Assuntos
Doenças Transmissíveis/complicações , Síndrome da Liberação de Citocina/diagnóstico , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/terapia , Animais , Doenças Transmissíveis/etiologia , Gerenciamento Clínico , Suscetibilidade a Doenças , Interações Hospedeiro-Patógeno , HumanosRESUMO
The cytokine storm syndrome has been suggested as a mechanism in the pathophysiology of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2; COVID-19 [coronavirus disease 2019]) infection. Drugs such as tocilizumab, an interleukin-6 antagonist, have shown good results in other scenarios of hyperinflammatory state and might also be effective in COVID-19 disease. However, the best dosing regimen and the timing of infusion is currently unknown, specifically in obese patients. We report the first cases of tocilizumab administration in obese patients during the first days of COVID-19 worsening hypoxemia. This infusion was not adjusted by weight, following the manufacturer maximal dose limit. We kept a strict monitoring for possible infections, prior and during the treatment. All patients showed good improvements on chest-computed tomography images and oxygenation and were discharged from hospital shortly after, without complications or intubation. This case series highlights that tocilizumab seems to be effective to treat hyperinflammation of critical COVID-19 obese patients, even when the infusion of the ideal dose is not feasible to be administered. It also shows the importance of early timing in the decision to treat and the relevance of infections exclusion prior to the induction of immunosuppression by tocilizumab.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Tratamento Farmacológico da COVID-19 , COVID-19/complicações , Síndrome da Liberação de Citocina/etiologia , Obesidade/complicações , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
The virus "acute respiratory syndrome coronavirus 2" (SARS-CoV-2) is the etiologic agent of coronavirus disease 2019 (COVID-19), initially responsible for an outbreak of pneumonia in Wuhan, China, which, due to the high level of contagion and dissemination, has become a pandemic. The clinical picture varies from mild to critical cases; however, all of these signs already show neurological problems, from sensory loss to neurological diseases. Thus, patients with multiple sclerosis (MS) infected with the new coronavirus are more likely to develop severe conditions; in addition to worsening the disease, this is due to the high level of pro-inflammatory cytokines, which is closely associated with increased mortality both in COVID-19 and MS. This increase is uncontrolled and exaggerated, characterizing the cytokine storm, so a possible therapy for this neuronal inflammation is the modulation of the cholinergic anti-inflammatory pathway, since acetylcholine (ACh) acts to reduce pro-inflammatory cytokines and acts directly on the brain for being released by cholinergic neurons, as well as acting on other cells such as immune and blood cells. In addition, due to tissue damage, there is an exacerbated release of adenosine triphosphate (ATP), potentiating the inflammatory process and activating purinergic receptors which act directly on neuroinflammation and positively modulate the inflammatory cycle. Associated with this, in neurological pathologies, there is greater expression of P2X7 in the cells of the microglia, which positively activates the immune inflammatory response. Thus, the administration of blockers of this receptor can act in conjunction with the action of ACh in the anticholinergic inflammatory pathway. Finally, there will be a reduction in the cytokine storm and triggered hyperinflammation, as well as the level of mortality in patients with multiple sclerosis infected with SARS-CoV-2 and the development of possible neurological damage.
Assuntos
COVID-19/metabolismo , Síndrome da Liberação de Citocina/metabolismo , Fatores Imunológicos/uso terapêutico , Esclerose Múltipla/metabolismo , Síndrome da Liberação de Citocina/etiologia , Citocinas/metabolismo , Humanos , Fatores Imunológicos/efeitos adversos , Microglia/metabolismo , Esclerose Múltipla/tratamento farmacológicoRESUMO
SARS-CoV-2 is a member of the family of coronaviruses associated with severe outbreaks of respiratory diseases in recent decades and is the causative agent of the COVID-19 pandemic. The recognition by and activation of the innate immune response recruits neutrophils, which, through their different mechanisms of action, form extracellular neutrophil traps, playing a role in infection control and trapping viral, bacterial, and fungal etiological agents. However, in patients with COVID-19, activation at the vascular level, combined with other cells and inflammatory mediators, leads to thrombotic events and disseminated intravascular coagulation, thus leading to a series of clinical manifestations in cerebrovascular, cardiac, pulmonary, and kidney disease while promoting severe disease and mortality. Previous studies of hospitalized patients with COVID-19 have shown that elevated levels of markers specific for NETs, such as free DNA, MPO, and H3Cit, are strongly associated with the total neutrophil count; with acute phase reactants that include CRP, D-dimer, lactate dehydrogenase, and interleukin secretion; and with an increased risk of severe COVID-19. This study analyzed the interactions between NETs and the activation pathways involved in immunothrombotic processes in patients with COVID-19.
