BACKGROUND: Current approaches for pathogen identification in community-acquired pneumonia (CAP) remain suboptimal, leaving most patients without a microbiological diagnosis. If better diagnostic... Show moreBACKGROUND: Current approaches for pathogen identification in community-acquired pneumonia (CAP) remain suboptimal, leaving most patients without a microbiological diagnosis. If better diagnostic tools were available for differentiating between viral and bacterial CAP. unnecessary antibacterial therapy could be avoided in viral CAP patients. METHODS: In 156 adults hospitalized with CAP classified to have bacterial. viral, or mixed viral-bacterial infection based on microbiological testing or both microbiological testing and procalcitonin (PCT) levels, we aimed to identify discriminatory host transcriptional signatures in peripheral blood samples acquired at hospital admission, by applying Dual-color-Reverse-Transcriptase-Multiplex-Ligation-dependent-Probe-Amplification (dc-RT MLPA). RESULTS: In patients classified by microbiological testing, a 9-transcript signature showed high accuracy for discriminating bacterial from viral CAP (AUC 0.91. 95% CI 0.85-0.96). while a 10-transcript signature similarly discriminated mixed viral-bacterial from viral CAP (AUC 0.91, 95% CI 0.86-0.96). In patients classified by both microbiological testing and PCT levels, a 13-transcript signature showed excellent accuracy for discriminating bacterial from viral CAP (AUC 1.00, 95% CI 1.00-1.00), while a 7-transcript signature similarly discriminated mixed viral-bacterial from viral CAP (AUC 0.93, 95% CI 0.87-0.98). CONCLUSION: Our findings support host transcriptional signatures in peripheral blood samples as a potential tool for guiding clinical decision-making and antibiotic stewardship in CAP. Show less
Purpose: Describe the differences in characteristics and outcomes between COVID-19 and other viral pneumonia patients admitted to Dutch ICUs. Materials and methods: Data from the National-Intensive... Show morePurpose: Describe the differences in characteristics and outcomes between COVID-19 and other viral pneumonia patients admitted to Dutch ICUs. Materials and methods: Data from the National-Intensive-Care-Evaluation-registry of COVID-19 patients admitted between February 15th and January 1th 2021 and other viral pneumonia patients admitted between January 1st 2017 and January 1st 2020 were used. Patients' characteristics, the unadjusted, and adjusted in-hospital mortality were compared. Results: 6343 COVID-19 and 2256 other viral pneumonia patients from 79 ICUs were included. The COVID-19 patients included more male (71.3 vs 49.8%), had a higher Body-Mass-Index (28.1 vs 25.5), less comorbidities (42.2 vs 72.7%), and a prolonged hospital length of stay (19 vs 9 days). The COVID-19 patients had a significantly higher crude in-hospital mortality rate (Odds ratio (OR) = 1.80), after adjustment for patient characteristics and ICU occupancy rate the OR was respectively 3.62 and 3.58. Conclusion: Higher mortality among COVID-19 patients could not be explained by patient characteristics and higher ICU occupancy rates, indicating that COVID-19 is more severe compared to other viral pneumonia. Our findings confirm earlier warnings of a high need of ICU capacity and high mortality rates among relatively healthy COVID-19 patients as this may lead to a higher mental workload for the staff. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/). Show less
Wittermans, E.; Garde, E.M.W. van de; Voorn, G.P.; Aldenkamp, A.F.; Janssen, R.; Grutters, J.C.; ... ; Santeon-CAP Study Grp 2022
Background: It is hypothesised that community-acquired pneumonia (CAP) patients with more severe disease or inflammation might benefit more from adjunctive corticosteroid treatment. Neutrophil... Show moreBackground: It is hypothesised that community-acquired pneumonia (CAP) patients with more severe disease or inflammation might benefit more from adjunctive corticosteroid treatment. Neutrophil count, lymphocyte count and neutrophil-lymphocyte ratio (NLR) have been associated with inflammation and disease severity in CAP. We investigated the interaction between these parameters and adjunctive dexamethasone effects on clinical outcomes in CAP. Methods: We conducted a post hoc analysis of the randomised placebo-controlled Santeon-CAP trial (n = 401), which showed a positive effect of adjunctive oral dexamethasone on length of stay (LOS) in CAP patients. White blood cell (WBC) count, neutrophil count, NLR (highest tertile vs. lowest two tertiles) and lymphocyte count (lowest tertile vs. highest two tertiles) were examined as potential effect modifiers of treatment with dexamethasone on LOS (primary outcome) and ICU-admission, 30-day mortality and hospital readmission. Results: WBC differential counts were available for 354 patients. The effect of dexamethasone on LOS was more pronounced in high WBC count, high neutrophil count or high NLR subgroups (difference in median LOS of 2 days versus zero days in the reference subgroups, p for interaction < 0.05). There was no effect modification for the other outcomes. Patients with low WBC and low neutrophil counts did not benefit from dexamethasone, while hospital readmission rate was higher in those treated with dexamethasone (6% vs. 11%). Conclusions: WBC count and/or neutrophil might be easily available biomarkers to guide selection of CAP patients who are more likely to benefit from adjunctive dexamethasone treatment. Future prospective trials are needed to confirm this predictive potential. Show less
