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Chimeric antigen receptor T-cell therapy represents an innovative approach to immunotherapy and currently stands out, particularly for oncohematological patients refractory to traditional treatments. Ongoing trials are further expanding its clinical use for new oncological and non-oncological indications, potentially leading to newer treatment options soon. This new approach, however, also presents challenges, including cardiovascular toxicity. Little is reported in pivotal studies, and some recent retrospective observations suggest a non-negligible incidence of side effects with presentation ranging from mild adverse cardiovascular events to fatal complications in which, in most cases, there is a direct or indirect association with cytokine release syndrome. In this literature review, the hypotheses of an important interface between cytokine release syndrome and cardiotoxicity by chimeric antigen receptor T-cell therapy will be addressed, as will current knowledge about risk factors for cardiotoxicity and recommendations for pre-therapy evaluation, post-infusion monitoring and clinical management of these complications.

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Background: Dengue fever is a mosquito-borne infectious disease endemic in over 100 countries around the world. Among the complications that dengue can cause the Hemophagocytic Lymphohistiocytosis is one of great concern for its severity and complex diagnosis. Case report: Hereby we document a case of this disease expressed on a previously healthy 6-year-old female patient whose dengue infection was so severe that needed intensive care management with vasoactive drugs and diuretics. After a short period of wellness began newly with fever, pancytopenia, hepatitis, and inflammatory response symptoms. Conclusions: A Dengue associated Hemophagocytic Lymphohistiocytosis syndrome was suspected and treated with intravenous corticosteroids on a 3-day scheme at no signs of malignancy with excellent response. The health care professionals must know about this not novel entity in order to reach an efficient diagnosis and treatment mostly, but not only, those in tropical and sub-tropical regions of the word were dengue virus is endemic.

Antecedentes: La fiebre por dengue es una enfermedad infecciosa transmitida por mosquitos, endémica en más de 100 países alrededor del mundo. La Linfohistiocitosis Hemofagocítica, dentro de las complicaciones que puede ocasionar el dengue, es una de las más preocupantes por su complejidad diagnostica y gravedad. Reporte de caso: Femenino de 6 años de edad, previamente sana, cuya infección por dengue fue tan grave que requirió manejo en cuidados intensivos. Después de un breve período de bienestar recrudeció la fiebre, además de pancitopenia, hepatitis y síntomas de respuesta inflamatoria. Conclusiones: Se sospechó síndrome de Linfohistiocitosis Hemofagocítica asociada a Dengue y se trató con corticoides intravenosos en un esquema de 3 días con excelente respuesta. Los profesionales de la salud deben conocer esta entidad no novedosa para poder llegar a un diagnóstico y tratamiento eficaz en su mayoría, pero no solo, en las regiones tropicales y subtropicales del mundo donde el virus del dengue es endémico.

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Abstract Background Coronavirus disease 2019 (COVID-19) is a viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although respiratory manifestations have received greater visibility during the pandemic caused by this virus, numerous neurological complaints related to coronavirus 2 infection have been documented in several countries. These records suggest that this pathogen presents neurotropism, and it can cause different neurological conditions of varying intensity. Objective To investigate the ability of coronavirus 2 to invade the central nervous system (CNS) and its neurological clinical outcomes. Methods The present study consists in a comprehensive literature review of the records available in the PubMed, SciELO, and Google Scholar databases. The descriptors COVID-19, brain and physiopathology, associated with the Boolean operator AND, were used in the search. Regarding the inclusion and exclusion criteria, we selected the papers published since 2020 with the highest number of citations. Results We selected 41 articles, most of them in English. The main clinical manifestation associated with COVID-19 patients was headache, but cases of anosmia, hyposmia, Guillain-Barré syndrome, and encephalopathies were also described with considerable frequency. Conclusion Coronavirus-2 presents neurotropism, and it can reach the CNS by hematogenous dissemination and by direct infection of the nerve endings. It causes brain injuries through several mechanisms, such as cytokine storm, microglial activation, and an increase in thrombotic factors.

