Single dose tocilizumab for COVID-19 associated cytokine storm syndrome: Less is more.

AIMS: We aim to evaluate the clinical pharmacokinetics of a single dose interleukin-6 (IL-6) antibody tocilizumab (TCZ) in methylprednisolone (MP)-treated COVID-19 patients with cytokine storm syndrome (CSS). METHODS: MP pre-treated patients with COVID-19-associated CSS, defined as at least two elevations of C-reactive protein (CRP) >100 mg/L, ferritin >900 µg/L or D-dimers >1500 µg/L, received intravenous TCZ (8 mg/kg, max. 800 mg) upon clinical deterioration. A nonlinear-mixed effects model was developed based on TCZ serum concentrations and dosing information. Population pharmacokinetic parameters were estimated and concentration-time profiles were plotted against individual predicted values. Fixed dose simulations were subsequently performed based on the final model. RESULTS: In total 40 patients (mean [SD] age: 62 [12] years, 20% female, body weight: 87 [17] kg) with COVID-19 induced CSS were evaluated on pharmacokinetics and laboratory parameters. A biphasic elimination of TCZ serum concentration was described by a homogeneous population pharmacokinetic model. Serum TCZ concentrations above the 1 µg/L target saturation threshold were covered for 16 days in all evaluated patients treated with a single dose of 8 mg/kg. In a simulation with TCZ 400 mg fixed dose, this condition of full IL-6 receptor occupancy at minimum serum concentration was also met. CONCLUSIONS: A single dose (8 mg/kg, max. 800 mg) is sufficient to cover a period of 16 days of IL-6-mediated hyperinflammation in COVID-19-induced CSS in MP-treated patients. Based on body weight PK simulations, a fixed-dose tocilizumab of 400 mg should be considered to prevent overtreatment, future drug shortage and unnecessary drug expenditure.

Aortic intramural haematoma associated with the use of nintedanib.

We report a 74-year-old patient who developed an acute aortic syndrome (AAS) with intramural haematoma (IMH) during treatment with nintedanib, a tyrosine kinase inhibitor. As we suspected a role for nintedanib, this was immediately interrupted. Four months later, a computed tomographic angiography (CTA) showed significant regression of the IMH. Therefore, we state that, when patients use nintedanib and develop acute chest or back pain, diagnostic work-up for AAS should be considered. Furthermore, other risk factors for AAS, such as hypertension, genetic diseases and comedication should be taken into account when prescription of medication of this class is considered.

Historically controlled comparison of glucocorticoids with or without tocilizumab versus supportive care only in patients with COVID-19-associated cytokine storm syndrome: results of the CHIC study.

OBJECTIVES: To prospectively investigate in patients with severe COVID-19-associated cytokine storm syndrome (CSS) whether an intensive course of glucocorticoids with or without tocilizumab accelerates clinical improvement, reduces mortality and prevents invasive mechanical ventilation, in comparison with a historic control group of patients who received supportive care only. METHODS: From 1 April 2020, patients with COVID-19-associated CSS, defined as rapid respiratory deterioration plus at least two out of three biomarkers with important elevations (C-reactive protein >100 mg/L; ferritin >900 µg/L; D-dimer >1500 µg/L), received high-dose intravenous methylprednisolone for 5 consecutive days (250 mg on day 1 followed by 80 mg on days 2-5). If the respiratory condition had not improved sufficiently (in 43%), the interleukin-6 receptor blocker tocilizumab (8 mg/kg body weight, single infusion) was added on or after day 2. Control patients with COVID-19-associated CSS (same definition) were retrospectively sampled from the pool of patients (n=350) admitted between 7 March and 31 March, and matched one to one to treated patients on sex and age. The primary outcome was ≥2 stages of improvement on a 7-item WHO-endorsed scale for trials in patients with severe influenza pneumonia, or discharge from the hospital. Secondary outcomes were hospital mortality and mechanical ventilation. RESULTS: At baseline all patients with COVID-19 in the treatment group (n=86) and control group (n=86) had symptoms of CSS and faced acute respiratory failure. Treated patients had 79% higher likelihood on reaching the primary outcome (HR: 1.8; 95% CI 1.2 to 2.7) (7 days earlier), 65% less mortality (HR: 0.35; 95% CI 0.19 to 0.65) and 71% less invasive mechanical ventilation (HR: 0.29; 95% CI 0.14 to 0.65). Treatment effects remained constant in confounding and sensitivity analyses. CONCLUSIONS: A strategy involving a course of high-dose methylprednisolone, followed by tocilizumab if needed, may accelerate respiratory recovery, lower hospital mortality and reduce the likelihood of invasive mechanical ventilation in COVID-19-associated CSS.