Background: Pediatric patients admitted for acute lung disease are treated and monitored in the hospital, after which full recovery is achieved at home. Many studies report in-hospital recovery,... Show moreBackground: Pediatric patients admitted for acute lung disease are treated and monitored in the hospital, after which full recovery is achieved at home. Many studies report in-hospital recovery, but little is known regarding the time to full recovery after hospital discharge. Technological innovations have led to increased interest in home-monitoring and digital biomarkers. The aim of this study was to describe at-home recovery of 3 common pediatric respiratory diseases using a questionnaire and wearable device. Methods: In this study, patients admitted due to pneumonia (n = 30), preschool wheezing (n = 30), and asthma exacerbation (AE; n = 11) were included. Patients were monitored with a smartwatch and a questionnaire during admission, with a 14-day recovery period and a 10-day "healthy" period. Median compliance was calculated, and a mixed-effects model was fitted for physical activity and heart rate (HR) to describe the recovery period, and the physical activity recovery trajectory was correlated to respiratory symptom scores. Results: Median compliance was 47% (interquartile range [IQR] 33-81%) during the entire study period, 68% (IQR 54-91%) during the recovery period, and 28% (IQR 0-74%) during the healthy period. Patients with pneumonia reached normal physical activity 12 days postdischarge, while subjects with wheezing and AE reached this level after 5 and 6 days, respectively. Estimated mean physical activity was closely correlated with the estimated mean symptom score. HR measured by the smartwatch showed a similar recovery trajectory for subjects with wheezing and asthma, but not for subjects with pneumonia. Conclusions: The digital biomarkers, physical activity, and HR obtained via smartwatch show promise for quantifying postdischarge recovery in a noninvasive manner, which can be useful in pediatric clinical trials and clinical care. Show less
Background: Lung ultrasound can adequately monitor disease severity in pneumonia and acute respiratory distress syndrome. We hypothesize lung ultrasound can adequately monitor COVID-19 pneumonia in... Show moreBackground: Lung ultrasound can adequately monitor disease severity in pneumonia and acute respiratory distress syndrome. We hypothesize lung ultrasound can adequately monitor COVID-19 pneumonia in critically ill patients.Methods: Adult patients with COVID-19 pneumonia admitted to the intensive care unit of two academic hospitals who underwent a 12-zone lung ultrasound and a chest CT examination were included. Baseline characteristics, and outcomes including composite endpoint death or ICU stay > 30 days were recorded. Lung ultrasound and CT images were quantified as a lung ultrasound score involvement index (LUSI) and CT severity involvement index (CTSI). Primary outcome was the correlation, agreement, and concordance between LUSI and CTSI. Secondary outcome was the association of LUSI and CTSI with the composite endpoints.Results: We included 55 ultrasound examinations in 34 patients, which were 88% were male, with a mean age of 63 years and mean P/F ratio of 151. The correlation between LUSI and CTSI was strong (r = 0.795), with an overall 15% bias, and limits of agreement ranging - 40 to 9.7. Concordance between changes in sequentially measured LUSI and CTSI was 81%. In the univariate model, high involvement on LUSI and CTSI were associated with a composite endpoint. In the multivariate model, LUSI was the only remaining independent predictor.Conclusions: Lung ultrasound can be used as an alternative for chest CT in monitoring COVID-19 pneumonia in critically ill patients as it can quantify pulmonary involvement, register changes over the course of the disease, and predict death or ICU stay > 30 days. Show less