Resumo Antecedentes A doença do coronavírus 2019 (coronavirus disease 2019, Covid-19, em inglês) é uma infecção viral provocada pelo coronavírus 2 da síndrome respiratória aguda grave (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, em inglês). Embora as manifestações respiratórias tenham recebido maior visibilidade ao longo da pandemia provocada por esse vírus, inúmeras queixas neurológicas relacionadas à infecção pelo coronavírus 2 foram documentadas em diversos países. Tais registros sugerem que esse patógeno apresenta neurotropismo, e é capaz de provocar quadros neurológicos diversos e de intensidade variáveis. Objetivo Investigar a capacidade de invasão do sistema nervoso central (SNC) pelo coronavírus 2 e seus principais desfechos clínicos neurológicos. Métodos O presente estudo consiste em uma ampla revisão de literatura a partir dos registros das bases de dados PubMed, SciELO e Google Acadêmico. Nesse contexto, os descritores COVID-19, cérebro e fisiopatologia, associados com o operador booleano AND, foram utilizados na busca. Quanto aos critérios de inclusão e exclusão, selecionou-se os trabalhos publicados a partir de 2020 com o maior número de citações. Resultados Foram selecionados 41 artigos, a maioria na língua inglesa. A principal manifestação clínica associada a pacientes acometidos pela COVID-19 foi a cefaleia, mas casos de anosmia, hiposmia, síndrome de Guillain-Barré e encefalopatias também foram descritos com frequência considerável. Conclusão O coronavírus 2 apresenta neurotropismo, e é capaz de alcançar o SNC por disseminação hematogênica e por infecção direta das terminações nervosas. Ele provoca injúria cerebral por meio de variados mecanismos, como tempestade de citocinas, ativação da micróglia e aumento dos fatores trombóticos.

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Chimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. Chimeric antigen receptor (CAR) is an engineered synthetic receptor of CAR-T, which give T cells the ability to recognize tumor antigens in a human leukocyte antigen-independent (HLA-independent) manner and enables them to recognize more extensive target antigens than natural T cell surface receptor (TCR), resulting in tumor destruction. CAR-T is composed of an extracellular single-chain variable fragment (scFv) of antibody, which serves as the targeting moiety, hinge region, transmembrane spacer, and intracellular signaling domain(s). CAR-T has been developing in many generations, which differ according to costimulatory domains. CAR-T therapy has several limitations that reduce its wide availability in immunotherapy which we can summarize in antigen escape that shows either partial or complete loss of target antigen expression, so multiplexing CAR-T cells are promoted to enhance targeting of tumor profiles. In addition, the large diversity in the tumor microenvironment also plays a major role in limiting this kind of treatment. Therefore, engineered CAR-T cells can evoke immunostimulatory signals that rebalance the tumor microenvironment. Using CAR-T therapy in treating the solid tumor is mainly restricted by the difficulty of CAR-T cells infiltrating the tumor site, so local administration was developed to improve the quality of treatment. The most severe toxicity after CAR-T therapy is on-target/on-tumor toxicity, such as cytokine release syndrome (CRS). Another type of toxicity is on-target/off-tumor toxicity which originates from the binding of CAR-T cells to target antigen that has shared expression on normal cells leading to damage in healthy cells and organs. Toxicity management should become a focus of implementation to permit management beyond specialized centers.

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BACKGROUND: Patients with Coronavirus Disease 2019 (COVID-19) frequently experience a hyperinflammatory syndrome leading to unfavorable outcomes. This condition resembles Secondary Hemophagocytic Lymphohistiocytosis (sHLH) described in neoplastic, rheumatic and other infectious diseases. A scoring system (HScore) that evaluates underlying immunosuppression, temperature, organomegaly, cytopenias, ferritin, triglycerides, fibrinogen and AST was validated for sHLH, and recently proposed to evaluate hyperinflammation in COVID-19. AIM: To assess the presence of sHLH among patients with COVID-19 admitted for hospitalization and to evaluate Hscore as a prognostic tool for poor outcomes. MATERIAL AND METHODS: One hundred forty-three patients aged 21-100 years (64% males) admitted because of COVID-19 were enrolled in a prospective study. HScore was calculated within 72 hours admission. The incidence of sHLH during hospitalization was evaluated. Additionally, the relationship between a HScore ≥ 130 points and either the requirement of mechanical ventilation or 60-days mortality was explored. RESULTS: The median HScore was 96 (33-169). A SHLH was diagnosed in one patient (incidence 0.7%), whose HScore was 169. After adjusting for age, sex, comorbidities and obesity, HScore ≥ 130 was independently associated with the composite clinical outcome (Hazard rartio 2.13, p = 0.022). CONCLUSIONS: sHLH is not frequent among COVID-19 patients. HScore can be useful to predict the risk for poor outcomes.

