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1.
Aging (Albany NY) ; 13(7): 9243-9252, 2021 04 03.
Artículo en Inglés | MEDLINE | ID: mdl-33811755

RESUMEN

BACKGROUND: Coronavirus disease (COVID-19) has spread rapidly since 2019. Approximately 15% of the patients will develop severe complications such as multiple organ disease syndrome related to cytokine release syndrome (CRS). Continuous renal replacement therapy (CRRT) can remove inflammatory cytokines through filtration or adsorption. We evaluated the effectiveness of CRRT in COVID-19 patients with CRS. METHODS: This retrospective, multicenter, descriptive study included 83 patients with CRS from three hospitals in Wuhan. RESULTS: In COVID-19 patients with CRS, the fatality rate was even higher in CRRT group (P=0.005). However, inflammatory markers such as C-reactive protein, neutrophil counts, and D-dimer decreased after CRRT (P<0.05). Results of Lasso model showed that tracheotomy (ß -1.31) and convalescent plasma (ß -1.41) were the protective factors. In contrast, CRRT (ß 1.07), respiratory failure (ß 1.61), consolidation on lung CT (ß 0.48), acute kidney injury (AKI) (ß 0.47), and elevated neutrophil count (ß 0.02) were the risk factors for death. CONCLUSIONS: Our results showed that although CRRT significantly reduced the inflammation, it did not decrease the fatality rate of patients with CRS. Therefore, the choice of CRRT indication, dialysis time and dialysis mode should be more careful and accurate in COVID-19 patients with CRS.


Asunto(s)
/terapia , Terapia de Reemplazo Renal Continuo , Enfermedad Crítica/terapia , Síndrome de Liberación de Citoquinas/terapia , Anciano , Proteína C-Reactiva/análisis , /complicaciones , China , Síndrome de Liberación de Citoquinas/sangre , Síndrome de Liberación de Citoquinas/etiología , Femenino , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Humanos , Inflamación/sangre , Inflamación/etiología , Inflamación/terapia , Masculino , Persona de Mediana Edad , Resultado del Tratamiento
2.
Mediators Inflamm ; 2021: 6635925, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33833618

RESUMEN

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was initially identified in China and currently worldwide dispersed, resulting in the coronavirus disease 2019 (COVID-19) pandemic. Notably, COVID-19 is characterized by systemic inflammation. However, the potential mechanisms of the "cytokine storm" of COVID-19 are still limited. In this study, fourteen peripheral blood samples from COVID-19 patients (n = 10) and healthy donors (n = 4) were collected to perform the whole-transcriptome sequencing. Lung tissues of COVID-19 patients (70%) presenting with ground-glass opacity. Also, the leukocytes and lymphocytes were significantly decreased in COVID-19 compared with the control group (p < 0.05). In total, 25,482 differentially expressed messenger RNAs (DE mRNA), 23 differentially expressed microRNAs (DE miRNA), and 410 differentially expressed long noncoding RNAs (DE lncRNAs) were identified in the COVID-19 samples compared to the healthy controls. Gene Ontology (GO) analysis showed that the upregulated DE mRNAs were mainly involved in antigen processing and presentation of endogenous antigen, positive regulation of T cell mediated cytotoxicity, and positive regulation of gamma-delta T cell activation. The downregulated DE mRNAs were mainly concentrated in the glycogen biosynthetic process. We also established the protein-protein interaction (PPI) networks of up/downregulated DE mRNAs and identified 4 modules. Functional enrichment analyses indicated that these module targets were associated with positive regulation of cytokine production, cytokine-mediated signaling pathway, leukocyte differentiation, and migration. A total of 6 hub genes were selected in the PPI module networks including AKT1, TNFRSF1B, FCGR2A, CXCL8, STAT3, and TLR2. Moreover, a competing endogenous RNA network showed the interactions between lncRNAs, mRNAs, and miRNAs. Our results highlight the potential pathogenesis of excessive cytokine production such as MSTRG.119845.30/hsa-miR-20a-5p/TNFRSF1B, MSTRG.119845.30/hsa-miR-29b-2-5p/FCGR2A, and MSTRG.106112.2/hsa-miR-6501-5p/STAT3 axis, which may also play an important role in the development of ground-glass opacity in COVID-19 patients. This study gives new insights into inflammation regulatory mechanisms of coding and noncoding RNAs in COVID-19, which may provide novel diagnostic biomarkers and therapeutic avenues for COVID-19 patients.


