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1.
mBio ; 12(2)2021 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-33879586

RESUMO

Newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic, which has caused extensive mortality and morbidity and wreaked havoc on socioeconomic structures. The urgent need to better understand SARS-CoV-2 biology and enable continued development of effective countermeasures is aided by the production of laboratory tools that facilitate SARS-CoV-2 research. We previously created a directly accessible SARS-CoV-2 toolkit containing user-friendly reverse genetic (RG) infectious clones of SARS-CoV-2. Here, using K18-human ACE2 (hACE2) mice, we confirmed the validity of RG-rescued SARS-CoV-2 viruses to reproduce the infection profile, clinical disease, and pathogenesis already established in mice infected with natural SARS-CoV-2 isolates, often patient derived. RG-rescued SARS-CoV-2-infected K18-hACE2 mice developed substantial clinical disease and weight loss by day 6 postinfection. RG-rescued SARS-CoV-2 was recovered from the lungs and brains of infected K18-hACE2 mice, and infection resulted in viral pneumonia with considerable changes in lung pathology, as seen previously with natural SARS-CoV-2 infection. In mice infected with RG-rescued SARS-CoV-2-mCherry, mCherry was detected in areas of lung consolidation and colocalized with clinically relevant SARS-CoV-2-assocated immunopathology. RG-rescued SARS-CoV-2 viruses successfully recapitulated many of the features of severe COVID-19 associated with the K18-hACE2 model of SARS-CoV-2 infection. With utility in vivo, the RG-rescued SARS-CoV-2 viruses will be valuable resources to advance numerous areas of SARS-CoV-2 basic research and COVID-19 vaccine development.IMPORTANCE To develop COVID-19 countermeasures, powerful research tools are essential. We produced a SARS-COV-2 reverse genetic (RG) infectious clone toolkit that will benefit a variety of investigations. In this study, we further prove the toolkit's value by demonstrating the in vivo utility of RG-rescued SARS-CoV-2 isolates. RG-rescued SARS-CoV-2 isolates reproduce disease signs and pathology characteristic of the K18-hACE2 mouse model of severe COVID-19 in infected mice. Having been validated as a model of severe COVID-19 previously using only natural SARS-CoV-2 isolated from patients, this is the first investigation of RG-rescued SARS-CoV-2 viruses in K18-hACE2 mice. The RG-rescued SARS-CoV-2 viruses will facilitate basic understanding of SARS-CoV-2 and the preclinical development of COVID-19 therapeutics.


Assuntos
/genética , /patogenicidade , Animais , /virologia , Síndrome da Liberação de Citocina/etiologia , Modelos Animais de Doenças , Feminino , Interações entre Hospedeiro e Microrganismos , Humanos , Mediadores da Inflamação/metabolismo , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Masculino , Camundongos , Camundongos Transgênicos , Pandemias , Pneumonia Viral/etiologia , Pneumonia Viral/virologia , Genética Reversa/métodos , /fisiologia , Tropismo Viral , Replicação Viral
2.
Aging (Albany NY) ; 13(7): 9243-9252, 2021 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-33811755

RESUMO

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.


Assuntos
/terapia , Terapia de Substituição Renal Contínua , Estado Terminal/terapia , Síndrome da Liberação de Citocina/terapia , Idoso , Proteína C-Reativa/análise , /complicações , China , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/etiologia , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Humanos , Inflamação/sangue , Inflamação/etiologia , Inflamação/terapia , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
3.
Int J Mol Sci ; 22(6)2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33802761

RESUMO

Among patients suffering from coronavirus disease 2019 (COVID-19) syndrome, one of the worst possible scenarios is represented by the critical lung damage caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-induced cytokine storm, responsible for a potentially very dangerous hyperinflammatory condition. Within such a context, interleukin-6 (IL-6) plays a key pathogenic role, thus being a suitable therapeutic target. Indeed, the IL-6-receptor antagonist tocilizumab, already approved for treatment of refractory rheumatoid arthritis, is often used to treat patients with severe COVID-19 symptoms and lung involvement. Therefore, the aim of this review article is to focus on the rationale of tocilizumab utilization in the SARS-CoV-2-triggered cytokine storm, as well as to discuss current evidence and future perspectives, especially with regard to ongoing trials referring to the evaluation of tocilizumab's therapeutic effects in patients with life-threatening SARS-CoV-2 infection.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Síndrome da Liberação de Citocina/tratamento farmacológico , /imunologia , Anticorpos Monoclonais Humanizados/química , /imunologia , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/fisiopatologia , Humanos , Interleucina-6/antagonistas & inibidores , Interleucina-6/fisiologia
4.
Int J Mol Sci ; 22(6)2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33808574

