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Background: Several clinical decision rules (CDRs) are available to exclude acute pulmonary embolism (PE), but they have not been directly compared. Objective: To directly compare the performance of 4 CDRs (Wells rule, revised Geneva score, simplified Wells rule, and simplified revised Geneva score) in combination with d-dimer testing to exclude PE. Design: Prospective cohort study. Setting: 7 hospitals in the Netherlands. Patients: 807 consecutive patients with suspected acute PE. Intervention: The clinical probability of PE was assessed by using a computer program that calculated all CDRs and indicated the next diagnostic step. Results of the CDRs and d-dimer tests guided clinical care. Measurements: Results of the CDRs were compared with the prevalence of PE identified by computed tomography or venous thromboembolism at 3-month follow-up. Results: Prevalence of PE was 23%. The proportion of patients categorized as PE-unlikely ranged from 62% (simplified Wells rule) to 72% (Wells rule). Combined with a normal d-dimer result, the CDRs excluded PE in 22% to 24% of patients. The total failure rates of the CDR and d-dimer combinations were similar (1 failure, 0.5% to 0.6% [upper-limit 95% CI, 2.9% to 3.1%]). Even though 30% of patients had discordant CDR outcomes, PE was not detected in any patient with discordant CDRs and a normal d-dimer result. Limitation: Management was based on a combination of decision rules and d-dimer testing rather than only 1 CDR combined with d-dimer testing. Conclusion: All 4 CDRs show similar performance for exclusion of acute PE in combination with a normal d-dimer result. This prospective validation indicates that the simplified scores may be used in clinical practice. Primary Funding Source: Academic Medical Center, VU University Medical Center, Rijnstate Hospital, Leiden University Medical Center, Maastricht University Medical Center, Erasmus Medical Center, and Maasstad Hospital. [ABSTRACT FROM AUTHOR]

Introduction: Neutrophils play a dichotomous role in community-acquired pneumonia (CAP), providing protection and potentially causing damage. Existing research on neutrophil function in CAP relies on animal studies, leaving a gap in patient-centered investigations., Methods: We used mass spectrometry to characterize the neutrophil proteome of moderately ill CAP patients at general ward admission and related the proteome to controls and clinical outcomes., Results: We prospectively included 57 CAP patients and 26 controls and quantified 3482 proteins in neutrophil lysates and 386 proteins in concurrently collected plasma. The extensively studied granule-related proteins in animal models did not drive the neutrophil proteome changes associated with human CAP. Proteome alterations were primarily characterized by an increased abundance of proteins related to (aerobic) metabolic activity and (m)RNA translation/processing, concurrent with a diminished presence of cytoskeletal organization-related proteins (all pathways p<0.001). Higher and lower abundances of specific proteins, primarily constituents of these pathways, were associated with prolonged time to clinical stability in CAP. Moreover, we identified a pronounced presence of platelet-related proteins in neutrophil lysates of particularly viral CAP patients, suggesting the existence of neutrophil-platelet complexes in non-critically ill CAP patients. Of the proteins measured in neutrophils, 4.3% were detected in plasma., Discussion: Our study presents new perspectives on the neutrophil proteome associated with CAP, laying the groundwork for forthcoming patient-centred investigations. Our results could pave the way for targeted strategies to fine-tune neutrophil responses, potentially improving CAP outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Michels, Chouchane, de Brabander, de Vos, Faber, Douma, Smit, Wiersinga, Biggelaar, Poll and Hoogendijk.)

Objectives: Lymphopenia at hospital admission occurs in over one-third of patients with community-acquired pneumonia (CAP), yet its clinical relevance and pathophysiological implications remain underexplored. We evaluated outcomes and immune features of patients with lymphopenic CAP (L-CAP), a previously described immunophenotype characterized by admission lymphocyte count <0.724 × 10 9 cells/L., Methods: Observational study in 149 patients admitted to a general ward for CAP. We measured 34 plasma biomarkers reflective of inflammation, endothelial cell responses, coagulation, and immune checkpoints. We characterized lymphocyte phenotypes in 29 patients using spectral flow cytometry., Results: L-CAP occurred in 45 patients (30.2%) and was associated with prolonged time-to-clinical-stability (median 5 versus 3 days), also when we accounted for competing events for reaching clinical stability and adjusted for baseline covariates (subdistribution hazard ratio 0.63; 95% confidence interval 0.45-0.88). L-CAP patients demonstrated a proportional depletion of CD4 T follicular helper cells, CD4 T effector memory cells, naïve CD8 T cells and IgG+ B cells. Plasma biomarker analyses indicated increased activation of the cytokine network and the vascular endothelium in L-CAP., Conclusions: L-CAP patients have a protracted clinical recovery course and a more broadly dysregulated host response. These findings highlight the prognostic and pathophysiological relevance of admission lymphopenia in patients with CAP., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Rationale: Lymphopenia in coronavirus disease (COVID-19) is associated with increased mortality. Objectives: To explore the association between lymphopenia, host response aberrations, and mortality in patients with lymphopenic COVID-19. Methods: We determined 43 plasma biomarkers reflective of four pathophysiological domains: endothelial cell and coagulation activation, inflammation and organ damage, cytokine release, and chemokine release. We explored if decreased concentrations of lymphocyte-derived proteins in patients with lymphopenia were associated with an increase in mortality. We sought to identify host response phenotypes in patients with lymphopenia by cluster analysis of plasma biomarkers. Measurements and Main Results: A total of 439 general ward patients with COVID-19 were stratified by baseline lymphocyte counts: normal (>1.0 × 10 9 /L; n  = 167), mild lymphopenia (>0.5 to ⩽1.0 × 10 9 /L; n  = 194), and severe lymphopenia (⩽0.5 × 10 9 /L; n  = 78). Lymphopenia was associated with alterations in each host response domain. Lymphopenia was associated with increased mortality. Moreover, in patients with lymphopenia ( n  = 272), decreased concentrations of several lymphocyte-derived proteins (e.g., CCL5, IL-4, IL-13, IL-17A) were associated with an increase in mortality (at P  < 0.01 or stronger significance levels). A cluster analysis revealed three host response phenotypes in patients with lymphopenia: "hyporesponsive" (23.2%), "hypercytokinemic" (36.4%), and "inflammatory-injurious" (40.4%), with substantially differing mortality rates of 9.5%, 5.1%, and 26.4%, respectively. A 10-biomarker model accurately predicted these host response phenotypes in an external cohort with similar mortality distribution. The inflammatory-injurious phenotype showed a remarkable combination of relatively high inflammation and organ damage markers with high antiinflammatory cytokine levels yet low proinflammatory cytokine levels. Conclusions: Lymphopenia in COVID-19 signifies a heterogenous group of patients with distinct host response features. Specific host responses contribute to lymphopenia-associated mortality in COVID-19, including reduced CCL5 levels.

