COVID-19 grave: entenda o papel da imunidade, do endotélio e da coagulação na prática clínica / Severe COVID-19: understanding the role of immunity, endothelium, and coagulation in clinical practice

Resumo O SARS-CoV-2 é o responsável pela pandemia da COVID-19. O sistema imunológico é fator determinante no combate à infecção viral e, quando atua equilibrada e eficientemente, a doença é autolimitada e benigna. Uma parcela significativa da população, porém, apresenta resposta imune exacerbada. Os indivíduos diabéticos, hipertensos, obesos e com doenças cardiovasculares, infectados pelo vírus, apresentam maior chance de progredir para formas graves. Essas doenças estão relacionadas a processos inflamatórios crônicos e disfunção endotelial. Os receptores do tipo Toll estão presentes nas células de defesa e participam da imunopatologia de doenças cardiovasculares e metabólicas, levando à produção de citocinas pró-inflamatórias quando ativados. Devido à ação viral e à hiperativação do sistema imune, estados de hiperinflamação, hiperativação plaquetária, disfunção endotelial e hipercoagulabilidade são desenvolvidos, predispondo a tromboses venosas e arteriais. Discutiremos sobre a interação entre a COVID-19, a imunidade, o endotélio e a coagulação, como também sobre as possíveis causas de doenças cardiometabólicas impactarem negativamente na evolução da COVID-19.

Abstract SARS-CoV-2 is responsible for the COVID-19 pandemic. The immune system is a determinant factor in defense against viral infections. Thus, when it acts in a balanced and effective manner the disease is self-limited and benign. Nevertheless, in a significant proportion of the population, the immune response is exaggerated. When infected, patients with diabetes, hypertension, obesity, and cardiovascular disease are more likely to progress to severe forms. These diseases are related to chronic inflammation and endothelial dysfunction. Toll-like receptors are expressed on immune cells and play an important role in the physiopathology of cardiovascular and metabolic diseases. When activated, they can induce release of inflammatory cytokines. Hypercoagulability, hyperinflammation, platelet hyperresponsiveness, and endothelial dysfunction occur in immune system hyperactivity caused by viral activity, thereby increasing the risk of arterial and venous thrombosis. We discuss the interactions between COVID-19, immunity, the endothelium, and coagulation, as well as why cardiometabolic diseases have a negative impact on COVID-19 prognosis.

Study of pro-thrombotic and pro-inflammatory factors in Chagas cardiomyopathy.

BACKGROUND: The relationship between inflammatory and prothrombotic activity in chagas cardiomyopathy and in other etiologies is unclear. OBJECTIVE: To study the profile of pro-thrombotic and pro-inflammatory markers in patients with Chagas' heart failure and compare them with patients of non-chagas etiology. METHODS: Cross-sectional cohort. INCLUSION CRITERIA: left ventricle ejection fraction (LVEF) < 45% and onset time to symptoms > one month. The patients were divided into two groups: group 1 (G1) - seropositive for Chagas - and group 2 (G2) - seronegative for Chagas. Pro-inflammatory factor: Ultra-sensitive CRP. Pro-thrombotic factors: thrombin-antithrombin factor, fibrinogen, von Willebrand factor antigen, plasma P-selectin and thromboelastography. Sample calculated for 80% power, assuming a standard deviation difference of 1/3; significant p if it is < 0.05. STATISTICAL ANALYSIS: Fisher's exact test for categorical variables; unpaired Student's t-test for parametric continuous variables and Mann-Whitney test for nonparametric continuous variables. RESULTS: Between January and June 2008, 150 patients were included, 80 in G1 and 70 in G2. Both groups maintained the averages of high sensitivity CRP above baseline values, however, there was no significant difference (p = 0.328). The fibrinogen levels were higher in G2 than in G1 (p = 0.015). Among the thromboelastography variables, the parameters MA (p=0.0013), G (p=0.0012) and TG (p =0.0005) were greater in G2 than in G1. CONCLUSION: There is no evidence of greater pro-thrombotic status among patients with Chagas disease. The levels of fibrinogen and the MA, G and TG parameters of the thromboelastography point to pro-thrombotic status among non-chagas patients. Both groups had increased inflammatory activity.

