Maroeska M. Rovers

Respiratory syncytial virus and recurrent wheeze in healthy preterm infants

BACKGROUND Respiratory syncytial virus (RSV) infection is associated with subsequent recurrent wheeze. Observational studies cannot determine whether RSV infection is the cause of recurrent wheeze or the first indication of preexistent pulmonary vulnerability in preterm infants. The monoclonal antibody palivizumab has shown efficacy in preventing severe RSV infection in high-risk infants. METHODS In the double-blind, placebo-controlled MAKI trial, we randomly assigned 429 otherwise healthy preterm infants born at a gestational age of 33 to 35 weeks to receive either monthly palivizumab injections (214 infants) or placebo (215 infants) during the RSV season. The prespecified primary outcome was the total number of parent-reported wheezing days in the first year of life. Nasopharyngeal swabs were taken during respiratory episodes for viral analysis. RESULTS Palivizumab treatment resulted in a relative reduction of 61% (95% confidence interval, 56 to 65) in the total number of wheezing days during the first year of life (930 of 53,075 days in the RSV-prevention group [1.8%] vs. 2309 of 51,726 days [4.5%] in the placebo group). During this time, the proportion of infants with recurrent wheeze was 10 percentage points lower in patients treated with palivizumab (11% vs. 21%, P=0.01). CONCLUSIONS In otherwise healthy preterm infants, palivizumab treatment resulted in a significant reduction in wheezing days during the first year of life, even after the end of treatment. These findings implicate RSV infection as an important mechanism of recurrent wheeze during the first year of life in such infants. (Funded by Abbott Laboratories and by the Netherlands Organization for Health Research and Development; MAKI Controlled Clinical Trials number, ISRCTN73641710.).

Preferred Reporting Items for a Systematic Review and Meta-analysis of Individual Participant Data The PRISMA-IPD Statement

IMPORTANCE Systematic reviews and meta-analyses of individual participant data (IPD) aim to collect, check, and reanalyze individual-level data from all studies addressing a particular research question and are therefore considered a gold standard approach to evidence synthesis. They are likely to be used with increasing frequency as current initiatives to share clinical trial data gain momentum and may be particularly important in reviewing controversial therapeutic areas. OBJECTIVE To develop PRISMA-IPD as a stand-alone extension to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) Statement, tailored to the specific requirements of reporting systematic reviews and meta-analyses of IPD. Although developed primarily for reviews of randomized trials, many items will apply in other contexts, including reviews of diagnosis and prognosis. DESIGN Development of PRISMA-IPD followed the EQUATOR Network framework guidance and used the existing standard PRISMA Statement as a starting point to draft additional relevant material. A web-based survey informed discussion at an international workshop that included researchers, clinicians, methodologists experienced in conducting systematic reviews and meta-analyses of IPD, and journal editors. The statement was drafted and iterative refinements were made by the project, advisory, and development groups. The PRISMA-IPD Development Group reached agreement on the PRISMA-IPD checklist and flow diagram by consensus. FINDINGS Compared with standard PRISMA, the PRISMA-IPD checklist includes 3 new items that address (1) methods of checking the integrity of the IPD (such as pattern of randomization, data consistency, baseline imbalance, and missing data), (2) reporting any important issues that emerge, and (3) exploring variation (such as whether certain types of individual benefit more from the intervention than others). A further additional item was created by reorganization of standard PRISMA items relating to interpreting results. Wording was modified in 23 items to reflect the IPD approach. CONCLUSIONS AND RELEVANCE PRISMA-IPD provides guidelines for reporting systematic reviews and meta-analyses of IPD.

Attributable mortality of ventilator-associated pneumonia: a meta-analysis of individual patient data from randomised prevention studies