RESUMO

COVID-19 is without any doubt the worst pandemic we have faced since the H1N1 virus outbreak. Even if vaccination against SARS-CoV-2 infection is becoming increasingly available, a more feasible approach for COVID-19 prevention and therapy is still needed. Evidence of a pathological link between metabolic diseases and severe forms of COVID-19 has stimulated critical reflection and new considerations. In particular, an abnormal immune response observed in certain patients with SARS-CoV-2 infection suggested possible common predisposing risk factors with autoimmune diseases such as Type 1 Diabetes (T1D). Correct supplementation with dietary factors may be key to preventing and counteracting both the underlying metabolic impairment and the complications of COVID-19. A set of agents may inhibit the cytokine storm and hypercoagulability that characterize severe COVID-19 infection: vitamin D3, omega-3 polyunsaturated fatty acids, polyphenols like pterostilbene, polydatin and honokiol, which can activate anti-inflammatory and antioxidant sirtuins pathways, quercetin, vitamin C, zinc, melatonin, lactoferrin and glutathione. These agents could be highly beneficial for subjects who have altered immune responses. In this review, we discuss the antiviral and metabolic effects of these dietary factors and propose their combination for potential applications in the prevention and treatment of COVID-19. Rigorous studies will be fundamental for validating preventive and therapeutic protocols that could be of assistance to mitigate disease progression following SARS-CoV-2 infection.


Assuntos
Doenças Autoimunes/dietoterapia , Dieta , Doenças Metabólicas/dietoterapia , Doenças Autoimunes/complicações , Síndrome da Liberação de Citocina/dietoterapia , Síndrome da Liberação de Citocina/etiologia , Progressão da Doença , Humanos , Doenças Metabólicas/complicações , Trombofilia/dietoterapia , Trombofilia/etiologia
5.
Mediators Inflamm ; 2021: 6635925, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33833618

RESUMO

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.


Assuntos
/sangue , RNA/sangue , RNA/genética , Adulto , Idoso , Estudos de Casos e Controles , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/genética , Citocinas/biossíntese , Citocinas/genética , Feminino , Expressão Gênica , Humanos , Mediadores da Inflamação/sangue , Masculino , MicroRNAs/sangue , MicroRNAs/genética , Pessoa de Meia-Idade , Pandemias , Mapas de Interação de Proteínas/genética , RNA Longo não Codificante/sangue , RNA Longo não Codificante/genética , RNA Mensageiro/sangue , RNA Mensageiro/genética , Análise de Sequência de RNA , Transdução de Sinais , Sequenciamento Completo do Exoma , Adulto Jovem
6.
Lancet Haematol ; 8(5): e355-e364, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33894170

RESUMO

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy can induce side-effects such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS), which often require intensive care unit admission. The aim of this study was to describe management of critically ill CAR T-cell recipients in intensive care. METHODS: This international, multicentre, observational cohort study was done in 21 intensive care units in France, Spain, the USA, the UK, Russia, Canada, Germany, and Austria. Eligible patients were aged 18 years or older; had received CAR T-cell therapy in the past 30 days; and had been admitted to intensive care for any reason. Investigators retrospectively included patients admitted between Feb 1, 2018, and Feb 1, 2019, and prospectively included patients admitted between March 1, 2019, and Feb 1, 2020. Demographic, clinical, laboratory, treatment, and outcome data were extracted from medical records. The primary endpoint was 90-day mortality. Factors associated with mortality were identified using a Cox proportional hazard model. FINDINGS: 942 patients received CAR T-cell therapy, of whom 258 (27%) required admission to intensive care and 241 (26%) were included in the analysis. Admission to intensive care was needed within median 4·5 days (IQR 2·0-7·0) of CAR T-cell infusion. 90-day mortality was 22·4% (95% CI 17·1-27·7; 54 deaths). At initial evaluation on admission, isolated cytokine release syndrome was identified in 101 patients (42%), cytokine release syndrome and ICANS in 93 (39%), and isolated ICANS in seven (3%) patients. Grade 3-4 cytokine release syndrome within 1 day of admission to intensive care was found in 50 (25%) of 200 patients and grade 3-4 ICANS in 38 (35%) of 108 patients. Bacterial infection developed in 30 (12%) patients. Life-saving treatments were used in 75 (31%) patients within 24 h of admission to intensive care, primarily vasoactive drugs in 65 (27%) patients. Factors independently associated with 90-day mortality by multivariable analysis were frailty (hazard ratio 2·51 [95% CI 1·37-4·57]), bacterial infection (2·12 [1·11-4·08]), and lifesaving therapy within 24 h of admission (1·80 [1·05-3·10]). INTERPRETATION: Critical care management is an integral part of CAR T-cell therapy and should be standardised. Studies to improve infection prevention and treatment in these high-risk patients are warranted. FUNDING: Groupe de Recherche Respiratoire en Réanimation Onco-Hématologique.