Assuntos
COVID-19/patologia , Armadilhas Extracelulares/metabolismo , Trombose/imunologia , Trombose/patologia , Biomarcadores/metabolismo , COVID-19/imunologia , COVID-19/virologia , Proteínas do Sistema Complemento/metabolismo , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/patologia , Coagulação Intravascular Disseminada/etiologia , Coagulação Intravascular Disseminada/patologia , Humanos , Neutrófilos/citologia , Neutrófilos/imunologia , Neutrófilos/metabolismo , SARS-CoV-2/isolamento & purificação , Trombose/metabolismoRESUMO
OBJECTIVE: To describe the laboratory parameters and biomarkers of the cytokine storm syndrome associated with severe and fatal COVID-19 cases. METHODS: A search with standardized descriptors and synonyms was performed on November 28th, 2020 of the MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, LILACS, and IBECS to identify studies of interest. Grey literature searches and snowballing techniques were additionally utilized to identify yet-unpublished works and related citations. Two review authors independently screened the retrieved titles and abstracts, selected eligible studies for inclusion, extracted data from the included studies, and then assessed the risk of bias using the Newcastle-Ottawa Scale. Eligible studies were those including laboratory parameters-including serum interleukin-6 levels-from mild, moderate, or severe COVID-19 cases. Laboratory parameters, such as interleukin-6, ferritin, hematology, C-Reactive Protein, procalcitonin, lactate dehydrogenase, aspartate aminotransferase, creatinine, and D-dimer, were extracted from the studies. Meta-analyses were conducted using the laboratory data to estimate mean differences with associated 95% confidence intervals. DATA SYNTHESIS: The database search yielded 9,620 records; 40 studies (containing a total of 9,542 patients) were included in the final analysis. Twenty-one studies (n = 4,313) assessed laboratory data related to severe COVID-19 cases, eighteen studies (n = 4,681) assessed predictors for fatal COVID-19 cases and one study (n = 548) assessed laboratory biomarkers related to severe and fatal COVID-19 cases. Lymphopenia, thrombocytopenia, and elevated levels of interleukin-6, ferritin, D-dimer, aspartate aminotransferase, C-Reactive-Protein, procalcitonin, creatinine, neutrophils and leucocytes were associated with severe and fatal COVID-19 cases. CONCLUSIONS: This review points to interleukin-6, ferritin, leukocytes, neutrophils, lymphocytes, platelets, C-Reactive Protein, procalcitonin, lactate dehydrogenase, aspartate aminotransferase, creatinine, and D-dimer as important biomarkers of cytokine storm syndrome. Elevated levels of interleukin-6 and hyperferritinemia should be considered as red flags of systemic inflammation and poor prognosis in COVID-19.