Objectives: The aim of this multicentre COVID-PREDICT study (a nationwide observational cohort study that aims to better understand clinical course of COVID-19 and to predict which COVID-19 patients should receive which treatment and which type of care) was to determine the association between atrial fibrillation (AF) and mortality, intensive care unit (ICU) admission, complications and discharge destination in hospitalised COVID-19 patients., Setting: Data from a historical cohort study in eight hospitals (both academic and non-academic) in the Netherlands between January 2020 and July 2021 were used in this study., Participants: 3064 hospitalised COVID-19 patients >18 years old., Primary and Secondary Outcome Measures: The primary outcome was the incidence of new-onset AF during hospitalisation. Secondary outcomes were the association between new-onset AF (vs prevalent or non-AF) and mortality, ICU admissions, complications and discharge destination, performed by univariable and multivariable logistic regression analyses., Results: Of the 3064 included patients (60.6% men, median age: 65 years, IQR 55-75 years), 72 (2.3%) patients had prevalent AF and 164 (5.4%) patients developed new-onset AF during hospitalisation. Compared with patients without AF, patients with new-onset AF had a higher incidence of death (adjusted OR (aOR) 1.71, 95% CI 1.17 to 2.59) an ICU admission (aOR 5.45, 95% CI 3.90 to 7.61). Mortality was non-significantly different between patients with prevalent AF and those with new-onset AF (aOR 0.97, 95% CI 0.53 to 1.76). However, new-onset AF was associated with a higher incidence of ICU admission and complications compared with prevalent AF (OR 6.34, 95% CI 2.95 to 13.63, OR 3.04, 95% CI 1.67 to 5.55, respectively)., Conclusion: New-onset AF was associated with an increased incidence of death, ICU admission, complications and a lower chance to be discharged home. These effects were far less pronounced in patients with prevalent AF. Therefore, new-onset AF seems to represent a marker of disease severity, rather than a cause of adverse outcomes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Community-acquired pneumonia (CAP) represents a major health burden worldwide. Dysregulation of the immune response plays an important role in adverse outcomes in patients with CAP., Methods: We analyzed peripheral blood mononuclear cells by 36-color spectral flow cytometry in adult patients hospitalized for CAP (n=40), matched control subjects (n=31), and patients hospitalized for COVID-19 (n=35)., Results: We identified 86 immune cell metaclusters, 19 of which (22.1%) were differentially abundant in patients with CAP versus matched controls. The most notable differences involved classical monocyte metaclusters, which were more abundant in CAP and displayed phenotypic alterations reminiscent of immunosuppression, increased susceptibility to apoptosis, and enhanced expression of chemokine receptors. Expression profiles on classical monocytes, driven by CCR7 and CXCR5, divided patients with CAP into two clusters with a distinct inflammatory response and disease course. The peripheral immune response in patients with CAP was highly similar to that in patients with COVID-19, but increased CCR7 expression on classical monocytes was only present in CAP., Conclusion: CAP is associated with profound cellular changes in blood that mainly relate to classical monocytes and largely overlap with the immune response detected in COVID-19., Competing Interests: Author AP was employed by the company Cytek Biosciences, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Reijnders, Schuurman, Verhoeff, van den Braber, Douma, Faber, Paul, Wiersinga, Saris, Garcia Vallejo and van der Poll.)

Background: Alterations in platelet function have been implicated in the pathophysiology of COVID-19 since the beginning of the pandemic. While early reports linked hyperactivated platelets to thromboembolic events in COVID-19, subsequent investigations demonstrated hyporeactive platelets with a procoagulant phenotype. Mitochondria are important for energy metabolism and the function of platelets., Objectives: Here, we sought to map the energy metabolism of platelets in a cohort of noncritically ill COVID-19 patients and assess platelet mitochondrial function, activation status, and responsiveness to external stimuli., Methods: We enrolled hospitalized COVID-19 patients and controls between October 2020 and December 2021. Platelets function and metabolism was analyzed by flow cytometry, metabolomics, glucose fluxomics, electron and fluorescence microscopy and western blot., Results: Platelets from COVID-19 patients showed increased phosphatidylserine externalization indicating a procoagulant phenotype and hyporeactivity to ex vivo stimuli, associated with profound mitochondrial dysfunction characterized by mitochondrial depolarization, lower mitochondrial DNA-encoded transcript levels, an altered mitochondrial morphology consistent with increased mitochondrial fission, and increased pyruvate/lactate ratios in platelet supernatants. Metabolic profiling by untargeted metabolomics revealed NADH, NAD + , and ATP among the top decreased metabolites in patients' platelets, suggestive of energy metabolism failure. Consistently, platelet fluxomics analyses showed a strongly reduced utilization of 13 C-glucose in all major energy pathways together with a rerouting of glucose to de novo generation of purine metabolites. Patients' platelets further showed evidence of oxidative stress, together with increased glutathione oxidation and synthesis. Addition of plasma from COVID-19 patients to normal platelets partially reproduced the phenotype of patients' platelets and disclosed a temporal relationship between mitochondrial decay and (subsequent) phosphatidylserine exposure and hyporeactivity., Conclusion: These data link energy metabolism failure in platelets from COVID-19 patients with a prothrombotic platelet phenotype with features matching cell death., (© 2023 The Authors.)

Background: Thrombocytopenia is associated with increased mortality in COVID-19 patients., Objective: To determine the association between thrombocytopenia and alterations in host response pathways implicated in disease pathogenesis in patients with severe COVID-19., Patients/methods: We studied COVID-19 patients admitted to a general hospital ward included in a national (CovidPredict) cohort derived from 13 hospitals in the Netherlands. In a subgroup, 43 host response biomarkers providing insight in aberrations in distinct pathophysiological domains (coagulation and endothelial cell function; inflammation and damage; cytokines and chemokines) were determined in plasma obtained at a single time point within 48 h after admission. Patients were stratified in those with normal platelet counts (150-400 × 10 9 /L) and those with thrombocytopenia (<150 × 10 9 /L)., Results: 6.864 patients were enrolled in the national cohort, of whom 1.348 had thrombocytopenia and 5.516 had normal platelets counts; the biomarker cohort consisted of 429 patients, of whom 85 with thrombocytopenia and 344 with normal platelet counts. Plasma D-dimer levels were not different in thrombocytopenia, although patients with moderate-severe thrombocytopenia (<100 × 10 9 /L) showed higher D-dimer levels, indicating enhanced coagulation activation. Patients with thrombocytopenia had lower plasma levels of many proinflammatory cytokines and chemokines, and antiviral mediators, suggesting involvement of platelets in inflammation and antiviral immunity. Thrombocytopenia was associated with alterations in endothelial cell biomarkers indicative of enhanced activation and a relatively preserved glycocalyx integrity., Conclusion: Thrombocytopenia in hospitalized patients with severe COVID-19 is associated with broad host response changes across several pathophysiological domains. These results suggest a role of platelets in the immune response during severe COVID-19., Competing Interests: Declaration of competing interest There is no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Coronavirus disease 2019 (COVID-19)-induced mortality occurs predominantly in older patients. Several immunomodulating therapies seem less beneficial in these patients. The biological substrate behind these observations is unknown. The aim of this study was to obtain insight into the association between ageing, the host response and mortality in patients with COVID-19., Methods: We determined 43 biomarkers reflective of alterations in four pathophysiological domains: endothelial cell and coagulation activation, inflammation and organ damage, and cytokine and chemokine release. We used mediation analysis to associate ageing-driven alterations in the host response with 30-day mortality. Biomarkers associated with both ageing and mortality were validated in an intensive care unit and external cohort., Results: 464 general ward patients with COVID-19 were stratified according to age decades. Increasing age was an independent risk factor for 30-day mortality. Ageing was associated with alterations in each of the host response domains, characterised by greater activation of the endothelium and coagulation system and stronger elevation of inflammation and organ damage markers, which was independent of an increase in age-related comorbidities. Soluble tumour necrosis factor receptor 1, soluble triggering receptor expressed on myeloid cells 1 and soluble thrombomodulin showed the strongest correlation with ageing and explained part of the ageing-driven increase in 30-day mortality (proportion mediated: 13.0%, 12.9% and 12.6%, respectively)., Conclusions: Ageing is associated with a strong and broad modification of the host response to COVID-19, and specific immune changes likely contribute to increased mortality in older patients. These results may provide insight into potential age-specific immunomodulatory targets in COVID-19., Competing Interests: Conflicts of interest: The authors declare no potential conflicts of interest., (Copyright ©The authors 2023.)