Assuntos
Síndrome da Liberação de Citocina/etiologia , Imunoterapia Adotiva/efeitos adversos , Síndromes Neurotóxicas/etiologia , Adulto , Cuidados Críticos , Feminino , Seguimentos , Humanos , Unidades de Terapia Intensiva , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/terapia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Modelos de Riscos Proporcionais , Sistema de Registros , Índice de Gravidade de Doença , Taxa de Sobrevida , Resultado do Tratamento
7.
Med Sci (Paris) ; 37(4): 333-341, 2021 Apr.
Artigo em Francês | MEDLINE | ID: mdl-33835019

RESUMO

The complement system is an essential component of the innate immune system. Its excessive activation during COVID-19 contributes to cytokine storm, disease-specific endothelial inflammation (endotheliitis) and thrombosis that comes with the disease. Targeted therapies of complement inhibition in COVID-19, in particular blocking the C5a-C5aR1 axis have to be taken into account in the establishment of potential biomarkers and development of therapeutic strategies in the most severe forms of the disease.


Assuntos
/imunologia , Ativação do Complemento/fisiologia , Proteínas do Sistema Complemento/fisiologia , Animais , Complemento C5a/imunologia , Complemento C5a/metabolismo , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/patologia , Humanos , Inflamação/complicações , Inflamação/imunologia , Inflamação/patologia , Índice de Gravidade de Doença , Transdução de Sinais/imunologia
8.
BMC Infect Dis ; 21(1): 241, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33673818

RESUMO

BACKGROUND: Cytokine storm triggered by Severe Coronavirus Disease 2019 (COVID-19) is associated with high mortality. With high Interleukin -6 (IL-6) levels reported in COVID-19 related deaths in China, IL-6 is considered to be the key player in COVID-19 cytokine storm. Tocilizumab, a monoclonal antibody against IL-6 receptor, is used on compassionate grounds for treatment of COVID-19 cytokine storm. The aim of this study was to assess effect of tocilizumab on mortality due to COVID-19 cytokine storm. METHOD: This retrospective, observational study included patients of severe COVID-19 pneumonia with persistent hypoxia (defined as saturation 94% or less on supplemental Oxygen of 15 L per minute through non-rebreathing mask or PaO2/FiO2 ratio of less than 200) who were admitted to a tertiary care center in Mumbai, India, between 31st March to 5th July 2020. In addition to standard care, single Inj. Tocilizumab 400 mg was given intravenously to 151 consecutive COVID-19 patients with persistent hypoxia, from 13th May to 5th July 2020. These 151 patients were retrospectively analysed and compared with historic controls, ie consecutive COVID-19 patients with persistent hypoxia, defined as stated above (N = 118, from our first COVID-19 admission on 31st March to 12th May 2020 i.e., till tocilizumab was available in hospital). Univariate and multivariate Cox regression analysis was performed for identifying predictors of survival. Statistical analysis was performed using IBM SPSS version 26. RESULTS: Out of 269 (151 in tocilizumab group and 118 historic controls) patients studied from 31st March to 5th July 2020, median survival in the tocilizumab group was significantly longer than in the control group; 18 days (95% CI, 11.3 to 24.7) versus 9 days (95% CI, 5.7 to 12.3); log rank p 0.007. On multivariate Cox regression analysis, independent predictors of survival were use of tocilizumab (HR 0.621, 95% CI 0.427-0.903, P 0.013) and higher oxygen saturation. CONCLUSION: Tocilizumab may improve survival in severe COVID-19 pneumonia with persistent hypoxia. Randomised controlled trials on use of tocilizumab as rescue therapy in patients of severe COVID-19 pneumonia with hypoxia (PaO2/FiO2 less than 200) due to hyperinflammatory state, are warranted.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Síndrome da Liberação de Citocina , Hipóxia , Interleucina-6/antagonistas & inibidores , Pneumonia Viral , /epidemiologia , /fisiopatologia , Ensaios de Uso Compassivo/estatística & dados numéricos , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/terapia , Feminino , Humanos , Hipóxia/etiologia , Hipóxia/terapia , Índia/epidemiologia , Interleucina-6/imunologia , Masculino , Pessoa de Meia-Idade , Pneumonia Viral/sangue , Pneumonia Viral/etiologia , Pneumonia Viral/mortalidade , Pneumonia Viral/terapia , Respiração Artificial/métodos , Estudos Retrospectivos , Índice de Gravidade de Doença , Análise de Sobrevida , Resultado do Tratamento
9.
Int J Mol Sci ; 22(4)2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33670394

