Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 943
Filtrar
1.
Front Immunol ; 12: 640093, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33717193

RESUMO

COVID-19 (SARS-CoV-2) disease severity and stages varies from asymptomatic, mild flu-like symptoms, moderate, severe, critical, and chronic disease. COVID-19 disease progression include lymphopenia, elevated proinflammatory cytokines and chemokines, accumulation of macrophages and neutrophils in lungs, immune dysregulation, cytokine storms, acute respiratory distress syndrome (ARDS), etc. Development of vaccines to severe acute respiratory syndrome (SARS), Middle East Respiratory Syndrome coronavirus (MERS-CoV), and other coronavirus has been difficult to create due to vaccine induced enhanced disease responses in animal models. Multiple betacoronaviruses including SARS-CoV-2 and SARS-CoV-1 expand cellular tropism by infecting some phagocytic cells (immature macrophages and dendritic cells) via antibody bound Fc receptor uptake of virus. Antibody-dependent enhancement (ADE) may be involved in the clinical observation of increased severity of symptoms associated with early high levels of SARS-CoV-2 antibodies in patients. Infants with multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 may also have ADE caused by maternally acquired SARS-CoV-2 antibodies bound to mast cells. ADE risks associated with SARS-CoV-2 has implications for COVID-19 and MIS-C treatments, B-cell vaccines, SARS-CoV-2 antibody therapy, and convalescent plasma therapy for patients. SARS-CoV-2 antibodies bound to mast cells may be involved in MIS-C and multisystem inflammatory syndrome in adults (MIS-A) following initial COVID-19 infection. SARS-CoV-2 antibodies bound to Fc receptors on macrophages and mast cells may represent two different mechanisms for ADE in patients. These two different ADE risks have possible implications for SARS-CoV-2 B-cell vaccines for subsets of populations based on age, cross-reactive antibodies, variabilities in antibody levels over time, and pregnancy. These models place increased emphasis on the importance of developing safe SARS-CoV-2 T cell vaccines that are not dependent upon antibodies.


Assuntos
Anticorpos Facilitadores , Mastócitos/imunologia , Coronavírus da Síndrome Respiratória do Oriente Médio/fisiologia , Fagócitos/imunologia , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Animais , Anticorpos Antivirais/metabolismo , Criança , Reações Cruzadas , Feminino , Humanos , Recém-Nascido , Transmissão Vertical de Doença Infecciosa , Modelos Imunológicos , Gravidez , Receptores Fc/metabolismo , Risco , Linfócitos T/imunologia
2.
J Trop Pediatr ; 67(1)2021 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-33787904

RESUMO

LAY SUMMARY: Clinical and laboratory parameters of multisystem inflammatory syndrome in children (MIS-C) mimic Kawasaki disease (KD). KD has been described in association with dengue, scrub typhus and leptospirosis. However, MIS-C with concomitant infection has rarely been reported in literature. A 14-year-old-girl presented with fever and rash with history of redness of eyes, lips and tongue. Investigations showed anemia, lymphopenia, thrombocytosis with elevated erythrocyte sedimentation rate, C-reactive protein, pro-brain natriuretic peptide, Interleukin-6, ferritin and d-dimer. Scrub typhus immunoglobulin M was positive. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin G (IgG) level was also elevated. A diagnosis of MIS-C with concomitant scrub typhus was proffered. Child received azithromycin, intravenous immunoglobulin and methylprednisolone. After an afebrile period of 2.5 days, child developed unremitting fever and rash. Repeat investigations showed anemia, worsening lymphopenia, thrombocytopenia, transaminitis, hypertriglyceridemia, hyperferritinemia and hypofibrinogenemia which were consistent with a diagnosis of macrophage activation syndrome (MAS). KD, MIS-C and MAS represent three distinct phenotypes of hyperinflammation seen in children during coronavirus disease pandemic. Several tropical infections may mimic or coexist with MIS-C which can be a diagnostic challenge for the treating physician. Identification of coexistence or differentiation between the two conditions is important in countries with high incidence of tropical infections to guide appropriate investigations and treatment.