ANTECEDENTES: Los pacientes con Enfermedad por Coronavirus 2019 (COVID-19), experimentan frecuentemente un síndrome hiperinflamatorio que lleva a resultados desfavorables. Esta situación se asemeja al Síndrome Hemofagocítico Secundario (sHLH) descrito en enfermedades neoplásicas, reumatológicas y por otros agentes infecciosos. Un sistema simple de puntaje (HScore) que evalúa inmunosupresión, temperatura organomegalia, citopenias, ferritina, triglicéridos, fibrinógeno y AST ha sido validado para el diagnóstico de sHLH y ha sido propuesto recientemente para evaluar la hiperinflamación en COVID-19. OBJETIVO: Medir la frecuencia de sHLH entre pacientes con COVID-19 hospitalizados, y evaluar a HScore como una herramienta pronóstica. MATERIAL Y MÉTODOS: Ciento cuarenta y tres pacientes de 21 a 100 años (64% hombres) fueron ingresados en este estudio de cohorte prospectivo, unicéntrico. Se calculó HScore dentro de las primeras 72 horas desde el ingreso, y se midió la incidencia de sHLH durante la hospitalización. Adicionalmente, se evaluó la relación entre HScore ≥ 130 puntos y un desenlace compuesto de ventilación mecánica o muerte a los 60 días. RESULTADOS: La mediana de HScore fue 96 (33-169) puntos. Un paciente fue diagnosticado con sHLH (incidencia 0,7%). Luego de ajustar por edad, sexo, comorbilidades y obesidad, un HScore ≥ 130 se asoció de manera independiente con el desenlace compuesto. CONCLUSIONES: El sHLH no es frecuente en los pacientes con COVID-19. El uso de HScore puede ser útil para predecir el riesgo de desenlaces clínicos desfavorables.

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ABSTRACT BACKGROUND: Coronavirus disease 2019 (COVID-19) can cause cytokine release syndrome (CRS), which leads to high mortality rates. Tocilizumab suppresses CRS by blocking the signal transduction of interleukin-6 (IL-6). OBJECTIVE: To evaluate the clinical and laboratory parameters associated with mortality among patients receiving tocilizumab treatment. DESIGN AND SETTING: Retrospective observational study conducted in the chest disease departments of two different training and research hospitals in the center of Ankara, Turkey. METHODS: Patients who were hospitalized and treated with tocilizumab in September 2020 were retrospectively analyzed. Their laboratory parameters and clinical characteristics were obtained from the hospital information system database. Comparative analyses were performed between the patients who died and the ones who survived. RESULTS: A total of 58 patients who received tocilizumab treatment were included in this study, among whom 35 (60.3%) died. There was no difference between the mortality and survival groups in terms of white blood cell (WBC), neutrophil, lymphocyte, ferritin or C-reactive protein (CRP) levels detected on admission. WBC, lymphocyte, neutrophil and CRP levels measured on the third and fifth days after tocilizumab administration were found to be significantly lower in the survival group (P < 0.05). In multiple logistic regression analysis, age and oxygen saturation were determined to be independent risk factors for mortality. CONCLUSION: Persistently high WBC, CRP and neutrophil levels and low lymphocyte levels could be considered to be valuable indicators of mortality among COVID-19 patients treated with tocilizumab. Age and low oxygen saturation are independent risk factors for mortality among patients receiving tocilizumab treatment.

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Sepsis is one of the leading causes of death in critically ill patients with COVID-19 and blood purification therapies have a role to immunomodulate the excessive inflammatory response and improve clinical results. One of the devices designed for these therapies is the oXiris® filter, allowing to perform renal replacement therapy combined with selective adsorption of endotoxins and cytokines. We report a 55-year-old male with COVID who developed a septic shock secondary to a sepsis caused by Pseudomona aeruginosa, refractory to the usual management. A veno-venous continuous hemofiltration was started using the oXiris® filter for 48 hours. Subsequently, there was an improvement in clinical perfusion parameters and a reduction in inflammatory markers. The patient was discharged from the intensive care one month later.