RESUMO

The novel coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global challenge. Currently, there is some information on the consequences of COVID-19 infection in multiple sclerosis (MS) patients, as it is a newly discovered coronavirus, but its far-reaching effects on participation in neurodegenerative diseases seem to be significant. Recent cases reports showed that SARS-CoV-2 may be responsible for initiating the demyelination process in people who previously had no symptoms associated with any nervous system disorders. It is presently known that infection of SARS-CoV-2 evokes cytokine storm syndrome, which may be one of the factors leading to the acute cerebrovascular disease. One of the substantial problems is the coexistence of cerebrovascular disease and MS in an individual's life span. Epidemiological studies showed an enhanced risk of death rate from vascular disabilities in MS patients of approximately 30%. It has been demonstrated that patients with severe SARS-CoV-2 infection usually show increased levels of D-dimer, fibrinogen, C-reactive protein (CRP), and overactivation of blood platelets, which are essential elements of prothrombotic events. In this review, the latest knowledge gathered during an ongoing pandemic of SARS-CoV-2 infection on the neurodegeneration processes in MS is discussed.


Assuntos
/complicações , Esclerose Múltipla/complicações , Doenças Neurodegenerativas/etiologia , Animais , /virologia , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/patologia , Síndrome da Liberação de Citocina/virologia , Humanos , Esclerose Múltipla/patologia , Esclerose Múltipla/virologia , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/virologia , Trombose/etiologia , Trombose/patologia
10.
Eur J Pharmacol ; 899: 174031, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33722593

RESUMO

Interleukin 6 (IL-6), which is involved in the cytokine storm phenomenon, is a therapeutic target in COVID-19, but monoclonal receptor antibody therapeutic agents such as tocilizumab have demonstrated mixed results. Could Vitamin D, which modulates IL-6, be more effective than currently deployed IL-6 antagonists, including tocilizumab, thereby presenting a useful therapeutic option in COVID-19? A narrative review of published trials examining the effect of Vitamin D administration in COVID-19 patients was conducted, and the theoretical basis for the use of tocilizumab as an IL-6 antagonist was compared with the immunomodulatory effect of Vitamin D on IL-6 production. Four of the six included studies reported a positive effect of Vitamin D on outcomes. While tocilizumab non-selectively blocks both anti-inflammatory and pro-inflammatory actions of IL-6, Vitamin D lowers immune cell IL-6 production, potentially reducing pro-inflammatory effects, but does not specifically target IL-6 receptors, avoiding any deleterious effect on the anti-inflammatory actions of IL-6. Vitamin D may have advantages over tocilizumab as an IL-6 immunomodulator, and, given that it is safe if administered under clinical supervision, there is a strong rationale for its use.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Interleucina-6/sangue , Vitamina D/uso terapêutico , Vitaminas/uso terapêutico , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/terapia , Humanos , Interleucina-6/antagonistas & inibidores
11.
Cancer J ; 27(2): 119-125, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33750071

RESUMO

ABSTRACT: The successful application of chimeric antigen receptor (CAR) T cells for the treatment of relapsed and refractory B-cell malignancies has ushered in a new frontier for the immunotherapy of cancer. Despite its successes, CAR T-cell therapy presents several challenges. Cytokine release syndrome (CRS) triggered by robust and exponential CAR T-cell expansion is the most common adverse effect and may be severe or life-threatening. Although modulation of the interleukin 6 axis was appreciated early on as a means to manage CRS, the exact underlying mechanisms leading to severe CRS remain to be elucidated. What is clear is that severe CRS involves recruitment of the broader immune system into a hyperinflammatory and unregulated state. Myeloid-derived cells appear to play a critical role in this regard and are at the center of active investigation. In this article, we will focus on important elements of CRS, the clinical manifestations, underlying biology, and management strategies including grading, supportive care, and treatment via immunosuppression.


