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Background: Central venous catheters (CVC) remain a commonly used vascular access option in haemodialysis, despite guidelines advising to preferably use arteriovenous fistulae. Compared to younger patients, the risk-benefit ratio of CVC in older patients might be more beneficial, but previous studies mainly focussed on catheter-related bacteraemia and/or assessed tunnelled CVC (TCVC) only. This study's aim was to compare all catheter-related infections and malfunctions in older patients with younger patients using all CVC subtypes., Materials and Methods: We used data from DUCATHO, a multicentre observational cohort study in The Netherlands. All adult patients in whom a CVC was placed for haemodialysis between 2012 and 2016 were included. The primary endpoint was the occurrence of catheter-related infections, comparing patients aged ⩾70 years with patients aged <70 years (reference). As secondary endpoints, catheter malfunctions and catheter removal due to either infection or malfunction were assessed. Using Cox proportional hazards and recurrent events modelling, hazard ratios (HR) with 95% confidence intervals (CI) were calculated with adjustment of prespecified confounders. Additionally, endpoints were assessed for non-tunnelled CVC (NTCVC) and TCVC separately., Results: A total of 1595 patients with 2731 CVC (66.5% NTCVC, 33.1% TCVC) were included. Of these patients, 1001 (62.8%) were aged <70 years and 594 (37.2%) ⩾70 years. No statistically significant difference was found for the occurrence of catheter-related infections (adjusted HR 0.80-95% CI 0.62-1.02), catheter malfunction (adjusted HR 0.94-95% CI 0.75-1.17) and catheter removal due to infection or malfunction (adjusted HR 0.94-95% CI 0.80-1.11). Results were comparable when assessing NTCVC and TCVC separately., Conclusion: Patients aged ⩾70 to <70 years have a comparable risk for the occurrence of catheter-related infections and catheter malfunction. These findings may help when discussing treatment options with older patients starting haemodialysis and may inform the current debate on the best vascular access for these patients., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The main limitations of central venous catheters for haemodialysis access are infections and catheter malfunction. Our objective was to assess whether precurved non-tunnelled central venous catheters are comparable to tunnelled central venous catheters in terms of infection and catheter malfunction and to assess whether precurved non-tunnelled catheters are superior to straight catheters., Materials and Methods: In this retrospective, observational cohort study, adult patients in whom a central venous catheter for haemodialysis was inserted between 2012 and 2016 were included. The primary endpoint was a combined endpoint consisting of the first occurrence of either an infection or catheter malfunction. The secondary endpoint was a combined endpoint of the removal of the central venous catheter due to either an infection or a catheter malfunction. Using multivariable analysis, cause-specific hazard ratios for endpoints were calculated for tunnelled catheter versus precurved non-tunnelled catheter, tunnelled catheter versus non-tunnelled catheter, and precurved versus straight non-tunnelled catheter., Results: A total of 1603 patients were included. No difference in reaching the primary endpoint was seen between tunnelled catheters, compared to precurved non-tunnelled catheters (hazard ratio, 0.91; 95% confidence interval, 0.70-1.19, p = 0.48). Tunnelled catheters were removed less often, compared to precurved non-tunnelled catheters (hazard ratio, 0.65; 95% confidence interval, 0.46-0.93; p = 0.02). A trend for less infections and catheter malfunctions was seen in precurved jugular non-tunnelled catheters compared to straight non-tunnelled catheters (hazard ratio, 0.60; 95% confidence interval, 0.24-1.50; p = 0.28) and were removed less often (hazard ratio, 0.41; 95% confidence interval, 0.18-0.93; p = 0.03)., Conclusion: Tunnelled central venous catheters and precurved non-tunnelled central venous catheters showed no difference in reaching the combined endpoint of catheter-related infections and catheter malfunction. Tunnelled catheters get removed less often because of infection/malfunction than precurved non-tunnelled catheters.