Scope: The Dutch Working Party on Antibiotic Policy constituted a multidisciplinary expert committee to provide evidence-based recommendation for the use of antibacterial therapy in hospitalized... Show moreScope: The Dutch Working Party on Antibiotic Policy constituted a multidisciplinary expert committee to provide evidence-based recommendation for the use of antibacterial therapy in hospitalized adults with a respiratory infection and suspected or proven 2019 Coronavirus disease (COVID-19).Methods: We performed a literature search to answer four key questions. The committee graded the evidence and developed recommendations by using Grading of Recommendations Assessment, Development, and Evaluation methodology.Questions addressed by the guideline and Recommendations: We assessed evidence on the risk of bacterial infections in hospitalized COVID-19 patients, the associated bacterial pathogens, how to diagnose bacterial infections and how to treat bacterial infections. Bacterial co-infection upon admission was reported in 3.5% of COVID-19 patients, while bacterial secondary infections during hospitalization occurred up to 15%. No or very low quality evidence was found to answer the other key clinical questions. Although the evidence base on bacterial infections in COVID-19 is currently limited, available evidence supports restrictive antibiotic use from an antibiotic stewardship perspective, especially upon admission. To support restrictive antibiotic use, maximum efforts should be undertaken to obtain sputum and blood culture samples as well as pneumococcal urinary antigen testing. We suggest to stop antibiotics in patients who started antibiotic treatment upon admission when representative cultures as well as urinary antigen tests show no signs of involvement of bacterial pathogens after 48 hours. For patients with secondary bacterial respiratory infection we recommend to follow other guideline recommendations on antibacterial treatment for patients with hospital-acquired and ventilator-associated pneumonia. An antibiotic treatment duration of five days in patients with COVID-19 and suspected bacterial respiratory infection is recommended upon improvement of signs, symptoms and inflammatory markers. Larger, prospective studies about the epidemiology of bacterial infections in COVID-19 are urgently needed to confirm our conclusions and ultimately prevent unnecessary antibiotic use during the COVID-19 pandemic. (C) 2020 The Author(s). Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases. Show less
Different aspects of respiratory tract infection have been studied. Automatic syndromic surveillance for early detection of infections is feasible. Peak in ILI in hospitals is most flu seasons... Show moreDifferent aspects of respiratory tract infection have been studied. Automatic syndromic surveillance for early detection of infections is feasible. Peak in ILI in hospitals is most flu seasons before rise in cases in primary care. Influenza vaccination can safely be given to oncology patients who use checkpoint inhibitors. we were unable to demonstrate an attenuation of immune response in patients treated with non-lytic rifampicin for pneumococcal pneumonia. Cardiac surgery during influenza season is a risk factor for postoperative ARDS. Show less
Background: Diagnosing pneumonia can be challenging in general practice but is essential to distinguish from other respiratory tract infections because of treatment choice and outcome prediction.... Show moreBackground: Diagnosing pneumonia can be challenging in general practice but is essential to distinguish from other respiratory tract infections because of treatment choice and outcome prediction. We determined predictive signs, symptoms and biomarkers for the presence of pneumonia in patients with acute respiratory tract infection in primary care.Methods: From March 2012 until May 2016 we did a prospective observational cohort study in three radiology departments in the Leiden-The Hague area, The Netherlands. From adult patients we collected clinical characteristics and biomarkers, chest X ray results and outcome. To assess the predictive value of C-reactive protein (CRP), procalcitonin and midregional pro-adrenomedullin for pneumonia, univariate and multivariate binary logistic regression were used to determine risk factors and to develop a prediction model.Results: Two hundred forty-nine patients were included of whom 30 (12%) displayed a consolidation on chest X ray. Absence of runny nose and whether or not a patient felt ill were independent predictors for pneumonia. CRP predicts pneumonia better than the other biomarkers but adding CRP to the clinical model did not improve classification (- 4%); however, CRP helped guidance of the decision which patients should be given antibiotics.Conclusions: Adding CRP measurements to a clinical model in selected patients with an acute respiratory infection does not improve prediction of pneumonia, but does help in giving guidance on which patients to treat with antibiotics. Our findings put the use of biomarkers and chest X ray in diagnosing pneumonia and for treatment decisions into some perspective for general practitioners. Show less
