Harmonized D-dimer levels upon admission for prognosis of COVID-19 severity: Results from a Spanish multicenter registry (BIOCOVID-Spain study).

Coagulopathy is a key feature of COVID-19 and D-dimer has been reported as a predictor of severity. However, because D-dimer test results vary considerably among assays, resolving harmonization issues is fundamental to translate findings into clinical practice. In this retrospective multicenter study (BIOCOVID study), we aimed to analyze the value of harmonized D-dimer levels upon admission for the prediction of in-hospital mortality in COVID-19 patients. All-cause in-hospital mortality was defined as endpoint. For harmonization of D-dimer levels, we designed a model based on the transformation of method-specific regression lines to a reference regression line. The ability of D-dimer for prediction of death was explored by receiver operating characteristic curves analysis and the association with the endpoint by Cox regression analysis. Study population included 2663 patients. In-hospital mortality rate was 14.3%. Harmonized D-dimer upon admission yielded an area under the curve of 0.66, with an optimal cut-off value of 0.945 mg/L FEU. Patients with harmonized D-dimer ≥ 0.945 mg/L FEU had a higher mortality rate (22.4% vs. 9.2%; p < 0.001). D-dimer was an independent predictor of in-hospital mortality, with an adjusted hazard ratio of 1.709. This is the first study in which a harmonization approach was performed to assure comparability of D-dimer levels measured by different assays. Elevated D-dimer levels upon admission were associated with a greater risk of in-hospital mortality among COVID-19 patients, but had limited performance as prognostic test.

Serum glutamate decarboxylase antibodies and neurological disorders: when to suspect their association?

OBJECTIVES: To explore different neurological manifestations with suspicion of being associated to serum glutamate decarboxylase antibodies (GAD-Abs) in order to better characterize anti-GAD neurological syndromes. METHODS: Observational retrospective study including all patients for whom GAD65-Abs titers in serum were requested by the Neurology Department at La Paz University Hospital between 2015 and 2019. GAD-Abs were measured by ELISA. Demographic data, neurological symptoms, comorbidity with diabetes mellitus (DM) or with another autoimmune disease, and GAD-Abs titers were studied. Stiff-person syndrome, ataxia, encephalitis, and epilepsy were considered typical anti-GAD neurological syndromes and were compared to other atypical manifestations. RESULTS: A total of 173 patients (51.7% men, mean age 51.62) were included. A progressive increase in requests of serum GAD-Abs has occurred over the last 5 years, especially in patients with atypical neurological manifestations. GAD-Abs were found in the serum of 22 patients (12.7%); of those, 15 (68.18%) suffered a typical anti-GAD syndrome. Presence of DM or another organ-specific autoimmune disease was predictive of GAD-AB seropositivity (p < 0.001). 6.6% of requested patients with an atypical syndrome had GAD-Abs, but serum levels were significantly lower than those found in patients with a typical syndrome (706.67 vs 1430.23 UI/mL; Mann-Whitney U, p = 0.034), and were finally diagnosed with another neurological disease. CONCLUSION: Serum GAD-Abs were infrequently found in patients with clinical phenotypes other than those classically described as anti-GAD disorders, and with very low titers. In typical anti-GAD syndromes, there is a high comorbidity with DM and with other autoimmune diseases, and high serum GAD-Abs levels are usually present.

CSF Aß40 Levels Do Not Correlate with the Clinical Manifestations of Alzheimer's Disease.

INTRODUCTION: Cerebrospinal fluid (CSF) biomarker quantification provides physicians with a reliable diagnosis of Alzheimer's disease (AD). However, the relationship between their concentration and disease course has not been clearly elucidated. This work aimed to investigate the clinical and prognostic significance of Aß40 CSF levels. METHODS: A retrospective cohort of 76 patients diagnosed with AD using a decreased Aß42/Aß40 ratio was subclassified into hyposecretors (Aß40 <7,755 pg/mL), normosecretors (Aß40 7,755-16,715 pg/mL), and hypersecretors (Aß40 >16,715 pg/mL). Potential differences in AD phenotype, Montreal Cognitive Assessment (MoCA) scores, and Global Deterioration Scale (GDS) stages were assessed. Correlation tests for biomarker concentrations were also performed. RESULTS: Participants were classified as hyposecretors (n = 22, median Aß40 5,870.500 pg/mL, interquartile range [IQR] 1,431), normosecretors (n = 47, median Aß40 10,817 pg/mL, IQR 3,622), and hypersecretors (n = 7, 19,767 pg/mL, IQR 3,088). The distribution of positive phosphorylated Tau (p-Tau) varied significantly between subgroups and was more common in the normo- and hypersecretor categories (p = 0.003). Aß40 and p-Tau concentrations correlated positively (ρ = 0.605, p < 0.001). No significant differences were found among subgroups regarding age, initial MoCA score, initial GDS stage, progression to the dementia stage, or changes in the MoCA score. CONCLUSION: In this study, we found no significant differences in clinical symptoms or disease progression in AD patients according to their CSF Aß40 concentration. Aß40 was positively correlated with p-Tau and total Tau concentrations, supporting their potential interaction in AD pathophysiology.