BACKGROUND Estimating attributable mortality of ventilator-associated pneumonia has been hampered by confounding factors, small sample sizes, and the difficulty of doing relevant subgroup analyses. We estimated the attributable mortality using the individual original patient data of published randomised trials of ventilator-associated pneumonia prevention. METHODS We identified relevant studies through systematic review. We analysed individual patient data in a one-stage meta-analytical approach (in which we defined attributable mortality as the ratio between the relative risk reductions [RRR] of mortality and ventilator-associated pneumonia) and in competing risk analyses. Predefined subgroups included surgical, trauma, and medical patients, and patients with different categories of severity of illness scores. FINDINGS Individual patient data were available for 6284 patients from 24 trials. The overall attributable mortality was 13%, with higher mortality rates in surgical patients and patients with mid-range severity scores at admission (ie, acute physiology and chronic health evaluation score [APACHE] 20-29 and simplified acute physiology score [SAPS 2] 35-58). Attributable mortality was close to zero in trauma, medical patients, and patients with low or high severity of illness scores. Competing risk analyses could be done for 5162 patients from 19 studies, and the overall daily hazard for intensive care unit (ICU) mortality after ventilator-associated pneumonia was 1·13 (95% CI 0·98-1·31). The overall daily risk of discharge after ventilator-associated pneumonia was 0·74 (0·68-0·80), leading to an overall cumulative risk for dying in the ICU of 2·20 (1·91-2·54). Highest cumulative risks for dying from ventilator-associated pneumonia were noted for surgical patients (2·97, 95% CI 2·24-3·94) and patients with mid-range severity scores at admission (ie, cumulative risks of 2·49 [1·81-3·44] for patients with APACHE scores of 20-29 and 2·72 [1·95-3·78] for those with SAPS 2 scores of 35-58). INTERPRETATION The overall attributable mortality of ventilator-associated pneumonia is 13%, with higher rates for surgical patients and patients with a mid-range severity score at admission. Attributable mortality is mainly caused by prolonged exposure to the risk of dying due to increased length of ICU stay. FUNDING None.

Cord Blood Vitamin D Deficiency is Associated With Respiratory Syncytial Virus Bronchiolitis

BACKGROUND: Respiratory syncytial virus (RSV) is the most important pathogen causing severe lower respiratory tract infection (LRTI) in infants. Epidemiologic and basic studies suggest that vitamin D may protect against RSV LRTI. OBJECTIVE: To determine the association between plasma vitamin D concentrations at birth and the subsequent risk of RSV LRTI. DESIGN: A prospective birth cohort study was performed in healthy term neonates. Concentrations of 25-hydroxyvitamin D (25-OHD) in cord blood plasma were related to RSV LRTI in the first year of life, defined as parent-reported LRTI symptoms in a daily log and simultaneous presence of RSV RNA in a nose-throat specimen. RESULTS: The study population included 156 neonates. Eighteen (12%) developed RSV LRTI. The mean plasma 25-OHD concentration was 82 nmol/L. Overall, 27% of neonates had 25-OHD concentrations <50 nmol/L, 27% had 50-74 nmol/L and only 46% had 25-OHD 75 nmol/L. Cord blood 25-OHD concentrations were strongly associated with maternal vitamin D3 supplementation during pregnancy. Concentrations of 25-OHD were lower in neonates who subsequently developed RSV LRTI compared with those who did not (65 nmol/L versus 84 nmol/L, P = .009). Neonates born with 25-OHD concentrations <50 nmol/L had a sixfold (95% confidence interval: 1.6-24.9; P = .01) increased risk of RSV LRTI in the first year of life compared with those with 25-OHD concentrations ≥75 nmol/L. CONCLUSIONS: Vitamin D deficiency in healthy neonates is associated with increased risk of RSV LRTI in the first year of life. Intensified routine vitamin D supplementation during pregnancy may be a useful strategy to prevent RSV LRTI during infancy.

Use of the Prostate Imaging Reporting and Data System (PI-RADS) for Prostate Cancer Detection with Multiparametric Magnetic Resonance Imaging: A Diagnostic Meta-analysis

CONTEXT In 2012, an expert panel of the European Society of Urogenital Radiology (ESUR) published the Prostate Imaging Reporting and Data System (PI-RADS) for prostate cancer (PC) detection with multiparametric magnetic resonance imaging (mp-MRI). Since then, many centers have reported their experiences. PURPOSE To review the diagnostic accuracy of PI-RADS for PC detection with mp-MRI. EVIDENCE ACQUISITION We searched Medline and Embase up to March 20, 2014. We included diagnostic accuracy studies since 2012 that used PI-RADS with mp-MRI for PC detection in men, using prostatectomy or biopsy as the reference standard. The methodological quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool by two independent reviewers. Data necessary to complete 2×2 contingency tables were obtained from the included studies, and test characteristics including sensitivity and specificity were calculated. Results were pooled and plotted in a summary receiver operating characteristics plot. EVIDENCE SYNTHESIS Fourteen studies (1785 patients) could be analyzed. The pooled data showed sensitivity of 0.78 (95% confidence interval [CI] 0.70-0.84) and specificity of 0.79 (95% CI 0.68-0.86) for PC detection, with negative predictive values ranging from 0.58 to 0.95. Sensitivity analysis revealed pooled sensitivity of 0.82 (95% CI 0.72-0.89) and specificity of 0.82 (95% CI 0.67-0.92) in studies with correct use of PI-RADS (ie, clear description in the methodology and no adjustment of criteria). For studies with a less strict or adjusted use of PI-RADS criteria, or unclear description of the methodology, had pooled sensitivity of 0.73 (95% CI 0.62-0.82) and specificity of 0.75 (95% CI 0.61-0.84). CONCLUSIONS In patients for whom PC is suspected, PI-RADS appears to have good diagnostic accuracy in PC detection, but no recommendation regarding the best threshold can be provided because of heterogeneity. PATIENT SUMMARY Pooling of results from all previous studies that used a relatively new 5-point scoring system for prostate magnetic resonance imaging showed that this scoring system appears to be able to detect prostate cancer accurately.

