Hyperinflammatory State and Low T1 Adaptive Immune Response in Severe and Critical Acute COVID-19 Patients.

Background: A better understanding of COVID-19 immunopathology is needed to identify the most vulnerable patients and improve treatment options. Objective: We aimed to identify immune system cell populations, cytokines, and inflammatory markers related to severity in COVID-19. Methods: 139 hospitalized patients with COVID-19-58 mild/moderate and 81 severe/critical-and 74 recovered patients were included in a prospective longitudinal study. Clinical data and blood samples were obtained on admission for laboratory markers, cytokines, and lymphocyte subsets study. In the recovered patients, lymphocyte subsets were analyzed 8-12 weeks after discharge. Results: A National Early Warning Score 2 >2 (OR:41.4; CI:10.38-167.0), ferritin >583 pg/mL (OR:16.3; CI: 3.88-69.9), neutrophil/lymphocyte ratio >3 (OR: 3.5; CI: 1.08-12.0), sIL-2rα (sCD25) >512 pg/mL (OR: 3.3; CI: 1.48-7.9), IL-1Ra >94 pg/mL (OR: 3.2; IC: 1.4-7.3), and IL-18 >125 pg/mL (OR: 2.4; CI: 1.1-5.0) were associated with severe/critical COVID-19 in the multivariate models used. Lower absolute values of CD3, CD4, CD8, and CD19 lymphocytes together with higher frequencies of NK cells, a CD4 and CD8 activated (CD38+HLA-DR+) memory T cell and effector memory CD45RA+ (EMRA) phenotype, and lower T regulatory cell frequencies were found in severe/critical patients relative to mild/moderate and recovered COVID-19 patients. A significant reduction in Th1, Tfh1, and Tc1 with higher Th2, Tfh2, Tc2, and plasma cell frequencies was found in the most severe cases. Conclusion: A characteristic hyperinflammatory state with significantly elevated neutrophil/lymphocyte ratio and ferritin, IL-1Ra, sIL-2rα, and IL-18 levels together with a "low T1 lymphocyte signature" was found in severe/critical COVID-19 patients.

Circulating levels of calprotectin, a signature of neutrophil activation in prediction of severe respiratory failure in COVID-19 patients: a multicenter, prospective study (CalCov study).

OBJECTIVE: Severe COVID-19 is characterized by a dysregulated immune response in which neutrophils play a critical role. Calprotectin reflects neutrophil activation and is involved in the self-amplifying thrombo-inflammatory storm in severe COVID-19. We aimed to evaluate the role of calprotectin in early prediction of severity in COVID-19 patients. METHODS: This was a multicenter prospective observational study enrolling consecutive adult COVID-19 patients. On arrival to emergency department, blood samples were collected for laboratory tests, including serum calprotectin. The primary outcome was severe respiratory failure requiring invasive mechanical ventilation and the secondary outcome was need for Intensive Care Unit (ICU) admission. RESULTS: Study population included 395 patients, 57 (14.4%) required invasive mechanical ventilation and 100 (25.3%) were admitted to ICU. Median serum calprotectin levels were significantly higher in intubated (3.73 mg/L vs. 2.63 mg/L; p < 0.001) and ICU patients (3.48 mg/L vs. 2.60 mg/L; p = 0.001). Calprotectin showed a significant accuracy to predict the need for invasive mechanical ventilation (ROC AUC 0.723) and ICU admission (ROC AUC 0.650). In multivariate analysis, serum calprotectin was an independent predictor of invasive mechanical ventilation (OR 1.161) and ICU admission (OR 1.068). CONCLUSION: Serum calprotectin can be used as an early predictor of severity in COVID-19 patients.

Predictive Immunological, Virological, and Routine Laboratory Markers for Critical COVID-19 on Admission.

