elevated arterial pH were added, while gastro-intestinal symptoms and hypotension were no longer significant. The area under the receiver operating characteristics curve was 0.66 (95% confidence interval 0.63–0.70) for the first model and 0.76 (95% confidence interval 0.73–0.79) for the second model. Conclusion In conclusion, in patients hospitalized with CAP, bacteraemia was moderately predictable using clinical parameters only. We recommend against the use of a risk prediction model for the decision to obtain blood cultures.