Asunto(s)
/sangre , ARN/sangre , ARN/genética , Adulto , Anciano , Estudios de Casos y Controles , Síndrome de Liberación de Citoquinas/sangre , Síndrome de Liberación de Citoquinas/etiología , Síndrome de Liberación de Citoquinas/genética , Citocinas/biosíntesis , Citocinas/genética , Femenino , Expresión Génica , Humanos , Mediadores de Inflamación/sangre , Masculino , MicroARNs/sangre , MicroARNs/genética , Persona de Mediana Edad , Pandemias , Mapas de Interacción de Proteínas/genética , ARN Largo no Codificante/sangre , ARN Largo no Codificante/genética , ARN Mensajero/sangre , ARN Mensajero/genética , Análisis de Secuencia de ARN , Transducción de Señal , Secuenciación del Exoma Completo , Adulto Joven
4.
Front Immunol ; 12: 613422, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33679753

RESUMEN

Hyper-inflammatory responses induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are a major cause of disease severity and death. Predictive prognosis biomarkers to guide therapeutics are critically lacking. Several studies have indicated a "cytokine storm" with the release of interleukin-1 (IL-1), IL-6, and IL-8, along with tumor necrosis factor alpha (TNFα) and other inflammatory mediators. Here, we proposed to assess the relationship between IL-6 and outcomes of patients with coronavirus disease 2019 (COVID-19). Our cohort consisted of 46 adult patients with PCR-proven SARS-CoV-2 infection admitted in a COVID-19 ward of the Hospital de Braga (HB) from April 7 to May 7, 2020, whose IL-6 levels were followed over time. We found that IL-6 levels were significantly different between the disease stages. Also, we found a significant negative correlation between IL-6 levels during stages IIb and III, peripheral oxygen saturation (SpO2), and partial pressure of oxygen in arterial blood (PaO2), showing that IL-6 correlates with respiratory failure. Compared to the inflammatory markers available in the clinic routine, we found a positive correlation between IL-6 and C-reactive protein (CRP). However, when we assessed the predictive value of these two markers, IL-6 behaves as a better predictor of disease progression. In a binary logistic regression, IL-6 level was the most significant predictor of the non-survivors group, when compared to age and CRP. Herein, we present IL-6 as a relevant tool for prognostic evaluation, mainly as a predictor of outcome.


Asunto(s)
Síndrome de Liberación de Citoquinas , Interleucina-6/sangre , /metabolismo , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Proteína C-Reactiva/metabolismo , /mortalidad , Síndrome de Liberación de Citoquinas/sangre , Síndrome de Liberación de Citoquinas/mortalidad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Oxígeno/sangre
5.
Iran J Immunol ; 18(1): 54-64, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33787514

RESUMEN

BACKGROUND: SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), is recognized for the first time in Wuhan, China. The cytokine storm is a known factor causing major clinical symptoms leading to death in COVID-19 patients. OBJECTIVE: To investigate and compare the serum levels of different cytokines in COVID-19 patients with different clinical severity. METHODS: Concentrations of serum cytokines, including IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, TNF-α, IFN-γ, and GM-CSF, were measured in 61 COVID-19 patients and 31 normal controls with ELISA. We investigated the correlation between the levels of these cytokines and clinical severity, CRP level, neutrophil and lymphocyte count in patients with COVID-19. RESULTS: Our data indicated that the levels of IL-1ß, IL-2, IL-4, IL-6, IL-8, TNF-α, IFN-γ, and GM-CSF, but not IL-10 were significantly increased in COVID-19 patients compared to normal controls. Statistical analysis showed that the level of IL-1ß, IL-2, IL-4, IL-6, IL-8, TNF-α, IFN-γ, and GM-CSF were higher in severe COVID-19 than those of mild cases. The concentrations of all mentioned cytokines were negatively associated with the absolute count of lymphocytes, and positively correlated with the CRP level and the absolute count of neutrophils. CONCLUSION: The current study suggests that high levels of various cytokines correlate with the disease severity and immunopathogenesis of COVID-19.


Asunto(s)
/inmunología , Síndrome de Liberación de Citoquinas/inmunología , Citocinas/sangre , /inmunología , Anciano , Biomarcadores/sangre , Proteína C-Reactiva/análisis , /diagnóstico , Estudios de Casos y Controles , Síndrome de Liberación de Citoquinas/sangre , Síndrome de Liberación de Citoquinas/diagnóstico , Síndrome de Liberación de Citoquinas/virología , Femenino , Interacciones Huésped-Patógeno , Humanos , Irán , Linfocitos/inmunología , Linfocitos/metabolismo , Linfocitos/virología , Masculino , Persona de Mediana Edad , Neutrófilos/inmunología , Neutrófilos/metabolismo , Neutrófilos/virología , Índice de Severidad de la Enfermedad
6.
Iran J Immunol ; 18(1): 65-73, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33787515