BACKGROUND: Early identification of COVID-19 patients at risk of critical illness is a challenging endeavor for clinicians. We aimed to establish immunological, virological, and routine laboratory markers, which, in combination with clinical information, may allow identifying such patients. METHODS: Blood tests to measure neutrophil/lymphocyte ratio (NLR) and levels of ferritin, CRP, D-dimer, complement components (C3 and C4), cytokines, and lymphocyte subsets, as well as SARS-Cov-2 RT-PCR tests, were performed in COVID-19-confirmed cases within 48 hours of admission. RT-PCR cycle threshold (Ct) values from oropharyngeal or nasopharyngeal swabs were determined on the day of admission. Symptom severity was categorized as mild (grade 1), severe (grade 2), or critical (grade 3). RESULTS: Of 120 patients who were included, 49 had mild, 32 severe, and 39 critical COVID-19. Levels of ferritin >370 ng/mL (OR 16.4, 95% CI 5.3-50.8), D-dimer >440 ng/mL (OR 5.45, 95% CI 2.36-12.61), CRP >7.65 mg/dL (OR 11.54, 95% CI 4.3-30.8), NLR >3.77 (OR 13.4, 95% CI 4.3-41.1), IL-6 >142.5 pg/mL (OR 8.76, 95% CI 3.56-21.54), IL-10 >10.8 pg/mL (OR 16.45, 95% CI 5.32-50.81), sIL-2rα (sCD25) >804.5 pg/mL (OR 14.06, 95% CI 4.56-43.28), IL-1Ra >88.4 pg/mL (OR 4.54, 95% CI 2.03-10.17), and IL-18 >144 pg/mL (OR 17.85, 95% CI 6.54-48.78) were associated with critical COVID-19 in the univariate age-adjusted analysis. This association was confirmed in the multivariate age-adjusted analysis only for ferritin, CRP, NLR, IL-10, sIL-2rα, and IL-18. T, B, and NK cells were significantly decreased in critical patients. SARS-CoV-2 was not detected in blood except in 3 patients who had indeterminate results. RT-PCR Ct values from oropharyngeal or nasopharyngeal swabs on admission were not related to symptom severity. CONCLUSION: Ferritin, D-dimer, CRP, NLR, cytokine (IL-18 and IL-10), and cytokine receptor (IL-6, IL1-Ra, and sCD25) test results combined with clinical data can contribute to the early identification of critical COVID-19 patients.

Assessment of a laboratory critical risk result notification protocol in a tertiary care hospital and their use in clinical decision making.

INTRODUCTION: Communication of laboratory critical risk results is essential for patient safety, as it allows early decision making. Our aims were: 1) to retrospectively evaluate the current protocol for telephone notification of critical risk results in terms of rates, efficiency and recipient satisfaction, 2) to assess their use in clinical decision making and 3) to suggest alternative tools for a better assessment of notification protocols. MATERIALS AND METHODS: The biochemical critical risk result notifications reported during 12 months by routine and STAT laboratories in a tertiary care hospital were reviewed. Total number of reports, time for the notification and main magnitudes with critical risk results were calculated. The use of notifications in clinical decision making was assessed by reviewing medical records. Satisfaction with the notification protocol was assessed through an online questionnaire to requesting physicians and nurses. RESULTS: Critical result was yielded by 0.1% of total laboratory tests. Median time for notification was 3.2 min (STAT) and 16.9 min (routine). The magnitudes with a greater number of critical results were glucose and potassium for routine analyses, and troponin, sodium for STAT. Most notifications were not reflected in the medical records. Overall mean satisfaction with the protocol was 4.2/5. CONCLUSION: The results obtained indicate that the current protocol is appropriate. Nevertheless, there are some limitations that hamper the evaluation of the impact on clinical decision making. Alternatives were proposed for a proper and precise evaluation.

Estudio retrospectivo de 1.193 componentes monoclonales detectados en Palma de Mallorca / Restrospective study of 1.193 monoclonal gammopathies detected in Palma of Mallorca

Introducción. El objetivo del estudio es realizar un análisis retrospectivo de los componentes monoclonales nuevos detectados durante los años 2004, 2005 y 2006 en el Laboratorio del Carmen, dependiente del Servicio de Análisis Clínicos del Hospital Universitario Son Dureta. Material y métodos. El material son los datos obtenidos de los pacientes a los que se realiza un proteinograma en el Laboratorio del Carmen durante los años 2004–2006. Se realizó un estudio epidemiológico de tasa de incidencia de componentes monoclonales (CM) en Baleares, su distribución, edad y sexo de los pacientes. También se registraron los isotipos de CM, así como determinados parámetros analíticos como proteínas, hemoglobina, albúmina, creatinina, concentración de inmunoglobulinas. Se clasificaron los diagnósticos de los pacientes en función del tipo de patología más frecuente asociado al CM. Resultados. Durante estos años, se atendieron en el laboratorio del Carmen 696.115 pacientes pertenecientes al Área Sanitaria de Mallorca, realizándose 83.305 electroforesis de proteínas séricas (11,96%), de los cuales solo el 1,43% obtuvo un resultado de inmunofijación electroforética positivo. Resultados. La tasa de incidencia global es de 70,98 casos nuevos/100.000 habitantes/año. En el 62,8% de los pacientes con presencia de CM no consta ningún diagnóstico (AU)