Study protocol for a multicentre prospective cohort study to identify predictors of adverse outcome in older medical emergency department patients (the Risk Stratification in the Emergency Department in Acutely Ill Older Patients (RISE UP) study).

BACKGROUND: Older patients (≥65 years old) experience high rates of adverse outcomes after an emergency department (ED) visit. Reliable tools to predict adverse outcomes in this population are lacking. This manuscript comprises a study protocol for the Risk Stratification in the Emergency Department in Acutely Ill Older Patients (RISE UP) study that aims to identify predictors of adverse outcome (including triage- and risk stratification scores) and intends to design a feasible prediction model for older patients that can be used in the ED. METHODS: The RISE UP study is a prospective observational multicentre cohort study in older (≥65 years of age) ED patients treated by internists or gastroenterologists in Zuyderland Medical Centre and Maastricht University Medical Centre+ in the Netherlands. After obtaining informed consent, patients characteristics, vital signs, functional status and routine laboratory tests will be retrieved. In addition, disease perception questionnaires will be filled out by patients or their caregivers and clinical impression questionnaires by nurses and physicians. Moreover, both arterial and venous blood samples will be taken in order to determine additional biomarkers. The discriminatory value of triage- and risk stratification scores, clinical impression scores and laboratory tests will be evaluated. Univariable logistic regression will be used to identify predictors of adverse outcomes. With these data we intend to develop a clinical prediction model for 30-day mortality using multivariable logistic regression. This model will be validated in an external cohort. Our primary endpoint is 30-day all-cause mortality. The secondary (composite) endpoint consist of 30-day mortality, length of hospital stay, admission to intensive- or medium care units, readmission and loss of independent living. Patients will be followed up for at least 30 days and, if possible, for one year. DISCUSSION: In this study, we will retrieve a broad range of data concerning adverse outcomes in older patients visiting the ED with medical problems. We intend to develop a clinical tool for identification of older patients at risk of adverse outcomes that is feasible for use in the ED, in order to improve clinical decision making and medical care. TRIAL REGISTRATION: Retrospectively registered on clinicaltrials.gov ( NCT02946398 ; 9/20/2016).

Circulating matrix metalloproteinases are associated with arterial stiffness in patients with type 1 diabetes: pooled analysis of three cohort studies.