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Introduction: The COVID-19 pandemic, caused by the coronavirus SARS-CoV-2, has impacted health across all sectors of society. A cytokine-release syndrome, combined with an inefficient response of innate immune cells to directly combat the virus, characterizes the severe form of COVID-19. While immune factors involved in the development of severe COVID-19 in the general population are becoming clearer, identification of the immune mechanisms behind severe disease in oncologic patients remains uncertain. Methods: Here we evaluated the systemic immune response through the analysis of soluble blood immune factors and anti-SARS-CoV-2 antibodies within the early days of a positive SARS-CoV-2 diagnostic in oncologic patients. Results: Individuals with hematologic malignancies that went on to die from COVID-19 displayed at diagnosis severe leukopenia, low antibody production against SARS-CoV-2 proteins, and elevated production of innate immune cell recruitment and activation factors. These patients also displayed correlation networks in which IL-2, IL-13, TNF-alpha, IFN-gamma, and FGF2 were the focal points. Hematologic cancer patients that showed highly networked and coordinated anti-SARS-CoV-2 antibody production, with central importance of IL-4, IL-5, IL-12A, IL-15, and IL-17A, presented only mild COVID-19. Conversely, solid tumor patients that had elevated levels of inflammatory cytokines IL-6, CXCL8, and lost the coordinate production of anti-virus antibodies developed severe COVID-19 and died. Patients that displayed positive correlation networks between anti-virus antibodies, and a regulatory axis involving IL-10 and inflammatory cytokines recovered from the disease. We also provided evidence that CXCL8 is a strong predictor of death for oncologic patients and could be an indicator of poor prognosis within days of the positive diagnostic of SARS-CoV-2 infection. Conclusion: Our findings defined distinct systemic immune profiles associated with COVID-19 clinical outcome of patients with cancer and COVID-19. These systemic immune networks shed light on potential immune mechanisms involved in disease outcome, as well as identify potential clinically useful biomarkers.

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Introducción: La inexistencia de una definición clara del síndrome de liberación de citocinas (SLC), permitió a este estudio, analizar la utilidad de la interleucina-6 (IL-6), ferritina y dímero-D (DD) con otras variables y su evolución clínica. Métodos: Se realizó un estudio prospectivo, observacional y analítico, desde octubre del 2020 hasta julio 2021, en 125 pacientes de la Unidad de Terapia Intensiva (UTI) del Hospital Obrero Nro. 2 de la Caja Nacional de Salud, Cochabamba-Bolivia; se solicitaron los tres marcadores y otros exámenes, para determinar correlaciones, sobrevida y relación con el SLC. Resultados: La media de ferritina fue 1193,7±814,8 ng/ml, del dímero-D 1427±1005 ng/ml y de la IL-6 58,5±34,1 pg/mL; no se constató asociación estadística entre estos marcadores, si un Rho de Spearman de 0,5 entre la ferritina y DD (p<0,05) en pacientes que fallecieron, además de asociaciones entre sexo masculino y ferritina; entre el DD y disnea; y la IL-6 con traqueostomía. La sobrevida fue 9 días IC 95% (8,02-9,98) con valores similares del DD y ferritina, tanto con los niveles normales y elevados. Los valores del área bajo la curva (ABC) no mostraron predicción en la mortalidad, si una tasa del 70%. La sobrevida en los que no padecieron un síndrome de distrés respiratorio agudo (SDRA) fue mejor, con ocho días (p=0,011). Discusión: No es posible relacionar al SLC con la IL-6, DD y ferritina, menos definirla con fiebre, leucocitosis, fallo renal, traqueostomía, por los valores heterogéneos de la IL-6 en relación con el COVID-19 y otras patologías inflamatorias; aún queda en duda la postura de una enfermedad hipoinflamatoria más que una hipercitocinemia.