Asten, L. van; Pinzon, A.L.; Lange, D.W. de; Jonge, E. de; Dijkstra, F.; Marbus, S.; ... ; Keizer, N.F. de 2018
Phosphorylcholine (PC) is an oxidation-specific epitope present on oxidized LDL and apoptotic cells, as well as the capsular polysaccharide of Streptococcus pneumoniae. PC is bound by naturally... Show morePhosphorylcholine (PC) is an oxidation-specific epitope present on oxidized LDL and apoptotic cells, as well as the capsular polysaccharide of Streptococcus pneumoniae. PC is bound by naturally occurring IgM antibodies and low levels of anti-PC IgM are a risk factor for atherosclerosis. Active immunization of atherosclerosis-prone mice with oxidized LDL, S. pneumoniae or PC conjugated to keyhole lympet hemocyanin (PC-KLH) induces high titers of anti-PC Abs and protects from atherosclerosis. However, it is unknown if existing vaccine preparations can be exploited as preventive vaccine in atherosclerosis. Our aim was to evaluate the potential atheroprotective effect of Prevenar®, a clinical-grade pneumococcal vaccine.Male apolipoprotein E-/-,mice (n=10 per group) were injected subcutaneously with 50μl Prevenar® (diluted 1:10 in PBS) at 8 and 12 weeks of age. PC-KLH and PBS were used as positive and negative controls, respectively. Mice were fed regular chow for the entire study. Serum anti-PC Abs were analyzed at baseline and 15 days after the second injection. After 20 weeks serum lipid levels were measured and atherosclerotic lesion size was quantified in the aortic root.Both vaccination with Prevenar® and PC-KLH induced high titers of anti-PC IgM and IgG Abs and resulted in reduced atherosclerosis compared to PBS injected mice (figure) despite similar serum cholesterol levels.The amount of residual PC in Prevenar® is sufficient to elicit atheroprotective anti-PC responses in apoE-/- mice. Since Prevenar® is already used in humans, its potential to prevent atherosclerosis and/or slow down atherosclerosis progression could readily be tested in clinical trials. Show less
Maaden, T. van der; Vet, H.C.W. de; Achterberg, W.P.; Boersma, F.; Schols, J.M.G.A.; Mehr, D.R.; ... ; Steen, J.T. van der 2016
Outline of the Thesis Part I Pneumocystis in kidney transplant recipients: transmission, risk factors , new diagnostic and chemo-prophylactic strategies. Chapter 2 describes the characteristics of... Show moreOutline of the Thesis Part I Pneumocystis in kidney transplant recipients: transmission, risk factors , new diagnostic and chemo-prophylactic strategies. Chapter 2 describes the characteristics of a large outbreak of Pneumocystis pneumonia among kidney transplant recipients. By performing a classical outbreak investigation and by application of new molecular genotyping techniques, the potential of the __interhuman transmission hypothesis__ is addressed and discussed. In Chapter 3 all currently available data on reported outbreaks of Pneumocystis pneumonia is systematically reviewed with the emphasis on mortality data, clinical risk factors and transmission analyses. In the case-control study described in Chapter 4, we performed a detailed risk factor analysis for development of PCP in kidney transplant recipients and used the multivariate output data to estimate the effects of several chemoprophylactic strategies by modeling the expected incidence and number-needed-to-treat to provide efficient PCP chemoprophylaxis over a 2-year period post transplantation. Chapter 5 reports the data of a prospective study on the serum markers S-adenosylmethionine and (1-->3)-_-D-glucan serum levels and correlation with clinical parameters in HIVnegative immunocompromised patients __ the majority kidney transplant recipients - with Pneumocystis pneumonia. Potential applicability for treatment monitoring and assessment of P. jirovecii pulmonary load is also discussed. Part II Genetic predisposition for development of invasive aspergillosis in stem cell transplant recipients Chapter 6 describes a multicenter study on the impact of the Y238X stop mutation in the human Dectin-1 receptor (which senses and attaches to glucan moieties of the fungal cell wall) on the risk of development of invasive aspergillosis in stem cell transplant recipients. In Chapter 7 a retrospective study of the influence of genetic variation in the macrophage activation route with respect to the relative additional risk for development of invasive aspergillosis is presented. Part III Experimental markers for detection of fungal infection: scintigraphic imaging. In Chapter 8 the clinical applicability of radiolabeled antimicrobial peptides and antifungal drugs for the diagnosis of invasive fungal infections is reviewed, together with a concise discussion about how promising agents should be further developed. The results of the thesis are summarized and discussed in Chapter 9. Show less
