Characterization of the endotheliopathy, innate-immune activation and hemostatic imbalance underlying CAR-T cell toxicities: laboratory tools for an early and differential diagnosis.

BACKGROUND: Chimeric antigen receptor (CAR)-T cell-based immunotherapy constitutes a revolutionary advance for treatment of relapsed/refractory hematological malignancies. Nevertheless, cytokine release and immune effector cell-associated neurotoxicity syndromes are life-threatening toxicities in which the endothelium could be a pathophysiological substrate. Furthermore, differential diagnosis from sepsis, highly incident in these patients, is challenging. Suitable laboratory tools could be determinant for their appropriate management. METHODS: Sixty-two patients treated with CAR-T cell immunotherapy for hematological malignancies (n=46 with CD19-positive diseases, n=16 with multiple myeloma) were included. Plasma samples were obtained: before CAR-T cell infusion (baseline); after 24-48 hours; at suspicion of any toxicity onset and 24-48 hours after immunomodulatory treatment. Biomarkers of endothelial dysfunction (soluble vascular cell adhesion molecule 1 (sVCAM-1), soluble TNF receptor 1 (sTNFRI), thrombomodulin (TM), soluble suppression of tumorigenesis-2 factor (ST2), angiopoietin-2 (Ang-2)), innate immunity activation (neutrophil extracellular traps (NETs), soluble C5b-9 (sC5b-9)) and hemostasis/fibrinolysis (von Willebrand Factor antigen (VWF:Ag), ADAMTS-13 (A13), α2-antiplasmin (α2-AP), plasminogen activator inhibitor-1 antigen (PAI-1 Ag)) were measured and compared with those in cohorts of patients with sepsis and healthy donors. RESULTS: Patients who developed CAR-T cell toxicities presented increased levels of sVCAM-1, sTNFRI and ST2 at the clinical onset versus postinfusion values. Twenty-four hours after infusion, ST2 levels were good predictors of any CAR-T cell toxicity, and combination of ST2, Ang-2 and NETs differentiated patients requiring intensive care unit admission from those with milder clinical presentations. Association of Ang-2, NETs, sC5b-9, VWF:Ag and PAI-1 Ag showed excellent discrimination between severe CAR-T cell toxicities and sepsis. CONCLUSIONS: This study provides relevant contributions to the current knowledge of the CAR-T cell toxicities pathophysiology. Markers of endotheliopathy, innate immunity activation and hemostatic imbalance appear as potential laboratory tools for their prediction, severity and differential diagnosis.

Clinical Presentation and Outcome of COVID-19 in a Latin American Versus Spanish Population: Matched Case-Control Study.

INTRODUCTION: Increased mortality has been reported in the Latin American population. The objective is to compare the clinical characteristics and outcome of Latin American and Spanish populations in a cohort of patients hospitalized with COVID-19 during the first year of the pandemic. METHODS: We retrospectively analysed all the Latin American patients (born in South or Central America) hospitalized in our centre from February 2020 to February 2021 and compared them with an age- and gender-matched group of Spanish subjects. Variables included were demographics, co-morbidities, clinical and analytical parameters at admission and treatment received. The primary outcomes were ICU admission and mortality at 60 days. A conditional regression analysis was performed to evaluate the independent baseline predictors of both outcomes. RESULTS: From the 3216 patients in the whole cohort, 216 pairs of case-controls (Latin American and Spanish patients, respectively) with same age and gender were analysed. COPD was more frequent in the Spanish group, while HIV was more prevalent in the Latin American group. Other co-morbidities showed no significant difference. Both groups presented with similar numbers of days from symptom onset, but the Latin American population had a higher respiratory rate (21 vs. 20 bpm, P = 0.041), CRP (9.13 vs. 6.22 mg/dl, P = 0.001), ferritin (571 vs. 383 ng/ml, P = 0.012) and procalcitonin (0.10 vs. 0.07 ng/ml, P = 0.020) at admission and lower cycle threshold of PCR (27 vs. 28.8, P = 0.045). While ICU admission and IVM were higher in the Latin American group (17.1% vs. 13% and 9.7% vs. 5.1%, respectively), this was not statistically significant. Latin American patients received remdesivir and anti-inflammatory therapies more often, and no difference in the 60-day mortality rate was found (3.2% for both groups). CONCLUSION: Latin American patients with COVID-19 have more severe disease than Spanish patients, requiring ICU admission, antiviral and anti-inflammatory therapies more frequently. However, the mortality rate was similar in both groups.

C-reactive protein cut-off for early tocilizumab and dexamethasone prescription in hospitalized patients with COVID-19.