Introduction: The lack of a clear definition of cytokine release syndrome (CRS) allowed this study to analyze the utility of interleukin-6 (IL-6), ferritin, and D-dimer (DD) with other variables and their clinical evolution. Methods: A prospective, observational, and analytical study was conducted from October 2020 to July 2021 in 125 patients in the intensive care unit (ICU) of Hospital Obrero Nro. 2 of the Caja Nacional de Salud in Cochabamba, Bolivia. The three markers and other exams were requested to determine correlations, survival, and relationship with CRS. Results: The mean ferritin was 1193.7±814.8 ng/ml, D-dimer 1427±1005 ng/ml, and IL-6 58.5±34.1 pg/mL. No statistical association was found between these markers, but a Spearman's Rho of 0.5 between ferritin and DD (p<0.05) was found in patients who died. In addition, there were associations between male gender and ferritin, DD and dyspnea, and IL-6 and tracheostomy. Survival was 9 days 95% CI (8.02-9.98) with similar values of DD and ferritin for both normal and elevated levels. The values of the area under the curve (AUC) did not show prediction of mortality, but a rate of 70%. Survival was better in those who did not suffer from acute respiratory distress syndrome (ARDS), with eight days (p=0.011). Conclusions: It is not possible to relate CRS to IL-6, DD, and ferritin, or to define it with fever, leukocytosis, renal failure, tracheostomy, due to the heterogeneous values of IL-6 in relation to COVID-19 and other inflammatory pathologies. The position of a hypoinflammatory disease rather than a hypercytokinemia remains in doubt.

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Background: In COVID-19, EGFR production is upregulated in the alveolar epithelial cells. EGFR overexpression further activates STAT-3 and increases lung pathology. The EGFR pathway is also one of the major nodes in pulmonary fibrosis. Methods: Nimotuzumab, a humanized anti-EGFR antibody, was used to treat three patients with severe or moderate COVID-19. The antibody was administered in combination with other drugs included in the national COVID-19 protocol. Results: Nimotuzumab was well tolerated. IL-6 decreased from the first antibody infusion. Clinical symptoms significantly improved after nimotuzumab administration, and the CT scans at discharge showed major resolution of the lung lesions and no signs of fibrosis. Conclusion: Safe anti-EGFR antibodies like nimotuzumab may modulate COVID-19-associated hyperinflammation and prevent fibrosis. Clinical Trial Registration: RPCEC00000369 (RPCEC rpcec.sld.cu).

Lay abstract Background: In COVID-19, the protein EGFR is overactive in the infected lung cells. Methods: Nimotuzumab, an anti-EGFR antibody, was used to treat three patients with severe or moderate COVID-19. The antibody was administered in combination with other drugs included in the national COVID-19 protocol. Results: Nimotuzumab was safe. The most important inflammatory markers decreased from the first administration. The patients' clinical symptoms and imaging results improved significantly. Conclusion: Anti-EGFR antibodies like nimotuzumab may contribute to the recovery of COVID-19 patients without long-term consequences.

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Chimeric antigen receptor T-cells (CAR-T cells) are a new modality of oncological treatment which has demonstrated impressive response in refractory or relapsed diseases, such as acute lymphoblastic leukemia (ALL), lymphomas, and myeloma but is also associated with unique and potentially life-threatening toxicities. The most common adverse events (AEs) include cytokine release syndrome (CRS), neurological toxicities, such as the immune effector cell-associated neurotoxicity syndrome (ICANS), cytopenias, infections, and hypogammaglobulinemia. These may be severe and require admission of the patient to an intensive care unit. However, these AEs are manageable when recognized early and treated by a duly trained team. The objective of this article is to report a consensus compiled by specialists in the fields of oncohematology, bone marrow transplantation, and cellular therapy describing recommendations on the Clinical Centers preparation, training of teams that will use CAR-T cells, and leading clinical questions as to their use and the management of potential complications.