Estudo de fatores pró-trombóticos e pró-inflamatórios na cardiomiopatia chagásica / Study of pro-thrombotic and pro-inflammatory factors in chagas cardiomyopathy

FUNDAMENTO: A relação entre atividade inflamatória e pró-trombótica na cardiomiopatia chagásica e em outras etiologias é obscura. OBJETIVO: Estudar o perfil de marcadores pró-trombóticos e pró-inflamatórios em pacientes com insuficiência cardíaca chagásica e compará-los com os de etiologia não chagásica. MÉTODOS: Coorte transversal. Critérios de inclusão: fração de ejeção do VE (FEVE) < 45 por cento e tempo de início de sintomas > um mês. Os pacientes foram divididos em dois grupos: grupo 1 (G1) - sorologias positivas para Chagas - e grupo 2 (G2) - sorologias negativas para Chagas. Fator pró-inflamatório: PCR ultrassensível. Fatores pró-trombóticos: fator trombina-antitrombina, fibrinogênio, antígeno do fator de von Willebrand, P-selectina plasmática e tromboelastograma. Amostra calculada para poder de 80 por cento, assumindo-se diferença de 1/3 de desvio-padrão; p significativo se < 0,05. Análise estatística: teste exato de Fischer para variáveis categóricas; teste t de Student não pareado para variáveis contínuas paramétricas e teste de Mann-Whitney para variáveis contínuas não paramétricas. RESULTADOS: Entre janeiro e junho de 2008, foram incluídos 150 pacientes, 80 no G1 e 70 no G2. Ambos os grupos mantinham médias de PCR ultrassensível acima dos valores de referência, porém, sem diferença significativa (p=0,328). Os níveis de fibrinogênio foram maiores no G2 do que no G1 (p=0,015). Entre as variáveis do tromboelastograma, os parâmetros MA (p=0,0013), G (p=0,0012) e TG (p=0,0005) foram maiores no G2 em comparação ao G1. CONCLUSÃO: Não há indícios de maior status pró-trombótico entre chagásicos. A dosagem de fibrinogênio e dos parâmetros MA, G e TG do tromboelastograma apontam para status pró-trombótico entre não chagásicos. Ambos os grupos tinham atividade inflamatória exacerbada.

BACKGROUND: The relationship between inflammatory and prothrombotic activity in chagas cardiomyopathy and in other etiologies is unclear. OBJECTIVE: To study the profile of pro-thrombotic and pro-inflammatory markers in patients with Chagas' heart failure and compare them with patients of non-chagas etiology. METHODS: Cross-sectional cohort. Inclusion criteria: left ventricle ejection fraction (LVEF) < 45 percent and onset time to symptoms > one month. The patients were divided into two groups: group 1 (G1) - seropositive for Chagas - and group 2 (G2) - seronegative for Chagas. Pro-inflammatory factor: Ultra-sensitive CRP. Pro-thrombotic factors: thrombin-antithrombin factor, fibrinogen, von Willebrand factor antigen, plasma P-selectin and thromboelastography. Sample calculated for 80 percent power, assuming a standard deviation difference of 1/3; significant p if it is < 0.05. Statistical analysis: Fisher's exact test for categorical variables; unpaired Student's t-test for parametric continuous variables and Mann-Whitney test for nonparametric continuous variables. RESULTS: Between January and June 2008, 150 patients were included, 80 in G1 and 70 in G2. Both groups maintained the averages of high sensitivity CRP above baseline values, however, there was no significant difference (p = 0.328). The fibrinogen levels were higher in G2 than in G1 (p = 0.015). Among the thromboelastography variables, the parameters MA (p=0.0013), G (p=0.0012) and TG (p =0.0005) were greater in G2 than in G1. CONCLUSION: There is no evidence of greater pro-thrombotic status among patients with Chagas disease. The levels of fibrinogen and the MA, G and TG parameters of the thromboelastography point to pro-thrombotic status among non-chagas patients. Both groups had increased inflammatory activity.