Assuntos
Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/terapia , Imunoterapia Adotiva/efeitos adversos , Animais , Modelos Animais de Doenças , Humanos , Imunoterapia Adotiva/métodos , Camundongos , Células Mieloides/imunologia , Células Mieloides/metabolismo , Células Mieloides/patologia
12.
Sci Signal ; 14(673)2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33688079

RESUMO

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.


Assuntos
/imunologia , Interleucina-1beta/sangue , Subpopulações de Linfócitos T/imunologia , /sangue , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Citometria de Fluxo , Humanos , Interleucina-1beta/farmacologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Monócitos/classificação , Monócitos/imunologia , Monócitos/metabolismo , NF-kappa B/sangue , Pandemias , Fosforilação , Receptores CCR6/sangue , Fatores de Transcrição STAT/sangue , Fatores de Transcrição STAT/imunologia , Transdução de Sinais/imunologia , Subpopulações de Linfócitos T/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/sangue
13.
Respir Med ; 178: 106322, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33550151

RESUMO

The global COVID-19 pandemic is currently underway. In December 2020, the European Agency of Medicine (EMA) licensed the first Sars-CoV-2 vaccine. Therapeutic management of the COVID-19 positive patient should primarily aim to avoid the severe complications and organ injury caused by generalized inflammation caused by a cytokine storm and occurring in the most severe stages of viral infection. Current knowledge of the pathophysiological mechanisms of SARS- CoV-2 suggests a central role for exaggerated activation of the innate immune system as an important contributor to the adverse outcomes of COVID-19. Several studies have shown that blocking the cytokine storm or acting early with prevention of it can be effective; studies are underway to evaluate agents that may be able to reduce this hyperinflammatory state. The search for effective management strategies for COVID-19 continues to evolve. The actions of colchicine, one of the oldest anti-inflammatory therapies, target multiple targets associated with excessive COVID-19 inflammation. Colchicine is easily administered, generally well tolerated, and inexpensive. This article reports the scientific and molecular rationale for the use of colchicine as monotherapy or in combination in the various stages of SARS-CoV-2 infection to modulate and control the inflammatory state. Low-dose colchicine may be considered safe and effective for the treatment and prevention of cytokine storm in patients with SARS-CoV-2 infection, particularly as an adjunctive remedy to other therapeutic agents. Well-organized clinical studies are needed in this direction.


Assuntos
/tratamento farmacológico , Colchicina/uso terapêutico , Síndrome da Liberação de Citocina/tratamento farmacológico , Moduladores de Tubulina/uso terapêutico , /complicações , Síndrome da Liberação de Citocina/etiologia , Humanos
14.
Eur J Haematol ; 106(5): 654-661, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33523540

RESUMO

INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a cytokine storm syndrome associated with mortality rates of up to 88%. Standard therapy with high-dose glucocorticoids and etoposide used in adults is extrapolated from pediatric trials, with significant toxicity in older patients and those with poor performance status. The JAK1/2 inhibitor ruxolitinib has recently gained attention as a treatment option for HLH due to its broad cytokine-modulating abilities and safety profile. Herein we report our center's experience using ruxolitinib in the treatment of adult-onset secondary HLH. CASE SERIES: We report four patients with profound secondary HLH provoked by diverse triggers, including invasive pulmonary aspergillosis on background systemic lupus erythematosus, disseminated tuberculosis, and T-cell lymphoma treated with ruxolitinib as monotherapy or combination therapy in upfront and salvage settings. RESULTS: All four patients had rapid, sustained improvement in clinical status, inflammatory markers, and hematological cell counts followed by durable remission. Three patients developed manageable infectious complications postruxolitinib. CONCLUSIONS: This series demonstrates the effective use of JAK inhibition with ruxolitinib to control pathological immune activation in critically ill patients with secondary HLH and otherwise limited therapeutic options. JAK inhibition is also an area of urgent investigation for the treatment of cytokine storm associated with COVID-19.