Assuntos
/complicações , Síndrome de Ativação Macrofágica/diagnóstico , Tifo por Ácaros/diagnóstico , Síndrome de Resposta Inflamatória Sistêmica , Adolescente , Azitromicina/uso terapêutico , Biomarcadores/sangue , /diagnóstico , Criança , Feminino , Febre/etiologia , Humanos , Imunoglobulina G/sangue , Imunoglobulinas Intravenosas/uso terapêutico , Síndrome de Ativação Macrofágica/complicações , Síndrome de Ativação Macrofágica/tratamento farmacológico , Síndrome de Ativação Macrofágica/imunologia , Metilprednisolona/administração & dosagem , Metilprednisolona/uso terapêutico , Pandemias , Tifo por Ácaros/complicações , Tifo por Ácaros/tratamento farmacológico , Síndrome de Resposta Inflamatória Sistêmica/sangue , Síndrome de Resposta Inflamatória Sistêmica/diagnóstico , Síndrome de Resposta Inflamatória Sistêmica/tratamento farmacológico , Síndrome de Resposta Inflamatória Sistêmica/imunologia
5.
Sci Immunol ; 6(57)2021 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-33653907

RESUMO

Pediatric COVID-19 following SARS-CoV-2 infection is associated with fewer hospitalizations and often milder disease than in adults. A subset of children, however, present with Multisystem Inflammatory Syndrome in Children (MIS-C) that can lead to vascular complications and shock, but rarely death. The immune features of MIS-C compared to pediatric COVID-19 or adult disease remain poorly understood. We analyzed peripheral blood immune responses in hospitalized SARS-CoV-2 infected pediatric patients (pediatric COVID-19) and patients with MIS-C. MIS-C patients had patterns of T cell-biased lymphopenia and T cell activation similar to severely ill adults, and all patients with MIS-C had SARS-CoV-2 spike-specific antibodies at admission. A distinct feature of MIS-C patients was robust activation of vascular patrolling CX3CR1+ CD8+ T cells that correlated with the use of vasoactive medication. Finally, whereas pediatric COVID-19 patients with acute respiratory distress syndrome (ARDS) had sustained immune activation, MIS-C patients displayed clinical improvement over time, concomitant with decreasing immune activation. Thus, non-MIS-C versus MIS-C SARS-CoV-2 associated illnesses are characterized by divergent immune signatures that are temporally distinct from one another and implicate CD8+ T cells in the clinical presentation and trajectory of MIS-C.


Assuntos
/imunologia , Ativação Linfocitária , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Linfócitos T/imunologia , Adolescente , Adulto , Envelhecimento/imunologia , Criança , Pré-Escolar , Feminino , Citometria de Fluxo , Humanos , Leucopenia/imunologia , Masculino , Adulto Jovem
6.
Front Immunol ; 12: 632890, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33732254

RESUMO

Coronavirus disease-19 (COVID-19) in children is usually mild but some are susceptible to a Kawasaki disease (KD)-like multisystem inflammatory syndrome in children (MIS-C) in the convalescent stage, posing a need to differentiate the phenotype, susceptibility, autoimmunity, and immunotherapy between KD and MIS-C, particularly in the upcoming mass vaccination of COVID-19. Patients with MIS-C are prone to gastrointestinal symptoms, coagulopathy, and shock in addition to atypical KD syndrome with fever, mucocutaneous lesions, lymphadenopathy, and/or cardiovascular events. MIS-C manifests KD-like symptoms that alert physicians to early recognize and adopt the KD treatment regimen for patients with MIS-C. MIS-C linked to COVID-19 teaches us infection-associated autoimmune vasculitis and vice versa. Studies on genetic susceptibility have identified certain human leukocyte antigen (HLA) locus and toll-like receptor (TLR) associated with KD and/or COVID-19. Certain HLA subtypes, such as HLA-DRB1 and HLA-MICA A4 are associated with KD. HLA-B*46:01 is proposed to be the risk allele of severe COVID-19 infection, and blood group O type is a protective factor of COVID-19. The autoimmune vasculitis of KD, KD shock syndrome (KDSS), or MIS-C is mediated by a genetic variant of HLA, FcγR, and/or antibody-dependent enhancement (ADE) resulting in hyperinflammation with T helper 17 (Th17)/Treg imbalance with augmented Th17/Th1 mediators: interleukin-6 (IL-6), IL-10, inducible protein-10 (IP-10), Interferon (IFNγ), and IL-17A, and lower expression of Treg-signaling molecules, FoxP3, and transforming growth factor (TGF-ß). There are certain similarities and differences in phenotypes, susceptibility, and pathogenesis of KD, KDSS, and MIS-C, by which a physician can make early protection, prevention, and precision treatment of the diseases. The evolution of immunotherapies for the diseases has shown that intravenous immunoglobulin (IVIG) alone or combined with corticosteroids is the standard treatment for KD, KDSS, and MIS-C. However, a certain portion of patients who revealed a treatment resistance to IVIG or IVIG plus corticosteroids, posing a need to early identify the immunopathogenesis, to protect hosts with genetic susceptibility, and to combat Th17/Treg imbalance by anti-cytokine or pro-Treg for reversal of the hyperinflammation and IVIG resistance. Based on physiological and pathological immunity of the diseases under genetic susceptibility and host milieu conditions, a series of sequential regimens are provided to develop a so-called "Know thyself, enemy (pathogen), and ever-victorious" strategy for the prevention and immunotherapy of KD and/or MIS-C.


