Baricitinib or imatinib in hospitalized COVID-19 patients: Results from COVINIB, an exploratory randomized clinical trial.

Baricitinib and imatinib are considered therapies for coronavirus disease 2019 (COVID-19), but their ultimate clinical impact remains to be elucidated, so our objective is to determine whether these kinase inhibitors provide benefit when added to standard care in hospitalized COVID-19 patients. Phase-2, open-label, randomized trial with a pick-the-winner design conducted from September 2020 to June 2021 in a single Spanish center. Hospitalized adults with COVID-19 pneumonia and a symptom duration ≤10 days were assigned to 3 arms: imatinib (400 mg qd, 7 days) plus standard-care, baricitinib (4 mg qd, 7 days) plus standard-care, or standard-care alone. Primary outcome was time to clinical improvement (discharge alive or a reduction of 2 points in an ordinal scale of clinical status) compared on a day-by-day basis to identify differences ≥15% between the most and least favorable groups. Secondary outcomes included oxygenation and ventilatory support requirements, additional therapies administered, all-cause mortality, and safety. One hundred and sixty-five patients analyzed. Predefined criteria for selection of the most advantageous arm were met for baricitinib, but not for imatinib. However, no statistically significant differences were observed in formal analysis, but a trend toward better results in patients receiving baricitinib was found compared to standard care alone (hazard ratio [HR] for clinical improvement: 1.41, 95% confidence intervals [CI]: 0.96-2.06; HR for discontinuing oxygen: 1.46, 95% CI: 0.94-2.28). No differences were found regarding additional therapies administered or safety. Baricitinib plus standard care showed better results for hospitalized COVID-19 patients, being the most advantageous therapeutic strategy among those proposed in this exploratory clinical trial.

Diagnostic and prognostic value of heart-type fatty acid-binding protein in the early hours of acute myocardial infarction.

BACKGROUND: Heart-type fatty acid-binding protein (H-FABP) is a cytosolic protein that is released into the bloodstream when the myocardium is injured. The aim was to determine the diagnostic and prognostic value of H-FABP in patients with suspected acute myocardial infarction (AMI) within the first 3-6 hours after the onset of chest pain. METHODS AND RESULTS: A consecutive series of 165 patients with chest pain lasting less than 6 hours were enrolled in a forward observational design in the emergency department.The diagnostic validity of H-FABP was evaluated according to sensitivity, specificity, and predictive values, likelihood ratios, ROC curves, and multivariate logistic regression analyses. The prognostic value of H-FABP at 6 months was checked using survival curves and the multivariate Cox proportional hazards model. The sensitivity of H-FABP was 81% (95% CI: 69.2-92.9). Its area under the ROC curve: 0.729 (95% CI: 0.63-0.83) and negative likelihood ratio (0.38; 95% CI: 0.22-0.65) were significantly better than both troponin (cTnI) and CK-MB, whereas its specificity, 53% (95% CI: 41.1-64.8), was lower than that of the other markers. Increased H-FABP added diagnostic information as it demonstrated independent association with AMI by logistic regression analysis. Increased H-FABP and cTnI were both strong and independent predictors of outcome in the 6-month follow-up (hazard ratio: 2.18; 95% CI: 1.07-4.42; and 2.34; 95% CI: 0.98-5.59, respectively). CONCLUSIONS: H-FABP is, within 6 hours and also within 3 hours, more sensitive than the other markers in the early diagnosis of AMI and it is an independent prediction factor of events within 6 months.

Clinical usefulness and safety of an age-adjusted D-dimer cutoff levels to exclude pulmonary embolism: a retrospective analysis.

Age-adjusted D-dimer (AADD) appears to increase the proportion of patients in whom pulmonary embolism (PE) can safely be excluded compared with conventional D-dimer (CDD), according to a limited number of studies. The aim if this study was to assess whether the use of an AADD might safely increase the clinical usefulness of CDD for the diagnosis of PE in our setting. Three hundred and sixty two consecutive outpatients with clinically suspected PE in whom plasma samples were obtained to measure D-dimer were included in this post hoc analysis of a previous study. CDD cutoff value was 500 ng/mL and AADD was calculated as (patient's age × 10) ng/mL in patients aged >50. Sensitivity, specificity, clinical usefulness (i.e., proportion of true-negative tests among all patients with suspected PE), and the proportion of false negatives were calculated for both AADD and CDD among patients with low-to-moderate clinical probability of PE according to Well's criteria. PE was confirmed in 98 patients (27%). Among 331 patients with low-to-moderate clinical probability of PE, sensitivity and clinical usefulness were 100 and 27.8% for CDD, respectively, and 100 and 36.5% for AADD, respectively. In 29 patients aged >50 with CDD >500 ng/mL, AADD showed values under its normal cutoff point, without false negatives for the diagnosis of PE (0%, 95% CI 0-11%). AADD increases clinical usefulness notably with respect to that of CDD in patients with clinical suspected PE without losing sensitivity in our cohort. The use of AADD apparently does not reduce the safety of CDD for the exclusion of PE.

