Mesenchymal stromal cell therapy for COVID-19 acute respiratory distress syndrome: a double-blind randomised controlled trial.

Mesenchymal stromal cells (MSC) have immunomodulatory and tissue-regenerative properties and have shown promising results in acute respiratory distress syndrome (ARDS) of multiple causes, including COVID-19. We conducted a randomised (1:1), placebo-controlled, double-blind clinical trial to assess the efficacy and safety of one bone marrow-derived MSC infusion in twenty patients with moderate to severe ARDS caused by COVID-19. The primary endpoint (increase in PaO2/FiO2 ratio from baseline to day 7, MSC 83.3 versus placebo 57.6) was not statistically significant, although a clinical improvement at day 7 in the WHO scale was observed in MSC patients (5, 50% vs 0, 0%, p = 0.033). Median time to discontinuation of supplemental oxygen was also shorter in the experimental arm (14 versus 23 days, p = 0.007), resulting in a shorter hospital stay (17.5 versus 28 days, p = 0.042). No significant differences were observed for other efficacy or safety secondary endpoints. No infusion or treatment-related serious adverse events occurred during the one-year follow-up. This study did not meet the primary endpoint of PaO2/FiO2 increase by day 7, although it suggests that MSC are safe in COVID-19 ARDS and may accelerate patients' clinical recovery and hospital discharge. Larger studies are warranted to elucidate their role in ARDS and other inflammatory lung disorders.Trial Registration: EudraCT Number: 2020-002193-27, registered on July 14th, 2020, https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-002193-27/ES . NCT number: NCT04615429, registered on November 4th, 2020, https://clinicaltrials.gov/ct2/show/NCT04615429 .

Impaired Antibody-Dependent Cellular Cytotoxicity in a Spanish Cohort of Patients With COVID-19 Admitted to the ICU.

SARS-CoV-2 infection causes COVID-19, ranging from mild to critical disease in symptomatic subjects. It is essential to better understand the immunologic responses occurring in patients with the most severe outcomes. In this study, parameters related to the humoral immune response elicited against SARS-CoV-2 were analysed in 61 patients with different presentations of COVID-19 who were recruited in Hospitals and Primary Healthcare Centres in Madrid, Spain, during the first pandemic peak between April and June 2020. Subjects were allocated as mild patients without hospitalization, severe patients hospitalized or critical patients requiring ICU assistance. Critical patients showed significantly enhanced levels of B cells with memory and plasmablast phenotypes, as well as higher levels of antibodies against SARS-CoV-2 with neutralization ability, which were particularly increased in male gender. Despite all this, antibody-dependent cell-mediated cytotoxicity was defective in these individuals. Besides, patients with critical COVID-19 also showed increased IgG levels against herpesvirus such as CMV, EBV, HSV-1 and VZV, as well as detectable CMV and EBV viremia in plasma. Altogether, these results suggest an enhanced but ineffectual immune response in patients with critical COVID-19 that allowed latent herpesvirus reactivation. These findings should be considered during the clinical management of these patients due to the potential contribution to the most severe disease during SARS-CoV-2 infection.

A multicenter randomized open-label clinical trial for convalescent plasma in patients hospitalized with COVID-19 pneumonia.

BACKGROUNDPassive immunotherapy with convalescent plasma (CP) is a potential treatment for COVID-19. Evidence from controlled clinical trials is inconclusive.METHODSWe conducted a randomized, open-label, controlled clinical trial at 27 hospitals in Spain. Patients had to be admitted for COVID-19 pneumonia within 7 days from symptom onset and not on mechanical ventilation or high-flow oxygen devices. Patients were randomized 1:1 to treatment with CP in addition to standard of care (SOC) or to the control arm receiving only SOC. The primary endpoint was the proportion of patients in categories 5 (noninvasive ventilation or high-flow oxygen), 6 (invasive mechanical ventilation or extracorporeal membrane oxygenation [ECMO]), or 7 (death) at 14 days. Primary analysis was performed in the intention-to-treat population.RESULTSBetween April 4, 2020, and February 5, 2021, 350 patients were randomly assigned to either CP (n = 179) or SOC (n = 171). At 14 days, proportion of patients in categories 5, 6, or 7 was 11.7% in the CP group versus 16.4% in the control group (P = 0.205). The difference was greater at 28 days, with 8.4% of patients in categories 5-7 in the CP group versus 17.0% in the control group (P = 0.021). The difference in overall survival did not reach statistical significance (HR 0.46, 95% CI 0.19-1.14, log-rank P = 0.087).CONCLUSIONCP showed a significant benefit in preventing progression to noninvasive ventilation or high-flow oxygen, invasive mechanical ventilation or ECMO, or death at 28 days. The effect on the predefined primary endpoint at 14 days and the effect on overall survival were not statistically significant.TRIAL REGISTRATIONClinicaltrials.gov, NCT04345523.FUNDINGGovernment of Spain, Instituto de Salud Carlos III.