Ischemic preconditioning in the animal kidney, a systematic review and meta-analysis.

Ischemic preconditioning (IPC) is a potent renoprotective strategy which has not yet been translated successfully into clinical practice, in spite of promising results in animal studies. We performed a unique systematic review and meta-analysis of animal studies to identify factors modifying IPC efficacy in renal ischemia/reperfusion injury (IRI), in order to enhance the design of future (clinical) studies. An electronic literature search for animal studies on IPC in renal IRI yielded fifty-eight studies which met our inclusion criteria. We extracted data for serum creatinine, blood urea nitrogen and histological renal damage, as well as study quality indicators. Meta-analysis showed that IPC reduces serum creatinine (SMD 1.54 [95%CI 1.16, 1.93]), blood urea nitrogen (SMD 1.42 [95% CI 0.97, 1.87]) and histological renal damage (SMD 1.12 [95% CI 0.89, 1.35]) after IRI as compared to controls. Factors influencing IPC efficacy were the window of protection (<24 h = early vs. ≥24 h = late) and animal species (rat vs. mouse). No difference in efficacy between local and remote IPC was observed. In conclusion, our findings show that IPC effectively reduces renal damage after IRI, with higher efficacy in the late window of protection. However, there is a large gap in study data concerning the optimal window of protection, and IPC efficacy may differ per animal species. Moreover, current clinical trials on RIPC may not be optimally designed, and our findings identify a need for further standardization of animal experiments.

Open and closed endotracheal suction systems in mechanically ventilated intensive care patients: a meta-analysis.

Background: Closed suction systems (CSS) are increasingly replacing open suction systems (OSS) to perform endotracheal toilet in mechanically ventilated intensive care unit patients. Yet effectiveness regarding patient safety and costs of these systems has not been carefully analyzed. Objective: To review effectiveness of CSS and OSS, with respect to patient outcome, bacterial contamination, and costs in adult intensive care unit patients. Data Source: Search of MEDLINE, CINAHL, EMBASE, and Cochrane databases and a manual review of article bibliographies. Study Selection: Randomized controlled trials comparing CSS and OSS in adult intensive care unit patients were retrieved. Data Extraction/Synthesis: Assessment of abstracts and study quality was performed by two reviewers. Data were combined in meta‐analyses by random effect models. Fifteen trials were identified. No significant differences were found in incidences of ventilator‐associated pneumonia (eight studies, 1,272 patients) and mortality (four studies, 1,062 patients). No conclusions could be drawn with respect to arterial oxygen saturation (five studies, 109 patients), arterial oxygen tension (two studies, 19 patients), and secretion removal (two studies, 37 patients). Compared with OSS, endotracheal suctioning with CSS significantly reduced changes in heart rate (four studies, 85 patients; weighted mean difference, −6.33; 95% confidence interval, −10.80 to −1.87) and changes in mean arterial pressure (three studies, 59 patients; standardized mean difference, −0.43; 95% confidence interval, −0.87 to 0.00) but increased colonization (two studies, 126 patients; relative risk, 1.51; 95% confidence interval, 1.12–2.04). CSS seems to be more expensive than OSS. Conclusions: Based on the results of this meta‐analysis, there is no evidence to prefer CSS more than OSS.