Background:  Activated platelets have been implicated in the proinflammatory and prothrombotic phenotype of coronavirus disease 2019 (COVID-19). While it is increasingly recognized that lipids have important structural and signaling roles in platelets, the lipidomic landscape of platelets during infection has remained unexplored., Objective:  To investigate the platelet lipidome of patients hospitalized for COVID-19., Methods:  We performed untargeted lipidomics in platelets of 25 patients hospitalized for COVID-19 and 23 noninfectious controls with similar age and sex characteristics, and with comparable comorbidities., Results:  Twenty-five percent of the 1,650 annotated lipids were significantly different between the groups. The significantly altered part of the platelet lipidome mostly comprised lipids that were less abundant in patients with COVID-19 (20.4% down, 4.6% up, 75% unchanged). Platelets from COVID-19 patients showed decreased levels of membrane plasmalogens, and a distinct decrease of long-chain, unsaturated triacylglycerols. Conversely, platelets from patients with COVID-19 displayed class-wide higher abundances of bis(monoacylglycero)phosphate and its biosynthetic precursor lysophosphatidylglycerol. Levels of these classes positively correlated with ex vivo platelet reactivity-as measured by P-selectin expression after PAR1 activation-irrespective of disease state., Conclusion:  Taken together, this investigation provides the first exploration of the profound impact of infection on the human platelet lipidome, and reveals associations between the lipid composition of platelets and their reactivity. These results warrant further lipidomic research in other infections and disease states involving platelet pathophysiology., Competing Interests: None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background: Community-acquired pneumonia (CAP) can be caused by a variety of pathogens, of which Streptococcus pneumoniae, Influenza and currently SARS-CoV-2 are the most common. We sought to identify shared and pathogen-specific host response features by directly comparing different aetiologies of CAP., Methods: We measured 72 plasma biomarkers in a cohort of 265 patients hospitalized for CAP, all sampled within 48 hours of admission, and 28 age-and sex matched non-infectious controls. We stratified the biomarkers into several pathophysiological domains- antiviral response, vascular response and function, coagulation, systemic inflammation, and immune checkpoint markers. We directly compared CAP caused by SARS-CoV-2 (COVID-19, n=39), Streptococcus pneumoniae (CAP-strep, n=27), Influenza (CAP-flu, n=22) and other or unknown pathogens (CAP-other, n=177). We adjusted the comparisons for age, sex and disease severity scores., Findings: Biomarkers reflective of a stronger cell-mediated antiviral response clearly separated COVID-19 from other CAPs (most notably granzyme B). Biomarkers reflecting activation and function of the vasculature showed endothelial barrier integrity was least affected in COVID-19, while glycocalyx degradation and angiogenesis were enhanced relative to other CAPs. Notably, markers of coagulation activation, including D-dimer, were not different between the CAP groups. Ferritin was most increased in COVID-19, while other systemic inflammation biomarkers such as IL-6 and procalcitonin were highest in CAP-strep. Immune checkpoint markers showed distinctive patterns in viral and non-viral CAP, with highly elevated levels of Galectin-9 in COVID-19., Interpretation: Our investigation provides insight into shared and distinct pathophysiological mechanisms in different aetiologies of CAP, which may help guide new pathogen-specific therapeutic strategies., Funding: This study was financially supported by the Dutch Research Council, the European Commission and the Netherlands Organization for Health Research and Development., Competing Interests: Declaration of interests JS was on the Data Safety Monitoring Board of the Pointer trial (ISRCTN33682933), and is the Vice President of the European Society of Gastrointestinal and Abdominal Radiology. All other authors declare no conflict of interests., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Evidence from the United States and United Kingdom suggests that ethnic minority populations are at an increased risk for developing severe coronavirus disease 2019 (COVID-19); however, data from other West-European countries are scarce., Methods: We analyzed data from 1439 patients admitted between February 2020 and January 2021 to 4 main hospitals in Amsterdam and Almere, the Netherlands. Differences in the risk for hospitalization were assessed by comparing demographics to the general population. Using a population-based cohort as reference, we determined differences in the association between comorbidities and COVID-19 hospitalization. Outcomes after hospitalization were analyzed using Cox regression., Results: The hospitalization risk was higher in all ethnic minority groups than in those of Dutch origin, with age-adjusted odds ratios ranging from 2.2 (95% confidence interval [CI], 1.7-2.6) in Moroccans to 4.5 (95% CI, 3.2-6.0) in Ghanaians. Hypertension and diabetes were similarly associated with COVID-19 hospitalization. For all other comorbidities, we found differential associations. Intensive care unit admission and mortality during 21-day follow-up after hospitalization was comparable between ethnicities., Conclusions: The risk of COVID-19 hospitalization was higher in all ethnic minority groups compared to the Dutch, but the risk of adverse outcomes after hospitalization was similar. Our results suggest that these inequalities may in part be attributable to comorbidities that can be prevented by targeted public health prevention measures. More work is needed to gain insight into the role of other potential factors such as social determinants of health, which might have contributed to the ethnic inequalities in COVID-19 hospitalization., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objective: To evaluate the association between overweight and obesity on the clinical course and outcomes in patients hospitalized with COVID-19., Design: Retrospective, observational cohort study., Methods: We performed a multicenter, retrospective, observational cohort study of hospitalized COVID-19 patients to evaluate the associations between overweight and obesity on the clinical course and outcomes., Results: Out of 1634 hospitalized COVID-19 patients, 473 (28.9%) had normal weight, 669 (40.9%) were overweight, and 492 (30.1%) were obese. Patients who were overweight or had obesity were younger, and there were more women in the obese group. Normal-weight patients more often had pre-existing conditions such as malignancy, or were organ recipients. During admission, patients who were overweight or had obesity had an increased probability of acute respiratory distress syndrome [OR 1.70 (1.26-2.30) and 1.40 (1.01-1.96)], respectively and acute kidney failure [OR 2.29 (1.28-3.76) and 1.92 (1.06-3.48)], respectively. Length of hospital stay was similar between groups. The overall in-hospital mortality rate was 27.7%, and multivariate logistic regression analyses showed that overweight and obesity were not associated with increased mortality compared to normal-weight patients., Conclusion: In this study, overweight and obesity were associated with acute respiratory distress syndrome and acute kidney injury, but not with in-hospital mortality nor length of hospital stay., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 van Son, Oussaada, Şekercan, Beudel, Dongelmans, van Assen, Eland, Moeniralam, Dormans, van Kalkeren, Douma, Rusch, Simsek, Liu, Kootte, Wyers, IJzerman, van den Bergh, Stehouwer, Nieuwdorp, ter Horst and Serlie.)

Objective: Develop and validate models that predict mortality of patients diagnosed with COVID-19 admitted to the hospital., Design: Retrospective cohort study., Setting: A multicentre cohort across 10 Dutch hospitals including patients from 27 February to 8 June 2020., Participants: SARS-CoV-2 positive patients (age ≥18) admitted to the hospital., Main Outcome Measures: 21-day all-cause mortality evaluated by the area under the receiver operator curve (AUC), sensitivity, specificity, positive predictive value and negative predictive value. The predictive value of age was explored by comparison with age-based rules used in practice and by excluding age from the analysis., Results: 2273 patients were included, of whom 516 had died or discharged to palliative care within 21 days after admission. Five feature sets, including premorbid, clinical presentation and laboratory and radiology values, were derived from 80 features. Additionally, an Analysis of Variance (ANOVA)-based data-driven feature selection selected the 10 features with the highest F values: age, number of home medications, urea nitrogen, lactate dehydrogenase, albumin, oxygen saturation (%), oxygen saturation is measured on room air, oxygen saturation is measured on oxygen therapy, blood gas pH and history of chronic cardiac disease. A linear logistic regression and non-linear tree-based gradient boosting algorithm fitted the data with an AUC of 0.81 (95% CI 0.77 to 0.85) and 0.82 (0.79 to 0.85), respectively, using the 10 selected features. Both models outperformed age-based decision rules used in practice (AUC of 0.69, 0.65 to 0.74 for age >70). Furthermore, performance remained stable when excluding age as predictor (AUC of 0.78, 0.75 to 0.81)., Conclusion: Both models showed good performance and had better test characteristics than age-based decision rules, using 10 admission features readily available in Dutch hospitals. The models hold promise to aid decision-making during a hospital bed shortage., Competing Interests: Competing interests: The COVID-predict consortium declare to have received non-financial support from Castor, who provided access and use of their database free of charge. Pacmed occasionally provided scientific support for methodology and analysis., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Inhibition of dipeptidyl peptidase (DPP-)4 could reduce coronavirus disease 2019 (COVID-19) severity by reducing inflammation and enhancing tissue repair beyond glucose lowering. We aimed to assess this in a prospective cohort study., Methods: We studied in 565 patients with type 2 diabetes in the CovidPredict Clinical Course Cohort whether use of a DPP-4 inhibitor prior to hospital admission due to COVID-19 was associated with improved clinical outcomes. Using crude analyses and propensity score matching (on age, sex and BMI), 28 patients using a DPP-4 inhibitor were identified and compared to non-users., Results: No differences were found in the primary outcome mortality (matched-analysis = odds-ratio: 0,94 [95% confidence interval: 0,69 - 1,28], p -value: 0,689) or any of the secondary outcomes (ICU admission, invasive ventilation, thrombotic events or infectious complications). Additional analyses comparing users of DPP-4 inhibitors with subgroups of non-users (subgroup 1: users of metformin and sulphonylurea; subgroup 2: users of any insulin combination), allowing to correct for diabetes severity, did not yield different results., Conclusions: We conclude that outpatient use of a DPP-4 inhibitor does not affect the clinical outcomes of patients with type 2 diabetes who are hospitalized because of COVID-19 infection., Competing Interests: Competing interestsThe authors have nothing to disclose., (© The Author(s) 2021.)

