Willem Jan W. Bos

Dexamethasone and length of hospital stay in patients with community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial

BACKGROUND Whether addition of corticosteroids to antibiotic treatment benefits patients with community-acquired pneumonia who are not in intensive care units is unclear. We aimed to assess effect of addition of dexamethasone on length of stay in this group, which might result in earlier resolution of pneumonia through dampening of systemic inflammation. METHODS In our double-blind, placebo-controlled trial, we randomly assigned adults aged 18 years or older with confirmed community-acquired pneumonia who presented to emergency departments of two teaching hospitals in the Netherlands to receive intravenous dexamethasone (5 mg once a day) or placebo for 4 days from admission. Patients were ineligible if they were immunocompromised, needed immediate transfer to an intensive-care unit, or were already receiving corticosteroids or immunosuppressive drugs. We randomly allocated patients on a one-to-one basis to treatment groups with a computerised randomisation allocation sequence in blocks of 20. The primary outcome was length of hospital stay in all enrolled patients. This study is registered with ClinicalTrials.gov, number NCT00471640. FINDINGS Between November, 2007, and September, 2010, we enrolled 304 patients and randomly allocated 153 to the placebo group and 151 to the dexamethasone group. 143 (47%) of 304 enrolled patients had pneumonia of pneumonia severity index class 4-5 (79 [52%] patients in the dexamethasone group and 64 [42%] controls). Median length of stay was 6·5 days (IQR 5·0-9·0) in the dexamethasone group compared with 7·5 days (5·3-11·5) in the placebo group (95% CI of difference in medians 0-2 days; p=0·0480). In-hospital mortality and severe adverse events were infrequent and rates did not differ between groups, although 67 (44%) of 151 patients in the dexamethasone group had hyperglycaemia compared with 35 (23%) of 153 controls (p<0·0001). INTERPRETATION Dexamethasone can reduce length of hospital stay when added to antibiotic treatment in non-immunocompromised patients with community-acquired pneumonia. FUNDING None.

Statins and prevention of infections: systematic review and meta-analysis of data from large randomised placebo controlled trials

Objective To evaluate whether the potential of statins to lower the risk of infections as published in observational studies is causal. Design Systematic review and meta-analysis of randomised placebo controlled trials. Data sources Medline, Embase, and the Cochrane Library. Study selection Randomised placebo controlled trials of statins (up to 10 March 2011) enrolling a minimum of 100 participants, with follow-up for at least one year. Data extraction Infection or infection related death. Results The first study selection yielded 632 trials. After screening of the corresponding abstracts and full text papers, 11 trials totalling 30 947 participants were included. 4655 of the participants (2368 assigned to statins and 2287 assigned to placebo) reported an infection during treatment. Meta-analysis showed no effect of statins on the risk of infections (relative risk 1.00, 95% confidence interval 0.96 to 1.05) or on infection related deaths (0.97, 0.83 to 1.13). Conclusion These findings do not support the hypothesis that statins reduce the risk of infections. Absence of any evidence for a beneficial effect in large placebo controlled trials reduces the likelihood of a causal effect as reported in observational studies.

Addition of Vitamin D Status to Prognostic Scores Improves the Prediction of Outcome in Community-Acquired Pneumonia

BACKGROUND Vitamin D plays a role in host defense against infection. Vitamin D deficiency is common worldwide. The prognostic value of vitamin D levels in pneumonia is unknown. In this study, we aimed to investigate the impact of vitamin D status on outcome in community-acquired pneumonia (CAP). METHODS We conducted a prospective cohort study in 272 hospitalized patients with CAP. Levels of 25-hydroxyvitamin D, leukocytes, C-reactive protein, and total cortisol and the Pneumonia Severity Index (PSI) and CURB-65 scores were measured on admission. Major outcome measures were intensive care unit (ICU) admission and 30-day mortality. RESULTS One hundred forty-three patients (53%) were vitamin D deficient (<50 nmol/L), 79 patients (29%) were vitamin D insufficient (50-75 nmol/L), and 50 patients (18%) were vitamin D sufficient (>75 nmol/L). Vitamin D deficiency was associated with an increased risk of ICU admission and 30-day mortality. Vitamin D status was an independent predictor of 30-day mortality (area under the curve [AUC] =0.69; 95% confidence interval [CI], .57-.80). Multivariate regression analysis including all predictors for outcome resulted in a final model including vitamin D status and the PSI score, with a significantly higher prognostic accuracy compared with the PSI score alone (AUC=0.83; 95% CI, .71-.94). CONCLUSIONS Vitamin D deficiency is associated with adverse outcome in CAP. Vitamin D status is an independent predictor of 30-day mortality and adds prognostic value to other biomarkers and prognostic scores, in particular the PSI score. CLINICAL TRIALS REGISTRATION NCT00471640.