Background: Treatment of community acquired pneumonia (CAP) patients with antibiotics before laboratory-confirmed diagnosis leads to loss of knowledge on the causative bacterial pathogen. Therefore, an increasing number of pneumococcal infections is identified using non-culture based techniques. However, methods for serotyping directly on the clinical specimen remain scarce. Here we present three approaches for detection and serotyping of pneumococci using samples from patients with CAP., Methods: The first approach is quantitative PCR (qPCR) analysis on blood samples (n = 211) followed by capsular sequence typing (CST) to identify the serotype. The second approach, a urinary antigen assay (n = 223), designated as inhibition multiplex immunoassay (IMIA), is based on Luminex technology targeting 14 serotypes. The third approach is a multiplex immunoassay (MIA) (n = 171) also based on Luminex technology which detects serologic antibody responses against 14 serotypes. The three alternative assays were performed on samples obtained from 309 adult hospitalized CAP patients in 2007-2010 and the results were compared with those obtained from conventional laboratory methods to detect pneumococcal CAP, i.e. blood cultures, sputum cultures and BinaxNOW urinary antigen tests., Results: Using qPCR, MIA and IMIA, we were able to detect the pneumococcus in samples of 56% more patients compared to conventional methods. Furthermore, we were able to assign a serotype to the infecting pneumococcus from samples of 25% of all CAP patients, using any of the three serotyping methods (CST, IMIA and MIA)., Conclusion: This study indicates the usefulness of additional molecular methods to conventional laboratory methods for the detection of pneumococcal pneumonia. Direct detection and subsequent serotyping on clinical samples will improve the accuracy of pneumococcal surveillance to monitor vaccine effectiveness.

Community-acquired pneumonia (CAP) is a major cause of morbidity and mortality worldwide. Increasing age has been associated with elevated circulating levels of pro-inflammatory mediators. We aimed to determine the impact of ageing on the systemic inflammatory response to CAP. In total 201 CAP patients were enrolled. Blood samples were obtained upon presentation, and on days 2, 3 and 5. For the current analysis patients≤50 and ≥80 years were included. The Pneumonia Severity Index (PSI) score was calculated at presentation. The study encompassed 46 CAP patients aged ≤50 years (median 37 years) and 41 CAP patients aged ≥80 years (median 84 years). In both groups Streptococcus pneumoniae was the common causative microorganism. Whereas most young patients had a PSI score of I (54%), 98% of elderly patients had a PSI score≥III (p<0.001). Four elderly patients died vs. none of the young patients (p 0.045). Older patients demonstrated lower serum C-reactive protein levels on admission and during the course of their hospitalization (p 0.001) in spite of more severe disease. Serum concentrations of pro-inflammatory (interleukin (IL)-6 and IL-8) and anti-inflammatory cytokines (IL-10 and IL-1 receptor antagonist) did not differ between age groups, although admission IL-8 levels tended to be higher in elderly patients (p 0.05). Cytokine levels were positively correlated with PSI in young but not in elderly patients. These results suggest that elderly patients show an absolute (C-reactive protein) or relative (cytokines) reduction in their systemic inflammatory response on admission for CAP., (© 2014 The Authors Clinical Microbiology and Infection © 2014 European Society of Clinical Microbiology and Infectious Diseases.)

Analysis of the Dutch national invasive pneumococcal disease (IPD) surveillance data by sex reveals an increase in the incidence of serotype-1 disease in young female adults in The Netherlands after the introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in the national immunization schedule. This has led to an overall increase in IPD in women aged 20-45 years, which was not observed in men of the same age. No other differences in serotype shifts possibly induced by the introduction of PCV7 were observed between the sexes in this age group. Serotype 1 is a naturally fluctuating serotype in Europe and it has been associated with disease in young healthy adults before. It remains uncertain whether or not there is an association between the observed increase in serotype-1 disease in young female adults and the implementation of PCV7 in The Netherlands.

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.

The influence of adjunctive corticosteroids on the cytokine response in community-acquired pneumonia (CAP) is largely unknown. In this study, we analyzed the effect of dexamethasone on the cytokine response in patients with CAP and evaluated whether this effect is dependent on the causative microorganism. We hypothesized that dexamethasone has a larger effect on the cytokine response in patients with pneumococcal pneumonia than in patients with pneumonia caused by an atypical bacterium. A total of 304 hospitalized, nonimmunocompromised patients with CAP were randomized to an adjunctive 4-day course of 5 mg dexamethasone once a day (n = 151) or a placebo (n = 153). Serum concentrations of interleukin-1 receptor antagonist (IL-1Ra), IL-6, IL-8, IL-10, IL-17, tumor necrosis factor alpha (TNF-α), gamma interferon (IFN-γ), macrophage inflammatory protein-1 alpha (MIP-1α), and monocyte chemotactic protein-1 (MCP-1) were measured on days 0, 1, 2, and 4 and at a control visit. Overall, the concentrations of IL-6 (P < 0.01), IL-8 (P < 0.01), MCP-1 (P < 0.01), and TNF-α (P < 0.01) were significantly lower on day 2 in the dexamethasone group than in the placebo group. In patients with pneumococcal pneumonia (n = 72), both treatment groups showed a rapid decrease of cytokine concentrations; only the concentration of TNF-α (P = 0.05) was significantly lower in the dexamethasone group on day 2. In patients with CAP caused by an atypical pathogen (Legionella pneumophila, Chlamydophila species, Coxiella burnetii, or Mycoplasma pneumoniae; n = 58), IL-1Ra (P < 0.01), IL-6 (P < 0.01), and MCP-1 (P = 0.03) decreased more rapidly in the dexamethasone group than in the placebo group. In conclusion, dexamethasone downregulates the cytokine response during CAP. This effect seems to be dependent on the causative microorganism. This study provides insight into which patients with CAP might benefit most from adjunctive dexamethasone.