RESUMEN

BACKGROUND: The role of cytokine storm in the immunopathogenesis of coronavirus disease 2019 (COVID-19) has been implicated. OBJECTIVE: To determine the association of microRNA (miRNA)-10b and serum levels of IL-2 and IL-8 in patients with COVID-19. METHODS: Blood samples were obtained from 33 COVID-19 patients and 29 healthy subjects. After RNA extraction and cDNA synthesis, the transcript level of miR-10b was determined by Real-time PCR. In addition, the serum levels of IL-2 and IL-8 were measured in subjects using ELISA. RESULTS: The patient group comprised of 33 patients with COVID-19 (62.4 ± 3.7 years old), 13 (39%) males and 20 (61%) females. In the control group, 29 subjects (56.6 ± 1.6 years old), 9 (31%) males and 20 (69%) females, were included. The expression of miR-10b was significantly downregulated in the peripheral blood of COVID-19 patients in comparison to the healthy controls (fold change= 0.12, P< 0.0001). The levels of IL-2 (P< 0.001) and IL-8 (P< 0.001) were significantly increased in the serum samples of COVID-19 patients compared to the healthy subjects. The expression level of miR-10b was correlated significantly with the serum levels of IL-2 and IL-8 as well as with the age of patients, ESR and CRP levels. CONCLUSIONS: miR-10b is downregulated in the COVID-19 patients and might result in increased levels of IL-2 and IL-8, hence contributing to cytokine storm.


Asunto(s)
/sangre , MicroARN Circulante/sangre , Interleucina-2/sangre , Interleucina-8/sangre , MicroARNs/sangre , /patogenicidad , Anciano , Biomarcadores/sangre , /inmunología , Estudios de Casos y Controles , MicroARN Circulante/genética , Síndrome de Liberación de Citoquinas/sangre , Síndrome de Liberación de Citoquinas/genética , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/virología , Femenino , Interacciones Huésped-Patógeno , Humanos , Masculino , MicroARNs/genética , Persona de Mediana Edad , /inmunología
7.
Sci Signal ; 14(673)2021 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-33688079

RESUMEN

IL-1ß is a key mediator of the cytokine storm linked to high morbidity and mortality from COVID-19, and IL-1ß blockade with anakinra and canakinumab during COVID-19 infection has entered clinical trials. Using mass cytometry of human peripheral blood mononuclear cells, we identified effector memory CD4+ T cells and CD4-CD8low/-CD161+ T cells, specifically those positive for the chemokine receptor CCR6, as the circulating immune subtypes with the greatest response to IL-1ß. This response manifested as increased phosphorylation and, thus, activation of the proinflammatory transcription factor NF-κB and was also seen in other subsets, including CD11c+ myeloid dendritic cells, classical monocytes, two subsets of natural killer cells (CD16-CD56brightCD161- and CD16-CD56dimCD161+), and lineage- (Lin-) cells expressing CD161 and CD25. IL-1ß also induced a rapid but less robust increase in the phosphorylation of the kinase p38 as compared to that of NF-κB in most of these immune cell subsets. Prolonged IL-1ß stimulation increased the phosphorylation of the transcription factor STAT3 and to a lesser extent that of STAT1 and STAT5 across various immune cell types. IL-1ß-induced production of IL-6 likely led to the activation of STAT1 and STAT3 at later time points. Interindividual heterogeneity and inhibition of STAT activation by anakinra raise the possibility that assays measuring NF-κB phosphorylation in response to IL-1ß in CCR6+ T cell subtypes could identify those patients at higher risk of cytokine storm and most likely to benefit from IL-1ß-neutralizing therapies.


Asunto(s)
/inmunología , Interleucina-1beta/sangre , Subgrupos de Linfocitos T/inmunología , /sangre , Síndrome de Liberación de Citoquinas/sangre , Síndrome de Liberación de Citoquinas/etiología , Síndrome de Liberación de Citoquinas/inmunología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Citometría de Flujo , Humanos , Interleucina-1beta/farmacología , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Monocitos/clasificación , Monocitos/inmunología , Monocitos/metabolismo , FN-kappa B/sangre , Pandemias , Fosforilación , Receptores CCR6/sangre , Factores de Transcripción STAT/sangre , Factores de Transcripción STAT/inmunología , Transducción de Señal/inmunología , Subgrupos de Linfocitos T/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/sangre
8.
Front Immunol ; 12: 629193, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33732251