Objective: To compare survival of individuals with coronavirus disease 2019 (COVID-19) treated in hospitals that either did or did not routinely treat patients with hydroxychloroquine or chloroquine., Methods: We analysed data of COVID-19 patients treated in nine hospitals in the Netherlands. Inclusion dates ranged from 27 February to 15 May 2020, when the Dutch national guidelines no longer supported the use of (hydroxy)chloroquine. Seven hospitals routinely treated patients with (hydroxy)chloroquine, two hospitals did not. Primary outcome was 21-day all-cause mortality. We performed a survival analysis using log-rank test and Cox regression with adjustment for age, sex and covariates based on premorbid health, disease severity and the use of steroids for adult respiratory distress syndrome, including dexamethasone., Results: Among 1949 individuals, 21-day mortality was 21.5% in 1596 patients treated in hospitals that routinely prescribed (hydroxy)chloroquine, and 15.0% in 353 patients treated in hospitals that did not. In the adjusted Cox regression models this difference disappeared, with an adjusted hazard ratio of 1.09 (95% CI 0.81-1.47). When stratified by treatment actually received in individual patients, the use of (hydroxy)chloroquine was associated with an increased 21-day mortality (HR 1.58; 95% CI 1.24-2.02) in the full model., Conclusions: After adjustment for confounders, mortality was not significantly different in hospitals that routinely treated patients with (hydroxy)chloroquine compared with hospitals that did not. We compared outcomes of hospital strategies rather than outcomes of individual patients to reduce the chance of indication bias. This study adds evidence against the use of (hydroxy)chloroquine in hospitalised patients with COVID-19., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: To systematically collect clinical data from patients with a proven COVID-19 infection in the Netherlands., Design: Data from 2579 patients with COVID-19 admitted to 10 Dutch centers in the period February to July 2020 are described. The clinical data are based on the WHO COVID case record form (CRF) and supplemented with patient characteristics of which recently an association disease severity has been reported., Methods: Survival analyses were performed as primary statistical analysis. These Kaplan-Meier curves for time to (early) death (3 weeks) have been determined for pre-morbid patient characteristics and clinical, radiological and laboratory data at hospital admission., Results: Total in-hospital mortality after 3 weeks was 22.2% (95% CI: 20.7% - 23.9%), hospital mortality within 21 days was significantly higher for elderly patients (> 70 years; 35, 0% (95% CI: 32.4% - 37.8%) and patients who died during the 21 days and were admitted to the intensive care (36.5% (95% CI: 32.1% - 41.3%)). Apart from that, in this Dutch population we also see a risk of early death in patients with co-morbidities (such as chronic neurological, nephrological and cardiac disorders and hypertension), and in patients with more home medication and / or with increased urea and creatinine levels., Conclusion: Early death due to a COVID-19 infection in the Netherlands appears to be associated with demographic variables (e.g. age), comorbidity (e.g. cardiovascular disease) but also disease char-acteristics at admission.

Introduction: Venous malformations (VMs) are ubiquitous, low-flow vascular anomalies known to be occasionally painful due to thrombotic episodes within the lesion. The prevalence of superficial or deep vein thrombosis is unclear., Methods: A cross-sectional study among outpatients aged ≥ 12 years with pure VMs was performed, quantifying the prevalence of thrombosis by screening all patients with compression ultrasonography (CUS). Additionally, we evaluated whether coagulation alterations were related to thrombosis observed with CUS., Results: In total, 69 patients with pure VMs were eligible, median age was 30 years (range 12-63) and 52% were female. A total of 68 patients underwent CUS. Superficial vein thrombosis was observed in 10 (15%) cases; 1 patient had a current asymptomatic deep venous thrombosis. Residual superficial or deep thrombosis was observed in 25 patients (36%). In total, 49% had either a history or current signs of a thrombotic event and overall 10% had venous thromboembolism. In approximately 50% of the patients the D-dimer level was above 0.5 mg/l. Median P-selectin and Von Willebrand factor levels were 29 ng/ml (interquartile range (IQR) 21-34) and 108% (IQR 83-132), respectively. No differences were observed in the coagulation parameters between the patients with and without current clots in their VM., Conclusion: This study shows that superficial or deep vein thrombosis is common among patients with a pure VM. Physicians should be aware of this high incidence, especially if other risk factors for thrombosis are present.

A normal computed tomography pulmonary angiography (CTPA) remains a controversial criterion for ruling out acute pulmonary embolism (PE) in patients with a likely clinical probability. We set out to determine the risk of VTE and fatal PE after a normal CTPA in this patient category and compare these risk to those after a normal pulmonary angiogram of 1.7 % (95 %CI 1.0-2.7 %) and 0.3 % (95 %CI 0.02-0.7 %). A patient-level meta-analysis from 4 prospective diagnostic management studies that sequentially applied the Wells rule, D-dimer tests and CTPA to consecutive patients with clinically suspected acute PE. The primary outcome was the 3-month VTE incidence after a normal CTPA. A total of 6,148 patients were included with an overall PE prevalence of 24 %. The 3-month VTE incidence in all 4,421 patients in whom PE was excluded at baseline was 1.2 % (95 %CI 0.48-2.6) and the risk of fatal PE was 0.11 % (95 %CI 0.02-0.70). In patients with a likely clinical probability the 3-month incidences of VTE and fatal PE were 2.0 % (95 %CI 1.0-4.1 %) and 0.48 % (95 %CI 0.20-1.1 %) after a normal CTPA. The 3-month incidence of VTE was 6.3 % (95 %CI 3.0-12) in patients with a Wells rule >6 points. In conclusion, this study suggests that a normal CTPA may be considered as a valid diagnostic criterion to rule out PE in the majority of patients with a likely clinical probability, although the risk of VTE is higher in subgroups such as patients with a Wells rule >6 points for which a closer follow-up should be considered.