Dexamethasone and tocilizumab have been associated with reduction in mortality, however, the beneficial effect is not for all patients and the impact on viral replication is not well defined. We hypostatized that C-reactive protein (CRP) could help in the identification of patients requiring anti-inflammatory therapy. Patients admitted for > 48 h in our hospital for a confirmed or suspected infection by SARS-CoV-2 from February 2020 to February 2021 were retrospectively evaluated. The primary outcome was mortality at 30 days. Demographics and the most relevant variables related with the outcome were included. CRP was stratified by percentiles. Univariate and multivariate analysis were performed. A total of 3218 patients were included with a median (IQR) age of 66 (74-78) years and 58.9% were males. The rate of intensive care unit admission was 24.4% and the 30-day mortality rate was 11.8%. Within the first 5 days from admission, 1018 (31.7%) patients received dexamethasone and 549 tocilizumab (17.1%). The crude analysis showed a mortality reduction in patients receiving dexamethasone when CRP was > 13.75 mg/dL and > 3.5 mg/dL for those receiving tocilizumab. Multivariate analysis identified the interaction of CRP > 13.75 mg/dL with dexamethasone (OR 0.57; CI 95% 0.37-0.89, P = 0014) and CRP > 3.5 mg/dL with tocilizumab (0.65; CI95%:0.44-0.95, P = 0.029) as independent predictors of mortality. Our results suggest that dexamethasone and tocilizumab are associated with a reduction in mortality when prescribed to patients with a certain inflammatory activity assessed by C-reactive protein.

Impact of remdesivir according to the pre-admission symptom duration in patients with COVID-19.

BACKGROUND: The use of remdesivir has demonstrated a significant reduction in the time to recovery in patients with COVID-19. However, the impact on mortality is still controversial. Therefore, it is necessary to evaluate whether there is a specific subgroup of patients in whom an active antiviral therapy also reduces the mortality. METHODS: Patients admitted for >48 h in our hospital for a SARS-CoV-2 confirmed or suspected infection from February 2020 to February 2021 were retrospectively analysed. The primary outcome of the study was mortality at 30 days. Univariate and multivariate analyses were performed to identify predictors of mortality. RESULTS: In total, 2607 patients (438 receiving remdesivir and 2169 not) were included with a median (IQR) age of 65 (54-77) years and 58% were male. Four hundred and seventy-six were admitted to the ICU (18.3%) and 264 required invasive mechanical ventilation (10.1%). The global 30 day mortality rate was 10.7%. Pre-admission symptom duration of 4-6 days and ≤3 days was associated with a 1.5- and 2.5-fold increase in the mortality rate, respectively, in comparison with >6 days and treatment with remdesivir was independently associated with a lower mortality rate (OR = 0.382, 95% CI = 0.218-0.671). The analysis showed that the major difference was among patients with shorter pre-admission symptom duration (<6 days). CONCLUSIONS: Patients with ≤3 days and 4-6 days from symptom onset to admission are associated with a 2.5- and 1.5-fold higher risk of death, respectively. Remdesivir was associated with 62% reduced odds of death versus standard-of-care and its survival benefit increased with shorter duration of symptoms.

Tocilizumab reduces the risk of ICU admission and mortality in patients with SARS-CoV-2 infection.

OBJECTIVE: In some patients the immune response triggered by SARS-CoV-2 is unbalanced, presenting an acute respiratory distress syndrome which in many cases requires intensive care unit (ICU) admission. The limitation of ICU beds has been one of the major burdens in the management around the world; therefore, clinical strategies to avoid ICU admission are needed. We aimed to describe the influence of tocilizumab on the need of transfer to ICU or death in non-critically ill patients. METHODS: A retrospective study of 171 patients with SARS-CoV-2 infection that did not qualify as requiring transfer to ICU during the first 24h after admission to a conventional ward, were included. The criteria to receive tocilizumab was radiological impairment, oxygen demand or an increasing of inflammatory parameters, however, the ultimate decision was left to the attending physician judgement. The primary outcome was the need of ICU admission or death whichever came first. RESULTS: A total of 77 patients received tocilizumab and 94 did not. The tocilizumab group had less ICU admissions (10.3% vs. 27.6%, P=0.005) and need of invasive ventilation (0 vs 13.8%, P=0.001). In the multivariable analysis, tocilizumab remained as a protective variable (OR: 0.03, CI 95%: 0.007-0.1, P=0.0001) of ICU admission or death. CONCLUSIONS: Tocilizumab in early stages of the inflammatory flare could reduce an important number of ICU admissions and mechanical ventilation. The mortality rate of 10.3% among patients receiving tocilizumab appears to be lower than other reports. This is a non-randomized study and the results should be interpreted with caution.

