Adjunctive treatment with oral dexamethasone in non-ICU patients hospitalised with community-acquired pneumonia: a randomised clinical trial.

BACKGROUND: Adjunctive intravenous corticosteroid treatment has been shown to reduce length of stay (LOS) in adults hospitalised with community-acquired pneumonia (CAP). We aimed to assess the effect of oral dexamethasone on LOS and whether this effect is disease severity dependent. METHODS: In this multicentre, stratified randomised, double-blind, placebo-controlled trial, immunocompetent adults with CAP were randomly assigned (1:1 ratio) to receive oral dexamethasone (6 mg once daily) or placebo for 4 days in four teaching hospitals in the Netherlands. Randomisation (blocks of four) was stratified by CAP severity (pneumonia severity index class I-III and IV-V). The primary outcome was LOS. RESULTS: Between December 2012 and November 2018, 401 patients were randomised to receive dexamethasone (n=203) or placebo (n=198). Median LOS was shorter in the dexamethasone group (4.5 days, 95% CI 4.0-5.0 days) than in the placebo group (5.0 days, 95% CI 4.6-5.4 days; p=0.033). Within both CAP severity subgroups, differences in LOS between treatment groups were not statistically significant. The secondary ICU admission rate was lower in the dexamethasone arm (5 (3%) versus 14 (7%); p=0.030); 30-day mortality did not differ between groups. In the dexamethasone group the rate of hospital readmission tended to be higher (20 (10%) versus 9 (5%); p=0.051) and hyperglycaemia (14 (7%) versus 1 (1%); p=0.001) was more prevalent. CONCLUSION: Oral dexamethasone reduced LOS and ICU admission rate in adults hospitalised with CAP. It remains unclear for which patients the risk-benefit ratio is optimal.

Corticosteroids in Patients Hospitalized With Community-Acquired Pneumonia: Systematic Review and Individual Patient Data Metaanalysis.

Background: Our aim was to evaluate the benefits and harms of adjunctive corticosteroids in adults hospitalized with community-acquired pneumonia (CAP) using individual patient data from randomized, placebo-controlled trials and to explore subgroup differences. Methods: We systematically searched Medline, Embase, Cochrane Central, and trial registers (all through July 2017). Data from 1506 individual patients in 6 trials were analyzed using uniform outcome definitions. We investigated prespecified effect modifiers using multivariable hierarchical regression, adjusting for pneumonia severity, age, and clustering effects. Results: Within 30 days of randomization, 37 of 748 patients (5.0%) assigned to corticosteroids and 45 of 758 patients (5.9%) assigned to placebo died (adjusted odds ratio [aOR], 0.75; 95% confidence interval [CI], .46 to 1.21; P = .24). Time to clinical stability and length of hospital stay were reduced by approximately 1 day with corticosteroids (-1.03 days; 95% CI, -1.62 to -.43; P = .001 and -1.15 days; 95% CI, -1.75 to -.55; P < .001, respectively). More patients with corticosteroids had hyperglycemia (160 [22.1%] vs 88 [12.0%]; aOR, 2.15; 95% CI, 1.60 to 2.90; P < .001) and CAP-related rehospitalization (33 [5.0%] vs 18 [2.7%]; aOR, 1.85; 95% CI, 1.03 to 3.32; P = .04). We did not find significant effect modification by CAP severity or degree of inflammation. Conclusions: Adjunct corticosteroids for patients hospitalized with CAP reduce time to clinical stability and length of hospital stay by approximately 1 day without a significant effect on overall mortality but with an increased risk for CAP-related rehospitalization and hyperglycemia.

YKL-40, CCL18 and SP-D predict mortality in patients hospitalized with community-acquired pneumonia.