BACKGROUND: Altered regulation of extracellular matrix (ECM) composition by matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs) may contribute to arterial stiffening. We investigated associations between circulating MMP-1, -2, -3, -9, -10 and TIMP-1, and carotid-femoral pulse wave velocity (cfPWV) and pulse pressure (PP), as markers of arterial stiffness in type 1 diabetic patients. METHODS: Individuals with type 1 diabetes from three different cohorts were included in this study: EURODIAB Prospective Complications study (n = 509), LEACE (n = 370) and PROFIL (n = 638). Linear regression analyses were used to investigate cross-sectional associations between circulating levels of MMP-1, -2, -3, -9, -10, and TIMP-1 and cfPWV (n = 614) as well as office PP (n = 1517). Data on 24-h brachial and 24-h central PP were available in 638 individuals from PROFIL. Analyses were adjusted for age, sex, duration of diabetes, HbA1c, mean arterial pressure (MAP), and eGFR, and additionally for other cardiovascular risk factors and presence of vascular complications. RESULTS: After adjustment for potential confounders and presence of vascular complications, circulating MMP-3 was associated with cfPWV [ß per 1 SD higher lnMMP3 0.29 m/s (0.02; 0.55)]. In addition, brachial and central 24-h PP measurements in PROFIL were significantly associated with MMP-2 [(1.40 (0.47:2.33) and 1.43 (0.63:2.23)]. Pooled data analysis showed significant associations of circulating levels of MMP-1 and MMP-2 with office PP [ß per 1 SD higher lnMMP-1 and lnMMP-2 = - 0.83 mmHg (95% CI - 1.50; - 0.16) and = 1.33 mmHg (0.55; 2.10), respectively]. CONCLUSIONS: MMPs-1, -2, and -3 are independently associated with markers of arterial stiffening in patients with type 1 diabetes and may become therapeutic targets.

Plasma levels of matrix metalloproteinase-2, -3, -10, and tissue inhibitor of metalloproteinase-1 are associated with vascular complications in patients with type 1 diabetes: the EURODIAB Prospective Complications Study.

BACKGROUND: Impaired regulation of extracellular matrix remodeling by matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase (TIMP) may contribute to vascular complications in patients with type 1 diabetes. We investigated associations between plasma MMP-1, -2, -3, -9, -10 and TIMP-1, and cardiovascular disease (CVD) or microvascular complications in type 1 diabetic patients. We also evaluated to which extent these associations could be explained by low-grade inflammation (LGI) or endothelial dysfunction (ED). METHODS: 493 type 1 diabetes patients (39.5 ± 9.9 years old, 51% men) from the EURODIAB Prospective Complications Study were included. Linear regression analysis was applied to investigate differences in plasma levels of MMP-1, -2, -3, -9, -10, and TIMP-1 between patients with and without CVD, albuminuria or retinopathy. All analyses were adjusted for age, sex, duration of diabetes, Hba1c and additionally for other cardiovascular risk factors including LGI and ED. RESULTS: Patients with CVD (n = 118) showed significantly higher levels of TIMP-1 [ß = 0.32 SD (95%CI: 0.12; 0.52)], but not of MMPs, than patients without CVD (n = 375). Higher plasma levels of MMP-2, MMP-3, MMP-10 and TIMP-1 were associated with higher levels of albuminuria (p-trends were 0.028, 0.004, 0.005 and 0.001, respectively). Severity of retinopathy was significantly associated with higher levels of MMP-2 (p-trend = 0.017). These associations remained significant after further adjustment for markers of LGI and ED. CONCLUSIONS: These data support the hypothesis that impaired regulation of matrix remodeling by actions of MMP-2, -3 and-10 and TIMP-1 contributes to the pathogenesis of vascular complications in type 1 diabetes.

Chronic Q fever in the Netherlands 5 years after the start of the Q fever epidemic: results from the Dutch chronic Q fever database.

Coxiella burnetii causes Q fever, a zoonosis, which has acute and chronic manifestations. From 2007 to 2010, the Netherlands experienced a large Q fever outbreak, which has offered a unique opportunity to analyze chronic Q fever cases. In an observational cohort study, baseline characteristics and clinical characteristics, as well as mortality, of patients with proven, probable, or possible chronic Q fever in the Netherlands, were analyzed. In total, 284 chronic Q fever patients were identified, of which 151 (53.7%) had proven, 64 (22.5%) probable, and 69 (24.3%) possible chronic Q fever. Among proven and probable chronic Q fever patients, vascular infection focus (56.7%) was more prevalent than endocarditis (34.9%). An acute Q fever episode was recalled by 27.0% of the patients. The all-cause mortality rate was 19.1%, while the chronic Q fever-related mortality rate was 13.0%, with mortality rates of 9.3% among endocarditis patients and 18% among patients with a vascular focus of infection. Increasing age (P=0.004 and 0.010), proven chronic Q fever (P=0.020 and 0.002), vascular chronic Q fever (P=0.024 and 0.005), acute presentation with chronic Q fever (P=0.002 and P<0.001), and surgical treatment of chronic Q fever (P=0.025 and P<0.001) were significantly associated with all-cause mortality and chronic Q fever-related mortality, respectively.