Mild AST elevation as an early sign of COVID-19 severity in a multicenter Madrid cohort.

INTRODUCTION: liver enzyme elevation has been reported in SARS-CoV-2 disease (COVID-19) in heterogeneous cohorts, mainly from China. Comprehensive reports from other countries are needed. In this study, we dissect the pattern, evolution, and predictive value of such abnormalities in a cohort from Madrid, Spain. METHODS: a retrospective study with a prospective 14-day follow-up of 373 patients with confirmed COVID-19 in five Madrid hospitals, including 50 outpatients. A COVID-19 severe course was defined as the need for mechanical ventilation. RESULTS: a total of 33.1 % of hospitalized patients showed baseline AST elevation and 28.5 % showed ALT elevation, compared with 12 % and 8 % of outpatients (p ≤ 0.001). Baseline AST, ALT and GGT levels correlated with LDH and C-reactive protein (CRP) levels (r ≤ 0.598, p < 0.005). AST elevation was associated with other severity markers such as male sex, lymphopenia, and pneumonia on X-Ray (p < 0.05 for all). ALP and bilirubin levels were rarely increased. Patients with elevated baseline AST showed a progressive normalization of this enzyme and an increase in ALT and GGT levels. Patients with normal baseline AST showed a flattened evolution pattern with levels within the range. Patients with a severe course of COVID-19 more frequently showed elevated baseline AST than those with a milder evolution (54.2 % vs. 25.4 %, p < 0.001). Age, AST and CRP were independent risk factors for a severe course of COVID-19. CONCLUSION: mild liver enzyme elevation is associated with COVID-19 severity. Baseline AST is an independent predictor of severe COVID-19 course, and tends to normalize over time. ALT and GGT show a late elevation.

Ischemic Heart Disease during Acute Exacerbations of COPD.

Patients with chronic obstructive pulmonary disease (COPD) have a higher risk of acute cardiovascular events, and around 30% die from cardiovascular diseases. Recent data suggest an increased risk of myocardial infarction in the following days of a severe exacerbation of COPD. Disruption in the balance during the exacerbation with tachycardia, increased inflammation and systemic oxidative stress as well as some other factors may confer an increased risk of subsequent cardiovascular events. A number of investigations may be useful to an early diagnosis, including electrocardiography, imaging techniques and blood test for biomarkers. Some drugs that have changed prognosis in the cardiovascular setting such as cardioselective beta-blockers may be underused in patients with COPD despite its demonstrated benefits. This review focuses on several aspects of exacerbation of COPD and cardiovascular events including epidemiology, possible mechanism, diagnosis and treatment.

Risk Factors of Poor Outcomes after Admission for a COPD Exacerbation: Multivariate Logistic Predictive Models.

The aim of this study was to identify a multivariate model to predict poor outcomes after admission for exacerbation of chronic obstructive pulmonary disease (COPD).  We performed a multicenter, observational, prospective study. Patients admitted to hospital for COPD were followed up for 3 months. Relevant clinical variables at admission were selected. For each variable, the best cut-offs for the risk of poor outcome were identified using receiver operating characteristic (ROC) curves. Finally, a stepwise logistic regression model was performed. A total of 106 patients with a mean age of 71.1 (9.8) years were included. The mean maximum expiratory volume in the first second (FEV1)(%) was 45.2%, and the mean COPD assessment test (CAT) score at admission was 24.8 (7.1). At 3 months, 39 (36.8%) patients demonstrated poor outcomes: death (2.8%), readmission (20.8%) or new exacerbation (13.2%). Variables included in the logistic model were: previous hospital admission, FEV1 < 45%, Charlson ≥ 3, hemoglobin (Hb)<13 g/L, PCO2 ≥ 46 mmHg, fibrinogen ≥ 554 g/L, C-reactive protein (CRP)≥45 mg/L, leukocyte count < 9810 × 109/L, purulent sputum, long-term oxygen therapy (LTOT) and CAT ≥ 31 at admission. The final model showed that Hb < 13 g/L (OR = 2.46, 95%CI 1.09-6.36), CRP ≥ 45 mg/L (OR = 2.91, 95%CI: 1.11-7.49) and LTOT (3.07, 95%CI: 1.07-8.82) increased the probability of poor outcome up to 82.4%. Adding a CAT ≥ 31 at admission increased the probability to 91.6% (AUC = 0.75; p = 0.001). Up to 36.8% of COPD patients had a poor outcome within 3 months after hospital discharge, with low hemoglobin and high CRP levels being the risk factors for poor outcome. A high CAT at admission increased the predictive value of the model.