Assuntos
Autoimunidade , /terapia , Predisposição Genética para Doença/genética , Imunoterapia/métodos , Síndrome de Linfonodos Mucocutâneos/imunologia , Síndrome de Linfonodos Mucocutâneos/terapia , Fenótipo , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Síndrome de Resposta Inflamatória Sistêmica/terapia , Adolescente , Corticosteroides/uso terapêutico , /virologia , Criança , Pré-Escolar , Citocinas/sangue , Feminino , Antígenos HLA/genética , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Lactente , Masculino , Síndrome de Linfonodos Mucocutâneos/genética , Síndrome de Resposta Inflamatória Sistêmica/genética , Síndrome de Resposta Inflamatória Sistêmica/virologia
7.
Medicine (Baltimore) ; 100(12): e24669, 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33761636

RESUMO

ABSTRACT: Neutrophils have crucial roles in defensing against infection and adaptive immune responses. This study aimed to investigate the genetic mechanism in neutrophils in response to sepsis-induced immunosuppression.The GSE64457 dataset was downloaded from the Gene Expression Omnibus database and the neutrophil samples (D3-4 and D6-8 post sepsis shock) were assigned into two groups. The differentially expressed genes (DEGs) were identified. The Short Time-series Expression Miner (STEM) clustering analysis was conducted to select the consistently changed DEGs post sepsis shock. The overlapping genes between the DEGs and the deposited genes associated with immune, sepsis, and immunosuppression in the AmiGO2 and Comparative Toxicogenomics Database were screened out and used for the construction of the protein-protein interaction (PPI) network. The expression of several hub genes in sepsis patients was validated using the PCR analysis. The drugs targeting the hub genes and the therapy strategies for sepsis or immunosuppression were reviewed and used to construct the drug-gene-therapy-cell network to illustrate the potential therapeutic roles of the hub genes.A total of 357 overlapping DEGs between the two groups were identified and were used for the STEM clustering analysis, which generated four significant profiles with 195 upregulated (including annexin A1, ANXA1; matrix metallopeptidase 9, MMP9; and interleukin 15, IL-15) and 151 downregulated DEGs (including, AKT1, IFN-related genes, and HLA antigen genes). Then, a total of 34 of the 151 downregulated DEGs and 39 of the 195 upregulated DEGs were shared between the databases and above DEGs, respectively. The PPI network analysis identified a downregulated module including IFN-related genes. The deregulation of DEGs including AKT1 (down), IFN-inducible protein 6 (IFI6, down), IL-15 (up), and ANXA1 (up) was verified in the neutrophils from patients with sepsis-induced immunosuppression as compared with controls. Literature review focusing on the therapy showed that the upregulation of IL-15, IFN, and HLA antigens are the management targets. Besides, the AKT1 gene was targeted by gemcitabine.These findings provided additional clues for understanding the mechanisms of sepsis-induced immunosuppression. The drugs targeting AKT1 might provide now clues for the management strategy of immunosuppression with the intention to prevent neutrophil infiltration.