BACKGROUND AND OBJECTIVE: The aim of this study was to investigate the prognostic value of four biomarkers, YKL-40, chemokine (C-C motif) ligand 18 (CCL18), surfactant protein-D (SP-D) and CA 15-3, in patients admitted with community-acquired pneumonia (CAP). These markers have been studied extensively in chronic pulmonary disease, but in acute pulmonary disease their prognostic value is unknown. METHODS: A total of 289 adult patients who were hospitalized with CAP and participated in a randomized controlled trial were enrolled. Biomarker levels were measured on the day of admission. Intensive care unit admission, 30-day, 1-year and long-term mortality (median follow-up of 5.4 years, interquartile range (IQR): 4.7-6.1) were recorded as outcomes. RESULTS: Median YKL-40 and CCL18 levels were significantly higher and levels of SP-D were significantly lower in CAP patients compared to healthy controls. Significantly higher YKL-40, CCL18 and SP-D levels were found in patients classified in pneumonia severity index classes 4-5 and with a CURB-65 score ≥2 compared to patients with less severe pneumonia. Furthermore, these three markers were significant predictors for long-term mortality in multivariate analysis and compared with C-reactive protein and procalcitonin level on admission, area under the curves were higher for 30-day, 1-year and long-term mortality. CA 15-3 levels were less predictive. CONCLUSION: YKL-40, CCL18 and SP-D levels were higher in patients with more severe pneumonia, possibly reflecting the extent of pulmonary inflammation. Of these, YKL-40 most significantly predicts mortality for CAP.

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

BACKGROUND AND OBJECTIVE: 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. METHODS: CTnT level on admission was measured (assay conducted in 2015) in 295 patients hospitalized with CAP who participated in a randomized placebo-controlled double-blind trial on adjunctive dexamethasone treatment. Outcome measures were short- (30-day) and long-term (4.1-year) mortalities. RESULTS: CTnT levels were elevated (≥14 ng/L) in 132 patients (45%). Pneumonia severity index (PSI) class was 4-5 in 137 patients (46%). Short- and long-term mortality were significantly higher in patients with elevated cTnT levels. cTnT level on admission combined with PSI classification was significantly better in predicting short-term mortality (area under the operating curve (AUC) = 0.903; 95% CI = 0.847-0.960), compared with PSI classification alone (AUC = 0.818; 95% CI = 0.717-0.919). An optimal cTnT cut-off level of 28 ng/L was independently associated with both short- and long-term mortality (OR = 21.9; 95% CI = 4.7-101.4 and 10.7; 95% CI = 5.0-22.8, respectively). CONCLUSION: Elevated cTnT level on admission is a strong predictor of short- and long-term mortalities in patients hospitalized with CAP.

Atypical aetiology in patients hospitalised with community-acquired pneumonia is associated with age, gender and season; a data-analysis on four Dutch cohorts.

BACKGROUND: Microorganisms causing community-acquired pneumonia (CAP) can be categorised into viral, typical and atypical (Legionella species, Coxiella burnetii, Mycoplasma pneumoniae, and Chlamydia species). Extensive microbiological testing to identify the causative microorganism is not standardly recommended, and empiric treatment does not always cover atypical pathogens. In order to optimize epidemiologic knowledge of CAP and to improve empiric antibiotic choice, we investigated whether atypical microorganisms are associated with a particular season or with the patient characteristics age, gender, or chronic obstructive pulmonary disease (COPD). METHODS: A data-analysis was performed on databases from four prospective studies, which all included adult patients hospitalised with CAP in the Netherlands (N = 980). All studies performed extensive microbiological testing. RESULTS: A main causative agent was identified in 565/980 (57.7 %) patients. Of these, 117 (20.7 %) were atypical microorganisms. This percentage was 40.4 % (57/141) during the non-respiratory season (week 20 to week 39, early May to early October), and 67.2 % (41/61) for patients under the age of 60 during this season. Factors that were associated with atypical causative agents were: CAP acquired in the non-respiratory season (odds ratio (OR) 4.3, 95 % CI 2.68-6.84), age <60 year (OR 2.9, 95 % CI 1.83-4.66), male gender (OR 1.7, 95 % CI 1.06-2.71) and absence of COPD (OR 0.2, 95 % CI 0.12-0.52). CONCLUSIONS: Atypical causative agents in CAP are associated with respectively non-respiratory season, age <60 years, male gender and absence of COPD. Therefore, to maximise its yield, extensive microbiological testing should be considered in patients <60 years old who are admitted with CAP from early May to early October. TRIAL REGISTRATION: NCT00471640 , NCT00170196 (numbers of original studies).