Treatment with anti‐inflammatory drugs in community‐acquired pneumonia

Abstract. Meijvis SCA, van de Garde EMW, Rijkers GT, Bos WJW (St. Antonius Hospital, Nieuwegein; Utrecht University, Utrecht; St. Antonius Hospital, Nieuwegein; and Roosevelt Academy, Middelburg, The Netherlands). Treatment with anti‐inflammatory drugs in community‐acquired pneumonia (Review). J Intern Med 2012; 272: 25–35.

The impact of renal function on platelet reactivity and clinical outcome in patients undergoing percutaneous coronary intervention with stenting

Patients with chronic kidney disease (CKD) have an increased risk of cardiovascular disease. Previous studies have suggested that patients with CKD have less therapeutic benefit of antiplatelet therapy. However, the relation between renal function and platelet reactivity is still under debate. On-treatment platelet reactivity was determined in parallel by ADP- and AA-induced light transmittance aggregometry (LTA) and the VerifyNow® System (P2Y12 and Aspirin) in 988 patients on dual antiplatelet therapy, undergoing elective coronary stenting. Patients were divided into two groups according to the presence or absence of moderate/severe CKD (GFR<60 ml/min/1.73 m²). Furthermore, the incidence of all-cause death, non-fatal acute myocardial infarction, stent thrombosis and stroke at one-year was evaluated. Patients with CKD (n=180) had significantly higher platelet reactivity, regardless of the platelet function test used. Patients with CKD more frequently had high on-clopidogrel platelet reactivity (HCPR) and high on-aspirin platelet reactivity (HAPR) regardless of the platelet function test used. After adjustment for potential confounders, this was no longer significant. The event-rate was the highest in patients with both high on-treatment platelet reactivity (HPR) and CKD compared to those with neither high on-treatment platelet reactivity nor CKD. In conclusion, the magnitude of platelet reactivity as well as the incidence of HPR was higher in patients with CKD. However, since the incidence of HPR was similar after adjustment, a higher rate of co-morbidities in patients with CKD might be the major cause for this observation rather than CKD itself. CKD-patients with HCPR were at the highest risk of long-term cardiovascular events.

Association of Traditional Cardiovascular Risk Factors With Venous Thromboembolism: An Individual Participant Data Meta-Analysis of Prospective Studies.