Background: The performance of different diagnostic strategies for pulmonary embolism (PE) in patient subgroups is unclear., Purpose: To evaluate and compare the efficiency and safety of the Wells rule with fixed or age-adjusted d-dimer testing overall and in inpatients and persons with cancer, chronic obstructive pulmonary disease, previous venous thromboembolism, delayed presentation, and age 75 years or older., Data Sources: MEDLINE and EMBASE from 1 January 1988 to 13 February 2016., Study Selection: 6 prospective studies in which the diagnostic management of PE was guided by the dichotomized Wells rule and quantitative d-dimer testing., Data Extraction: Individual data of 7268 patients; risk of bias assessed by 2 investigators with the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2) tool., Data Synthesis: The proportion of patients in whom imaging could be withheld based on a "PE-unlikely" Wells score and a negative d-dimer test result (efficiency) was estimated using fixed (≤500 µg/L) and age-adjusted (age × 10 µg/L in patients aged >50 years) d-dimer thresholds; their 3-month incidence of symptomatic venous thromboembolism (failure rate) was also estimated. Overall, efficiency increased from 28% to 33% when the age-adjusted (instead of the fixed) d-dimer threshold was applied. This increase was more prominent in elderly patients (12%) but less so in inpatients (2.6%). The failure rate of age-adjusted d-dimer testing was less than 3% in all examined subgroups., Limitation: Post hoc analysis, between-study differences in patient characteristics, use of various d-dimer assays, and limited statistical power to assess failure rate., Conclusion: Age-adjusted d-dimer testing is associated with a 5% absolute increase in the proportion of patients with suspected PE in whom imaging can be safely withheld compared with fixed d-dimer testing. This strategy seems safe across different high-risk subgroups, but its efficiency varies., Primary Funding Source: None.

Introduction: Among patients with clinically suspected pulmonary embolism (PE), imaging and anticoagulant treatment can be safely withheld in approximately one-third of patients based on the combination of a "PE unlikely" Wells score and a D-dimer below the age-adjusted threshold. The clinical utility of this diagnostic approach in cancer patients is less clear., Aim: To evaluate the efficiency and failure rate of the original and simplified Wells rules in combination with age-adjusted D-dimer testing in patients with active cancer., Materials and Methods: Individual patient data were used from 6 large prospective studies in which the diagnostic management of PE was guided by the original Wells rule and D-dimer testing. Study physicians classified patients as having active cancer if they had new, recurrent, or progressive cancer (excluding basal-cell or squamous-cell skin carcinoma), or cancer requiring treatment in the last 6 months. We evaluated the dichotomous Wells rule and its simplified version (Table). The efficiency of the algorithm was defined as the proportion of patients with a "PE unlikely" Wells score and a negative age-adjusted D-dimer, defined by a D-dimer below the threshold of a patient's age times 10 μg/L in patients aged ≥51 years. A diagnostic failure was defined as a patient with a "PE unlikely" Wells score and negative age-adjusted D-dimer who had symptomatic venous thromboembolism during 3 months follow-up. A one-stage random effects meta-analysis was performed to estimate the efficiency and failure., Results: The dataset comprised 938 patients with active cancer with a mean age of 63 years. The most frequent cancer types were breast (13%), gastrointestinal tract (11%), and lung (8%). The type of cancer was not specified in 42%. The pooled PE prevalence was 29% (95% CI 25-32). PE could be excluded in 122 patients based on a "PE unlikely" Wells score and a negative age-adjusted D-dimer (efficiency 13%; 95% CI 11-15). Two of 122 patients were diagnosed with non-fatal symptomatic venous thromboembolism during follow-up (failure rate 1.5%; 95% CI 0.13-14.8). The simplified Wells score in combination with a negative age-adjusted D-dimer had an efficiency of 3.9% (95% CI 2.0-7.6) and a failure rate of 2.4% (95% CI 0.3-15)., Conclusions: Among cancer patients with clinically suspected PE, imaging and anticoagulant treatment can be withheld in 1 out of every 8 patients by the original Wells rule and age-adjusted D-dimer testing. The simplified Wells rule was neither efficient nor safe in this population., (© 2016 Elsevier Ltd. All rights reserved.)

Since late 2015, an unprecedented outbreak of Zika virus is spreading quickly across Southern America. The large size of the current outbreak in The Americas will also result in an increase in Zika virus infections among travelers returning from endemic areas. We report five cases of imported Zika virus infection to The Netherlands. Although the clinical course is usually mild, establishing the diagnosis is important, mainly because of the association with congenital microcephaly and the possibility of sexual transmission., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Computed tomography pulmonary angiogram (CTPA) has become the standard test in the diagnostic workup of patients with suspected pulmonary embolism (PE). However, young patients may have an increased risk of cancer with CTPA. Perfusion scanning combined with chest X-ray (X/Q) may offer an adequate alternative, but has never been prospectively validated. We directly compared this strategy with CTPA in patients aged ≤50years with suspected PE., Methods: Consecutive patients with a likely clinical probability or an abnormal D-dimer level underwent both CTPA and X/Q. Two trained and experienced nuclear physicians independently analyzed the X/Q-scans. The accuracy of X/Q according to the PISAPED criteria was calculated in terms of sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV)., Results: Seventy-six patients were included, with a PE rate of 33%. The inter-observer agreement for X/Q-scan reading was high (κ=0.89). After consensus reading, 21 patients (28%) were categorized as 'PE present', 53 (70%) as 'PE absent', and two (2.6%) as 'non-diagnostic'. In 22%, there was a discrepancy between the X/Q-scan and CPTA for the diagnosis or exclusion of PE. The PPV and NPV were 71% and 83%, respectively., Conclusion: In patients with a high risk of PE, a diagnostic strategy of chest X-ray and perfusion scanning using the PISAPED criteria seems less safe than CTPA. Additional studies should further investigate this diagnostic algorithm., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: An 'unlikely' clinical decision rule with a negative D-dimer result safely excludes pulmonary embolism (PE) in 30% of presenting patients. We aimed to simplify this diagnostic approach and to increase its efficiency., Methods: Data for 723 consecutive patients with suspected PE were analyzed (prevalence of PE, 22%). After constructing a logistic regression model with the D-dimer test result and items from the Wells' score, we identified the most prevalent combinations of influential items and selected new D-dimer positivity thresholds. The performance was separately validated with data from 2785 consecutive patients with suspected PE., Results: Three Wells items significantly added incremental value to the D-dimer test: hemoptysis, signs of deep vein thrombosis and 'PE most likely'. Based on the most frequent combinations of these three items, we identified two groups: (i) none of these three items positive (41%); (ii) one or more of these items positive (59%). When applying a 1000 μg/L D-dimer threshold in group 1 and 500 μg/L in group 2, PE could be excluded without CT scanning in 36%, at a false-negative rate of 1.2% (95%, 0.04-3.3%). In the validation set, these proportions were 46% and 1.9% (95% CI, 1.2-2.7%), respectively. Using the conventional Wells score with a normal D-dimer result, these rates were, respectively, 22% and 0.6% (95% CI, 0.10-2.4%)., Conclusion: Combining Wells items with the D-dimer test resulted in a simplified decision rule, which reduces the need for CT scanning in patients with suspected PE. A prospective validation is required before it can be implemented in clinical practice., (© 2015 International Society on Thrombosis and Haemostasis.)

The systematic assessment of residual thromboembolic obstruction after treatment for acute pulmonary embolism (PE) has been understudied. This assessment is of potential clinical importance, should clinically suspected recurrent PE occur, or as tool for risk stratification of cardiopulmonary complications or recurrent venous thromboembolism (VTE). This study aimed to assess the rate of PE resolution and its implications for clinical outcome. In this prospective, multi-center cohort study, 157 patients with acute PE diagnosed by CT pulmonary angiography (CTPA) underwent follow-up CTPA-imaging after six months of anticoagulant treatment. Two expert thoracic radiologists independently assessed the presence of residual thromboembolic obstruction. The degree of obstruction at baseline and follow-up was calculated using the Qanadli obstruction index. All patients were followed-up for 2.5 years. At baseline, the median obstruction index was 27.5 %. After six months of treatment, complete PE resolution had occurred in 84.1 % of the patients (95 % confidence interval (CI): 77.4-89.4 %). The median obstruction index of the 25 patients with residual thrombotic obstruction was 5.0 %. During follow-up, 16 (10.2 %) patients experienced recurrent VTE. The presence of residual thromboembolic obstruction was not associated with recurrent VTE (adjusted hazard ratio: 0.92; 95 % CI: 0.2-4.1).This study indicates that the incidence of residual thrombotic obstruction following treatment for PE is considerably lower than currently anticipated. These findings, combined with the absence of a correlation between residual thrombotic obstruction and recurrent VTE, do not support the routine use of follow-up CTPA-imaging in patients treated for acute PE.