RESUMEN

Hyper-induction of pro-inflammatory cytokines, also known as a cytokine storm or cytokine release syndrome (CRS), is one of the key aspects of the currently ongoing SARS-CoV-2 pandemic. This process occurs when a large number of innate and adaptive immune cells activate and start producing pro-inflammatory cytokines, establishing an exacerbated feedback loop of inflammation. It is one of the factors contributing to the mortality observed with coronavirus 2019 (COVID-19) for a subgroup of patients. CRS is not unique to the SARS-CoV-2 infection; it was prevalent in most of the major human coronavirus and influenza A subtype outbreaks of the past two decades (H5N1, SARS-CoV, MERS-CoV, and H7N9). With a comprehensive literature search, we collected changing the cytokine levels from patients upon infection with the viral pathogens mentioned above. We analyzed published patient data to highlight the conserved and unique cytokine responses caused by these viruses. Our curation indicates that the cytokine response induced by SARS-CoV-2 is different compared to other CRS-causing respiratory viruses, as SARS-CoV-2 does not always induce specific cytokines like other coronaviruses or influenza do, such as IL-2, IL-10, IL-4, or IL-5. Comparing the collated cytokine responses caused by the analyzed viruses highlights a SARS-CoV-2-specific dysregulation of the type-I interferon (IFN) response and its downstream cytokine signatures. The map of responses gathered in this study could help specialists identify interventions that alleviate CRS in different diseases and evaluate whether they could be used in the COVID-19 cases.


Asunto(s)
/inmunología , Síndrome de Liberación de Citoquinas/inmunología , Virus de la Influenza A/inmunología , Gripe Humana/inmunología , Coronavirus del Síndrome Respiratorio de Oriente Medio/inmunología , Virus del SRAS/inmunología , Síndrome Respiratorio Agudo Grave/inmunología , Índice de Severidad de la Enfermedad , /sangre , /virología , Síndrome de Liberación de Citoquinas/sangre , Síndrome de Liberación de Citoquinas/virología , Citocinas/sangre , Humanos , Inflamación/inmunología , Gripe Humana/sangre , Gripe Humana/virología , Síndrome Respiratorio Agudo Grave/sangre , Síndrome Respiratorio Agudo Grave/virología
11.
Cell Stress Chaperones ; 26(3): 515-525, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33629254

RESUMEN

Hyperinflammation distinguishes COVID-19 patients who develop a slight disease or none, from those progressing to severe and critical conditions. CIGB-258 is a therapeutic option for the latter group of patients. This drug is an altered peptide ligand (APL) derived from the cellular stress protein 60 (HSP60). In preclinical models, this peptide developed anti-inflammatory effects and increased regulatory T cell (Treg) activity. Results from a phase I clinical trial with rheumatoid arthritis (RA) patients indicated that CIGB-258 was safe and reduced inflammation. The aim of this study was to examine specific biomarkers associated with hyperinflammation, some cytokines linked to the cytokine storm granzyme B and perforin in a cohort of COVID-19 patients treated with this peptide. All critically ill patients were under invasive mechanical ventilation and received the intravenous administration of 1 or 2 mg of CIGB-258 every 12 h. Seriously ill patients were treated with oxygen therapy receiving 1 mg of CIGB-258 every 12 h and all patients recovered from their severe condition. Biomarker levels associated with hyperinflammation, such as interleukin (IL)-6, IL-10, tumor necrosis factor (TNF-α), granzyme B, and perforin, significantly decreased during treatment. Furthermore, we studied the ability of CIGB-258 to induce Tregs in COVID-19 patients and found that Tregs were induced in all patients studied. Altogether, these results support the therapeutic potential of CIGB-258 for diseases associated with hyperinflammation. Clinical trial registry: RPCEC00000313.


Asunto(s)
Antiinflamatorios/uso terapéutico , Chaperonina 60/uso terapéutico , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antiinflamatorios/química , /complicaciones , Chaperonina 60/química , Síndrome de Liberación de Citoquinas/sangre , Síndrome de Liberación de Citoquinas/complicaciones , Femenino , Humanos , Inflamación/sangre , Inflamación/complicaciones , Inflamación/tratamiento farmacológico , Interleucina-10/sangre , Interleucina-6/sangre , Masculino , Persona de Mediana Edad , Linfocitos T Reguladores/efectos de los fármacos , Factor de Necrosis Tumoral alfa/sangre , Adulto Joven
12.
J Infect Dis ; 223(8): 1322-1333, 2021 04 23.
Artículo en Inglés | MEDLINE | ID: mdl-33524124

RESUMEN

The clinical spectrum of COVID-19 varies and the differences in host response characterizing this variation have not been fully elucidated. COVID-19 disease severity correlates with an excessive proinflammatory immune response and profound lymphopenia. Inflammatory responses according to disease severity were explored by plasma cytokine measurements and proteomics analysis in 147 COVID-19 patients. Furthermore, peripheral blood mononuclear cell cytokine production assays and whole blood flow cytometry were performed. Results confirm a hyperinflammatory innate immune state, while highlighting hepatocyte growth factor and stem cell factor as potential biomarkers for disease severity. Clustering analysis revealed no specific inflammatory endotypes in COVID-19 patients. Functional assays revealed abrogated adaptive cytokine production (interferon-γ, interleukin-17, and interleukin-22) and prominent T-cell exhaustion in critically ill patients, whereas innate immune responses were intact or hyperresponsive. Collectively, this extensive analysis provides a comprehensive insight into the pathobiology of severe to critical COVID-19 and highlights potential biomarkers of disease severity.