The role of vitamin D in chronic obstructive pulmonary disease, asthma and other respiratory diseases.

There has been growing interest in recent years in the extraosseous effects of vitamin D. In this article, we review the physiology of vitamin D, the physiopathological effects associated with vitamin D deficit and the available evidence on its etiopathogenic role in respiratory diseases. Given the pleiotropic actions of vitamin D, it is biologically plausible that the deficit of this vitamin could play a pathogenic role of in the development of various respiratory diseases. However, the many epidemiological studies that have shown an association between low vitamin D levels and a higher risk of developing various respiratory diseases or a poorer prognosis if they do appear, were unable to show causality. Post-hoc analyses of some clinical trials, particularly in chronic obstructive pulmonary disease (COPD) and asthma, appear to suggest that some patient subtypes may benefit from correction of a vitamin D deficit. In this respect, it would be interesting to determine if the interindividual differences found in the effect of vitamin D deficit and responses to correcting this deficit could be explained by the genetic variants involved in vitamin D metabolism. Ultimately, only appropriately designed clinical trials will determine whether 25-OHD supplements can prevent or improve the course of the various respiratory diseases in which an epidemiological association between prognosis and vitamin D deficit has been described.

Safety of withholding anticoagulant therapy in patients with suspected pulmonary embolism with a negative multislice computed tomography pulmonary angiography.

BACKGROUND: To assess the safety of withholding anticoagulant therapy in patients with clinically suspected pulmonary embolism with a negative multislice computed tomography pulmonary angiography (MCTPA). METHODS: Three hundred and eighty six patients who were consecutively assessed in the emergency room of our institution for suspected pulmonary embolism were eligible for our study. Patients with either a low or an intermediate clinical probability of pulmonary embolism according to the Wells score and a negative MCTPA for pulmonary embolism were enrolled. Patients with anticoagulant therapy for other medical conditions were excluded from this study. We assessed the percentage of patients in whom venous thromboembolic events or death related to this condition within three months after the negative CT. RESULTS: Two hundred and forty two patients were included in our series [mean age+/-standard deviation (SD) (63.1+/-18.1)]. Only one patient (0.41% [95% confidence interval -0.4%-1.22%]) showed a non-fatal pulmonary embolism during the three-month follow-up period after an initial negative CT scan (negative predictive value, 99.58%). Eleven patients died during the follow-up period due to conditions unrelated to venous thromboembolic disease (pneumonia [n=5], lung cancer [n=2], wasting syndrome [n=1], acute myocardial infarction [n=1], leiomyosarcoma [n=1], and severe pulmonary hypertension [n=1]). CONCLUSIONS: Withholding anticoagulant therapy in patients with suspected venous thromboembolic disease with a negative result on MCTPA seems to be safe in our clinical setting.

Papel de la vitamina D en enfermedad pulmonar obstructiva crónica, asma y otras enfermedades respiratorias / The Role of Vitamin D in Chronic Obstructive Pulmonary Disease, Asthma and Other Respiratory Diseases

En los últimos años existe un creciente interés por las acciones extraóseas de la vitamina D. En este artículo revisamos la fisiología de la vitamina D, los aspectos fisiopatológicos asociados a su déficit y la evidencia existente sobre su papel etiopatogénico en enfermedades respiratorias. Teniendo en cuenta las acciones pleiotrópicas de la vitamina D, existe plausibilidad biológica sobre un potencial papel patogénico del déficit de esta vitamina en el desarrollo de diversas enfermedades respiratorias. Sin embargo, los numerosos estudios epidemiológicos que han encontrado asociación entre niveles bajos de vitamina D y mayor riesgo de desarrollar diversas enfermedades respiratorias o de conllevar un peor pronóstico no permiten demostrar causalidad. Los análisis post hoc de algunos ensayos clínicos, especialmente en enfermedad pulmonar obstructiva crónica (EPOC) y asma, parecen demostrar que ciertos subtipos de pacientes podrían beneficiarse de la corrección del déficit de vitamina D. En este sentido, resultará interesante averiguar si las variantes genéticas implicadas en el metabolismo de la vitamina D pueden explicar las diferencias interindividuales encontradas en cuanto al efecto del déficit de vitamina D y la respuesta a su corrección. En último término, solo los ensayos clínicos adecuadamente diseñados permitirán determinar si los suplementos de 25-OH D pueden tener un efecto preventivo o mejorar la evolución de las distintas enfermedades respiratorias en las que se ha descrito asociación epidemiológica entre su pronóstico y el déficit de esta vitamina