Cardiac troponin and COVID-19 severity: Results from BIOCOVID study.

BACKGROUND: Myocardial injury is a common finding in COVID-19 strongly associated with severity. We analysed the prevalence and prognostic utility of myocardial injury, characterized by elevated cardiac troponin, in a large population of COVID-19 patients, and further evaluated separately the role of troponin T and I. METHODS: This is a multicentre, retrospective observational study enrolling patients with laboratory-confirmed COVID-19 who were hospitalized in 32 Spanish hospitals. Elevated troponin levels were defined as values above the sex-specific 99th percentile upper reference limit, as recommended by international guidelines. Thirty-day mortality was defined as endpoint. RESULTS: A total of 1280 COVID-19 patients were included in this study, of whom 187 (14.6%) died during the hospitalization. Using a nonspecific sex cut-off, elevated troponin levels were found in 344 patients (26.9%), increasing to 384 (30.0%) when a sex-specific cut-off was used. This prevalence was significantly higher (42.9% vs 21.9%; P < .001) in patients in whom troponin T was measured in comparison with troponin I. Sex-specific elevated troponin levels were significantly associated with 30-day mortality, with adjusted odds ratios (ORs) of 3.00 for total population, 3.20 for cardiac troponin T and 3.69 for cardiac troponin I. CONCLUSION: In this multicentre study, myocardial injury was a common finding in COVID-19 patients. Its prevalence increased when a sex-specific cut-off and cardiac troponin T were used. Elevated troponin was an independent predictor of 30-day mortality, irrespective of cardiac troponin assay and cut-offs to detect myocardial injury. Hence, the early measurement of cardiac troponin may be useful for risk stratification in COVID-19.

Characteristics and laboratory findings on admission to the emergency department among 2873 hospitalized patients with COVID-19: the impact of adjusted laboratory tests in multicenter studies. A multicenter study in Spain (BIOCOVID-Spain study).

Identification of predictors for severe disease progression is key for risk stratification in COVID-19 patients. We aimed to describe the main characteristics and identify the early predictors for severe outcomes among hospitalized patients with COVID-19 in Spain. This was an observational, retrospective cohort study (BIOCOVID-Spain study) including COVID-19 patients admitted to 32 Spanish hospitals. Demographics, comorbidities and laboratory tests were collected. Outcome was in-hospital mortality. For analysis, laboratory tests values were previously adjusted to assure the comparability of results among participants. Cox regression was performed to identify predictors. Study population included 2873 hospitalized COVID-19 patients. Nine variables were independent predictors for in-hospital mortality, including creatinine (Hazard ratio [HR]:1.327; 95% Confidence Interval [CI]: 1.040-1.695, p = .023), troponin (HR: 2.150; 95% CI: 1.155-4.001; p = .016), platelet count (HR: 0.994; 95% CI: 0.989-0.998; p = .004) and C-reactive protein (HR: 1.037; 95% CI: 1.006-1.068; p = .019). This is the first multicenter study in which an effort was carried out to adjust the results of laboratory tests measured with different methodologies to guarantee their comparability. We reported a comprehensive information about characteristics in a large cohort of hospitalized COVID-19 patients, focusing on the analytical features. Our findings may help to identify patients early at a higher risk for an adverse outcome.

Classification, prevalence, and outcomes of anticancer therapy-induced cardiotoxicity: the CARDIOTOX registry.