Pharmacokinetics of oral vs. intravenous dexamethasone in patients hospitalized with community-acquired pneumonia.

AIM: The use of corticosteroids as adjunctive therapy might be effective in patients with community-acquired pneumonia (CAP). Oral administration of dexamethasone is a practical and safer alternative to the intravenous route. Since patients hospitalized with pneumonia might have delayed gastric emptying, this study explored systemic exposure in terms of area under the concentration-time curve (AUC) of oral dexamethasone in patients hospitalized with CAP. METHODS: In this randomized, open label study, 30 patients admitted with CAP were randomized to receive either 4 mg intravenous or 6 mg oral dexamethasone for 4 consecutive days. Serial blood samples were obtained before and after drug administration. RESULTS: Median AUC to infinity was 626 µg l(-1) h (IQR 401-1161) for the intravenous group and 774 µg l(-1) h (IQR 618-1146) for the oral group. The AUC ratio of 6 mg oral and 4 mg intravenous dexamethasone was 1.22 (95% confidence interval (CI) 0.81, 1.82), which represents a bioavailability of 81% (95% CI 54, 121) after correction for differences in dexamethasone dose. CONCLUSIONS: Bioavailability of oral dexamethasone in patients hospitalized with pneumonia is sufficient. This makes oral dexamethasone an appropriate alternative for intravenous administration in these patients.

Microbial aetiology, outcomes, and costs of hospitalisation for community-acquired pneumonia; an observational analysis.

BACKGROUND: The aim of this study was to investigate the clinical outcome and especially costs of hospitalisation for community-acquired pneumonia (CAP) in relation to microbial aetiology. This knowledge is indispensable to estimate cost-effectiveness of new strategies aiming to prevent and/or improve clinical outcome of CAP. METHODS: We performed our observational analysis in a cohort of 505 patients hospitalised with confirmed CAP between 2004 and 2010. Hospital administrative databases were extracted for all resource utilisation on a patient level. Resource items were grouped in seven categories: general ward nursing, nursing on ICU, clinical chemistry laboratory tests, microbiology exams, radiology exams, medication drugs, and other.linear regression analyses were conducted to identify variables predicting costs of hospitalisation for CAP. RESULTS: Streptococcus pneumoniae was the most identified causative pathogen (25%), followed by Coxiella burnetii (6%) and Haemophilus influenzae (5%). Overall median length of hospital stay was 8.5 days, in-hospital mortality rate was 4.8%.Total median hospital costs per patient were €3,899 (IQR 2,911-5,684). General ward nursing costs represented the largest share (57%), followed by nursing on the intensive care unit (16%) and diagnostic microbiological tests (9%). In multivariate regression analysis, class IV-V Pneumonia Severity Index (indicative for severe disease), Staphylococcus aureus, or Streptococcus pneumonia as causative pathogen, were independent cost driving factors. Coxiella burnetii was a cost-limiting factor. CONCLUSIONS: Median costs of hospitalisation for CAP are almost €4,000 per patient. Nursing costs are the main cause of these costs.. Apart from prevention, low-cost interventions aimed at reducing length of hospital stay therefore will most likely be cost-effective.

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.

Incidence and predictive value of proteinuria in community-acquired pneumonia.