Risk stratification for COPD diagnosis through an active search strategy in primary care.

BACKGROUND: The aim of this study was to identify the percentage of undiagnosed patients with COPD through the implementation of an active search strategy in a selected subject population. METHODS: An observational, cross-sectional, multicenter study was conducted in a primary care setting in Spain. General practitioners gave their diagnostic impression of COPD (yes/no) on the basis of clinical criteria of subjects with respiratory symptoms and tobacco exposure. Subsequently, post-bronchodilator spirometry and quality-of-life tests were performed. Multivariate logistic regression techniques using receiver operating characteristic (ROC) curves were used to identify the combination of variables that best discriminates COPD. RESULTS: A total of 2,758 patients were screened at 368 primary care centers, of which 1,725 patients were included in the study. Seven hundred and ninety-three patients (46%) were diagnosed with COPD. Clinical judgment resulted in suspected COPD in 1,393 (81%) of the subjects. The best variables to discriminate COPD were a history of lower respiratory tract infections, cough, and dyspnea. This combination identified COPD with a ROCAUC of 0.61 denoting a poor discriminative ability. CONCLUSION: Employing an active search strategy leads to a new COPD diagnosis in almost half of the subjects. Screening of COPD with post-bronchodilator spirometry should be considered mandatory for any high-risk subject visiting the general practitioner clinic for any reason.

Validación de la versión en español del cuestionario COPD-Q/EPOC-Q de conocimiento de la EPOC / Validation of the Spanish Version of the COPD-Q Questionnaire on COPD Knowledge

Fundamentos: A pesar de que el reconocimiento de la importancia de la formación de los pacientes con EPOC ha crecido en los últimos años, no se está midiendo el grado de conocimiento de dicha enfermedad por falta de instrumentos específicos. El objetivo de este estudio es validar el cuestionario de conocimiento de la EPOC (EPOC-Q) de 13 ítems. Métodos: Tras la doble traducción del EPOC-Q se llevó a cabo la validación lógica y de contenido por un grupo de neumólogos expertos en EPOC y 8 pacientes con la enfermedad. La fiabilidad se estudió en un grupo independiente de 59 pacientes con EPOC grave vistos en planta o en consultas de neumología de 6 centros de varias regiones de España (Andalucía, Baleares, Castilla-La Mancha, Galicia y Madrid). Esta muestra también se usó para otras validaciones internas y externas. Resultados: El grupo tenía una media de edad de aproximadamente 70 años y una alfabetización en salud media baja. El número de respuestas acertadas fue de 8,3 (DE: 1,9), con una mediana de 8 y un rango entre 3 y 13. Los efectos suelo y techo fueron 0 y 1,5%, respectivamente. La consistencia interna del cuestionario es buena (alfa de Cronbach de 0,85) y la fiabilidad también alta, siendo el coeficiente kappa > 0,6 en todos los ítems y el coeficiente de correlación intraclase de la puntuación total de 0,84. Conclusión: El cuestionario EPOC-Q de 13 ítems es un instrumento válido, aplicable y fiable para evaluar el conocimiento de la EPOC

Rationale: Although recognition of the importance of educating chronic obstructive pulmonary disease (COPD) patients has grown in recent years, their understanding of this disease is not being measured due to a lack of specific instruments. The aim of this study was to validate the COPD-Q questionnaire, a 13-item instrument for determining COPD knowledge. Methods: The COPD-Q was translated and backtranslated, and subsequently submitted to logic and content validation by a group of COPD experts and 8 COPD patients. Reliability was studied in an independent group of 59 patients with severe COPD seen in the pulmonology ward or clinics of 6 hospitals in Spain (Andalusia, Baleares, Castilla-La Mancha, Galicia and Madrid). This sample was also used for other internal and external validations. Results: The mean age of the group was approximately 70 years and their health awareness was low-to-medium. The number of correct answers was 8.3 (standard deviation: 1.9), median 8, range 3-13. Floor and ceiling effects were 0% and 1.5%, respectively. Internal consistency of the questionnaire was good (Cronbach's alpha = 0.85) and reliability was also high, with a kappa coefficient > 0.6 for all items and an intraclass correlation efficient of 0.84 for the total score. Conclusion: The 13-item COPD-Q is a valid, applicable and reliable instrument for determining patients' knowledge of COPD

Validation of the Spanish Version of the COPD-Q Questionnaire on COPD Knowledge.