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One of the most dreadful complications that can occur during the course of COVID-19 is the cytokine storm-also known as cytokine release syndrome-a form of systemic inflammatory response syndrome triggered by SARS-CoV-2 infection. The cytokine storm is an activation cascade of auto-amplifying cytokines, which leads to excessive activation of immune cells and generation of pro-inflammatory cytokines. It occurs when large numbers of white blood cells are activated and release inflammatory cytokines, in turn activating even more white blood cells, finally resulting in an exaggerated pro-inflammatory-mediated response and ineffective anti-inflammatory control, leading to tissue damage, multiorgan failure, acute respiratory distress syndrome and death. Although cytokine storm pathogenesis is multifactorial, we hypothesize there is a close association between hypoxemia and cytokine storms in COVID-19, although it is difficult to establish the direction of this relationship. Most probably they coexist and, given enough time, one triggers the other in a chain reaction. Careful analysis of the day-to-day clinical evolution of COVID-19 indicates that there are short and slight periods of hypoxemia (confirmed by pulse oximetry and arterial gasometry), even on the day of the onset of persistent cough and/or shortness of breath. We propose the use of continuous positive airway pressure in early stages of COVID-19, at the onset of respiratory symptoms. This non-invasive ventilation method may be useful in individualized treatments to prevent early hypoxemia in COVID-19 patients and thus avoid triggering a cytokine storm. We believe such an approach is relevant everywhere, and in Cuba in particular, since the country has initiated national production of mechanical ventilation systems, including non-invasive ventilators. Moreover, as Cuba's COVID-19 protocols ensure early patient admission to isolation centers or hospitals, clinicians can prescribe the early use of continuous positive airway pressure as soon as respiratory symptoms begin, averting early hypoxemia and its triggering effect on cytokine storm development, and consequently, avoiding acute respiratory distress syndrome, multi-organ failure, and death.

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In COVID-19, the inflammatory cytokine-release syndrome is associated with the progression of the disease. Itolizumab is a monoclonal antibody that recognizes human CD6 expressed in activated T cells. The antibody has shown to be safe and efficacious in the treatment of moderate to severe psoriasis. Its effect is associated with the reduction of pro-inflammatory cytokines release, including IFN-γ, IL-6 and TNF-α. Here, we report the outcome of three severe and critically ill COVID-19 patients treated with itolizumab as part of an expanded access protocol. Itolizumab was able to reduce IL-6 concentrations in all the patients. Two of the three patients showed respiratory and radiological improvement and were fully recovered. We hypothesize this anti-inflammatory therapy in addition to antiviral and anticoagulant therapy could reduce COVID-19 associated morbidity and mortality.

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BACKGROUND: Since the COVID-19 outbreak an unprecedented challenge for healthcare systems around the world has been placed. In Cuba, the first case of COVID-19 was reported on March 11. Elderly with multiple comorbidities have been the most risky population. Although most patients present a mild to moderate disease, some have developed severe symptoms. One of the possible mechanisms underlying rapid disease progression is a cytokine storm, in which interleukin (IL) -6 seems to be a major mediator. Itolizumab is a humanized recombinant anti-CD6 monoclonal antibody (MAb), with the ability of reducing serum interferon gamma (INF-γ), tumour necrosis factor alpha (TNFα) and IL-6. Based on these previous results in patients with psoriasis and rheumatoid arthritis, an expanded access clinical trial was approved by the Cuban regulatory agency for COVID-19 critically, severely and moderately ill patients. RESULTS: We show here a short kinetic of IL-6 serum concentration in the first 24 COVID-19 patients treated with itolizumab. Most of patients were elderly with multiple comorbidities. We found that with one itolizumab dose, the circulating IL-6 decreased in critically and severely ill patients, whereas in moderately ill patients the values didn't rise as compared to their low baseline levels. CONCLUSION: These findings suggest that itolizumab could be an attractive therapeutic option to decrease the negative outcome of the cytokine storm in COVID-19 patients. TRIAL REGISTRATION: CECMED IIC RD-EC 179, RPCEC00000311. Registered 4 May 2020 - Retrospectively registered, http://rpcec.sld.cu/ensayos/RPCEC00000311-Sp or http://rpcec.sld.cu/trials/RPCEC00000311-En.

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In December 2019 a novel coronavirus (SARS-CoV-2) was identified in Wuhan, China, and became rapidly the worst pandemic in 100 years. Coronaviruses are respiratory viruses that can cause diseases ranging from mild to fatal lower respiratory tract infections. In a fraction of the affected patients, coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, can lead to acute respiratory distress syndrome (ARDS) and intensive care unit (ICU) admission, both associated with high mortality. To date, the existing evidence suggests a leading role of the immune system in the pathogenesis of severe COVID-19, including mechanisms associated with hyperinflammation, immune evasion, cytokine release syndrome, depletion of functional T cells, and ineffective humoral immunity. Here we discuss the current evidence regarding these findings.

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