Bench-to-bedside review: Candida infections in the intensive care unit.

Invasive mycoses are life-threatening opportunistic infections and have emerged as a major cause of morbidity and mortality in critically ill patients. This review focuses on recent advances in our understanding of the epidemiology, diagnosis and management of invasive candidiasis, which is the predominant fungal infection in the intensive care unit setting. Candida spp. are the fourth most common cause of bloodstream infections in the USA, but they are a much less common cause of bloodstream infections in Europe. About one-third of episodes of candidaemia occur in the intensive care unit. Until recently, Candida albicans was by far the predominant species, causing up to two-thirds of all cases of invasive candidiasis. However, a shift toward non-albicans Candida spp., such as C. glabrata and C. krusei, with reduced susceptibility to commonly used antifungal agents, was recently observed. Unfortunately, risk factors and clinical manifestations of candidiasis are not specific, and conventional culture methods such as blood culture systems lack sensitivity. Recent studies have shown that detection of circulating beta-glucan, mannan and antimannan antibodies may contribute to diagnosis of invasive candidiasis. Early initiation of appropriate antifungal therapy is essential for reducing the morbidity and mortality of invasive fungal infections. For decades, amphotericin B deoxycholate has been the standard therapy, but it is often poorly tolerated and associated with infusion-related acute reactions and nephrotoxicity. Azoles such as fluconazole and itraconazole provided the first treatment alternatives to amphotericin B for candidiasis. In recent years, several new antifungal agents have become available, offering additional therapeutic options for the management of Candida infections. These include lipid formulations of amphotericin B, new azoles (voriconazole and posaconazole) and echinocandins (caspofungin, micafungin and anidulafungin)

Association between smoking and recurrence of venous thromboembolism and bleeding in elderly patients with past acute venous thromboembolism.

BACKGROUND: While the association between smoking and arterial cardiovascular events has been well established, the association between smoking and venous thromboembolism (VTE) remains controversial. OBJECTIVES: To assess the association between smoking and the risk of recurrent VTE and bleeding in patients who have experienced acute VTE. PATIENTS/METHODS: This study is part of a prospective Swiss multicenter cohort that included patients aged ≥65years with acute VTE. Three groups were defined according to smoking status: never, former and current smokers. The primary outcome was the time to a first symptomatic, objectively confirmed VTE recurrence. Secondary outcomes were the time to a first major and clinically relevant non-major bleeding. Associations between smoking status and outcomes were analysed using proportional hazard models for the subdistribution of a competing risk of death. RESULTS: Among 988 analysed patients, 509 (52%) had never smoked, 403 (41%) were former smokers, and 76 (8%) current smokers. After a median follow-up of 29.6months, we observed a VTE recurrence rate of 4.9 (95% confidence interval [CI] 3.7-6.4) per 100 patient-years for never smokers, 6.6 (95% CI 5.1-8.6) for former smokers, and 5.2 (95% CI 2.6-10.5) for current smokers. Compared to never smokers, we found no association between current smoking and VTE recurrence (adjusted sub-hazard ratio [SHR] 1.05, 95% CI 0.49-2.28), major bleeding (adjusted SHR 0.59, 95% CI 0.25-1.39), and clinically relevant non-major bleeding (adjusted SHR 1.21, 95% CI 0.73-2.02). CONCLUSIONS: In this multicentre prospective cohort study, we found no association between smoking status and VTE recurrence or bleeding in elderly patients with VTE

Association between computed tomography obstruction index and mortality in elderly patients with acute pulmonary embolism: A prospective validation study.