Asunto(s)
Inmunidad Adaptativa/inmunología , Inmunidad Innata/inmunología , Anciano , Biomarcadores/sangre , /virología , Síndrome de Liberación de Citoquinas/sangre , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/virología , Citocinas/inmunología , Femenino , Humanos , Inflamación/sangre , Inflamación/inmunología , Inflamación/virología , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/virología , Linfopenia/sangre , Linfopenia/inmunología , Linfopenia/virología , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad
14.
J Clin Immunol ; 41(4): 738-747, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33459964

RESUMEN

We describe the cytokine profiles of a large cohort of hospitalized patients with moderate to critical COVID-19, focusing on IL-6, sIL2R, and IL-10 levels before and after receiving immune modulating therapies, namely, tocilizumab and glucocorticoids. We also discuss the possible roles of sIL2R and IL-10 as markers of ongoing immune dysregulation after IL-6 inhibition. We performed a retrospective chart review of adult patients admitted to a tertiary care center with moderate to critical SARS-CoV-2 infection. Disease severity was based on maximum oxygen requirement during hospital stay to maintain SpO2 > 93% (moderate, 0-3 L NC; severe, 4-6 L NC or non-rebreather; critical, HFNC, NIPPV, or MV). All patients were treated using the institution's treatment algorithm, which included consideration of tocilizumab for severe and critical disease. The most common cytokine elevations among all patients included IL-6, sIL2R, IFN-γ, and IL-10; patients who received tocilizumab had higher incidence of IL-6 and sIL2R elevations. Pre-tocilizumab IL-6 levels increased with disease severity (p = .0151). Both IL-6 and sIL2R levels significantly increased after administration of tocilizumab in all severity groups; IL-10 levels decreased in severe (p = .0203), but not moderate or critical, patients after they received tocilizumab. Cluster analysis revealed association between higher admission IL-6, sIL2R, and CRP levels and disease severity. Mean IL-6, sIL2R, and D-dimer were associated with mortality, and tocilizumab-treated patients with elevated IL-6, IL-10, and D-dimer were more likely to also receive glucocorticoids. Accessible clinical cytokine panels may be useful for monitoring response to treatment in COVID-19. The increase in sIL2R post-tocilizumab, despite administration of glucocorticoids, may indicate the need for combination therapy in order to modulate more than one hyperinflammatory pathway in COVID-19. We also discuss the role of cytokines as potential biomarkers for use of adjunct glucocorticoid therapy.


Asunto(s)
/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/diagnóstico , Citocinas/sangre , Factores Inmunológicos/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/uso terapéutico , Biomarcadores/sangre , /diagnóstico , Síndrome de Liberación de Citoquinas/sangre , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/prevención & control , Citocinas/inmunología , Quimioterapia Combinada/métodos , Estudios de Factibilidad , Femenino , Glucocorticoides/uso terapéutico , Hospitalización , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Adulto Joven
15.
Cardiol Rev ; 29(1): 43-47, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-32947478

RESUMEN

The novel coronavirus (severe acute respiratory syndrome CoV-2 [SARS-CoV-2]), also known as COVID-19, is a single-stranded enveloped RNA virus that created a Public Health Emergency of International Concern in January 2020, with a global case burden of over 15 million in just 7 months. Infected patients develop a wide range of clinical manifestations-typically presenting with fever, cough, myalgia, and fatigue. Severely ill patients may fall victim to acute respiratory distress syndrome, acute heart injuries, neurological manifestations, or complications due to secondary infections. These critically ill patients are also found to have disrupted coagulation function, predisposing them to consumptive coagulopathies, and both venous and thromboembolic complications. Common laboratory findings include thrombocytopenia, elevated D-dimer, fibrin degradation products, and fibrinogen, all of which have been associated with greater disease severity. Many cases of pulmonary embolism have been noted, along with deep vein thrombosis, ischemic stroke, myocardial infarction, and systemic arterial embolism. The pathogenesis of coronavirus has not been completely elucidated, but the virus is known to cause excessive inflammation, endothelial injury, hypoxia, and disseminated intravascular coagulation, all of which contribute to thrombosis formation. These patients are also faced with prolonged immobilization while staying in the hospital or intensive care unit. It is important to have a high degree of suspicion for thrombotic complications as patients may rapidly deteriorate in severe cases. Evidence suggests that prophylaxis with anticoagulation may lead to a lower risk of mortality, although it does not eliminate the possibility. The risks and benefits of anticoagulation treatment should be considered in each case. Patients should be regularly evaluated for bleeding risks and thrombotic complications.