Pneumonia exhibits a broad range of severity, from mildly symptomatic at one end to fulminant septic shock and death at the other. Although an adequate inflammatory response is necessary for the clearance of microorganisms, excessive inflammation can lead to ongoing local and systemic damage. Because of this extended inflammatory response despite appropriate antibiotic therapy, as well as increasing antibiotic resistance, adjuvant therapy for pneumonia that can favourably modify the immune response has become an increasingly relevant approach to improve prognosis. Different adjuvant treatment options for pneumonia have recently been proposed. Promising treatment options include corticosteroids, statins, macrolides and Toll-like receptor antagonists. The aim of this review is to summarize the inflammatory response during pneumonia and discuss the current knowledge and future perspectives regarding the anti-inflammatory treatment options for patients with pneumonia., (© 2012 The Association for the Publication of the Journal of Internal Medicine.)

In community-acquired pneumonia (CAP), the cortisol level on admission can be a useful biomarker for prognosis. Serial cortisol measurements during the clinical course of disease and their association with disease outcome have never been reported. Furthermore, the time to recovery of the hypothalamic-pituitary-adrenal axis after a short course of dexamethasone during infection is unclear. We analyzed data from 270 hospitalized patients with CAP. Total serum cortisol was measured on presentation, day 1, 2, 4, and on control visit (day 30). Intensive care unit (ICU) admission and mortality were assessed. Additionally, to study the influence of dexamethasone on the kinetics of the cortisol response, we analyzed serial cortisol values of 43 patients treated with a four-day regimen of dexamethasone 5 mg. During hospital stay, 26/270 patients (9.6%) were admitted to the ICU and 15/270 patients (5.6%) died. Compared to patients with an uneventful recovery, cortisol on presentation was significantly higher in patients with an adverse outcome (360 μg/L, IQR 209-597 vs. 238 μg/L, IQR 151-374) (p:0.01), and also remained significantly higher throughout the course of disease. Dexamethasone treatment resulted in nearly complete suppression of the endogenous cortisol production after the first dose, but cortisol production was fully recovered on control visit. In conclusion, we showed that an adverse outcome of CAP was associated with persisting higher total serum cortisol throughout the course of disease. Delta-cortisol could be another meaningful biomarker in CAP. Next, our data indicate that a four-day dexamethasone regimen during CAP does not lead to prolonged secondary adrenal insufficiency., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

In this study, the effect of dexamethasone on the formation of pneumococcal antibodies during community-acquired pneumonia (CAP) was investigated. No differences between CAP patients receiving dexamethasone as additional therapy and patients receiving a placebo were found with respect to immune response rates and mean baseline and convalescent-phase antibody concentrations.

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., (Copyright © 2013 S. Karger AG, Basel.)

Recent initiation of proton-pump inhibitor (PPI) treatment may increase the risk of community-acquired pneumonia (CAP), hypothetically by allowing colonisation of the oropharynx by gastrointestinal bacteria. The aim of this study was to assess the causal pathway by considering microbial aetiology of pneumonia and indications for initiation of PPI treatment. This was a population-based, case-control study with 430 cases with pneumonia and 1,720 matched controls. An elaborate diagnostic protocol was used to identify the causative microorganism of pneumonia. For patients recently starting PPI treatment, indications for treatment were assessed. Recent initiation of PPI treatment (<30 days) was associated with an increased risk of CAP (adjusted OR 3.1, 95% CI 1.4-7.1). Oropharyngeal bacteria were evenly distributed among current users, past users and nonusers of PPIs (p=0.41). Gastrointestinal bacteria were identified in only five (1.2%) patients with pneumonia (two current users and three nonusers). Excluding patients who were possibly prescribed PPI treatment for early symptoms of pneumonia (protopathic bias) did not alter the study findings. This study reaffirmed that use of PPIs is associated with an increased risk of CAP, especially when treatment has recently been started. Neither protopathic bias nor shifts in microbial aetiology seem to explain the association.

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.