Introduction: The value of diagnostic strategies in patients with clinically suspected recurrent pulmonary embolism (PE) has not been established. The aim was to determine the safety of a simple diagnostic strategy using the Wells clinical decision rule (CDR), quantitative D-dimer testing and computed tomography pulmonary angiography (CTPA) in patients with clinically suspected acute recurrent PE., Materials and Methods: Multicenter clinical outcome study in 516 consecutive patients with clinically suspected acute recurrent PE without using anticoagulants., Results: An unlikely clinical probability (Wells rule 4 points or less) was found in 182 of 516 patients (35%), and the combination of an unlikely CDR-score and normal D-dimer result excluded PE in 88 of 516 patients (17%), without recurrent venous thromboembolism (VTE) during 3month follow-up (0%; 95% CI 0.0-3.4%). CTPA was performed in all other patients and confirmed recurrent PE in 172 patients (overall prevalence of PE 33%) and excluded PE in the remaining 253 patients (49%). During follow-up, seven of these 253 patients returned with recurrent VTE (2.8%; 95% CI 1.2-5.5%), of which in one was fatal (0.4 %; 95 % CI 0.02-1.9%). The diagnostic algorithm was feasible in 98% of patients., Conclusions: A diagnostic algorithm consisting of a clinical decision rule, D-dimer test and CTPA is effective in the management of patients with clinically suspected acute recurrent PE. CTPA provides reasonable safety in excluding acute recurrent PE in patients with a likely clinical probability or an elevated D-dimer test for recurrent PE, with a low risk for fatal PE at follow-up., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Importance: D-dimer measurement is an important step in the diagnostic strategy of clinically suspected acute pulmonary embolism (PE), but its clinical usefulness is limited in elderly patients., Objective: To prospectively validate whether an age-adjusted D-dimer cutoff, defined as age × 10 in patients 50 years or older, is associated with an increased diagnostic yield of D-dimer in elderly patients with suspected PE., Design, Settings, and Patients: A multicenter, multinational, prospective management outcome study in 19 centers in Belgium, France, the Netherlands, and Switzerland between January 1, 2010, and February 28, 2013., Interventions: All consecutive outpatients who presented to the emergency department with clinically suspected PE were assessed by a sequential diagnostic strategy based on the clinical probability assessed using either the simplified, revised Geneva score or the 2-level Wells score for PE; highly sensitive D-dimer measurement; and computed tomography pulmonary angiography (CTPA). Patients with a D-dimer value between the conventional cutoff of 500 µg/L and their age-adjusted cutoff did not undergo CTPA and were left untreated and formally followed-up for a 3-month period., Main Outcomes and Measures: The primary outcome was the failure rate of the diagnostic strategy, defined as adjudicated thromboembolic events during the 3-month follow-up period among patients not treated with anticoagulants on the basis of a negative age-adjusted D-dimer cutoff result., Results: Of the 3346 patients with suspected PE included, the prevalence of PE was 19%. Among the 2898 patients with a nonhigh or an unlikely clinical probability, 817 patients (28.2%) had a D-dimer level lower than 500 µg/L (95% CI, 26.6%-29.9%) and 337 patients (11.6%) had a D-dimer between 500 µg/L and their age-adjusted cutoff (95% CI, 10.5%-12.9%). The 3-month failure rate in patients with a D-dimer level higher than 500 µg/L but below the age-adjusted cutoff was 1 of 331 patients (0.3% [95% CI, 0.1%-1.7%]). Among the 766 patients 75 years or older, of whom 673 had a nonhigh clinical probability, using the age-adjusted cutoff instead of the 500 µg/L cutoff increased the proportion of patients in whom PE could be excluded on the basis of D-dimer from 43 of 673 patients (6.4% [95% CI, 4.8%-8.5%) to 200 of 673 patients (29.7% [95% CI, 26.4%-33.3%), without any additional false-negative findings., Conclusions and Relevance: Compared with a fixed D-dimer cutoff of 500 µg/L, the combination of pretest clinical probability assessment with age-adjusted D-dimer cutoff was associated with a larger number of patients in whom PE could be considered ruled out with a low likelihood of subsequent clinical venous thromboembolism., Trial Registration: clinicaltrials.gov Identifier: NCT01134068.

Background: CT pulmonary angiography (CTPA) is commonly used as the first imaging test in the diagnostic workup of patients with suspected pulmonary embolism (PE). Other CTPA findings may provide an alternative explanation for signs and symptoms in these patients, but the clinical impact is not clear., Methods: In 203 consecutive patients with suspected PE, we prospectively evaluated the clinical implication of abnormalities on CTPA. Alternative diagnoses were defined on clinical grounds before and after CTPA. Subsequent diagnostic tests and therapeutic consequences were assessed by criteria defined a priori., Results: Sixty-one of the 203 patients (30%) had no abnormality on CTPA. Thirty-nine patients (19%) were given a diagnosis of PE. Before CTPA, alternative diagnoses were suspected in 97 patients (48%). Findings supporting an alternative diagnosis were detected in 88 patients (43%). In 28 patients, this was a new finding; in 18, a conclusive and previously unknown alternative diagnosis was made on the basis of the CTPA results. Overall, the findings supporting alternative diagnoses had therapeutic consequences in 10 patients (4.9%). Incidental findings (nodules and enlarged lymph nodes) requiring diagnostic procedures were present in 17 patients (8.4%), with one (0.5%) having a therapeutic consequence., Conclusions: In patients undergoing CTPA for suspected PE, findings supporting an alternative diagnosis were found in almost one-half of the patients. However, in only a few patients, the alternative diagnosis had therapeutic consequences. Hence, CTPA should principally be used to confirm or exclude PE in high-probability cases but not to establish an alternative diagnosis.