Asunto(s)
Trastornos de la Coagulación Sanguínea/sangre , Embolia/sangre , Trombosis/sangre , Anticoagulantes/uso terapéutico , Trastornos de la Coagulación Sanguínea/tratamiento farmacológico , Trastornos de la Coagulación Sanguínea/etiología , Trastornos de la Coagulación Sanguínea/metabolismo , /tratamiento farmacológico , Síndrome de Liberación de Citoquinas/sangre , Síndrome de Liberación de Citoquinas/complicaciones , Síndrome de Liberación de Citoquinas/metabolismo , Coagulación Intravascular Diseminada/sangre , Coagulación Intravascular Diseminada/etiología , Coagulación Intravascular Diseminada/metabolismo , Coagulación Intravascular Diseminada/prevención & control , Embolia/etiología , Embolia/metabolismo , Embolia/prevención & control , Endotelio Vascular/metabolismo , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Fibrinógeno/metabolismo , Humanos , Hipoxia/sangre , Hipoxia/etiología , Hipoxia/metabolismo , Inmovilización , Inflamación/sangre , Inflamación/etiología , Inflamación/metabolismo , /etiología , /prevención & control , Infarto del Miocardio/sangre , Infarto del Miocardio/etiología , Infarto del Miocardio/metabolismo , Infarto del Miocardio/prevención & control , Guías de Práctica Clínica como Asunto , Embolia Pulmonar/sangre , Embolia Pulmonar/etiología , Embolia Pulmonar/metabolismo , Embolia Pulmonar/prevención & control , Índice de Severidad de la Enfermedad , Trombocitopenia/sangre , Trombocitopenia/etiología , Trombosis/etiología , Trombosis/metabolismo , Trombosis/prevención & control , Trombosis de la Vena/sangre , Trombosis de la Vena/etiología , Trombosis de la Vena/metabolismo
16.
Eur Cytokine Netw ; 31(3): 81-93, 2020 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-33361013

RESUMEN

Coronavirus disease (COVID-19) reached pandemic proportions at the beginning of 2020 and continues to be a worldwide concern. End organ damage and acute respiratory distress syndrome are the leading causes of death in severely or critically ill patients. The elevated cytokine levels in severe patients in comparison with mildly affected patients suggest that cytokine release syndrome (CRS) occurs in the severe form of the disease. In this paper, the significant role of pro-inflammatory cytokines, including IL-1, IL-6, and TNF-alpha, and their mechanism of action in the CRS cascade is explained. Potential therapeutic approaches involving anti-IL-6 and anti-TNF-alpha antibodies to fight COVID-19 and reduce mortality rate in severe cases are also discussed.


Asunto(s)
Anticuerpos/uso terapéutico , Síndrome de Liberación de Citoquinas , Interleucina-6/antagonistas & inhibidores , Pandemias , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , /sangre , /tratamiento farmacológico , Síndrome de Liberación de Citoquinas/sangre , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/etiología , Síndrome de Liberación de Citoquinas/mortalidad , Humanos , Interleucina-6/sangre , Factor de Necrosis Tumoral alfa/sangre
17.
Front Immunol ; 11: 598404, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33329592

RESUMEN

Background: Bacterial sepsis has been used as a prototype to understand the pathogenesis of severe coronavirus disease 2019 (COVID-19). In addition, some management programs for critically ill COVID-19 patients are also based on experience with bacterial sepsis. However, some differences may exist between these two types of sepsis. Methods: This retrospective study investigated whether there are differences in the immune system status of these two types of sepsis. A total of 64 bacterial sepsis patients and 43 patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sepsis were included in this study. Demographic data were obtained from medical records. Laboratory results within 24 h after the diagnosis of sepsis were provided by the clinical laboratory. Results: The results of blood routine (neutrophil, lymphocyte, and monocyte counts), infection biomarkers (C-reactive protein, ferritin, and procalcitonin levels), lymphocyte subset counts (total T lymphocyte, CD4+ T cell, CD8+ T cell, B cell, and NK cell counts), and lymphocyte subset functions (the proportions of PMA/ionomycin-stimulated IFN-γ positive cells in CD4+, CD8+ T cells, and NK cells) were similar in bacterial sepsis patients and SARS-CoV-2 sepsis patients. Cytokine storm was milder, and immunoglobulin and complement protein levels were higher in SARS-CoV-2 sepsis patients. Conclusions: There are both similarities and differences in the immune system status of bacterial sepsis and SARS-CoV-2 sepsis. Our findings do not support blocking the cytokine storm or supplementing immunoglobulins in SARS-CoV-2 sepsis, at least in the early stages of the disease. Treatments for overactivation of the complement system and lymphocyte depletion may be worth exploring further.