AIM: Cardiotoxicity (CTox) is a major side effect of cancer therapies, but uniform diagnostic criteria to guide clinical and research practices are lacking. METHODS AND RESULTS: We prospectively studied 865 patients, aged 54.7 ± 13.9; 16.3% men, scheduled for anticancer therapy related with moderate/high CTox risk. Four groups of progressive myocardial damage/dysfunction were considered according to current guidelines: normal, normal biomarkers (high-sensitivity troponin T and N-terminal natriuretic pro-peptide), and left ventricular (LV) function; mild, abnormal biomarkers, and/or LV dysfunction (LVD) maintaining an LV ejection fraction (LVEF) ≥50%; moderate, LVD with LVEF 40-49%; and severe, LVD with LVEF ≤40% or symptomatic heart failure. Cardiotoxicity was defined as new or worsening of myocardial damage/ventricular function from baseline during follow-up. Patients were followed for a median of 24 months. Cardiotoxicity was identified in 37.5% patients during follow-up [95% confidence interval (CI) 34.22-40.8%], 31.6% with mild, 2.8% moderate, and 3.1% with severe myocardial damage/dysfunction. The mortality rate in the severe CTox group was 22.9 deaths per 100 patients-year vs. 2.3 deaths per 100 patients-year in the rest of groups, hazard ratio of 10.2 (95% CI 5.5-19.2) (P < 0.001). CONCLUSIONS: The majority of patients present objective data of myocardial injury/dysfunction during or after cancer therapy. Nevertheless, severe CTox, with a strong prognostic relationship, was comparatively rare. This should be reflected in protocols for clinical and research practices.

Autochthonous Crimean-Congo Hemorrhagic Fever in Spain.

Crimean-Congo hemorrhagic fever (CCHF) is a widely distributed, viral, tickborne disease. In Europe, cases have been reported only in the southeastern part of the continent. We report two autochthonous cases in Spain. The index patient acquired the disease through a tick bite in the province of Ávila - 300 km away from the province of Cáceres, where viral RNA from ticks was amplified in 2010. The second patient was a nurse who became infected while caring for the index patient. Both were infected with the African 3 lineage of this virus. (Funded by Red de Investigación Cooperativa en Enfermedades Tropicales [RICET] and Efficient Response to Highly Dangerous and Emerging Pathogens at EU [European Union] Level [EMERGE].).

Specificity of B-Type Natriuretic Peptide Assays: Cross-Reactivity with Different BNP, NT-proBNP, and proBNP Peptides.

BACKGROUND: B-type natriuretic peptides (BNPs) are used clinically to diagnose and monitor heart failure and are present in the circulation as multiple proBNP-derived fragments. We investigated the specificity of BNP immunoassays with glycosylated and nonglycosylated BNP, N-terminal proBNP (NT-proBNP), and proBNP peptides to probe the cross-reactivity of each assay. METHODS: Nine B-type natriuretic peptides were studied,including synthetic and recombinant BNP (Shionogi, Scios, Mayo), human and synthetic glycosylated and nonglycosylated NT-proBNP (HyTest, Roche Diagnostics), and human glycosylated and nonglycosylated proBNP (HyTest, Scios). Five BNP [Abbott, Abbott POC, Alere, Beckman Coulter, Siemens (Centaur)], 9 NT-proBNP [Ortho-Clinical Diagnostics, Roche, Response, bioMerieux, Siemens (Dimension, Immulite, Stratus CS), Mitsubishi] and 3 research-use-only proBNP immunoassays [Biosite (Alere), Bio-Rad, Goetze] were evaluated. Specificity was assessed by calculating the recovery between baseline and peptide-spiked human plasma pools at target concentrations of 100 ng/L BNP, 300 ng/L proBNP, or 450 ng/L NT-proBNP. All assays were performed in duplicate. RESULTS: BNP and NT-proBNP assays demonstrated substantial cross-reactivity with proBNP peptides. NT-proBNP assays do not detect glycosylated forms of either NT-proBNP or proBNP. proBNP assays preferentially detect the BNP 1-32 peptide and have minimal cross-reactivity with BNP peptides and glycosylated proBNP. CONCLUSIONS: BNP or NT-proBNP results are not transferable among the current existing immunoassays owing to their differences in cross-reactivity and ability to detect various glycosylated forms of proBNP-derived fragments. Opportunities remain to standardize and harmonize BNP and NT-proBNP assays, as well as to develop specific proBNP assays, to widen their clinical scope of use.

Cardiovascular risk factors during cancer treatment. Prevalence and prognostic relevance: insights from the CARDIOTOX registry.