Assuntos
Janus Quinases/antagonistas & inibidores , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Adulto , Terapia Combinada , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/etiologia , Citocinas/sangue , Feminino , Humanos , Aspergilose Pulmonar Invasiva/complicações , Lúpus Eritematoso Sistêmico/complicações , Linfo-Histiocitose Hemofagocítica/etiologia , Linfoma de Células T/complicações , Masculino , Pessoa de Meia-Idade , Terapia de Salvação , Tuberculose/complicações , Adulto Jovem
15.
Infect Genet Evol ; 90: 104773, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33607284

RESUMO

The third pandemic of coronavirus infection, called COVID-19 disease, was first detected in November 2019th. Various determinants of disease progression such as age, sex, virus mutations, comorbidity, lifestyle, host immune response, and genetic background variation have caused clinical variability of COVID-19. The causative agent of COVID-19 is an enveloped coronavirus named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that invades host cells using an endocytic pathway. The SARS-CoV-2 spike protein is the main viral protein that contributes to the fusion of the virus particle to the host cell through angiotensin-converting enzyme 2 (ACE2). The highly conserved expression of ACE2 is found in various animals, which indicates its pivotal physiological function. The ACE2 has a crucial role in vascular, renal, and myocardial physiology. Genetic factors contributing to the outcome of SARS-CoV-2 infection are unknown; however, variants in the specific sites of ACE2 gene could be regarded as a main genetic risk factor for COVID-19. Given that ACE2 is the main site for virus landing on host cells, the effect of amino acid sequences of ACE2 on host susceptibility to COVID-19 seems reasonable. It would likely have a substantial role in the occurrence of a wide range of clinical symptoms. Several ACE2 variants can affect the protein stability, influencing the interaction between spike protein and ACE2 through imposing conformational changes while some other variants are known to cause a decrease or an increase in the ligand-receptor affinity. The other variations are located at the proteolytic cleavage site, which can influence virus infection; because soluble ACE2 can act as a decoy receptor for virus and decrease virus intake by cell surface ACE2. Notably, polymorphisms of regulatory and non-coding regions such as promoter in ACE2, can play crucial role in different expression levels of ACE2 among different individuals. Many studies should be performed to investigate the involvement of ACE2 polymorphism with susceptibility to COVID-19. Herein, we discuss some reported associations between variants of ACE2 and COVID-19 in details. In addition, the mode of action of ACE2 and its role in SARS-CoV-2 infection are highlighted which is followed by addressing the effects of several ACE2 variants on its protein stability, viral tropism or ligand-receptor affinity, secondary and tertiary structure or protein conformation, proteolytic cleavage site, and finally inter-individual clinical variability in COVID-19. The polymorphisms of regulatory regions of ACE2 and their effect on expression levels of ACE2 are also provided in this review. Such studies can improve the prediction of the affinity of mutant ACE2 variations with spike protein, and help the biopharmaceutical industry to design effective approaches for recombinant hACE2 therapy and vaccination of COVID-19 disease.


Assuntos
/genética , /virologia , Suscetibilidade a Doenças , Variação Genética , Interações Hospedeiro-Patógeno , /fisiologia , /metabolismo , /metabolismo , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/metabolismo , Gerenciamento Clínico , Interações Hospedeiro-Patógeno/imunologia , Humanos , Evasão da Resposta Imune , Imunidade Inata , Polimorfismo de Nucleotídeo Único , Prognóstico , Ligação Proteica , Receptores Virais/metabolismo , Índice de Gravidade de Doença
16.
Mar Biotechnol (NY) ; 23(1): 149-155, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33566210

RESUMO

An array of infections, including the novel coronavirus (SARS-CoV-2), trigger macrophage activation syndrome (MAS) and subsequently hypercytokinemia, commonly referred to as a cytokine storm (CS). It is postulated that CS is mainly responsible for critical COVID-19 cases, including acute respiratory distress syndrome (ARDS). Recognizing the therapeutic potential of Spirulina blue-green algae (Arthrospira platensis), in this in vitro stimulation study, LPS-activated macrophages and monocytes were treated with aqueous extracts of Spirulina, cultivated in either natural or controlled light conditions. We report that an extract of photosynthetically controlled Spirulina (LED Spirulina), at a concentration of 0.1 µg/mL, decreases macrophage and monocyte-induced TNF-α secretion levels by over 70% and 40%, respectively. We propose prompt in vivo studies in animal models and human subjects to determine the putative effectiveness of a natural, algae-based treatment for viral CS and ARDS, and explore the potential of a novel anti-TNF-α therapy.