Asunto(s)
Infecciones Bacterianas , Síndrome de Liberación de Citoquinas , Subgrupos Linfocitarios , Sepsis , Adulto , Anciano , Infecciones Bacterianas/sangre , Infecciones Bacterianas/inmunología , /inmunología , Síndrome de Liberación de Citoquinas/sangre , Síndrome de Liberación de Citoquinas/inmunología , Femenino , Humanos , Recuento de Linfocitos , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , /metabolismo , Sepsis/sangre , Sepsis/inmunología
18.
PLoS One ; 15(12): e0244628, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33382773

RESUMEN

INTRODUCTION: Coronavirus disease 2019 (COVID-19) appeared in China in December 2019 and has spread around the world. High Interleukin-6 (IL-6) levels in COVID-19 patients suggest that a cytokine storm may play a major role in the pathophysiology and are considered as a relevant parameter in predicting most severe course of disease. The aim of this study was to assess repeated IL-6 levels in critically ill COVID-19 patients admitted to our Intensive Care Unit (ICU) and to evaluate their relationship with patient's severity and outcome. METHODS: We conducted a retrospective study on patients admitted to the ICU with a diagnosis of COVID-19 between March 10 (i.e. the date of the first admitted patients) and April 30, 2020. Demographic, clinical and laboratory data were collected at admission. On the day of IL-6 blood concentration measurement, we also collected results of D-Dimers, C-Reactive Protein, white blood cells and lymphocytes count, lactate dehydrogenase (LDH) and ferritin as well as microbiological samples, whenever present. RESULTS: Of a total of 65 patients with COVID-19 admitted to our ICU we included 41 patients with repeated measure of IL-6. There was a significant difference in IL-6 levels between survivors and non-survivors over time (p = 0.001); moreover, non survivors had a significantly higher IL-6 maximal value when compared to survivors (720 [349-2116] vs. 336 [195-646] pg/mL, p = 0.01). The IL-6 maximal value had a significant predictive value of ICU mortality (AUROC 0.73 [95% CI 0.57-0.89]; p = 0.01). CONCLUSIONS: Repeated measurements of IL-6 can help clinicians in identifying critically ill COVID-19 patients with the highest risk of poor prognosis.


Asunto(s)
/sangre , Síndrome de Liberación de Citoquinas/sangre , Síndrome de Liberación de Citoquinas/mortalidad , Interleucina-6/sangre , Enfermedad Crítica , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Tasa de Supervivencia
19.
Mol Med Rep ; 22(6): 4485-4491, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33173966

RESUMEN

In December 2019, an emergence of pneumonia was detected in patients infected with a novel coronavirus (CoV) in Wuhan (Hubei, China). The International Committee on Taxonomy of Viruses named the virus severe acute respiratory syndrome­CoV­2 and the disease CoV disease­19 (COVID­19). Patients with COVID­19 present with symptoms associated with respiratory system dysfunction and hematological changes, including lymphopenia, thrombocytopenia and coagulation disorders. However, to the best of our knowledge, the pathogenesis of COVID­19 remains unclear. Therefore, understanding the mechanisms underlying the hematological changes that manifest during COVID­19 may aid in the development of treatments and may improve patient prognosis.


Asunto(s)
Betacoronavirus , Infecciones por Coronavirus/sangre , Neumonía Viral/sangre , Anticuerpos Antivirales/inmunología , Complejo Antígeno-Anticuerpo/inmunología , Antivirales/farmacología , Antivirales/uso terapéutico , Betacoronavirus/inmunología , Microambiente Celular , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/terapia , Síndrome de Liberación de Citoquinas/sangre , Síndrome de Liberación de Citoquinas/etiología , Síndrome de Liberación de Citoquinas/prevención & control , Citocinas/sangre , Pruebas Diagnósticas de Rutina , Endotelio Vascular/patología , Pruebas Hematológicas , Hematopoyesis/efectos de los fármacos , Células Madre Hematopoyéticas/patología , Humanos , Hipoalbuminemia/etiología , Hígado/fisiopatología , Pulmón/fisiopatología , Linfopenia/etiología , Linfopenia/fisiopatología , Pandemias , Neumonía Viral/complicaciones , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/terapia , Daño por Reperfusión/etiología , Trombocitopenia/etiología , Trombocitopenia/fisiopatología , Trombofilia/etiología
20.
Trials ; 21(1): 934, 2020 Nov 19.
Artículo en Inglés | MEDLINE | ID: mdl-33213529