Introduction: Although quality of life (QoL) is recognized as an important indicator of the course of a disease, it has rarely been addressed in studies evaluating the outcome of care for patients with pulmonary embolism (PE). This study primarily aimed to evaluate the QoL of patients with acute PE in comparison to population norms and to patients with other cardiopulmonary diseases, using a generic QoL questionnaire. Secondary, the impact of time period from diagnosis and clinical patient characteristics on QoL was assessed, using a disease-specific questionnaire., Methods: QoL was assessed in 109 consecutive out-patients with a history of objectively confirmed acute PE (mean age 60.4 ± 15.0 years, 56 females), using the generic Short Form-36 (SF-36) and the disease specific Pulmonary Embolism Quality of Life questionnaire (PEmb-QoL). The score of the SF-36 were compared with scores of the general Dutch population and reference populations with chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF), a history of acute myocardial infarction (AMI), derived from the literature. Scores on the SF-35 and PEmb-QoL were used to evaluate QoL in the short-term and long-term clinical course of patients with acute PE. In addition, we examined correlations between PEmb-QoL scores and clinical patient characteristics., Results: Compared to scores of the general Dutch population, scores of PE patients were worse on several subscales of the SF-36 (social functioning, role emotional, general health (P<0.001), role physical and vitality (P<0.05)). Compared to patients with COPD and CHF, patients with PE scored higher (=better) on all subscales of the SF-36 (P ≤ 0.004) and had scores comparable with patients with AMI the previous year. Comparing intermediately assessed QoL with QoL assessed in long-term follow-up, PE patients scored worse on SF-36 subscales: physical functioning, social functioning, vitality (P<0.05), and on the PEmb-QoL subscales: emotional complaints and limitations in ADL (P ≤ 0.03). Clinical characteristics did not correlate with QoL as measured by PEmb-QoL., Conclusion: Our study demonstrated an impaired QoL in patients after treatment of PE. The results of this study provided more knowledge about QoL in patients treated for PE., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: To review the diagnostic accuracy of D-dimer testing in older patients (>50 years) with suspected venous thromboembolism, using conventional or age adjusted D-dimer cut-off values., Design: Systematic review and bivariate random effects meta-analysis., Data Sources: We searched Medline and Embase for studies published before 21 June 2012 and we contacted the authors of primary studies., Study Selection: Primary studies that enrolled older patients with suspected venous thromboembolism in whom D-dimer testing, using both conventional (500 µg/L) and age adjusted (age × 10 µg/L) cut-off values, and reference testing were performed. For patients with a non-high clinical probability, 2 × 2 tables were reconstructed and stratified by age category and applied D-dimer cut-off level., Results: 13 cohorts including 12,497 patients with a non-high clinical probability were included in the meta-analysis. The specificity of the conventional cut-off value decreased with increasing age, from 57.6% (95% confidence interval 51.4% to 63.6%) in patients aged 51-60 years to 39.4% (33.5% to 45.6%) in those aged 61-70, 24.5% (20.0% to 29.7% in those aged 71-80, and 14.7% (11.3% to 18.6%) in those aged >80. Age adjusted cut-off values revealed higher specificities over all age categories: 62.3% (56.2% to 68.0%), 49.5% (43.2% to 55.8%), 44.2% (38.0% to 50.5%), and 35.2% (29.4% to 41.5%), respectively. Sensitivities of the age adjusted cut-off remained above 97% in all age categories., Conclusions: The application of age adjusted cut-off values for D-dimer tests substantially increases specificity without modifying sensitivity, thereby improving the clinical utility of D-dimer testing in patients aged 50 or more with a non-high clinical probability.

Introduction: Little is known about the natural history of clot resolution in the initial weeks of anticoagulant therapy in patients with acute pulmonary embolism (PE). Clot resolution of acute PE was assessed with either computed tomography pulmonary angiography scan (CT-scan) or perfusion scintigraphy scan (Q-scan) after 3 weeks of treatment., Methods: This was a predefined safety analysis of the Einstein PE study, including PE patients, randomized to either enoxaparin with vitamin K antagonist (VKA) or rivaroxaban. A similar scan as at baseline was repeated after 3 weeks. The percentage of vascular obstruction (PVO) was calculated on the basis of a weighted semiquantitative estimation of obstruction. Clot resolution was assessed blindly by calculating the relative change after 3 weeks., Results: PE was diagnosed in 264 patients with CT-scan and in 83 with Q-scan. Baseline characteristics were similar. At baseline, the mean PVO assessed with CT-scan (PVO-CT) and the mean PVO assessed with Q-scan (PVO-Q) were both 21% (standard deviation [SD] 13%) (P = 0.9). The mean relative decrease in PVO was 71% (SD 33%) for PVO-CT, and 62% (SD 36%) for PVO-Q (P = 0.02); complete resolution was observed in 44% (116/264; 95% confidence interval [CI] 38-50%) and 31% (26/83; 95% CI 22-42%) with CT-scan and Q-scan, respectively (P = 0.04). No difference in clot resolution between enoxaparin/VKA and rivaroxaban was found., Conclusion: In patients with acute PE, only 3 weeks of anticoagulant treatment leads to complete clot resolution in a considerable proportion of patients, and normalization is more often observed with CT-scan than with Q-scan., (© 2013 International Society on Thrombosis and Haemostasis.)

Background: D-dimer testing to rule out deep vein thrombosis is less useful in older patients because of a lower specificity. An age-adjusted D-dimer cut-off value increased the proportion of older patients (>50 years) in whom pulmonary embolism could be excluded. We retrospectively validated the efficacy of this cut-off combined with clinical probability for the exclusion of deep vein thrombosis., Design and Methods: Five management study cohorts of 2818 consecutive outpatients with suspected deep vein thrombosis were used. Patients with non-high or unlikely probability of deep vein thrombosis were included in the analysis; four different D-dimer tests were used. The proportion of patients with a normal D-dimer test and the failure rates were calculated using the conventional (500 μg/L) and the age-adjusted D-dimer cut-off (patient's age x 10 μg/L in patients >50 years)., Results: In 1672 patients with non-high probability, deep vein thrombosis could be excluded in 850 (51%) patients with the age-adjusted cut-off value versus 707 (42%) patients with the conventional cut-off value. The failure rates were 7 (0.8; 95% confidence interval 0.3-1.7%) for the age-adjusted cut-off value and 5 (0.7%, 0.2-1.6%) for the conventional cut-off value. The absolute increase in patients in whom deep vein thrombosis could be ruled out using the age-adjusted cut-off value was largest in patients >70 years: 19% among patients with non-high probability., Conclusions: The age-adjusted cut-off of the D-dimer combined with clinical probability greatly increases the proportion of older patients in whom deep vein thrombosis can be safely excluded.

Background: Klippel-Trenaunay syndrome (KTS) is characterized by vascular malformations and disturbed soft tissue or bony growth, involving one or more extremities. A high incidence of venous thromboembolism (VTE) has been reported in this disorder, along with cases of belated diagnosed chronic thromboembolic (CTE) pulmonary hypertension (CTEPH). We performed a cross-sectional study to investigate the prevalence of CTE in patients with KTS., Methods: Those from our KTS patient cohort willing to participate were examined with a sequential diagnostic workup including perfusion scintigraphy, computed tomography, and echocardiography., Results: Of 68 patients, 48 patients participated in the study (median age 43 years; 29 [60%] were female). Eleven patients (23%) had an abnormal perfusion scan result, of whom computed tomographic scanning showed signs of CTE in two patients (4.2%; 95% confidence interval [CI] 1.2%-14%); both patients had a history of VTE. Echocardiography showed no signs of CTEPH in these patients. In total, 23 patients (48%; 95% CI 35%-62%) had a history of superficial vein thrombosis and 8 patients (17%; 95% CI 8.7%-30%) had a history of deep vein thrombosis or pulmonary embolism, which was associated with more shortness of breath., Limitations: Echocardiography was only performed in patients with CTE., Conclusion: A large proportion of patients with KTS had a history of VTE. The prevalence of CTE in the total KTS cohort, however, appeared less alarming than previously assumed. Based on these results, we suggest that there is only a limited indication for CTEPH screening among patients with KTS. Nevertheless, awareness for CTEPH remains appropriate, especially among patients presenting with shortness of breath and a history of VTE., (Copyright © 2011 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)

The clinical presentation of pulmonary embolism (PE) varies widely, ranging from only limited symptoms to severe cardiogenic shock. Treatment of PE comprises initial therapy--with low-molecular-weight heparin (LMWH), fondaparinux, or unfractionated heparin--and long-term treatment, most commonly with vitamin-K antagonists (VKAs). Methods of risk stratification, to determine whether a patient will benefit from thrombolysis, are currently under investigation. However, at present, insufficient evidence exists that hemodynamically stable patients who demonstrate echocardiographic right ventricular strain (submassive PE) benefit from thrombolysis. By contrast, thrombolysis is a widely accepted treatment strategy for patients with hemodynamic shock (massive PE). The duration of VKA treatment is commonly 3-12 months and depends on the type of PE and on the balance between the risks of recurrent PE, major bleeding, and the patient's preference. In patients with a malignancy, treatment with LMWH during the first 6 months after diagnosis of PE is recommended. Several new oral anticoagulants, such as factor IIa and factor Xa inhibitors, are now being investigated. For prevention of recurrent PE in situations where anticoagulation is contraindicated, a temporary inferior vena cava filter might be useful. Some patients with PE can be safely treated at home, but few outcome studies in this setting have been published.