Evaluation of early hospital discharge after allogeneic bone marrow transplantation for chronic myeloid leukemia.

CONTEXT AND OBJECTIVE: The increasing number of patients waiting for bone marrow transplantation in our service led to the implement of an early hospital discharge program with the intention of reducing the interval between diagnosis and transplantation. In this study we analyzed the results from early discharge, with outpatient care for patients with chronic myeloid leukemia who underwent allogeneic bone marrow transplantation. DESIGN AND SETTING: Retrospective study at the Bone Marrow Transplantation Unit of Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo. METHODS: We compared clinical outcomes within 100 days post-transplantation, for 51 patients with chronic myeloid leukemia (CML) who received partially outpatient-based allogeneic hematopoietic stem cell transplantation, and the results were compared with a historical control group of 49 patients who received inpatient-based hematopoietic stem cell transplantation. RESULTS: There were significantly fewer days of hospitalization (p = 0.004), Pseudomonas-positive cultures (p = 0.006) and nausea and vomiting of grade 2-3 (p < 0.001) in the outpatient group. There were no significant differences in mortality between the groups and no deaths occurred within the first 48 days post-transplantation in the outpatient group. CONCLUSIONS: This partially outpatient-based hematopoietic stem cell transplantation program allowed an increased number of transplantations in our institution, in cases of CML and other diseases, since it reduced the median length of hospital stay without increasing morbidity and mortality.

Evaluation of early hospital discharge after allogeneic bone marrow transplantation for chronic myeloid leukemia

CONTEXT AND OBJECTIVE: The increasing number of patients waiting for bone marrow transplantation in our service led to the implement of an early hospital discharge program with the intention of reducing the interval between diagnosis and transplantation. In this study we analyzed the results from early discharge, with outpatient care for patients with chronic myeloid leukemia who underwent allogeneic bone marrow transplantation. DESIGN AND SETTING: Retrospective study at the Bone Marrow Transplantation Unit of Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo. METHODS: We compared clinical outcomes within 100 days post-transplantation, for 51 patients with chronic myeloid leukemia (CML) who received partially outpatient-based allogeneic hematopoietic stem cell transplantation, and the results were compared with a historical control group of 49 patients who received inpatient-based hematopoietic stem cell transplantation. RESULTS: There were significantly fewer days of hospitalization (p = 0.004), Pseudomonas-positive cultures (p = 0.006) and nausea and vomiting of grade 2-3 (p < 0.001) in the outpatient group. There were no significant differences in mortality between the groups and no deaths occurred within the first 48 days post-transplantation in the outpatient group. CONCLUSIONS: This partially outpatient-based hematopoietic stem cell transplantation program allowed an increased number of transplantations in our institution, in cases of CML and other diseases, since it reduced the median length of hospital stay without increasing morbidity and mortality.

CONTEXTO E OBJETIVO: O número crescente de pacientes com indicação de transplante de medula óssea levou à implantação da alta hospitalar precoce em nosso serviço, com o intuito de reduzir o intervalo entre o diagnóstico e o transplante. Neste trabalho, avaliamos os resultados da alta precoce, com acompanhamento ambulatorial dos pacientes submetidos ao transplante de medula óssea alogênico portadores de leucemia mielóide crônica. TIPO E ESTUDO E LOCAL: Estudo retrospectivo, realizado no Serviço de Transplante de Medula Ossea do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. MÉTODOS: Foram avaliados os resultados do transplante de medula óssea alogênico, de doadores aparentados, até o dia 100 pós-transplante, de 51 pacientes portadores de leucemia mielóide crônica que receberam alta precoce, antes da pega medular. Os resultados foram comparados com o controle histórico constituído por 49 pacientes que receberam alta somente após a pega medular. RESULTADOS: Houve significativamente menos dias de hospitalização (p = 0,004), culturas positivas para Pseudomonas sp. (p = 0,006) e náusea e vômitos graus 2-3 (p < 0,001) no grupo de alta precoce. Não houve diferença significativa entre os grupos quanto à mortalidade e não ocorreu nenhum óbito até o dia 48 pós-transplante no grupo de alta precoce. CONCLUSÕES: O programa de alta precoce permitiu aumento do número de transplantes em leucemia mielóide crônica e outras doenças em nosso serviço, com redução do número de dias de internação hospitalar sem aumento da morbidade ou da mortalidade.