Computed tomography pulmonary angiography (CTPA) has not only become the method of choice for diagnosing acute pulmonary embolism (PE), it also allows for risk stratification of patients with PE. To date, no study has specifically examined the predictive value of CTPA findings to assess short-term prognosis in elderly patients with acute PE who are particularly vulnerable to adverse outcomes. We studied 291 patients aged ≥65 years with acute symptomatic PE in a prospective multicenter cohort. Outcomes were 90-day overall and PE-related mortality, recurrent venous thromboembolism (VTE), and length of hospital stay (LOS). We examined associations of the computed tomography obstruction index (CTOI) and the right ventricular (RV) to left ventricular (LV) diameter ratio with mortality and VTE recurrence using survival analysis, adjusting for provoked VTE, Pulmonary Embolism Severity Index (PESI), and anticoagulation as a time-varying covariate. Overall, 15 patients died within 90 days. There was no association between the CTOI and 90-day overall mortality (adjusted hazard ratio per 10% CTOI increase 0.92; 95% confidence interval [CI] 0.70-1.21; P = 0.54), but between the CTOI and PE-related 90-day mortality (adjusted sub-hazard ratio per 10% CTOI increase 1.36; 95% CI 1.03-1.81; P = 0.03). The RV/LV diameter ratio was neither associated with overall nor PE-related 90-day mortality. The CTOI and the RV/LV diameter ratio were significantly associated with VTE recurrence and LOS. In elderly patients with acute PE, the CTOI was associated with PE-related 90-day mortality but not with overall 90-day mortality. The RV/LV diameter ratio did not predict mortality. Both measures predicted VTE recurrence and LOS. The evaluated CTPA findings do not appear to offer any advantage over the PESI in terms of mortality prediction

Educational Level, Anticoagulation Quality, and Clinical Outcomes in Elderly Patients with Acute Venous Thromboembolism: A Prospective Cohort Study.

Whether the level of education is associated with anticoagulation quality and clinical outcomes in patients with acute venous thromboembolism (VTE) is uncertain. We thus aimed to investigate the association between educational level and anticoagulation quality and clinical outcomes in elderly patients with acute VTE. We studied 817 patients aged ≥65 years with acute VTE from a Swiss prospective multicenter cohort study (09/2009-12/2013). We defined three educational levels: 1) less than high school, 2) high school, and 3) post-secondary degree. The primary outcome was the anticoagulation quality, expressed as the percentage of time spent in the therapeutic INR range (TTR). Secondary outcomes were the time to a first recurrent VTE and major bleeding. We adjusted for potential confounders and periods of anticoagulation. Overall, 56% of patients had less than high school, 25% a high school degree, and 18% a post-secondary degree. The mean percentage of TTR was similar across educational levels (less than high school, 61%; high school, 64%; and post-secondary, 63%; P = 0.36). Within three years of follow-up, patients with less than high school, high school, and a post-secondary degree had a cumulative incidence of recurrent VTE of 14.2%, 12.9%, and 16.4%, and a cumulative incidence of major bleeding of 13.3%, 15.1%, and 15.4%, respectively. After adjustment, educational level was neither associated with anticoagulation quality nor with recurrent VTE or major bleeding. In elderly patients with VTE, we did not find an association between educational level and anticoagulation quality or clinical outcomes

Comparison of Cardiac and Non-Cardiac Biomarkers for Risk Stratification in Elderly Patients with Non-Massive Pulmonary Embolism.

Biomarkers unrelated to myocardial necrosis, such as cystatin C, copeptin, and mid-regional pro-adrenomedullin (MR-proADM), showed promise for cardiovascular risk prediction. Knowing whether they are comparable to cardiac biomarkers such as high-sensitive cardiac-troponin T (hs-cTnT) or N-terminal pro-Brain natriuretic peptide (NT-proBNP) in elderly patients with acute non-massive pulmonary embolism (NMPE) remains elusive. This study aims at comparing the prognostic accuracy of cardiac and non-cardiac biomarkers in patients with NMPE aged ≥65 years over time. In the context of the SWITCO65+ cohort, we evaluated 227 elderly patients with an available blood sample taken within one day from diagnosis. The primary study endpoint was defined as PE-related mortality and the secondary endpoint as PE-related complications. The biomarkers' predictive ability at 1, 3, 12 and 24 months was determined using C-statistics and Cox regression. For both study endpoints, C-statistics (95% confidence interval) were stable over time for all biomarkers, with the highest value for hs-cTnT, ranging between 0.84 (0.68-1.00) and 0.80 (0.70-0.90) for the primary endpoint, and between 0.74 (0.63-0.86) and 0.65 (0.57-0.73) for the secondary endpoint. For both study endpoints, cardiac biomarkers were found to be independently associated with risk, NT-proBNP displaying a negative predictive value of 100%. Among non-cardiac biomarkers, only copeptin and MR-proADM were independent predictors of PE-related mortality but they were not independent predictors of PE-related complications, and displayed lower negative predictive values. In elderly NMPE patients, cardiac biomarkers appear to be valuable prognostic to identify very low-risk individuals. ClinicalTrials.gov NCT00973596

In-hospital mortality is associated with high NT-proBNP level.