Introduction. The aim of this study is to carry out a retrospective analysis of monoclonal gammopathies detected during the period of 2004, 2005 and 2006 in the “El Carmen” laboratory, which is part of the Clinical Laboratory of Son Dureta Hospital. We studied the most important aspects related to these patients and the study of the monoclonal gammopathies detected. Material and methods. An epidemiological study was carried out on all the data, in order to find the incidence of monoclonal gammopathies, as well as its distribution, and the age and sex of the patients. We also studied the immunochemical types of the monoclonal components, as well as some analytical parameters. The patient diagnosis was classified according to the most common pathology associated to the monoclonal component. Results. During these years, 696,115 patients belonging to the Healthy Area of Mallorca were seen in the “El Carmen” laboratory and 83,305 (11.96%) serum protein electrophoreses were performed. Results. Only 1.43% had a positive result with electrophoretic immunofixation. The overall incidence was 70.98 new cases/100,000 inhabitants/year. The majority of patients (62.8%) with a monoclonal component had no diagnosis (AU)

Nuevos marcadores en el síndrome coronario agudo / New biomarkers in acute coronary syndrome

La cardiopatía isquémica supone el 1,3% de los casos de atención en un servicio de urgencias hospitalario en España. El manejo del paciente es complejo por el riesgo de producir una alta médica incorrecta, el beneficio de instaurar una revascularización rápida y el gasto excesivo por admisiones injustificadas. La última década ha permitido un importante avance en el desarrollo de nuevos marcadores cardíacos. Tradicionalmente los marcadores del síndrome coronario agudo han sido indicadores de necrosis cardíaca. Esta función se ha ampliado actualmente. Aún hay muchas limitaciones en la medición de estos marcadores, como la falta de un procedimiento estandarizado o materiales de referencia certificados. Además de las troponinas cardíacas y el electrocardiograma, medir la albúmina modificada por isquemia puede ayudar a excluir un síndrome coronario agudo en pacientes con baja probabilidad de isquemia miocárdica. La proteína fijadora de ácidos grasos-H es un marcador de necrosis útil en el diagnóstico precoz del infarto agudo de miocardio. En el pronóstico del síndrome coronario agudo, la proteína C reactiva, los péptidos natriuréticos y la mieloperoxidasa complementan el valor pronóstico de la troponina. El ligando soluble CD40 permite la clasificación e individualización del tratamiento del síndrome coronario agudo. Actualmente no hay suficiente evidencia para que ningún nuevo marcador sustituya a los que recomiendan las sociedades científicas ni se dispone de procedimientos de medición rápidos para algunos de ellos. Deben establecerse paneles utilizando la evidencia científica disponible y tomando como objetivo su contribución a una mejor evolución del paciente(AU)

Myocardical ischemia involves 1.3% of the patients attending emergency departments in Spain. The management of these patients is complex, due to the risk of an incorrect discharge diagnosis, the benefit of rapid revascularization and the excessive cost due to unnecessary admissions. There has been a significant improvement in the development of new cardiac biomarkers over the last ten years. Biomarkers traditionally used for identifying acute coronary syndrome were indicators of myocardial necrosis. This role has currently been expanded. There are still some limitations in the measurement of these biomarkers, due to lack of standardised assays or certified calibrators. Ischemia-modified albumin in conjunction with cardiac troponin and electrocardiogram, can help to rule out an acute coronary syndrome in patients with a low probability of having myocardical ischemia. Heart-type fatty acid-binding protein is a strong necrosis biomarker in the early diagnosis of acute myocardical infarction. C-reactive protein, natriuretic peptides and myeloperoxidase have been shown to complement cardiac troponin in the prognosis of acute coronary syndrome. Soluble CD40 ligand enables the identification of a subgroup of patients who will benefit from a treatment in acute coronary syndrome. There is currently not enough evidence to replace new biomarkers with any of these already been recommended by the scientific societies. Also, the assays of some of them are not sufficiently rapid. A multimarker strategy must be created to take into account the existing scientific-based evidence, with the aim of improving outcomes in patients(AU)