Deferring diagnostic evaluation of suspected deep vein thrombosis using direct oral anticoagulant or low-molecular-weight heparin as a single dose anticoagulant: A prospective real-world study in a regionwide care pathway.

BACKGROUND: Patients with suspected deep vein thrombosis (DVT) are typically referred to the emergency department for immediate evaluation. To enhance efficiency, our hospital implemented a regional, general practitioner (GP)-driven DVT care pathway, deferring diagnostic evaluation to a scheduled outpatient DVT clinic appointment the following day. Patients receive a single dose anticoagulant from their GP to prevent thrombosis progression while awaiting diagnostic workup. This prospective study aimed to evaluate the safety and patient preferences regarding the DVT care pathway and the type of single dose anticoagulant (low-molecular-weight heparin (LMWH) vs. direct oral anticoagulant (DOAC)). METHODS: Patients enrolled in the DVT care pathway between June 2021 and July 2023 were eligible. Until July 2022, LMWH was administered, and thereafter, the protocol recommended DOAC as the single dose anticoagulant. Patients completed questionnaires, incorporating patient-reported outcome and experience measures (PROMs/PREMs), during their DVT clinic visit and after five days. The primary endpoint was bleeding events within 72 h of receiving the single dose anticoagulant. RESULTS: Of 460 included patients, 229 received LMWH and 231 received DOAC as the single dose anticoagulant. DVT was confirmed in 24.8 % of patients. No major or clinically relevant non-major bleeding were reported. LMWH was associated with more minor bleedings (22.3 % vs. DOAC 13.4 %), primarily attributed to injection site hematomas. Patients reported high satisfaction with the DVT care pathway (96.5 %) and generally preferred DOAC over LMWH. CONCLUSION: Deferring diagnostic evaluation for DVT using a single dose of either LMWH or DOAC in a real-world population is deemed safe. Considering practical advantages, patient preferences, and fewer skin hematomas, we favor DOACs as the single dose anticoagulant in this care pathway.

Deferring diagnostic evaluation for suspected deep venous thrombosis using a single dose of anticoagulant: Real-world data from a regionwide care pathway.

BACKGROUND: Patients with suspected deep venous thrombosis (DVT) are typically referred to the emergency department (ED) for immediate evaluation. However, this often contributes to ED overcrowding and necessitates round-the-clock sonographic examinations. Therefore, we implemented a regionwide care pathway for deferring diagnostic workup of suspected DVT until the following day. Patients receive a single anticoagulant dose from their general practitioner (GP) to prevent progression of DVT in the interval between referral and diagnostic evaluation. The next day, patients undergo comprehensive evaluation at our outpatient DVT clinic, including venous ultrasound. This retrospective study aims to provide real-world data on the safety of this care pathway regarding the occurrence of bleeding complications and pulmonary embolism (PE). METHODS: We included all GP-referred patients with suspected DVT in 2018 and 2019. Patients with absolute contraindications to deferred evaluation or anticoagulation were excluded. The primary endpoint was the occurrence of bleeding complications. Secondary endpoints included PE events and all-cause mortality within seven days following DVT evaluation. RESULTS: Among 1,024 included patients, DVT was confirmed in 238 patients (23.2%) and superficial thrombophlebitis in 98 patients (9.6%). No bleeding events were recorded in patients in whom DVT was ruled out. PE was confirmed in eight patients on the same day as DVT evaluation (0.8%, 95%CI 0.4-1.6) and in six patients within seven days following DVT evaluation (0.6%, 0.2-1.3%). No deaths occurred during this timeframe. CONCLUSION: This real-world study observed a very low incidence of bleeding complications and PE events, indicating that this care pathway of deferred DVT workup is safe and may offer a more streamlined diagnostic approach for patients with suspected DVT.