Assuntos
Regulação da Expressão Gênica/imunologia , Tolerância Imunológica/genética , Neutrófilos/imunologia , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Idoso , Anexina A1/genética , Anexina A1/metabolismo , Estudos de Casos e Controles , Biologia Computacional , Conjuntos de Dados como Assunto , Feminino , Perfilação da Expressão Gênica , Redes Reguladoras de Genes/imunologia , Humanos , Interleucina-15/genética , Interleucina-15/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Neutrófilos/metabolismo , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas/imunologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/imunologia , Síndrome de Resposta Inflamatória Sistêmica/sangue , Síndrome de Resposta Inflamatória Sistêmica/genética
10.
J Clin Invest ; 131(6)2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33497356

RESUMO

Multisystem inflammatory syndrome associated with the SARS-CoV-2 pandemic has recently been described in children (MIS-C), partially overlapping with Kawasaki disease (KD). We hypothesized that (a) MIS-C and prepandemic KD cytokine profiles may be unique and justify the clinical differences observed, and (b) SARS-CoV-2-specific immune complexes (ICs) may explain the immunopathology of MIS-C. Seventy-four children were included: 14 with MIS-C, 9 patients positive for SARS-CoV-2 by PCR without MIS-C (COVID), 14 with prepandemic KD, and 37 healthy controls (HCs). Thirty-four circulating cytokines were quantified in pretreatment serum or plasma samples and the presence of circulating SARS-CoV-2 ICs was evaluated in MIS-C patients. Compared with HCs, the MIS-C and KD groups showed most cytokines to be significantly elevated, with IFN-γ-induced response markers (including IFN-γ, IL-18, and IP-10) and inflammatory monocyte activation markers (including MCP-1, IL-1α, and IL-1RA) being the main triggers of inflammation. In linear discriminant analysis, MIS-C and KD profiles overlapped; however, a subgroup of MIS-C patients (MIS-Cplus) differentiated from the remaining MIS-C patients in IFN-γ, IL-18, GM-CSF, RANTES, IP-10, IL-1α, and SDF-1 and incipient signs of macrophage activation syndrome. Circulating SARS-CoV-2 ICs were not detected in MIS-C patients. Our findings suggest a major role for IFN-γ in the pathogenesis of MIS-C, which may be relevant for therapeutic management.


Assuntos
/etiologia , Citocinas/sangue , Síndrome de Linfonodos Mucocutâneos/etiologia , Síndrome de Resposta Inflamatória Sistêmica/etiologia , Adolescente , Anticorpos Antivirais/sangue , Complexo Antígeno-Anticorpo/sangue , Antígenos Virais/sangue , /virologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Lactente , Interferon gama/sangue , Masculino , Modelos Imunológicos , Síndrome de Linfonodos Mucocutâneos/imunologia , Pandemias , /imunologia , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Síndrome de Resposta Inflamatória Sistêmica/virologia
12.
Viruses ; 12(12)2020 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-33322160

RESUMO

Innate immune interferons (IFNs), including type I and III IFNs, constitute critical antiviral mechanisms. Recent studies reveal that IFN dysregulation is key to determine COVID-19 pathogenesis. Effective IFN stimulation or prophylactic administration of IFNs at the early stage prior to severe COVID-19 may elicit an autonomous antiviral state, restrict the virus infection, and prevent COVID-19 progression. Inborn genetic flaws and autoreactive antibodies that block IFN response have been significantly associated with about 14% of patients with life-threatening COVID-19 pneumonia. In most severe COVID-19 patients without genetic errors in IFN-relevant gene loci, IFN dysregulation is progressively worsened and associated with the situation of pro-inflammation and immunopathy, which is prone to autoimmunity. In addition, the high correlation of severe COVID-19 with seniority, males, and individuals with pre-existing comorbidities will be plausibly explained by the coincidence of IFN aberrance in these situations. Collectively, current studies call for a better understanding of the IFN response regarding the spatiotemporal determination and subtype-specificity against SARS-CoV-2 infections, which are warranted to devise IFN-related prophylactics and therapies.