Trends in mortality of hospitalised COVID-19 patients: A single centre observational cohort study from Spain.

BACKGROUND: We aimed to describe changes in characteristics and treatment strategies of hospitalised patients with COVID-19 and detail the mortality trend over time. METHODS: Observational cohort study of all consecutive patients admitted ≥ 48 h to Hospital Clinic of Barcelona for COVID-19 (1 March-30 September 2020). FINDINGS: A total of 1645 consecutive patients with COVID-19 were assessed over a 7-month period. Overall mortality (≤30 days) was 9.7% (159 patients), 7.7% in patients hospitalised in regular wards and 16.7 % in patients requiring ICU admission. Overall mortality decreased from 11.6% in the first month to 1.4% in the last month, reflecting a progressive, significant downward trend (p for trend <0.001). Patients' age changed over time, peaking in June. Most changes in the use of antivirals and anti-inflammatory treatments were documented. Age (OR 1.1, CI 1.1-1.12), chronic heart disease, (OR 1.7, CI 1.1-2.9), D-dimer>700 ng/mL (OR 2.3, CI 1.3-4.1), ferritin>489 ng/mL (OR 1.9; CI 1.5-3.2), C-RP>7 mg/dL (OR 2.6; CI 1.5-4.6), and shorter duration from symptom onset to hospital admission (OR 1.11; CI 1.04-1.17) were factors associated with 30-day mortality at hospital admission. Conversely, hospital admission in the last months (OR 0.80; CI 0.65-0.98) was significantly associated with lower mortality. INTERPRETATION: In-hospital mortality has decreased in patients with COVID-19 over the last, few months, even though main patient characteristics remain similar. Several changes made when managing patients may explain this decreasing trend. Our study provides current data on mortality of patients hospitalised with COVID-19 that might be useful in establishing quality of standard of care. FUNDING: EIT Health, European Union´s Horizon 2020 Research and Innovation Programme), EDRD. PPA [CM18/00132], NGP [FI19/00133], and CGV [FIS PI18/01061], have received grants from Ministerio de Sanidad y Consumo, ISCIII.

CONTEXTO: Nuestro objetivo es describir los cambios en las características y las estrategias de tratamiento de los pacientes hospitalizados por COVID-19, y detallar la tendencia de la mortalidad en el tiempo. MÉTODOS: Estudio observacional de cohortes de todos los pacientes consecutivos, ingresados por COVID-19 durante más de 48 horas, en el Hospital Clínic de Barcelona (del 1 de marzo al 30 de septiembre de 2020). RESULTADOS: Un total de 1645 pacientes consecutivos fueron evaluados durante un período de 7 meses. La mortalidad global (≤30 días) fue del 9.7% (159 pacientes): 7.7% en pacientes hospitalizados en salas convencionales, y 16.7% en pacientes que requirieron ingreso en UCI. La mortalidad global disminuyó del 11.6% en el primer mes al 1.4% en el último mes evaluado, reflejando una progresiva y significativa tendencia a la baja (p para la tendencia <0.001). La edad de los pacientes ha cambiado con el tiempo, habiendo alcanzado su pico en junio. La mayoría de cambios en el uso de antivirales y antiinflamatorios se han documentado. La edad (OR 1.1; CI 1.1­1.12), cardiopatía crónica (OR 1.7; CI 1.1­2.9), dímero-D>700 ng/mL (OR 2.3; CI 1.3­4.1), ferritina>489 ng/mL (OR 1.9; CI 1.5­3.2), PCR>7 mg/dL (OR 2.6; CI 1.5­4.6), y una menor duración desde el inicio de síntomas a la hospitalización (OR 1.11; CI 1.04­1.17) fueron factores asociados a la mortalidad intrahospitalaria a 30 días. Por el contrario, el ingreso hospitalario previo en los últimos meses (OR 0.80; CI 0.65­0.98) se asoció significativamente a una menor mortalidad. DISCUSIÓN: La mortalidad intrahospitalaria ha disminuido en los pacientes con COVID-19 durante los últimos meses, incluso siendo similares las características de los pacientes. Algunos cambios realizados en el manejo de estos pacientes podrían explicar esta tendencia decreciente. Nuestro estudio aporta datos actualizados en la mortalidad de los pacientes hospitalizados con COVID-19, que podrían ser útiles de cara a establecer unos cuidados estándar de calidad. FINANCIACIÓN: EIT Health, European Union´s Horizon 2020 Research and Innovation Programme, EDRD. PPA [CM18/00132], NGP [FI19/00133] y CGV [FIS PI18/01061], han recibido becas del Ministerio de Sanidad y Consumo, ISCIII.