The incidence and outcome of AKI in patients with sepsis in the emergency department applying different definitions of AKI and sepsis.

BACKGROUND: Sepsis is often accompanied with acute kidney injury (AKI). The incidence of AKI in patients visiting the emergency department (ED) with sepsis according to the new SOFA criteria is not exactly known, because the definition of sepsis has changed and many definitions of AKI exist. Given the important consequences of early recognition of AKI in sepsis, our aim was to assess the epidemiology of sepsis-associated AKI using different AKI definitions (RIFLE, AKIN, AKIB, delta check, and KDIGO) for the different sepsis classifications (SIRS, qSOFA, and SOFA). METHODS: We retrospectively enrolled patients with sepsis in the ED in three hospitals and applied different AKI definitions to determine the incidence of sepsis-associated AKI. In addition, the association between the different AKI definitions and persistent kidney injury, hospital length of stay, and 30-day mortality were evaluated. RESULTS: In total, 2065 patients were included. The incidence of AKI was 17.7-51.1%, depending on sepsis and AKI definition. The highest incidence of AKI was found in qSOFA patients when the AKIN and KDIGO definitions were applied (51.1%). Applying the AKIN and KDIGO definitions in patients with sepsis according to the SOFA criteria, AKI was present in 37.3% of patients, and using the SIRS criteria, AKI was present in 25.4% of patients. Crude 30-day mortality, prolonged length of stay, and persistent kidney injury were comparable for patients diagnosed with AKI, regardless of the definition used. CONCLUSION: The incidence of AKI in patients with sepsis is highly dependent on how patients with sepsis are categorised and how AKI is defined. When AKI (any definition) was already present at the ED, 30-day mortality was high (22.2%). The diagnosis of AKI in sepsis can be considered as a sign of severe disease and helps to identify patients at high risk of adverse outcome at an early stage.

Sex differences in clinical presentation and mortality in emergency department patients with sepsis.

BACKGROUND: There is growing awareness that sex differences are associated with different patient outcomes in a variety of diseases. Studies investigating the effect of patient sex on sepsis-related mortality remain inconclusive and mainly focus on patients with severe sepsis and septic shock in the intensive care unit. We therefore investigated the association between patient sex and both clinical presentation and 30-day mortality in patients with the whole spectrum of sepsis severity presenting to the emergency department (ED) who were admitted to the hospital. MATERIALS AND METHODS: In our multi-centre cohort study, we retrospectively investigated adult medical patients with sepsis in the ED. Multivariable analysis was used to evaluate the association between patient sex and all-cause 30-day mortality. RESULTS: Of 2065 patients included, 47.6% were female. Female patients had significantly less comorbidities, lower Sequential Organ Failure Assessment score and abbreviated Mortality Emergency Department Sepsis score, and presented less frequently with thrombocytopenia and fever, compared to males. For both sexes, respiratory tract infections were predominant while female patients more often had urinary tract infections. Females showed lower 30-day mortality (10.1% vs. 13.6%; p = .016), and in-hospital mortality (8.0% vs. 11.1%; p = .02) compared to males. However, a multivariable logistic regression model showed that patient sex was not an independent predictor of 30-day mortality (OR 0.90; 95% CI 0.67-1.22; p = .51). CONCLUSIONS: Females with sepsis presenting to the ED had fewer comorbidities, lower disease severity, less often thrombocytopenia and fever and were more likely to have a urinary tract infection. Females had a lower in-hospital and 30-day mortality compared to males, but sex was not an independent predictor of 30-day mortality. The lower mortality in female patients may be explained by differences in comorbidity and clinical presentation compared to male patients.KEY MESSAGESOnly limited data exist on sex differences in sepsis patients presenting to the emergency department with the whole spectrum of sepsis severity.Female sepsis patients had a lower incidence of comorbidities, less disease severity and a different source of infection, which explains the lower 30-day mortality we found in female patients compared to male patients.We found that sex was not an independent predictor of 30-day mortality; however, the study was probably underpowered to evaluate this outcome definitively.