Assuntos
Biomarcadores/sangue , COVID-19/patologia , Síndrome da Liberação de Citocina/diagnóstico , Proteína C-Reativa/análise , COVID-19/complicações , COVID-19/mortalidade , COVID-19/virologia , Síndrome da Liberação de Citocina/etiologia , Ferritinas/sangue , Humanos , Interleucina-6/sangue , Leucócitos/citologia , Leucócitos/metabolismo , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de DoençaRESUMO
Primary and secondary haemophagocytic lymphohistiocytosis (HLH) are hyperferritinaemic hyperinflammatory syndromes with a common terminal pathway triggered by different etiopathogenetic factors. HLH is characterised by a decreased capacity of interferon gamma production with an activated NK phenotype profile similar to other hyperinflammatory syndromes. Viruses are closely linked to the development of HLH as infectious triggers, and the break of tolerance to self-antigens is considered a critical mechanism involved in the development of immune-mediated conditions triggered by viral infections. Emerging studies in patients with COVID-19 are suggesting a key role of monocytes/macrophages in the pathogenesis of this viral infection, and there is a significant overlap between several features reported in severe COVID-19 and the features included in the HLH-2004 diagnostic criteria. Therefore, SARS-Cov-2, as other respiratory viruses, may also be considered a potential etiological trigger of HLH. The frequency of HLH in adult patients with severe COVID-19 is lower than 5%, although this figure could be underestimated considering that most reported cases lacked information about some specific criteria (mainly the histopathological criteria and the measurement of NK cell function and sCD25 levels). Because HLH is a multi-organ syndrome, the diagnostic approach in a patient with severe COVID-19 in whom HLH is suspected must be carried out in a syndromic and holistic way, and not in the light of isolated clinical or laboratory features. In COVID-19 patients presenting with persistent high fever, progressive pancytopenia, and hepatosplenic involvement, together with the characteristic triad of laboratory abnormalities (hyperferritinaemia, hypertriglyceridaemia, and hypofibrinogenaemia), the suspicion of HLH is high, and the diagnostic workup must be completed with specific immunological and histopathological studies.
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Síndrome da Liberação de Citocina/diagnóstico , Linfo-Histiocitose Hemofagocítica/diagnóstico , Síndrome de Ativação Macrofágica/diagnóstico , Adulto , COVID-19/classificação , COVID-19/diagnóstico , Criança , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/fisiopatologia , Diagnóstico Diferencial , Humanos , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/fisiopatologia , Síndrome de Ativação Macrofágica/fisiopatologia , Pandemias , Reumatologia/métodos , SARS-CoV-2RESUMO
PURPOSE: To prospectively evaluate the effectiveness of risk-adapted preemptive tocilizumab (PT) administration in preventing severe cytokine release syndrome (CRS) after CTL019, a CD19 chimeric antigen receptor T-cell therapy. METHODS: Children and young adults with CD19-positive relapsed or refractory B-cell acute lymphoblastic leukemia were assigned to high- (≥ 40%) or low- (< 40%) tumor burden cohorts (HTBC or LTBC) based on a bone marrow aspirate or biopsy before infusion. HTBC patients received a single dose of tocilizumab (8-12 mg/kg) after development of high, persistent fevers. LTBC patients received standard CRS management. The primary end point was the frequency of grade 4 CRS (Penn scale), with an observed rate of ≤ 5 of 15 patients in the HTBC pre-defined as clinically meaningful. In post hoc analyses, the HTBC was compared with a historical cohort of high-tumor burden patients from the initial phase I CTL019 trial. RESULTS: The primary end point was met. Seventy patients were infused with CTL019, 15 in the HTBC and 55 in the LTBC. All HTBC patients received the PT intervention. The incidence of grade 4 CRS was 27% (95% CI, 8 to 55) in the HTBC and 3.6% (95% CI, 0.4 to 13) in the LTBC. The best overall response rate was 87% in the HTBC and 100% in the LTBC. Initial CTL019 expansion was greater in the HTBC than the LTBC (P < .001), but persistence was not different (P = .73). Event-free and overall survival were worse in the HTBC (P = .004, P < .001, respectively). In the post hoc analysis, grade 4 CRS was observed in 27% versus 50% of patients in the PT and prior phase I cohorts, respectively (P = .18). CONCLUSION: Risk-adapted PT administration resulted in a decrease in the expected incidence of grade 4 CRS, meeting the study end point, without adversely impacting the antitumor efficacy or safety of CTL019.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antígenos CD19/imunologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Imunoterapia Adotiva/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Terapia de Salvação , Adolescente , Adulto , Criança , Pré-Escolar , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/patologia , Feminino , Seguimentos , Humanos , Lactente , Masculino , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Projetos Piloto , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Adulto JovemRESUMO
Coronavirus disease 2019 (COVID-19) is a virus-induced respiratory disease that may progress to acute respiratory distress syndrome (ARDS) and is triggered by immunopathological mechanisms that cause excessive inflammation and leukocyte dysfunction. Neutrophils play a critical function in the clearance of bacteria with specific mechanisms to combat viruses. The aim of this review is to highlight the current advances in the pathways of neutrophilic inflammation against viral infection over the past ten years, focusing on the production of neutrophil extracellular traps (NETs) and its impact on severe lung diseases, such as COVID-19. We focused on studies regarding hyperinflammation, cytokine storms, neutrophil function, and viral infections. We discuss how the neutrophil's role could influence COVID-19 symptoms in the interaction between hyperinflammation (overproduction of NETs and cytokines) and the clearance function of neutrophils to eliminate the viral infection. We also propose a more in-depth investigation into the neutrophil response mechanism targeting NETosis in the different phases of COVID-19.