BACKGROUND/AIMS: The presence of baseline proteinuria predicts the outcome in patients with chronic kidney disease and in the general population, independent of renal function. However, the predictive value of proteinuria during an episode of acute illness has not been reported yet. Therefore, we investigated the incidence and predictive value of proteinuria in patients with community-acquired pneumonia. METHODS: An analysis of prospectively collected data, obtained from patients >18 years of age, was performed. Patients were hospitalized with community-acquired pneumonia in two hospitals in the Netherlands and participated in two consecutive clinical trials. A total protein/creatinine (P/C) ratio was measured in a urine sample from the day of admission. Patients were categorized in quartiles of P/C ratio. Primary outcome was length of hospital stay. RESULTS: 198/319 patients (62%) had a P/C ratio >23 mg/mmol creatinine. In multivariate analysis, proteinuria turned out to be an independent predictor for length of stay and admission to the intensive care unit. CONCLUSION: The incidence of proteinuria during pneumonia is high and proteinuria is an independent predictor for length of hospital stay and admission to the intensive care unit. Proteinuria is a cheap and easily accessible marker for outcome and might be used to assess the severity of pneumonia.

Inter-hospital variation in the utilization of diagnostics and their proportionality in the management of adult community-acquired pneumonia.

BACKGROUND: Utilization of diagnostics and biomarkers are the second largest cost drivers in the management of patients hospitalized with community-acquired pneumonia (CAP). The present study aimed to systematically assess the inter-hospital variation in these cost drivers in relation to antibiotic use in CAP. METHODS: Detailed resource utilization data from 300 patients who participated in a multicenter placebo-controlled trial investigating dexamethasone as adjunctive treatment for community-acquired pneumonia was grouped into 3 categories: clinical chemistry testing, radiological exams, and microbiological testing. Based on the identified top 5 items per category, average costs were calculated per category and per hospital. Antibiotic de-escalation at day 3 and secondary ICU admission were assessed as outcomes for proportionality of diagnostics use. RESULTS: The mean costs for diagnostics varied between hospitals from 350 (SD 31) to 841 (SD 37) euro per patient (p < 0.001). This difference was primarily explained by variation in costs for microbiological testing (mean 195 vs. 726 euro per patient, p < 0.001). There was no difference in number of secondary ICU admissions but there was an inverse association between the costs of microbiological testing and level of antibiotic de-escalation. De-escalation occurred most frequently in the hospital with the lowest cost for microbiological testing (48% vs. 30%; p = 0.018). The latter hospital had an automated physician alert system in place to consider a timely iv-to-oral switch of antibiotics. CONCLUSIONS: Large inter-hospital variation exists in resource utilization, mainly in microbiological diagnostics in the management of adult patients with community-acquired pneumonia. A counterintuitive inverse association between the magnitude of these costs and the amount of antibiotic de-escalation was found. Future studies about the optimal cost-effective set of microbiological testing for antimicrobial stewardship in pneumonia patients should acknowledge the interaction between testing, way of communication of results and triggered physician alert systems. TRIAL REGISTRATION: ClinicalTrials.gov NCT01743755.

Course of SP-D, YKL-40, CCL18 and CA 15-3 in adult patients hospitalised with community-acquired pneumonia and their association with disease severity and aetiology: A post-hoc analysis.

BACKGROUND AND AIM: SP-D, YKL-40, CCL18 and CA 15-3 are pulmonary markers that have been extensively investigated in different chronic pulmonary diseases. However, in acute pulmonary diseases, such as community-acquired pneumonia (CAP), little is known about the course of these markers and their relationship with the aetiological agent. The aim of this study was to investigate the course of these four markers in CAP and to study influence of disease severity, aetiology and antibiotic use prior to admission on their course. METHODS: We included 291 adult patients hospitalised with CAP and 20 healthy controls. Measurements were performed in serum of day 0, 2, and 4, and at least 30 days after admission. RESULTS: Our most important results were: 1) At all time-points, including 30 days after admission, YKL-40 and CCL18 levels were higher in CAP patients compared to healthy controls; and 2) Patients with CAP caused by an intracellular, atypical bacterium had lower YKL-40 and especially CCL18 levels on and during admission in comparison with other or unknown CAP aetiology. CONCLUSIONS: Our findings suggest that these pulmonary markers could be useful to assess CAP severity and, especially YKL-40 and CCL18 by helping predict CAP caused by atypical pathogens.