Assuntos
/complicações , Extratos Celulares/farmacologia , Extratos Celulares/uso terapêutico , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/terapia , Macrófagos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Células Cultivadas , Humanos , Técnicas In Vitro , Spirulina/química
17.
Ann Hematol ; 100(5): 1295-1301, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33580280

RESUMO

Cytokine release syndrome (CRS), occurring in more than 70% of HLA-haploidentical hematopoietic stem-cell transplantations with post-transplant cyclophosphamide (PT/CY-haplo), can lead to hemodynamic instability and worsen clinical outcomes. A calcineurin inhibitor is initiated after cyclophosphamide administration in the commonly used PT/CY regimens. Here, we conducted a phase I/II, prospective, single-center trial of PT/CY-haplo to evaluate the safety and efficacy of cyclophosphamide on days 3 and 5 along with cyclosporin and mycophenolate mofetil started from day - 1. Thirty-five adults with hematologic malignancies were enrolled. Myeloablative and reduced-intensity conditioning were used in 25 and 10 patients, respectively. Graft sources were bone marrow in 11 patients and mobilized peripheral blood stem cells in 24 patients. Disease-free survival on day 100, the primary endpoint, was 86% (95% confidence interval (CI), 69-94), which was over the predefined threshold of 50%. Unexpectedly, only 20% (95% CI, 8.4-37) of patients developed fever of > 38 °C early after graft infusion, all CRS grade 1, and all of which resolved just after cyclophosphamide administration. The cumulative incidences of grades II-IV acute graft-versus-host disease (GVHD), III-IV acute GVHD, and moderate-severe chronic GVHD were 23% (95% CI, 11-38), 6% (95% CI, 1-17), and 11% (95% CI, 4-25), respectively. The 3-year overall survival rate was 49% (95% CI, 31-64). Our results suggest that administration of cyclosporine and mycophenolate mofetil prior to PT/CY can reduce the frequency and severity of CRS without increasing GVHD. UMIN Clinical Trial Registry numbers: 000006631 and 000015694.


Assuntos
Ciclofosfamida/uso terapêutico , Ciclosporina/uso terapêutico , Síndrome da Liberação de Citocina/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunossupressores/uso terapêutico , Ácido Micofenólico/uso terapêutico , Adolescente , Adulto , Idoso , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Ciclosporina/administração & dosagem , Ciclosporina/efeitos adversos , Síndrome da Liberação de Citocina/etiologia , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Incidência , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/efeitos adversos , Estudos Prospectivos , Transplante Haploidêntico/efeitos adversos , Adulto Jovem
18.
Cytokine Growth Factor Rev ; 58: 82-91, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33573850

RESUMO

SARS-COV-2 infection represents the greatest pandemic of the world, counting daily increasing number of subjects positive to the virus and, sadly, increasing number of deaths. Current studies reported that the cytokine/chemokine network is crucial in the onset and maintenance of the "cytokine storm", the event occurring in those patients in whom the progression of COVID-19 will progress, in most cases, to a very severe and potentially threatening disease. Detecting a possible "immune signature" in patients, as assessed by chemokines status in patients with COVID-19, could be helpful for individual risk stratification for developing a more or less severe clinical course of the disease. The present review is specifically aimed at overviewing current evidences provided by in vitro and in vivo studies addressing the issue of which chemokines seems to be involved, at least at present, in COVID-19. Currently available experimental and clinical studies regarding those chemokines more deeply studied in COVID-19, with a specific focus on their role in the cytokine storm and ultimately with their ability to predict the clinical course of the disease, will be taken into account. Moreover, similarities and differences between chemokines and cytokines, which both contribute to the onset of the pro-inflammatory loop characterizing SARS-COV-2 infection, will be briefly discussed. Future studies will rapidly accumulate in the next months and their results will hopefully provide more insights as to the complex physiopathology of COVID-19-related cytokine storm. This will likely make the present review somehow "dated" in a short time, but still the present review provides an overview of the scenario of the current knowledge on this topic.