RESUMEN

OBJECTIVES: Zilucoplan (complement C5 inhibitor) has profound effects on inhibiting acute lung injury post COVID-19, and can promote lung repair mechanisms that lead to improvement in lung oxygenation parameters. The purpose of this study is to investigate the efficacy and safety of Zilucoplan in improving oxygenation and short- and long-term outcome of COVID-19 patients with acute hypoxic respiratory failure. TRIAL DESIGN: This is a phase 2 academic, prospective, 2:1 randomized, open-label, multi-center interventional study. PARTICIPANTS: Adult patients (≥18y old) will be recruited at specialized COVID-19 units and ICUs at 9 Belgian hospitals. The main eligibility criteria are as follows: 1) Inclusion criteria: a. Recent (≥6 days and ≤16 days) SARS-CoV-2 infection. b. Chest CT scan showing bilateral infiltrates within the last 2 days prior to randomisation. c. Acute hypoxia (defined as PaO2/FiO2 below 350 mmHg or SpO2 below 93% on minimal 2 L/min supplemental oxygen). d. Signs of cytokine release syndrome characterized by either high serum ferritin, or high D-dimers, or high LDH or deep lymphopenia or a combination of those. 2) Exclusion criteria: e. Mechanical ventilation for more than 24 hours prior to randomisation. f. Active bacterial or fungal infection. g. History of meningococcal disease (due to the known high predisposition to invasive, often recurrent meningococcal infections of individuals deficient in components of the alternative and terminal complement pathways). INTERVENTION AND COMPARATOR: Patients in the experimental arm will receive daily 32,4 mg Zilucoplan subcutaneously and a daily IV infusion of 2g of the antibiotic ceftriaxone for 14 days (or until hospital discharge, whichever comes first) in addition to standard of care. These patients will receive additional prophylactic antibiotics until 14 days after the last Zilucoplan dose: hospitalized patients will receive a daily IV infusion of 2g of ceftriaxone, discharged patients will switch to daily 500 mg of oral ciprofloxacin. The control group will receive standard of care and a daily IV infusion of 2g of ceftriaxone for 1 week (or until hospital discharge, whichever comes first), to control for the effects of antibiotics on the clinical course of COVID-19. MAIN OUTCOMES: The primary endpoint is the improvement of oxygenation as measured by mean and/or median change from pre-treatment (day 1) to post-treatment (day 6 and 15 or at discharge, whichever comes first) in PaO2/FiO2 ratio, P(A-a)O2 gradient and a/A PO2 ratio. (PAO2= Partial alveolar pressure of oxygen, PaO2=partial arterial pressure of oxygen, FiO2=Fraction of inspired oxygen). RANDOMISATION: Patients will be randomized in a 2:1 ratio (Zilucoplan: control). Randomization will be done using an Interactive Web Response System (REDCap). BLINDING (MASKING): In this open-label trial neither participants, caregivers, nor those assessing the outcomes will be blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 81 patients will be enrolled: 54 patients will be randomized to the experimental arm and 27 patients to the control arm. TRIAL STATUS: ZILU-COV protocol Version 4.0 (June 10 2020). Participant recruitment started on June 23 2020 and is ongoing. Given the uncertainty of the pandemic, it is difficult to predict the anticipated end date. TRIAL REGISTRATION: The trial was registered on Clinical Trials.gov on May 11th, 2020 (ClinicalTrials.gov Identifier: NCT04382755 ) and on EudraCT (Identifier: 2020-002130-33 ). FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Asunto(s)
Complemento C5/antagonistas & inhibidores , Infecciones por Coronavirus/complicaciones , Hipoxia/tratamiento farmacológico , Neumonía Viral/complicaciones , Insuficiencia Respiratoria/tratamiento farmacológico , Enfermedad Aguda , Adulto , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Bélgica/epidemiología , Betacoronavirus/aislamiento & purificación , Estudios de Casos y Controles , Ceftriaxona/administración & dosificación , Ceftriaxona/uso terapéutico , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/fisiopatología , Infecciones por Coronavirus/virología , Síndrome de Liberación de Citoquinas/sangre , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Quimioterapia Combinada , Humanos , Infusiones Intravenosas , Inyecciones Subcutáneas , Oxígeno/sangre , Pandemias , Neumonía Viral/epidemiología , Neumonía Viral/fisiopatología , Neumonía Viral/virología , Estudios Prospectivos , Seguridad , Resultado del Tratamiento
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