Pulmonary embolism in hospitalized COVID-19 patients: Short- and long-term clinical outcomes.

Introduction: Pulmonary embolism (PE) is a frequent complication in COVID-19. However, the influence of PE on the prognosis of COVID-19 remains unclear as previous studies were affected by misclassification bias. Therefore, we evaluated a cohort of COVID-19 patients whom all underwent systematic screening for PE (thereby avoiding misclassification) and compared clinical outcomes between patients with and without PE. Materials and methods: We included all COVID-19 patients who were admitted through the ED between April 2020 and February 2021. All patients underwent systematic work-up for PE in the ED using the YEARS-algorithm. The primary outcome was a composite of in-hospital mortality and ICU admission. We also evaluated long-term outcomes including PE occurrence within 90 days after discharge and one-year all-cause mortality. Results: 637 ED patients were included in the analysis. PE was diagnosed in 46 of them (7.2%). The occurrence of the primary outcome did not differ between patients with PE and those without (28.3% vs. 26.9%, p = 0.68). The overall rate of PE diagnosed in-hospital (after an initial negative PE screening in the ED) and in the first 90 days after discharge was 3.9% and 1.2% respectively. One-year all-cause mortality was similar between patients with and without PE (26.1% vs. 24.4%, p = 0.83). Conclusions: In a cohort of COVID-19 patients who underwent systematic PE screening in the ED, we found no differences in mortality rate and ICU admissions between patients with and without PE. This may indicate that proactive PE screening, and thus timely diagnosis and treatment of PE, may limit further clinical deterioration and associated mortality in COVID-19 patients.

Systematic screening versus clinical gestalt in the diagnosis of pulmonary embolism in COVID-19 patients in the emergency department.

BACKGROUND: Diagnosing concomitant pulmonary embolism (PE) in COVID-19 patients remains challenging. As such, PE may be overlooked. We compared the diagnostic yield of systematic PE-screening based on the YEARS-algorithm to PE-screening based on clinical gestalt in emergency department (ED) patients with COVID-19. METHODS: We included all ED patients who were admitted because of COVID-19 between March 2020 and February 2021. Patients already receiving anticoagulant treatment were excluded. Up to April 7, 2020, the decision to perform CT-pulmonary angiography (CTPA) was based on physician's clinical gestalt (clinical gestalt cohort). From April 7 onwards, systematic PE-screening was performed by CTPA if D-dimer level was ≥1000 ug/L, or ≥500 ug/L in case of ≥1 YEARS-item (systematic screening cohort). RESULTS: 1095 ED patients with COVID-19 were admitted. After applying exclusion criteria, 289 were included in the clinical gestalt and 574 in the systematic screening cohort. The number of PE diagnoses was significantly higher in the systematic screening cohort compared to the clinical gestalt cohort: 8.2% vs. 1.0% (3/289 vs. 47/574; p<0.001), even after adjustment for differences in patient characteristics (adjusted OR 8.45 (95%CI 2.61-27.42, p<0.001) for PE diagnosis). In multivariate analysis, D-dimer (OR 1.09 per 1000 µg/L increase, 95%CI 1.06-1.13, p<0.001) and CRP >100 mg/L (OR 2.78, 95%CI 1.37-5.66, p = 0.005) were independently associated with PE. CONCLUSION: In ED patients with COVID-19, the number of PE diagnosis was significantly higher in the cohort that underwent systematic PE screening based on the YEARS-algorithm in comparison with the clinical gestalt cohort, with a number needed to test of 7.1 CTPAs to detect one PE.