Effectiveness of adenotonsillectomy in children with mild symptoms of throat infections or adenotonsillar hypertrophy: open, randomised controlled trial

Abstract Objective To assess the effectiveness of adenotonsillectomy in children with mild symptoms of throat infections or adenotonsillar hypertrophy. Design Open, randomised controlled trial. Setting 21 general hospitals and three academic centres in the Netherlands. Participants 300 children aged 2-8 years requiring adenotonsillectomy. Intervention Adenotonsillectomy compared with watchful waiting. Main outcome measures Episodes of fever, throat infections, upper respiratory tract infections, and health related quality of life. Results During the median follow up period of 22 months, children in the adenotonsillectomy group had 2.97 episodes of fever per person year compared with 3.18 in the watchful waiting group (difference −0.21, 95% confidence interval −0.54 to 0.12), 0.56 throat infections per person year compared with 0.77 (−0.21, −0.36 to −0.06), and 5.47 upper respiratory tract infections per person year compared with 6.00 (−0.53, −0.97 to −0.08). No clinically relevant differences were found for health related quality of life. Adenotonsillectomy was more effective in children with a history of three to six throat infections than in those with none to two. 12 children had complications related to surgery. Conclusion Adenotonsillectomy has no major clinical benefits over watchful waiting in children with mild symptoms of throat infections or adenotonsillar hypertrophy.

Estimating the attributable mortality of ventilator-associated pneumonia from randomized prevention studies.

Objective:To assess the attributable mortality of ventilator-associated pneumonia using results from randomized controlled trials on ventilator-associated pneumonia prevention. Data Sources:A systematic search was performed in PubMed, Embase, Web of Science, and Cochrane Library from their inception until July 2010. In addition, a reference and related article search was performed. Study Selection:Randomized ventilator-associated pneumonia prevention studies in which all patients were mechanically ventilated and from which ventilator-associated pneumonia and mortality rates of intervention and control group could be extracted were included. Data Extraction/Synthesis:Fifty-three papers were identified describing 58 comparisons. Statistical significant reductions in ventilator-associated pneumonia incidences were reported in 20 of the 58 comparisons, whereas none of these trials reported a significant reduction of mortality. Pooled estimates of the relative risk reductions of both ventilator-associated pneumonia and mortality were calculated and the attributable mortality was estimated as the ratio between the relative risk reductions of mortality and ventilator-associated pneumonia. Effects of study quality, diagnostic methods used, and effectiveness of preventing ventilator-associated pneumonia on the mortality rate of ventilator-associated pneumonia were assessed in subgroup analyses. The overall attributable mortality of ventilator-associated pneumonia was estimated as 9%. In subgroup analyses, the attributable mortality varied between 3% and 17%. Conclusion:Based on the results of 58 randomized studies on ventilator-associated pneumonia prevention, the attributable mortality rate of ventilator-associated pneumonia was estimated to be 9% and ranged between 3% and 17% in subgroup analyses. Together with the results of other recent studies, there is cumulative evidence that the attributable mortality resulting from ventilator-associated pneumonia is approximately 10%.

Traffic-related air pollution and otitis media

Background Otitis media is one of the most common infections in young children. Although exposure to environmental tobacco smoke is a known risk factor associated with otitis media, little information is available regarding the potential association with air pollution. Objective We set out to study the relationship between exposure to traffic-related air pollution and otitis media in two birth cohorts. Methods Individual estimates of outdoor concentrations of traffic-related air pollutants—nitrogen dioxide, fine particles [particulate matter with aerodynamic diameters ≤ 2.5 μm (PM2.5)], and elemental carbon—were calculated for home addresses of approximately 3,700 and 650 infants from birth cohort studies in the Netherlands and Germany, respectively. Air pollution exposure was analyzed in relation to physician diagnosis of otitis media in the first 2 years of life. Results Odds ratios (adjusted for known major risk factors) for otitis media indicated positive associations with traffic-related air pollutants. An increase in 3 μg/m3 PM2.5, 0.5 μg/m3 elemental carbon, and 10 μg/m3 NO2 was associated with odds ratios of 1.13 (95% confidence interval, 1.00–1.27), 1.10 (1.00–1.22), and 1.14 (1.03–1.27) in the Netherlands and 1.24 (0.84–1.83), 1.10 (0.86–1.41), and 1.14 (0.87–1.49) in Germany, respectively. Conclusions These findings indicate an association between exposure to traffic-related air pollutants and the incidence of otitis media. Given the ubiquitous nature of air pollution exposure and the importance of otitis media to children’s health, these findings have significant public health implications.