Assuntos
/complicações , Quimiocinas/fisiologia , Síndrome da Liberação de Citocina/etiologia , /patogenicidade , Quimiocinas/metabolismo , Síndrome da Liberação de Citocina/imunologia , Citocinas/metabolismo , Citocinas/fisiologia , Humanos , /imunologia
19.
N Engl J Med ; 384(8): 705-716, 2021 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-33626253

RESUMO

BACKGROUND: Idecabtagene vicleucel (ide-cel, also called bb2121), a B-cell maturation antigen-directed chimeric antigen receptor (CAR) T-cell therapy, has shown clinical activity with expected CAR T-cell toxic effects in patients with relapsed and refractory multiple myeloma. METHODS: In this phase 2 study, we sought to confirm the efficacy and safety of ide-cel in patients with relapsed and refractory myeloma. Patients with disease after at least three previous regimens including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody were enrolled. Patients received ide-cel target doses of 150 × 106 to 450 × 106 CAR-positive (CAR+) T cells. The primary end point was an overall response (partial response or better); a key secondary end point was a complete response or better (comprising complete and stringent complete responses). RESULTS: Of 140 patients enrolled, 128 received ide-cel. At a median follow-up of 13.3 months, 94 of 128 patients (73%) had a response, and 42 of 128 (33%) had a complete response or better. Minimal residual disease (MRD)-negative status (<10-5 nucleated cells) was confirmed in 33 patients, representing 26% of all 128 patients who were treated and 79% of the 42 patients who had a complete response or better. The median progression-free survival was 8.8 months (95% confidence interval, 5.6 to 11.6). Common toxic effects among the 128 treated patients included neutropenia in 117 patients (91%), anemia in 89 (70%), and thrombocytopenia in 81 (63%). Cytokine release syndrome was reported in 107 patients (84%), including 7 (5%) who had events of grade 3 or higher. Neurotoxic effects developed in 23 patients (18%) and were of grade 3 in 4 patients (3%); no neurotoxic effects higher than grade 3 occurred. Cellular kinetic analysis confirmed CAR+ T cells in 29 of 49 patients (59%) at 6 months and 4 of 11 patients (36%) at 12 months after infusion. CONCLUSIONS: Ide-cel induced responses in a majority of heavily pretreated patients with refractory and relapsed myeloma; MRD-negative status was achieved in 26% of treated patients. Almost all patients had grade 3 or 4 toxic effects, most commonly hematologic toxic effects and cytokine release syndrome. (Funded by bluebird bio and Celgene, a Bristol-Myers Squibb company; KarMMa ClinicalTrials.gov number, NCT03361748.).


Assuntos
Imunoterapia Adotiva , Mieloma Múltiplo/terapia , Receptores de Antígenos Quiméricos/uso terapêutico , Adulto , Idoso , Biomarcadores/sangue , Síndrome da Liberação de Citocina/etiologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Doenças Hematológicas/induzido quimicamente , Humanos , Imunoterapia Adotiva/efeitos adversos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/imunologia , Intervalo Livre de Progressão , Recidiva
20.
J Endocrinol Invest ; 44(5): 891-904, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33559848

RESUMO

BACKGROUND: COVID-19 is now a worldwide pandemic. Among the many extra-pulmonary manifestations of COVID-19, recent evidence suggested a possible occurrence of thyroid dysfunction. PURPOSE: The Aim of the present review is to summarize available studies regarding thyroid function alterations in patients with COVID-19 and to overview the possible physio-pathological explanations. CONCLUSIONS: The repercussions of the thyroid of COVID-19 seem to be related, in part, with the occurrence of a "cytokine storm" that would, in turn, induce a "non-thyroidal illness". Some specific cytokines and chemokines appear to have a direct role on the hypothalamus-pituitary-thyroid axis. On the other hand, some authors have observed an increased incidence of a destructive thyroiditis, either subacute or painless, in patients with COVID-19. The hypothesis of a direct infection of the thyroid by SARS-Cov-2 stems from the observation that its receptor, ACE2, is strongly expressed in thyroid tissue. Lastly, it is highly probable that some pharmaceutical agents largely used for the treatment of COVID-19 can act as confounding factors in the laboratory evaluation of thyroid function parameters.


Assuntos
/metabolismo , Síndrome da Liberação de Citocina/metabolismo , Hormônios Tireóideos/metabolismo , Antivirais/efeitos adversos , Antivirais/uso terapêutico , /tratamento farmacológico , Síndrome da Liberação de Citocina/etiologia , Citocinas/sangue , Humanos , Tireoidite/etiologia
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