Assuntos
Antivirais/imunologia , Interferons/imunologia , /patogenicidade , Antivirais/uso terapêutico , /patologia , Progressão da Doença , Humanos , Interferons/deficiência , Interferons/uso terapêutico , Cinética , Prognóstico , Transdução de Sinais , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Síndrome de Resposta Inflamatória Sistêmica/patologia
13.
Ned Tijdschr Geneeskd ; 1642020 10 22.
Artigo em Holandês | MEDLINE | ID: mdl-33331715

RESUMO

Paediatric Multisystem Inflammatory Syndrome Temporally Related to SARS-CoV-2 (PIMS-TS) is a rare novel clinical entity observed in children and adolescents with evidence of a recent COVID-19 infection, and is characterized by a marked hyperinflammatory state with involvement of multiple organ systems.We report a case of a previously healthy 15-year-old female patient, who was admitted to paediatric intensive care with cardiac failure and was subsequently shown to have positive COVID-19 serology. The presenting symptoms were fever, cough, chest pain and gastro-intestinal symptoms. She was supported with milrinone and a low dose of vasopressors. Her hyperinflammatory state was treated with intravenous immunoglobulins, high dose aspirin and high-dose methylprednisolone. PIMS-TS is a rare, potentially life threatening novel clinical entity in children and adolescents with evidence of a COVID-19 infection. Clinicians need to be aware of the possibility of this new disease, to ensure prompt recognition and treatment.


Assuntos
Aspirina/administração & dosagem , Imunoglobulinas Intravenosas/administração & dosagem , Metilprednisolona/administração & dosagem , Milrinona/administração & dosagem , Síndrome de Resposta Inflamatória Sistêmica , Vasoconstritores/administração & dosagem , Adolescente , Anti-Inflamatórios/administração & dosagem , /fisiopatologia , Cardiotônicos/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/etiologia , Humanos , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Síndrome de Resposta Inflamatória Sistêmica/fisiopatologia , Resultado do Tratamento
14.
BMJ Open ; 10(11): e041989, 2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-33184086

RESUMO

OBJECTIVE: The reliable risk factors for mortality of COVID-19 has not evaluated in well-characterised cohort. This study aimed to identify risk factors for in-hospital mortality within 56 days in patients with severe infection of COVID-19. DESIGN: Retrospective multicentre cohort study. SETTING: Five tertiary hospitals of Daegu, South Korea. PARTICIPANTS: 1005 participants over 19 years old confirmed COVID-19 using real-time PCR from nasopharyngeal and oropharyngeal swabs. METHODS: The clinical and laboratory features of patients with COVID-19 receiving respiratory support were analysed to ascertain the risk factors for mortality using the Cox proportional hazards regression model. The relationship between overall survival and risk factors was analysed using the Kaplan-Meier method. OUTCOME: In-hospital mortality for any reason within 56 days. RESULTS: Of the 1005 patients, 289 (28.8%) received respiratory support, and of these, 70 patients (24.2%) died. In multivariate analysis, high fibrosis-4 index (FIB-4; HR 2.784), low lymphocyte count (HR 0.480), diabetes (HR 1.917) and systemic inflammatory response syndrome (HR 1.714) were found to be independent risk factors for mortality in patients with COVID-19 receiving respiratory support (all p<0.05). Regardless of respiratory support, survival in the high FIB-4 group was significantly lower than in the low FIB-4 group (28.8 days vs 44.0 days, respectively, p<0.001). A number of risk factors were also significantly related to survival in patients with COVID-19 regardless of respiratory support (0-4 risk factors, 50.2 days; 49.7 days; 44.4 days; 32.0 days; 25.0 days, respectively, p<0.001). CONCLUSION: FIB-4 index is a useful predictive marker for mortality in patients with COVID-19 regardless of its severity.