Assuntos
COVID-19/imunologia , Inflamação/imunologia , Neutrófilos/imunologia , SARS-CoV-2 , COVID-19/complicações , COVID-19/virologia , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/virologia , Armadilhas Extracelulares/imunologia , Armadilhas Extracelulares/virologia , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Imunidade Inata , Inflamação/etiologia , Inflamação/virologia , Mediadores da Inflamação/imunologia , Pulmão/imunologia , Pulmão/virologia , Modelos Imunológicos , Neutrófilos/virologia , Pandemias , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/imunologia , Síndrome do Desconforto Respiratório/virologia , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidadeRESUMO
The disease caused by a new coronavirus, which started in 2019, was named COVID-19 and declared a pandemic on March 11, 2020 by the World Health Organization. Although it is true that the first reports emphasized the respiratory manifestations of this disease as an initial clinical presentation, little by little cases with different initial manifestations began to appear, involving other systems. In cases where central nervous system involvement was identified, the most frequent findings were dizziness, headache, and alteration of alertness. Regarding the cardiovascular system, elevation of cardiac biomarkers and myocarditis are one of the most frequent findings. The main gastrointestinal symptoms described so far are: anorexia, nausea, vomiting, diarrhea, abdominal pain and/or discomfort. Venous thromboembolism is a frequent complication and a public health problem. Skin manifestations remain a field of investigation. Maculopapular rashes, reticular livedo, acral gangrene, among others, have been identified. Health personnel must be updated on new clinical findings and the forms of presentation of this partially known disease, which will make it possible to make more accurate and timely diagnoses, thus impacting the prognosis of these patients.
La enfermedad causada por un nuevo coronavirus, que inició en 2019, fue denominada COVID-19 y declarada pandemia el 11 de marzo de 2020 por la Organización Mundial de la Salud. Si bien es cierto que los primeros reportes enfatizaron las manifestaciones respiratorias de esta enfermedad como presentación clínica inicial, poco a poco empezaron a aparecer casos con manifestaciones iniciales distintas, involucrando otros sistemas. En los casos en los que se identificó afectación del sistema nervioso central, los hallazgos más frecuentes fueron mareo, cefalea y alteración del estado de alerta. Respecto al sistema cardiovascular, la elevación de biomarcadores cardiacos y la miocarditis son unos de los hallazgos más frecuentes. Los principales síntomas gastrointestinales descritos hasta el momento son anorexia, náuseas, vómitos, diarrea y dolor o disconfort abdominal. La tromboembolia venosa es una complicación frecuente y un problema de salud pública. Las manifestaciones cutáneas siguen siendo un campo de investigación. Se han identificado exantemas maculopapulares, livedo reticular y gangrena acral, entre otros. El personal sanitario debe estar actualizado sobre los nuevos hallazgos clínicos y las formas de presentación de esta enfermedad solo parcialmente conocida, lo que permitirá hacer diagnósticos más precisos y oportunos, y así impactar en el pronóstico de estos enfermos.