RATIONALE: Although recognition of the importance of educating chronic obstructive pulmonary disease (COPD) patients has grown in recent years, their understanding of this disease is not being measured due to a lack of specific instruments. The aim of this study was to validate the COPD-Q questionnaire, a 13-item instrument for determining COPD knowledge. METHODS: The COPD-Q was translated and backtranslated, and subsequently submitted to logic and content validation by a group of COPD experts and 8 COPD patients. Reliability was studied in an independent group of 59 patients with severe COPD seen in the pulmonology ward or clinics of 6 hospitals in Spain (Andalusia, Baleares, Castilla-La Mancha, Galicia and Madrid). This sample was also used for other internal and external validations. RESULTS: The mean age of the group was approximately 70 years and their health awareness was low-to-medium. The number of correct answers was 8.3 (standard deviation: 1.9), median 8, range 3-13. Floor and ceiling effects were 0% and 1.5%, respectively. Internal consistency of the questionnaire was good (Cronbach's alpha=0.85) and reliability was also high, with a kappa coefficient >0.6 for all items and an intraclass correlation efficient of 0.84 for the total score. CONCLUSION: The 13-item COPD-Q is a valid, applicable and reliable instrument for determining patients' knowledge of COPD.

The CAT (COPD Assessment Test) questionnaire as a predictor of the evolution of severe COPD exacerbations.

INTRODUCTION: Since exacerbations of chronic obstructive pulmonary disease (COPD) cause both a great impact on the progression of the disease and generate high health expenditures, there is a need to develop tools to evaluate their prognosis. METHOD: Multicenter, observational, prospective study that evaluated the prognostic utility of the COPD Assessment Test (CAT) in severe exacerbations of COPD. Anthropometric and clinical variables were analyzed: smoking, history of exacerbations during the previous year, drug treatment, degree of baseline dyspnea, comorbidities; laboratory variables at admission (complete blood count, arterial blood gas and biochemistry) and CAT scores in the first 24 h of admission, on the third day, at discharge and at 3 months. RESULTS: We evaluated 106 patients (91 males) with a mean age of 71.1 (SD 9.8 years), mean FEV1 45.2% (14.7%) and average CAT score at admission of 24.7 points (7.1). At three months after discharge, treatment failure was observed in 39 (36.8%) patients: 14 (13.2%) presented an exacerbation without the need for hospital admission, 22 were readmitted (20.8%) and 3 (2.8%) died during follow-up. The three factors associated with increased risk of failure were a reduction less than 4 units in the CAT at discharge compared to admission, lower hemoglobin levels and treatment with domiciliary oxygen. CONCLUSIONS: A change of ≤4 points in the CAT score at discharge compared to that obtained at admission due to a severe exacerbation of COPD, helps to predict therapeutic failure such as a new exacerbation, readmission or death in the subsequent three months.

Multicentric study on the beta-blocker use and relation with exacerbations in COPD.

Chronic obstructive pulmonary disease (COPD) is frequently associated with chronic heart failure (CHF) or coronary artery disease (CAD). In spite of the recommendation to use beta-blockers (BB) they are likely under-prescribed to patients with concurrent COPD and heart diseases. To find out the prevalence of use of BB, 256 COPD patients were consecutively recruited by pulmonary physicians from 14 hospitals in 7 regions of Spain in their outpatient offices if they had a diagnosis of COPD, were not on long-term oxygen therapy, had CHF or CAD, and met the criteria for BB treatment. In patients with indication 58% (95%CI, 52-64%) of the COPD patients and 97% of the non-COPD patients were on BB (p < 0.001). In patients with COPD, several factors were independently related to at least one visit to the emergency room in the previous year such as use of BB, adjusted OR = 0.27 (95% CI 0.15-0.50), GOLD stage D, OR = 2.52 (1.40-4.53), baseline heart rate >70, OR 2.19 (1.24-3.86) use of long-acting beta2-agonists OR = 2.18 (1.29-3.68), previous episodes of left ventricular failure OR 2.27 (1.19-4.33) and diabetes, OR = 1.82 (1.08-3.38). We conclude that, according to what is recommended by current guidelines, BB are still under-prescribed in COPD patients. COPD patients with CHF or CAD using BB suffer fewer exacerbations and visits to the ER. GOLD stage, use of long-acting beta2-agonists, baseline heart rate and comorbidities are also risk factors for exacerbations in this population.