Assuntos
Fatores Etários , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Infecções por Coronavirus/sangue , Mortalidade Hospitalar , Linfopenia/sangue , Contagem de Plaquetas , Pneumonia Viral/sangue , Idoso , Idoso de 80 Anos ou mais , Antivirais/uso terapêutico , Betacoronavirus , Estudos de Coortes , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/terapia , Diabetes Mellitus/epidemiologia , Feminino , Humanos , Fatores Imunológicos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/mortalidade , Pneumonia Viral/terapia , Modelos de Riscos Proporcionais , República da Coreia , Respiração Artificial , Estudos Retrospectivos , Medição de Risco , Síndrome de Resposta Inflamatória Sistêmica/imunologia
15.
Front Immunol ; 11: 2055, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33042116

RESUMO

The clinical and laboratory features of COVID-19 are reviewed with attention to the immunologic manifestations of the disease. Recent COVID-19 publications describe a variety of clinical presentations including an asymptomatic state, pneumonia, a hemophagocytic lymphohistiocytosis like syndrome, Multisystem Inflammatory Syndrome in Children (MIS-C) but, also called Pediatric Inflammatory Multisystem Syndrome-Toxic Shock (PIMS-TS), Kawasaki Disease, and myocarditis. A common theme amongst multiple reports suggests an overexuberant autoimmune component of the disease but a common pathophysiology to explain the variations in clinical presentation has been elusive. Review of the basic science of other viral induced autoimmune disorders may give clues as to why immunosuppressive and immunomodulating regimens now appear to have some efficacy in COVID-19. Review of the immunopathology also reveals other therapies that have yet to be explored. There is potential use of T cell depleting therapies and possibly anti-CD20 therapy for COVID-19 and clinical research using these medications is warranted.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus , Imunossupressores/uso terapêutico , Depleção Linfocítica , Pandemias , Pneumonia Viral , Síndrome de Resposta Inflamatória Sistêmica , Linfócitos T , Criança , Pré-Escolar , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Infecções por Coronavirus/terapia , Humanos , Linfo-Histiocitose Hemofagocítica/imunologia , Linfo-Histiocitose Hemofagocítica/patologia , Linfo-Histiocitose Hemofagocítica/terapia , Linfo-Histiocitose Hemofagocítica/virologia , Síndrome de Linfonodos Mucocutâneos/imunologia , Síndrome de Linfonodos Mucocutâneos/patologia , Síndrome de Linfonodos Mucocutâneos/terapia , Síndrome de Linfonodos Mucocutâneos/virologia , Miocardite/imunologia , Miocardite/terapia , Miocardite/virologia , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Pneumonia Viral/terapia , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Síndrome de Resposta Inflamatória Sistêmica/patologia , Síndrome de Resposta Inflamatória Sistêmica/terapia , Síndrome de Resposta Inflamatória Sistêmica/virologia , Linfócitos T/imunologia , Linfócitos T/patologia
16.
J Pediatric Infect Dis Soc ; 9(5): 622-625, 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-32951037

RESUMO

The pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 infection is a severe complication of coronavirus disease 2019. Since impaired coagulation and thrombosis/endotheliitis are suspected pathomechanisms, we treated 2 patients with defibrotide, a profibrinolytic, antithrombotic, antiinflammatory oligonucleotide. Symptoms resolved during treatment. Moreover, coagulation parameters indicating hypofibrinolysis and complement activation normalized. The pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 infection is a severe complication of coronavirus disease 2019. Since impaired coagulation and thrombosis/endotheliitis are suspected pathomechanisms, 2 patients received defibrotide, a profibrinolytic, antithrombotic, antiinflammatory oligonucleotide. Symptoms resolved and hypofibrinolysis/complement activation normalized during treatment.


Assuntos
Infecções por Coronavirus/complicações , Inibidores da Agregação de Plaquetas/uso terapêutico , Pneumonia Viral/complicações , Polidesoxirribonucleotídeos/uso terapêutico , Síndrome de Resposta Inflamatória Sistêmica/tratamento farmacológico , Dor Abdominal/etiologia , Adolescente , Betacoronavirus , Fatores de Coagulação Sanguínea/análise , Criança , Infecções por Coronavirus/diagnóstico , Feminino , Febre/etiologia , Humanos , Pandemias , Pneumonia Viral/diagnóstico , Síndrome de Resposta Inflamatória Sistêmica/sangue , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Linfócitos T/imunologia
17.
Proc Natl Acad Sci U S A ; 117(41): 25254-25262, 2020 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-32989130