Liposomal daunorubicin and dexamethasone as a treatment for multiple myeloma: the DD Protocol

CONTEXTO E OBJETIVO: A daunorrubicina lipossomal tem sido usada no tratamento em várias doenças hematológicas malignas, incluindo mieloma múltiplo (MM). O objetivo deste estudo foi avaliar a eficácia, efeitos colaterais e toxicidade da daunorrubicina lipossomal and dexametasona no Protocolo DD. TIPO DE ESTUDO E LOCAL: Estudo prospectivo, realizado nos hospitais Sírio Libanês, São Camilo, Brasil e no Hospital Alemão Oswaldo Cruz. MÉTODOS: 20 pacientes com MM ativo receberam daunoxome (25-30 mg/m²/dia) por três dias consecutivos, mensal, por quatro meses (total de quatro ciclos), e dexametasona, 10 mg a cada seis horas por quatro dias consecutivos (dia 1 - 4, 9 - 12 e 17 - 20), também mensal. RESULTADOS: A mediana entre o diagnóstico e o início do protocolo DD foi de 13 meses. Quinze pacientes receberam alguma quimioterapia anterior ao protocolo DD. Uma redução maior que 50% do pico monoclonal sérico foi observada em seis paciente após o primeiro ciclo do DD (30%), em seis pacientes após o segundo ciclo (30%), em quatro pacientes após o terceiro ciclo (20%) e em quatro pacientes não houve redução (20%). No início do protocolo, 17 pacientes (85%) apresentavam anemia e em 12 destes pacientes (70%) a anemia foi corrigida. Doença progressiva foi observada em três pacientes (15%), um apresentava resposta mínima, quatro pacientes (20%) apresentaram resposta parcial e 12 (60%) apresentaram resposta completa. A toxicidade hematológica foi aceitável.Toxicidade em trato gastrointestinal foi leve, consistindo em náusea (10%) e anorexia (15%), sem episódios de vômito. CONCLUSÃO: Este tratamento apresentou uma baixa toxicidade, uma boa taxa de resposta e pode ser usado previamente ao transplante de medula óssea autogênico.

Liposomal daunorubicin and dexamethasone as a treatment for multiple myeloma--the DD Protocol.

CONTEXT AND OBJECTIVE: Liposomal daunorubicin has been used to treat hematological malignancies, including multiple myeloma (MM). The goal was to evaluate efficacy, side-effects and toxicity of liposomal daunorubicin and dexamethasone ("DD Protocol"). DESIGN AND SETTING: Prospective study at Sírio-Libanês, São Camilo, Brasil and Alemão Oswaldo Cruz hospitals. METHODS: Twenty consecutive patients with active MM received four cycles of liposomal daunorubicin intravenously for two hours (25-30 mg/m(2)/day) on three consecutive days per month, with oral dexamethasone (10 mg every six hours) on four consecutive days three times a month. RESULTS: The male/female ratio was 1:1 and median age 60. Nine patients were stage IIA, ten IIIA and one IIIB. The median from diagnosis to starting DD was 13 months. All patients received four cycles, except one. Fifteen had already received chemotherapy before DD. Responses of > 50% reduction in serum monoclonal paraprotein were observed in six patients after first cycle (30%), six after second (30%) and four after third (20%), while four (20%) did not obtain this. Initially, 17 patients (85%) had anemia: 12 (70%) achieved correction. Progressive disease was observed in three patients (15%), while one had minimal response, four (20%) partial and 12 (60%) complete. Hematological toxicity was acceptable: three patients (15%) had neutrophils < 1,000/mm(3); none had thrombocytopenia. Gastrointestinal toxicity was mild: nausea (10%), anorexia (15%) and no vomiting. CONCLUSIONS: This treatment has mild toxicity and good response rate. It may therefore be feasible before autologous bone marrow transplantation.