PD Control Compensation Based on a Cascade Neural Network Applied to a Robot Manipulator.

A Proportional Integral Derivative (PID) controller is commonly used to carry out tasks like position tracking in the industrial robot manipulator controller; however, over time, the PID integral gain generates degradation within the controller, which then produces reduced stability and bandwidth. A proportional derivative (PD) controller has been proposed to deal with the increase in integral gain but is limited if gravity is not compensated for. In practice, the dynamic system non-linearities frequently are unknown or hard to obtain. Adaptive controllers are online schemes that are used to deal with systems that present non-linear and uncertainties dynamics. Adaptive controller use measured data of system trajectory in order to learn and compensate the uncertainties and external disturbances. However, these techniques can adopt more efficient learning methods in order to improve their performance. In this work, a nominal control law is used to achieve a sub-optimal performance, and a scheme based on a cascade neural network is implemented to act as a non-linear compensation whose task is to improve upon the performance of the nominal controller. The main contributions of this work are neural compensation based on a cascade neural networks and the function to update the weights of neural network used. The algorithm is implemented using radial basis function neural networks and a recompense function that leads longer traces for an identification problem. A two-degree-of-freedom robot manipulator is proposed to validate the proposed scheme and compare it with conventional PD control compensation.

Blackwater fever in a non-immune patient with Plasmodium falciparum malaria after intravenous artesunate.

Blackwater fever was typically reported after quinine administration, although it is poor recognized in patients receiving artesunate. This case describes a blackwater fever in a non-immune patient after artesunate for severe malaria. It highlights the importance of monitoring haemolytic parameters in severe malaria to avoid renal impairment or severe anaemia.

[Survival and neurological outcome in out-of-hospital cardiac arrests due to shockable rhythms treated with mild therapeutic hypothermia]. / Supervivencia y pronóstico neurológico en paradas cardiorrespiratorias extrahospitalarias por ritmos desfibrilables tratadas con hipotermia terapéutica moderada.

OBJECTIVE: To analyze survival and neurological outcome at short and medium term in patients treated with mild therapeutic hypothermia (HTM) in our hospital after suffering an out-of-hospital cardiac arrest (CA) secondary to a shockable rhythm. DESIGN: Prospective, observational study from September 1, 2010 to December 31, 2012, with a follow up of 6 months. SETTING: Tertiary hospital. PATIENTS: All patients who suffer an out-of-hospital CA due to shockable rhythms. EXCLUSION CRITERIA: non-shockable rhythms, resuscitation >45 minutes without pulse recovery, septic shock, previous coagulopathy, terminal illness or order for withholding treatment. INTERVENTION: Mild hypothermia (33°C) and postresuscitation care on the basis of standardized protocols. MAIN VARIABLES: Demographic and epidemiological data, CA data and survival and neurological outcome at hospital discharge and after 6 months. To assess the patients' neurological status, Cerebral Performance Categories (CPC) scale was used. RESULTS: A total of 54 patients were analyzed. 37 patients were discharged to hospital, representing a survival at discharge of 68.5%, which remains 6 months later because no discharged patient died during the follow up period. Regarding neurological outcome, 44.4% of patients were alive and with CPC 1-2 at discharge and up to 54.71% at 6 months. CONCLUSIONS: The results of survival and neurological functional status obtained in our center after implementation of HTM are comparable to those published in the literature.

Anti-MDA5 positive clinically amyopathic dermatomyositis presenting with severe cardiomyopathy.

BACKGROUND: Anti-MDA5 (Melanoma differentiation-associated gene 5) positive dermatomyositis is a new variant of clinically amyopathic dermatomyositis that presents with characteristic mucocutaneous findings and is associated with a higher risk of developing rapidly progressive interstitial lung disease. Because its presentation differs from that of classical dermatomyositis, this entity can be a diagnostic challenge for the clinician. METHODS & RESULTS: We present the case of a 55-year-old male with a 7-month history of chill sensation, constitutional symptoms and polyarthralgia. Within 3 months, the patient developed progressive heart failure with dyspnoea and orthopnoea, together with characteristic cutaneous lesions. Skin biopsies demonstrated thrombosis of small and medium-sized arteries in the reticular dermis, together with an evolved lobular panniculitis and prominent mucin deposits. CONCLUSIONS: Clinicians should be aware of the characteristic clinical and histopathologic presentation of this variant of dermatomyositis to establish an early diagnosis. Further evidence is needed to clarify the risk of cardiac involvement in this subset of patients.