Background: Much controversy surrounds the association of traditional cardiovascular disease risk factors with venous thromboembolism (VTE). Methods: We performed an individual level random-effect meta-analysis including 9 prospective studies with measured baseline cardiovascular disease risk factors and validated VTE events. Definitions were harmonized across studies. Traditional cardiovascular disease risk factors were modeled categorically and continuously using restricted cubic splines. Estimates were obtained for overall VTE, provoked VTE (ie, VTE occurring in the presence of 1 or more established VTE risk factors), and unprovoked VTE, pulmonary embolism, and deep-vein thrombosis. Results: The studies included 244 865 participants with 4910 VTE events occurring during a mean follow-up of 4.7 to 19.7 years per study. Age, sex, and body mass index-adjusted hazard ratios for overall VTE were 0.98 (95% confidence interval [CI]: 0.89−1.07) for hypertension, 0.97 (95% CI: 0.88−1.08) for hyperlipidemia, 1.01 (95% CI: 0.89−1.15) for diabetes mellitus, and 1.19 (95% CI: 1.08−1.32) for current smoking. After full adjustment, these estimates were numerically similar. When modeled continuously, an inverse association was observed for systolic blood pressure (hazard ratio=0.79 [95% CI: 0.68−0.92] at systolic blood pressure 160 vs 110 mm Hg) but not for diastolic blood pressure or lipid measures with VTE. An important finding from VTE subtype analyses was that cigarette smoking was associated with provoked but not unprovoked VTE. Fully adjusted hazard ratios for the associations of current smoking with provoked and unprovoked VTE were 1.36 (95% CI: 1.22−1.52) and 1.08 (95% CI: 0.90−1.29), respectively. Conclusions: Except for the association between cigarette smoking and provoked VTE, which is potentially mediated through comorbid conditions such as cancer, the modifiable traditional cardiovascular disease risk factors are not associated with increased VTE risk. Higher systolic blood pressure showed an inverse association with VTE.Background: Much controversy surrounds the association of traditional cardiovascular disease risk factors with venous thromboembolism (VTE). Methods: We performed an individual level random-effect meta-analysis including 9 prospective studies with measured baseline cardiovascular disease risk factors and validated VTE events. Definitions were harmonized across studies. Traditional cardiovascular disease risk factors were modeled categorically and continuously using restricted cubic splines. Estimates were obtained for overall VTE, provoked VTE (ie, VTE occurring in the presence of 1 or more established VTE risk factors), and unprovoked VTE, pulmonary embolism, and deep-vein thrombosis. Results: The studies included 244 865 participants with 4910 VTE events occurring during a mean follow-up of 4.7 to 19.7 years per study. Age, sex, and body mass index-adjusted hazard ratios for overall VTE were 0.98 (95% confidence interval [CI]: 0.89−1.07) for hypertension, 0.97 (95% CI: 0.88−1.08) for hyperlipidemia, 1.01 (95% CI: 0.89−1.15) for diabetes mellitus, and 1.19 (95% CI: 1.08−1.32) for current smoking. After full adjustment, these estimates were numerically similar. When modeled continuously, an inverse association was observed for systolic blood pressure (hazard ratio=0.79 [95% CI: 0.68−0.92] at systolic blood pressure 160 vs 110 mm Hg) but not for diastolic blood pressure or lipid measures with VTE. An important finding from VTE subtype analyses was that cigarette smoking was associated with provoked but not unprovoked VTE. Fully adjusted hazard ratios for the associations of current smoking with provoked and unprovoked VTE were 1.36 (95% CI: 1.22−1.52) and 1.08 (95% CI: 0.90−1.29), respectively. Conclusions: Except for the association between cigarette smoking and provoked VTE, which is potentially mediated through comorbid conditions such as cancer, the modifiable traditional cardiovascular disease risk factors are not associated with increased VTE risk. Higher systolic blood pressure showed an inverse association with VTE. # Clinical Perspective {#article-title-33}

High-sensitivity cardiac troponin T predicts mortality after hospitalization for community-acquired pneumonia

Mortality after hospitalization with community‐acquired pneumonia (CAP) is high, compared with age‐matched controls. Available evidence suggests a strong link with cardiovascular disease. Our aim was to explore the prognostic value of high‐sensitivity cardiac troponin T (cTnT) for mortality in patients hospitalized with CAP.

The role of vitamin D supplementation in the risk of developing pneumonia: three independent case–control studies

Background Vitamin D plays a role in host defence against infection. Vitamin D deficiency has been associated with an increased risk of respiratory tract infections in children and adults. This study aimed to examine whether vitamin D supplementation is associated with a lower pneumonia risk in adults. Methods Three independent case–control studies were performed including a total of 33 726 cases with pneumonia in different settings with respect to hospitalisation status and a total of 105 243 controls. Cases and controls were matched by year of birth, gender and index date. The major outcome measure was exposure to vitamin D supplementation at the time of pneumonia diagnosis. Conditional logistic regression was used to compute ORs for the association between vitamin D supplementation and occurrence of pneumonia. Results Vitamin D supplementation was not associated with a lower risk of pneumonia. In studies 1 and 2, adjustment for confounding resulted in non-significant ORs of 1.814 (95% CI 0.865 to 3.803) and 1.007 (95% CI 0.888 to 1.142), respectively. In study 3, after adjustment for confounding, the risk of pneumonia remained significantly higher among vitamin D users (OR 1.496, 95% CI 1.208 to 1.853). Additional analyses showed significant modification of the association through co-use of corticosteroids and drugs that affect bone mineralisation. For patients using these drugs, ORs below one were found combined with higher ORs for patients not using these drugs. Conclusions This study showed no preventive association between vitamin D supplementation and the risk of pneumonia in adults.