RESUMO

Multisystem Inflammatory Syndrome in Children (MIS-C) associated with COVID-19 is a newly recognized condition in children with recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. These children and adult patients with severe hyperinflammation present with a constellation of symptoms that strongly resemble toxic shock syndrome, an escalation of the cytotoxic adaptive immune response triggered upon the binding of pathogenic superantigens to T cell receptors (TCRs) and/or major histocompatibility complex class II (MHCII) molecules. Here, using structure-based computational models, we demonstrate that the SARS-CoV-2 spike (S) glycoprotein exhibits a high-affinity motif for binding TCRs, and may form a ternary complex with MHCII. The binding epitope on S harbors a sequence motif unique to SARS-CoV-2 (not present in other SARS-related coronaviruses), which is highly similar in both sequence and structure to the bacterial superantigen staphylococcal enterotoxin B. This interaction between the virus and human T cells could be strengthened by a rare mutation (D839Y/N/E) from a European strain of SARS-CoV-2. Furthermore, the interfacial region includes selected residues from an intercellular adhesion molecule (ICAM)-like motif shared between the SARS viruses from the 2003 and 2019 pandemics. A neurotoxin-like sequence motif on the receptor-binding domain also exhibits a high tendency to bind TCRs. Analysis of the TCR repertoire in adult COVID-19 patients demonstrates that those with severe hyperinflammatory disease exhibit TCR skewing consistent with superantigen activation. These data suggest that SARS-CoV-2 S may act as a superantigen to trigger the development of MIS-C as well as cytokine storm in adult COVID-19 patients, with important implications for the development of therapeutic approaches.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Pneumonia Viral/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Superantígenos/metabolismo , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Motivos de Aminoácidos , Betacoronavirus/química , Betacoronavirus/genética , Betacoronavirus/metabolismo , Infecções por Coronavirus/genética , Infecções por Coronavirus/patologia , Enterotoxinas/química , Epitopos de Linfócito T , Humanos , Molécula 1 de Adesão Intercelular/química , Modelos Moleculares , Mutação , Neurotoxinas/química , Pandemias , Pneumonia Viral/genética , Pneumonia Viral/patologia , Ligação Proteica , Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/genética , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Superantígenos/química , Superantígenos/genética , Síndrome de Resposta Inflamatória Sistêmica/genética , Síndrome de Resposta Inflamatória Sistêmica/patologia
18.
Asian Pac J Allergy Immunol ; 38(3): 170-177, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32990448

RESUMO

The disease course of coronavirus disease 2019 (COVID-19) is usually mild and self-limiting in previously healthy children, but they may also develop severe disease. Severe COVID-19 infection is especially observed in very young children or those with underlying comorbidities. Moreover, a multisystem inflammatory syndrome that mimics the Kawasaki disease shock syndrome can develop in children that are genetically predisposed to displaying an overactive immune response to SARS-CoV-2 infection. In this review, we describe the clinical phenotypes of mild and severe COVID-19 and multisystem inflammatory syndrome in children (MIS-C). We also discuss the possible immunobiological mechanisms that may be involved in the protection of children against COVID-19 and the development of multisystem inflammatory syndrome.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/virologia , Pneumonia Viral/virologia , Síndrome de Resposta Inflamatória Sistêmica/virologia , Adolescente , Idade de Início , Betacoronavirus/imunologia , Criança , Pré-Escolar , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/epidemiologia , Síndrome da Liberação de Citocina/imunologia , Citocinas/imunologia , Suscetibilidade a Doenças , Feminino , Interações Hospedeiro-Patógeno , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/virologia , Lactente , Recém-Nascido , Ativação Linfocitária , Ativação de Macrófagos , Masculino , Pandemias , Fenótipo , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Prognóstico , Fatores de Risco , Índice de Gravidade de Doença , Síndrome de Resposta Inflamatória Sistêmica/epidemiologia , Síndrome de Resposta Inflamatória Sistêmica/imunologia
19.
Cell ; 183(4): 982-995.e14, 2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-32991843