Validating the RISE UP score for predicting prognosis in patients with COVID-19 in the emergency department: a retrospective study.

OBJECTIVE: To mitigate the burden of COVID-19 on the healthcare system, information on the prognosis of the disease is needed. The recently developed Risk Stratification in the Emergency Department in Acutely ill Older Patients (RISE UP) score has very good discriminatory value for short-term mortality in older patients in the emergency department (ED). It consists of six readily available items. We hypothesised that the RISE UP score could have discriminatory value for 30-day mortality in ED patients with COVID-19. DESIGN: Retrospective analysis. SETTING: Two EDs of the Zuyderland Medical Centre, secondary care hospital in the Netherlands. PARTICIPANTS: The study sample consisted of 642 adult ED patients diagnosed with COVID-19 between 3 March and until 25 May 2020. Inclusion criteria were (1) admission to the hospital with symptoms suggestive of COVID-19 and (2) positive result of the PCR or (very) high suspicion of COVID-19 according to the chest CT scan. OUTCOME: Primary outcome was 30-day mortality, secondary outcome was a composite of 30-day mortality and admission to intensive care unit (ICU). RESULTS: Within 30 days after presentation, 167 patients (26.0%) died and 102 patients (15.9%) were admitted to ICU. The RISE UP score showed good discriminatory value for 30-day mortality (area under the receiver operating characteristic curve (AUC) 0.77, 95% CI 0.73 to 0.81) and for the composite outcome (AUC 0.72, 95% CI 0.68 to 0.76). Patients with RISE UP scores below 10% (n=121) had favourable outcome (zero deaths and six ICU admissions), while those with scores above 30% (n=221) were at high risk of adverse outcome (46.6% mortality and 19.0% ICU admissions). CONCLUSION: The RISE UP score is an accurate prognostic model for adverse outcome in ED patients with COVID-19. It can be used to identify patients at risk of short-term adverse outcome and may help guide decision-making and allocating healthcare resources.

Value of biomarkers in predicting mortality in older medical emergency department patients: a Dutch prospective study.

OBJECTIVE: Older emergency department (ED) patients are at high risk of mortality, and it is important to predict which patients are at highest risk. Biomarkers such as lactate, high-sensitivity cardiac troponin T (hs-cTnT), N-terminal pro-B-type natriuretic peptide (NT-proBNP), D-dimer and procalcitonin may be able to identify those at risk. We aimed to assess the discriminatory value of these biomarkers for 30-day mortality and other adverse outcomes. DESIGN: Prospective cohort study. On arrival of patients, five biomarkers were measured. Area under the curves (AUCs) and interval likelihood ratios (LRs) were calculated to investigate the discriminatory value of the biomarkers. SETTING: ED in the Netherlands. PARTICIPANTS: Older (≥65 years) medical ED patients, referred for internal medicine or gastroenterology. PRIMARY AND SECONDARY OUTCOME MEASURES: 30-day mortality was the primary outcome measure, while other adverse outcomes (intensive care unit/medium care unit admission, prolonged length of hospital stay, loss of independent living and unplanned readmission) were the composite secondary outcome measure. RESULTS: The median age of the 450 included patients was 79 years (IQR 73-85). In total, 51 (11.3%) patients died within 30 days. The AUCs of all biomarkers for prediction of mortality were sufficient to good, with the highest AUC of 0.73 for hs-cTnT and NT-proBNP. Only for the highest lactate values, the LR was high enough (29.0) to be applicable for clinical decision making, but this applied to a minority of patients. The AUC for the composite secondary outcome (intensive and medium care admission, length of hospital stay >7 days, loss of independent living and unplanned readmission within 30 days) was lower, ranging between 0.58 and 0.67. CONCLUSIONS: Although all five biomarkers predict 30-day mortality in older medical ED patients, their individual discriminatory value was not high enough to contribute to clinical decision making. TRIAL REGISTRATION NUMBER: NCT02946398; Results.