There has been a growing interest in recent years in the extraosseous effects of vitamin D. In this article, we review the physiology of vitamin D, the physiopathological effects associated with vitamin D deficit and the available evidence on its etiopathogenic role in respiratory diseases. Given the pleiotropic actions of vitamin D, it is biologically plausible that the deficit of this vitamin could play a pathogenic role in the development of various respiratory diseases. However, the many epidemiological studies that have shown an association between low vitamin D levels and a higher risk of developing various respiratory diseases, or a poorer prognosis if they do appear, were unable to show causality. Post hoc analyses of some clinical trials, particularly in chronic obstructive pulmonary disease (COPD) and asthma, appear to suggest that some patient subtypes may benefit from correction of a vitamin D deficit. In this respect, it would be interesting to determine if the interindividual differences found in the effect of vitamin D deficit and responses to correcting this deficit could be explained by the genetic variants involved in vitamin D metabolism. Ultimately, only appropriately designed clinical trials will determine whether 25-OH D supplements can prevent or improve the course of the various respiratory diseases in which an epidemiological association between prognosis and vitamin D deficit has been described

Distinctive pattern of cytokine production and adhesion molecule expression in peripheral blood memory CD4+ T cells from patients with active Crohn's disease.

An expansion of both circulating and intestinal lamina propria CD4+ CD45RO+ T cells has been described in patients with Crohn's disease. We studied both the cytokine profile and the expression of adhesion molecules on this T-cell subset. Peripheral blood CD4+ CD45RO+ T cells from patients with Crohn's disease (n=45) were assessed by flow cytometry and RT-PCR methods. The cytokine profile was also measured in intestinal lamina propria from seven patients. They were classified according to the CDAI and the results were compared with those of patients with ulcerative colitis (n=21) and noninflammatory intestinal conditions (n=15), and healthy controls (n=39). The mean percentage of circulating CD4+ CD45RO+ T cells producing intracellular TNF was higher in active than in inactive Crohn's disease patients (p < 0.001), active (p = 0.49) and inactive ulcerative colitis (p = 0.019), and healthy controls (p =0. 017). TNF expression correlated with CDAI (p < 0.001). An increased expression of intracellular IL-2, IL-6, and IL-10 in active Crohn's disease patients was also found. CD62L was downregulated in active Crohn's disease patients while no differences were observed in CD49d and CD11a expression. Lamina propria CD4+ CD45RO+ T cells from active Crohn's disease lesions showed an increased intracellular staining of TNF, IFN-gamma, and IL-10. Both peripheral and intestinal mucosa CD4+ CD45RO+ T cells from active Crohn's disease patients show an increased production of TNF. In addition, the circulating CD4+ CD45RO+ T-cell subset expresses a pattern of adhesion molecules that promotes homing to extranodal lymphoid tissues. This T-cell subset may play a relevant role in the immunopathogenesis of Crohn's disease.

Active Crohn's disease patients show a distinctive expansion of circulating memory CD4+CD45RO+CD28null T cells.

In a previous study we found an expansion of circulating memory (CD45RO(+)) CD4(+) T cells in patients with Crohn's disease (CD). The aim of this work was to investigate the phenotypic and functional characteristics of this T-cell subset in CD. We analyzed in peripheral blood CD4(+)CD45RO(+) T cells from CD patients the expression of surface markers associated to immune activation, costimulation, and apoptosis. In sorted CD4(+)CD45RO(+) T cells apoptosis was quantified by fluorescent annexin V binding. Healthy subjects and patients with ulcerative colitis and acute bacterial enterocolitis served as control groups. An increased percentage of memory CD4(+)CD45RO(+) T cells lacking the expression of costimulatory receptor CD28 was detected in patients with active CD when compared to the other groups evaluated. This expanded CD4(+)CD45RO(+)CD28(null) T-cell subset expressed mostly the effector-cell marker CD57(+). Both CD28 downregulation and CD57 expression correlated to CDAI and surrogate markers of disease activity. These phenotypic changes observed on CD4(+)CD45RO(+) T cells from active CD returned to values similar to healthy controls after clinical remission. Moreover, this memory CD28(null) T-cell subset might express more intracytoplasmic TNF and IFN-gamma than their CD28(+) counterpart. Significantly lower frequencies of memory CD4(+)CD45RO(+) T cells expressing CD95 apoptosis receptor were found in patients with active CD. Moreover, sorted CD4(+)CD45RO(+)and CD4(+)CD45RO(+) CD28(null) T cells from patients with active CD exhibited a lower apoptotic rate than that found in healthy controls and inactive CD patients. According to our data, circulating T lymphocytes from active CD patients show distinctive phenotypic and functional changes, characterized by an expansion of memory CD4(+)CD45RO(+)CD28(null) T cells expressing effector-associated cell surface molecules and displaying enhanced resistance to apoptosis.