RESUMO

Initially, children were thought to be spared from disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, a month into the epidemic, a novel multisystem inflammatory syndrome in children (MIS-C) emerged. Herein, we report on the immune profiles of nine MIS-C cases. All MIS-C patients had evidence of prior SARS-CoV-2 exposure, mounting an antibody response with intact neutralization capability. Cytokine profiling identified elevated signatures of inflammation (IL-18 and IL-6), lymphocytic and myeloid chemotaxis and activation (CCL3, CCL4, and CDCP1), and mucosal immune dysregulation (IL-17A, CCL20, and CCL28). Immunophenotyping of peripheral blood revealed reductions of non-classical monocytes, and subsets of NK and T lymphocytes, suggesting extravasation to affected tissues. Finally, profiling the autoantigen reactivity of MIS-C plasma revealed both known disease-associated autoantibodies (anti-La) and novel candidates that recognize endothelial, gastrointestinal, and immune-cell antigens. All patients were treated with anti-IL-6R antibody and/or IVIG, which led to rapid disease resolution.


Assuntos
Inflamação/patologia , Síndrome de Resposta Inflamatória Sistêmica/patologia , Adolescente , Anticorpos Antivirais/sangue , Autoanticorpos/sangue , Betacoronavirus/imunologia , Betacoronavirus/isolamento & purificação , Quimiocina CCL3/metabolismo , Criança , Pré-Escolar , Infecções por Coronavirus/complicações , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Feminino , Humanos , Imunidade Humoral , Lactente , Recém-Nascido , Inflamação/metabolismo , Interleucina-17/metabolismo , Interleucina-18/metabolismo , Células Matadoras Naturais/citologia , Células Matadoras Naturais/metabolismo , Masculino , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Síndrome de Resposta Inflamatória Sistêmica/metabolismo , Linfócitos T/citologia , Linfócitos T/metabolismo , Adulto Jovem
20.
Ann Surg ; 272(4): 604-610, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32932316

RESUMO

OBJECTIVES: Sepsis and sterile both release "danger signals' that induce the systemic inflammatory response syndrome (SIRS). So differentiating infection from SIRS can be challenging. Precision diagnostic assays could limit unnecessary antibiotic use, improving outcomes. METHODS: After surveying human leukocyte cytokine production responses to sterile damage-associated molecular patterns (DAMPs), bacterial pathogen-associated molecular patterns, and bacteria we created a multiplex assay for 31 cytokines. We then studied plasma from patients with bacteremia, septic shock, "severe sepsis," or trauma (ISS ≥15 with circulating DAMPs) as well as controls. Infections were adjudicated based on post-hospitalization review. Plasma was studied in infection and injury using univariate and multivariate means to determine how such multiplex assays could best distinguish infective from noninfective SIRS. RESULTS: Infected patients had high plasma interleukin (IL)-6, IL-1α, and triggering receptor expressed on myeloid cells-1 (TREM-1) compared to controls [false discovery rates (FDR) <0.01, <0.01, <0.0001]. Conversely, injury suppressed many mediators including MDC (FDR <0.0001), TREM-1 (FDR <0.001), IP-10 (FDR <0.01), MCP-3 (FDR <0.05), FLT3L (FDR <0.05), Tweak, (FDR <0.05), GRO-α (FDR <0.05), and ENA-78 (FDR <0.05). In univariate studies, analyte overlap between clinical groups prevented clinical relevance. Multivariate models discriminated injury and infection much better, with the 2-group random-forest model classifying 11/11 injury and 28/29 infection patients correctly in out-of-bag validation. CONCLUSIONS: Circulating cytokines in traumatic SIRS differ markedly from those in health or sepsis. Variability limits the accuracy of single-mediator assays but machine learning based on multiplexed plasma assays revealed distinct patterns in sepsis- and injury-related SIRS. Defining biomarker release patterns that distinguish specific SIRS populations might allow decreased antibiotic use in those clinical situations. Large prospective studies are needed to validate and operationalize this approach.


Assuntos
Citocinas/sangue , Sepse/sangue , Sepse/diagnóstico , Síndrome de Resposta Inflamatória Sistêmica/sangue , Síndrome de Resposta Inflamatória Sistêmica/diagnóstico , Relatórios Anuais como Assunto , Diagnóstico Diferencial , Cirurgia Geral , Testes Hematológicos/métodos , Humanos , Estudos Prospectivos , Sepse/imunologia , Sociedades Médicas , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Estados Unidos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...