AIMS: The actual usefulness of cardiovascular (CV) risk factor assessment in the prognostic evaluation of cancer patients treated with cardiotoxic treatment remains largely unknown. Prospective multicentre study in patients scheduled to receive anticancer therapy related with moderate/high cardiotoxic risk. METHODS AND RESULTS: A total of 1324 patients underwent follow-up in a dedicated cardio-oncology clinic from April 2012 to October 2017. Special care was given to the identification and control of CV risk factors. Clinical data, blood samples, and echocardiographic parameters were prospectively collected according to protocol, at baseline before cancer therapy and then at 3 weeks, 3 months, 6 months, 1 year, 1.5 years, and 2 years after initiation of cancer therapy. At baseline, 893 patients (67.4%) presented at least one risk factor, with a significant number of patients newly diagnosed during follow-up. Individual risk factors were not related with worse prognosis during a 2-year follow-up. However, a higher Systemic Coronary Risk Estimation (SCORE) was significantly associated with higher rates of severe cardiotoxicity (CTox) and all-cause mortality [hazard ratio (HR) 1.79 (95% confidence interval, CI 1.16-2.76) for SCORE 5-9 and HR 4.90 (95% CI 2.44-9.82) for SCORE ≥10 when compared with patients with lower SCORE (0-4)]. CONCLUSIONS: This large cohort of patients treated with a potentially cardiotoxic regimen showed a significant prevalence of CV risk factors at baseline and significant incidence during follow-up. Baseline CV risk assessment using SCORE predicted severe CTox and all-cause mortality. Therefore, its use should be considered in the evaluation of cancer patients.

Effect of Dynamic Hyperinflation on Cardiac Response to Exercise of Patients With Chronic Obstructive Pulmonary Disease.

INTRODUCTION: Although the major limitation to exercise performance in patients with COPD is dynamic hyperinflation (DH), little is known about its relation with cardiac response to exercise. Our objectives were to compare the exercise response of stroke volume (SV) and cardiac output (CO) between COPD patients with or without DH and control subjects, and to assess the main determinants. METHODS: Fifty-seven stable COPD patients without cardiac comorbidity and 25 healthy subjects were recruited. Clinical evaluation, baseline function tests, computed tomography and echocardiography were conducted in all subjects. Patients performed consecutive incremental exercise tests with measurement of operating lung volumes and non-invasive measurement of SV, CO and oxygen uptake (VO2) by an inert gas rebreathing method. Biomarkers of systemic inflammation and oxidative stress, tissue damage/repair, cardiac involvement and airway inflammation were measured. RESULTS: COPD patients showed a lower SV/VO2 slope than control subjects, while CO response was compensated by a higher heart rate increase. COPD patients with DH experienced a reduction of SV/VO2 and CO/VO2 compared to those without DH. In COPD patients, the end-expiratory lung volume (EELV) increase was related to SV/VO2 and CO/VO2 slopes, and it was the only independent predictor of cardiac response to exercise. However, in the regression models without EELV, plasma IL-1ß and high-sensitivity cardiac troponin T were also retained as independent predictors of SV/VO2 slope. CONCLUSION: Dynamic hyperinflation decreases the cardiac response to exercise of COPD patients. This effect is related to systemic inflammation and myocardial stress but not with left ventricle diastolic dysfunction.

Experience on how to implement a preanalytical and POCT unit in Madrid's IFEMA field hospital during this unprecedented COVID-19 emergency.

To fight the virus SARS-CoV-2 spread to Europe from China and to give support to the collapsed public health system, the Spanish Health Authorities developed a field hospital located in the facilities of Madrid exhibition centre (IFEMA) to admit and treat patients diagnosed with SARS-CoV-2 infectious disease (COVID-19). The Department of Laboratory Medicine of La Paz University Hospital in Madrid (LMD-HULP) was designated to provide laboratory services. Due to the emergency, the IFEMA field hospital had to be prepared for patient admission in less than 1 week and the laboratory professionals had to collaborate in a multidisciplinary group to assure that resources were available to start on time. The LMD-HULP participated together with the managers in the design of the tests portfolio and the integration of the healthcare information systems (IS) (hospital IS, laboratory IS and POCT management system). Laboratorians developed a strategy to quickly train clinicians and nurses on test requests, sample collection procedures and management/handling of the POCT blood gas analyser both by written materials and training videos. The IFEMA´s preanalytical unit managed 3782 requests, and more than 11,000 samples from March 27th to April 30th. Furthermore, 1151 samples were measured by blood gas analysers. In conclusion, laboratory professionals must be resilient and have to respond timely in emergencies as this pandemic. The lab's personnel selection, design and monitoring indicators to maintain and further improve the quality and value of laboratory services is crucial to support medical decision making and provide better patient care.