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., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The role of individual cytokines and polymorphisms in pneumonia has been described, but the relationship between different cytokines and polymorphisms in relation to causative microorganisms, antibiotics, corticosteroids and clinical course has not. This study questions the relationship between cytokines, polymorphisms and clinical characteristics of pneumonia. Patients diagnosed with pneumonia were included in the study. Serum cytokine levels were measured during hospital stay, genotyping was performed, causative microorganisms were identified and patients were monitored throughout the hospital stay. In 201 patients with pneumonia interleukin (IL)-1 receptor antagonist (IL-1RA), IL-6, IL-8 and IL-10 acted as acute phase proteins. After admission, the levels of these cytokines decreased rapidly. Single nucleotide polymorphisms did not influence cytokine production and were not associated with clinical outcome. Cytokine serum levels were significantly higher in patients with pneumococcal pneumonia. The decrease in levels of cytokines was independently influenced by the start of corticosteroid therapy. IL-1RA, IL-6, IL-8 and IL-10 are acute phase proteins, independent of genotype. Their levels are influenced by the nature of the causative microorganism and the start of corticosteroids therapy.

In up to half of all cases of community-acquired pneumonia (CAP), no pathogen can be identified with conventional diagnostic methods. The most common identified causative agent is Streptococcus pneumoniae. In this study, pneumococcal antibody responses during CAP were analyzed to estimate the contribution of the pneumococcus to all cases of CAP for epidemiological purposes. Pneumococcal antibodies against 14 different serotypes were measured in serum of hospitalized CAP patients. Patients participated in one of two consecutive clinical trials in a general 600-bed teaching hospital in the Netherlands (between October 2004 and June 2009). A significant pneumococcal immune response was defined as at least a 2-fold increase in antibody concentrations against a single serotype between an early (day 1) and a late (day 30) serum sample of each patient with an end concentration above 0.35 μg/ml. A total of 349 adult CAP patients participated in two consecutive clinical trials. For 200 patients, sufficient serum samples were available to determine antibody responses: 62 pneumococcal pneumonia patients, 57 nonpneumococcal pneumonia patients, and 81 patients with an unidentified causative agent. A significant immune response was detected in 45% (28/62 patients) of pneumococcal pneumonia patients, in 5% (3/57) of nonpneumococcal pneumonia patients, and in 28% (23/81) of patients with an unidentified causative agent. The estimated contribution of pneumococci in patients with an unidentified causative agent was calculated to be 57% (95% confidence interval, 36 to 86%). A substantial fraction of pneumococcal pneumonia patients do not elicit a serotype-specific immune response.

Background: Mannose-binding lectin (MBL) and ficolin-2 (FCN) are activators of the lectin pathway of complement and act as primary defences against infection. Single-nucleotide polymorphisms (SNPs) in the MBL2 and FCN2 genes influence the functionality of the proteins. Both proteins are capable of binding staphylococci, which are pathogens that frequently cause peritonitis in patients on continuous ambulatory peritoneal dialysis (CAPD). We studied the role of polymorphisms in the MBL2 and FCN2 genes as a risk factor for developing CAPD peritonitis caused by staphylococci., Methods: We analysed SNPs in the MBL2 and FCN2 genes in 40 CAPD patients with staphylococcal peritonitis and in 65 CAPD patients without any history of peritonitis. Additionally, we analysed the prevalence of exit site infections and nasal Staphylococcus aureus carriage in both groups., Results: The + 6359C > T SNP leading to the Thr236Met amino acid alteration in the FCN2 gene, associated with decreased substrate binding, was significantly more prevalent in CAPD patients with a history of staphylococcal peritonitis compared with patients on CAPD without a history of peritonitis (P = 0.037). No difference was found in MBL2 genotypes between the two groups. In CAPD patients with a history of staphylococcal peritonitis, exit site infection with S. aureus was also more prevalent (P < 0.01), while S. aureus carriage was not (P = 0.073)., Conclusions: In addition to known risk factors such as exit site infection, the + 6359C > T SNP in the FCN2 gene might be a risk factor for staphylococcal peritonitis in CAPD patients due to decreased binding of FCN to staphylococci.

Community-acquired pneumonia (CAP) is a common and serious disease with significant mortality, morbidity and associated healthcare costs. Severity of pneumonia is related to the extent of the inflammatory response. Primary goal in the treatment of pneumonia is starting adequate antibiotic therapy as soon as possible. However, antimicrobial resistance among the most common bacteria causing pneumonia is increasing. For those two reasons, extended inflammatory response and increasing antibiotic resistance, it is interesting to look at adjunctive non-antibiotic therapeutic strategies aimed at modulation of the inflammatory response or at the micro-organism itself. In this review, we discuss the current knowledge regarding these therapies and their possible role in the future.

The diagnosis of adult-onset Still's disease (ASD) is difficult to establish due to the nonspecific clinical and laboratory findings. A markedly raised serum ferritin level is a typical finding, although it is not well understood why ferritin levels are extremely high in ASD. We discuss several possible explanations leading to the extremely high levels of ferritin.