Outcomes of persons with coronavirus disease 2019 in hospitals with and without standard treatment with (hydroxy)chloroquine.

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.

Concerns of older patients and their caregivers in the emergency department.

BACKGROUND: Older emergency department (ED) patients often have complex problems and severe illnesses with a high risk of adverse outcomes. It is likely that these older patients are troubled with concerns, which might reflect their preferences and needs concerning medical care. However, data regarding this topic are lacking. METHODS: This study is a sub study of a prospective, multicenter, observational cohort study among older medical ED patients (≥65 years). Patients or their caregivers were asked about their illness-related concerns during the first stage of the ED visit using a questionnaire. All concerns were categorized into 10 categories, and differences between patients and caregivers, and between age groups were analyzed. Odds Ratios were calculated to determine the association of the concerns for different adverse outcomes. RESULTS: Most of the 594 included patients (or their caregivers) were concerned (88%) about some aspects of their illness or their need for medical care. The most often reported concerns were about the severity of disease (43.6%), functional decline (9.4%) and dying (5.6%). Caregivers were more frequently concerned than patients (p<0.001) especially regarding the severity of disease (50.5 vs 39.6%, p = 0.016) and cognitive decline (10.8 vs. 0.3%, p <0.001). We found no difference between age groups. The concern about dying was associated with 30-day mortality (OR 2.89; 95%CI: 1.24-6.70) and the composite endpoint (intensive- or medium care admission, length of hospital stay >7 days, loss of independent living and unplanned readmission within 30 days) (OR 2.32; 95%CI: 1.12-4.82). In addition, unspecified concerns were associated with mortality (OR 1.88; 95%CI: 1.09-3.22). CONCLUSION: The majority of older patients and especially their caregivers are concerned about their medical condition or need for medical care when they visit the ED. These concerns are associated with adverse outcomes and most likely reflect their needs regarding medical care. More attention should be paid to these concerns because they may offer opportunities to reduce anxiety and provide care that is adjusted to their needs. TRIAL REGISTRATION: This study was registered on clinicalTriagls.gov (NCT02946398).

A new simplified model for predicting 30-day mortality in older medical emergency department patients: The rise up score.

BACKGROUND/OBJECTIVES: Currently, accurate clinical models that predict short-term mortality in older (≥ 65 years) emergency department (ED) patients are lacking. We aimed to develop and validate a prediction model for 30-day mortality in older ED patients that is easy to apply using variables that are readily available and reliably retrievable during the short phase of an ED stay. METHODS: Prospective multi-centre cohort study in older medical ED patients. The model was derived through logistic regression analyses, externally validated and compared with other well-known prediction models (Identification of Seniors at Risk (ISAR), ISAR-Hospitalised Patients, Acute Physiology and Chronic Health Evaluation II (APACHE II) and Modified Early Warning Score (MEWS)). RESULTS: Within 30 days after presentation, 66 (10.9%) of 603 patients in the derivation cohort and 105 (13.3%) of 792 patients in the validation cohort died. The newly developed model included 6 predictors: age, ≥2 abnormal vital signs, serum albumin, blood urea nitrogen, lactate dehydrogenase, and bilirubin. The discriminatory value of the model for mortality was very good with an AUC of 0.84 in the derivation and 0.83 in the validation cohort. The final model was excellently calibrated (Hosmer-Lemeshow p-value 0.89). The discriminatory value of the model was significantly higher than that of the four risk stratification scores (highest AUC of 0.69 for ISAR score, p-value 0.007). CONCLUSION: We developed and externally validated an accurate and simplified prediction model for 30-day mortality in older ED patients. This model may be useful to identify patients at risk of short-term mortality and to apply personalised medical care.