Prognostic value of serum angiotensin-converting enzyme activity for outcome of community-acquired pneumonia.

Abstract Background: In a previous study, a relation between decreased serum angiotensin-converting enzyme (ACE) activity and physiological parameters was observed in patients with community-acquired pneumonia. The present study aims to further assess the prognostic value of serum ACE activity for outcome of community-acquired pneumonia. Methods: This was a prospective observational study including two cohorts of patients with community-acquired pneumonia (2004–2006; n=157 and 2007–2010; n=138). Serum ACE activity was measured at time of hospital admission. Based on reference values in healthy persons, patients were divided into subgroups of serum ACE activity: normal, low and extremely low. Physiological parameters, clinical outcomes and etiology were compared between the subgroups. Results: A total of 265 patients were enrolled in this study. Mean age was 60±19 years. In patients with low serum ACE activity (<20 U/L, n=53), compared to patients with normal serum ACE activity (≥20 U/L, n=212), C-reactive protein (CRP) was significantly increased, systolic blood pressure was significantly lower and there was a trend for higher heart rate and leukocyte counts. Furthermore, Streptococcus pneumoniae was significantly more identified in patients with low serum ACE activity. Serum ACE activity <24 U/L was independently associated with bacteremia (adjusted OR 3.93 [95% CI 1.57–9.87]). Low serum ACE activity was not prognostic for length of hospital stay nor mortality. Conclusions: This study did not show prognostic value for serum ACE activity regarding clinical outcome in patients with community-acquired pneumonia. Serum ACE activity <24 U/L at time of hospitalization appeared an independent indicator for the presence of bacteremia. Further research should elucidate the role of ACE in systemic infection and sepsis during pneumonia.

Pneumococcal conjugate vaccination response in patients after community-acquired pneumonia, differences in patients with S. pneumoniae versus other pathogens

OBJECTIVES The goal of this study is to investigate the immune response to the 13-valent pneumococcal conjugate vaccine (PCV13) in former pneumococcal CAP patients. We hypothesize that an impaired or suboptimal humoral immune response against (specific) pneumococcal serotypes might explain the vulnerability for pneumococcal disease. METHODS Hospitalised adult CAP patients who participated in two trials (2004-2006 (n=201) and, 2007-2009 (n=304)) were screened. Patients eligible for inclusion had CAP caused by either S. pneumoniae (pneuCAP) or due to another well-defined pathogen (otherCAP). Serotype-specific pneumococcal antibody concentrations (total IgG and IgG2/IgG1) before and 3-4weeks after PCV13 administration were measured (Luminex) and compared between pneuCAP and otherCAP patients. RESULTS We vaccinated 60 patients:i.e. 34 pneuCAP and 26 otherCAP patients. In the pneuCAP group, 74% of patients were categorized as good responders (≥9/13 serotypes with concentration≥1300ng/ml), versus 77% in the otherCAP group. Significantly fewer full responders (i.e. 13/13 serotypes with a concentration≥1300ng/mL) were identified in the pneuCAP group (15% vs 42% respectively, p=0.02). For serotype 1, total IgG and IgG2/IgG1 subset post-vaccination concentrations were significantly lower among pneuCAP patients. Our additional case-series showed that of 16 pneuCAP patients who were infected by a serotype included in PCV13 three patients did not respond against the serotype originally responsible for their CAP episode, including one former bacteraemic pneumococcal CAP patient who also failed to show a response against the serotype responsible for CAP during infection. Thirteen patients did respond to the previously infecting serotype following PCV13 including three patients who had bacteraemic pneumococcal pneumonia and did not show a response during infection against the serotype responsible for CAP. CONCLUSIONS Our results confirm the immunogenic properties of PCV13 in former pneumococcal CAP patients including patients previously regarded as potential hyporesponders. A slightly diminished overall humoral response to polysaccharides characterizes the former pneumococcal CAP patients. ClinicalTrials.gov Identifier: NCT02141009.