Background: In patients with suspected pulmonary embolism (PE), an unlikely or non-high probability assessment combined with a normal D-dimer test can safely exclude the diagnosis. We studied the influence of early D-dimer knowledge on clinical probability assessment., Methods: A questionnaire was sent to 150 randomly selected pulmonologists and internists in the Netherlands, presenting six hypothetical case-descriptions of patients with suspected PE. Physicians were randomized to receive one of three versions. The version contained a normal, an abnormal or no D-dimer result with each case-description. Each version contained two cases with an abnormal D-dimer result, two cases with a normal D-dimer result and two cases with no D-dimer result., Results: A total of 71 physicians (47%) returned the questionnaire; the three versions were equally represented. Compared to the control cases in which no D-dimer was given, knowledge of an abnormal D-dimer resulted in more "likely" clinical scores using the Wells' score (absolute increase in "likely" of 25-37%, p=0.005, 0.111 and 0.144), while knowledge of a normal D-dimer resulted in more "unlikely" scores (absolute increase in "unlikely" of 27-44%, p=0.001 and 0.070). D-dimer knowledge did not influence the probability assessment when the clinical suspicion was very high., Conclusion: Knowledge of the D-dimer test influences the physician in how the clinical probability for PE is scored. This will have direct clinical consequences, such as unnecessary imaging testing or inappropriate exclusion of the diagnosis. Physicians should therefore make sure that they examine the patient before they take notice of the D-dimer test result., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Patients with malignancy frequently present with clinically suspected pulmonary embolism (PE). However, the safe and efficient combination of a clinical decision rule (CDR) and D-dimer test to rule out PE performs less well in patients with malignancy. We examined potential explanations and analysed whether elevating the D-dimer cut-off could improve the clinical utility. We used data on consecutive patients with suspected PE included in a multicenter management study. The performance of the Wells CDR and the D-dimer test was compared between patients with and without malignancy and multivariable analysis was used to compare the weights of the CDR variables. Furthermore, we combined the CDR (cut-off ≤4) with different D-dimer cut-off levels for the exclusion of PE. Of 3,306 patients with suspected PE, 475 (14%) had cancer. The Wells rule variables were less diagnostic in cancer patients. Increasing the D-dimer cut-off level to 700 μg/l for all ages or using an age-dependent cut-off resulted in an increase in the proportion of patients in whom PE could be excluded from 8.4% to 13% and 12%, respectively. The corresponding false-negative rates were 1.6% (95% confidence interval 0.3-8.7%) and 0.0% (0.0-6.3%). The Wells CDR and D-dimer perform less well in patients with suspected PE if they have cancer. Individual variables in the Wells rule are less diagnostic in cancer patients than in non-cancer patients with suspected PE. A CDR combined with an age-dependent D-dimer cut-off shows a modest improvement of the strategy in cancer patients.

Pulmonary embolism (PE) is a frequently occurring, acute, and potentially fatal condition. Numerous risk factors for PE, both inherited and acquired, have been identified. Adequate diagnosis is mandatory to prevent PE-related morbidity and mortality on the one hand, and unnecessary treatment on the other. Only around 1 in 5 individuals with suspected PE will have the diagnosis confirmed, therefore, the diagnostic work-up for PE should comprise safe, efficient, and noninvasive methods. The first step in the approach to diagnosis of patients with suspected PE is to determine the clinical probability and to perform a D-dimer test. PE can be excluded in patients with a 'low', 'intermediate' or 'unlikely' clinical probability and a normal D-dimer test. Additional imaging is required for those with a 'high' or 'likely' clinical probability or a positive D-dimer test. CT pulmonary angiography or ventilation-perfusion scintigraphy, followed by additional testing is the next step when test results are nondiagnostic. Although various diagnostic strategies have been introduced and validated, selected patients may require a tailored approach.

Background: In secondary care the Wells clinical decision rule (CDR) combined with a quantitative D-dimer test can exclude pulmonary embolism (PE) safely. The introduction of point-of-care (POC) D-dimer tests facilitates a similar diagnostic strategy in primary care.We estimated failure-rate and efficiency of a diagnostic strategy using the Wells-CDR combined with a POC-D-dimer test for excluding PE in primary care.We considered ruling out PE safe if the failure rate was <2% with a maximum upper confidence limit of 2.7%., Methods: We performed a scenario-analysis on data of 2701 outpatients suspected of PE. We used test characteristics of two qualitative POC-D-dimer tests, as derived from a meta-analysis and combined these with the Wells-CDR-score., Results: In scenario 1 (SimpliRed-D-dimer sensitivity 85%, specificity 74%) PE was excluded safely in 23.8% of patients but only by lowering the cut-off value of the Wells rule to <2. (failure rate: 1.4%, 95% CI 0.6-2.6%)In scenario 2 (Simplify-D-dimer sensitivity 87%, specificity 62%) PE was excluded safely in 12.4% of patients provided that the Wells-cut-off value was set at 0. (failure rate: 0.9%, 95% CI 0.2-2.6%), Conclusion: Theoretically a diagnostic strategy using the Wells-CDR combined with a qualitative POC-D-dimer test can be used safely to exclude PE in primary care albeit with only moderate efficiency.

Introduction: Careful re-evaluation of CT-scans for cancer staging frequently reveals unsuspected venous thromboembolism (VTE) on CT-scans. However, it is unknown how often these findings lead to anticoagulant treatment in daily clinical practice., Methods: Reports from thoracic and/or abdominal CT-scans performed in a consecutive series of patients to stage cancer were retrospectively evaluated to determine the prevalence of incidental venous thromboembolism (iVTE). Presence of pre-existing signs of VTE, anticoagulant treatment and 3-month follow-up were analysed in patients with iVTE., Results: A total of 1466 staging scans (838 patients) from the year 2006 were included in the analysis. The prevalence of VTE in patients was 2.5% (21/838 patients, 95% confidence interval 1.6-3.8%); the prevalence of VTE on scans was 1.4% (21/1466 scans, 95% CI 0.9-2.2%). Incidental PE or deep vein thrombosis (DVT) was observed in 11 (1.3%, 0.7-2.3%) and abdominal vein thrombosis in 9 patients (1.1%, 0.6-2.0%; in the portal (5), mesenteric (3) and renal vein (1), respectively). Nine out of eleven patients with PE/DVT were treated with anticoagulants, while none of the patients with thrombosis in other locations received anticoagulants. One of these patients developed symptomatic PE one month later; otherwise, follow up was uneventful in the untreated patients., Conclusion: The prevalence of iVTE in patients with cancer in clinical practice is relatively low and most patients with PE or DVT are treated with anticoagulants. For patients with thrombi in other locations, further research is necessary to understand the natural history of these thrombi in order to develop adequate guidelines., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Current strategies for diagnosing pulmonary embolism (PE) include a clinical decision rule (CDR), followed by a D-dimer assay in patients with an unlikely clinical probability. We assessed the implementation of the current guidelines for the diagnosis of PE. A first questionnaire was sent to internists and pulmonologists to assess the proportion of physicians that adequately applied the guidelines. Two versions of a second questionnaire were sent presenting five hypothetical cases of which in two cases with an intermediate clinical probability an abnormal D-dimer test result was added to one version. We assessed the variation of the CDR and compared the proportions of a likely clinical probability between the two versions. A total of 65 physicians responded to the first questionnaire (response rate 75%). Half of the physicians (N=29; 46%) indicated that they use a CDR in all patients and 22 physicians (45%) indicated that they review the D-dimer result after they examined patients. Sixty-two physicians responded on the second questionnaire (response rate 36%). A shift was observed from an unlikely to a likely probability when an abnormal D-dimer test result was added to the clinical information (22% to 41%; p=0.22 and 26% to 50%; p<0.05). Our findings indicate that physicians do not use the guidelines for diagnosis of PE consistently. Furthermore, the knowledge of an abnormal D-dimer test result before seeing the patient leads to a higher CDR score. Physicians should therefore first examine patients before taking note of the D-dimer test result.