To compare in-hospital mortality in unselected adult patients according to N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. Retrospective study including 3833 adult patients (median age 72 years, 45% women) hospitalized between January 2013 and April 2015 in a Swiss university hospital, with at least one NT-proBNP level measurement during hospitalization. Patients were categorized in quintiles regarding their highest NT-proBNP level. In-hospital mortality and length of stay (LOS) were compared between the highest and the other quintiles. In-hospital mortality rate and LOS (average±standard deviation) were higher in the fifth quintile than in the others (6.5% vs 20.3%, and 20.8±24.0 vs. 14.9±26.5 days respectively, both p<0.001). After multivariate adjustment on age, gender, principal diagnoses, stage 5 renal failure and type of management, patients in the fifth quintile had a hazard ratio [95% confidence interval] of 1.97 [1.57-2.46] for in-hospital mortality and an adjusted LOS (average±standard error) of 20.4±1.0 vs. 14.9±0.5 days for the other quintiles (p<0.001). Further stratification on the main diagnosis at discharge led to similar findings. Patients with high levels of NT-proBNP are at higher risk of in-hospital mortality and longer LOS, regardless of their clinical characteristics. NT-proBNP level can be a helpful tool for predicting in-hospital patient outcome in unselected adult patients

The VEINES-QOL/Sym questionnaire is a reliable and valid disease-specific quality of life measure for deep vein thrombosis in elderly patients

Purpose: To prospectively evaluate the psychometric properties of the Venous Insufficiency Epidemiological and Economic Study (VEINES-QOL/Sym) questionnaire, an instrument to measure disease-specific quality of life and symptoms in elderly patients with deep vein thrombosis (DVT), and to validate a German version of the questionnaire. Methods: In a prospective multicenter cohort study of patients aged ≥65years with acute venous thromboembolism, we used standard psychometric tests and criteria to evaluate the reliability, validity, and responsiveness of the VEINES-QOL/Sym in patients with acute symptomatic DVT. We also performed an exploratory factor analysis. Results: Overall, 352 French- and German-speaking patients were enrolled (response rate of 87%). Both language versions of the VEINES-QOL/Sym showed good acceptability (missing data, floor and ceiling effects), reliability (internal consistency, item-total and inter-item correlations), validity (convergent, discriminant, known-groups differences), and responsiveness to clinical change over time in elderly patients with DVT. The exploratory factor analysis of the VEINES-QOL/Sym suggested three underlying dimensions: limitations in daily activities, DVT-related symptoms, and psychological impact. Conclusions: The VEINES-QOL/Sym questionnaire is a practical, reliable, valid, and responsive instrument to measure quality of life and symptoms in elderly patients with DVT and can be used with confidence in prospective studies to measure outcomes in such patients

Do hospital doctors test for thrombophilia in patients with venous thromboembolism?

The predictive value of factor V Leiden and the G20210A prothrombin mutation regarding recurrent venous thromboembolism (VTE) is limited and does not influence subsequent patient management. Systematic testing for such genetic thrombophilia should be avoided, but to which extent such testing is practiced in a Swiss Hospital is unknown. To examine the current practice of factor V Leiden and/or G20210A prothrombin mutation testing in a University Hospital, and to assess the clinical consequences of testing on patients. 1388 adult patients (48.7% women) with a main diagnosis of VTE hospitalized at the Lausanne university hospital between January 2013 and December 2015. FV Leiden and/or prothrombin G20210A mutation testing was performed in 61 (4.4%) patients with VTE, an average of 20 patients/year. On multivariable analysis, age < 65 years [odds ratio and (95% confidence interval) 5.91 (3.12-11.19)], being admitted in a medical ward [5.71 (2.02-16.16)] and staying in the intensive care unit [0.34 (0.12-0.97)] were associated with thrombophilia testing. No differences were found between patients with and without testing regarding in-hospital mortality [OR and 95% CI for tested vs. non-tested: 0.23 (0.03-1.73), p = 0.153] and length of stay (multivariable adjusted average ± standard error: 16.9 ± 3.3 vs. 20.0 ± 0.7 days for tested and non-tested patients, respectively, p = 0.875). Thrombophilia testing in hospitalized patients with a main diagnosis of VTE is seldom performed. FV Leiden and/or prothrombin G20210A mutation should not be routinely assessed in patients with acute VTE