Immunothrombosis and COVID-19 ‒ a nested post-hoc analysis from a 3186 patient cohort in a Latin American public reference hospital

Abstract Objective COVID-19 is associated with an elevated risk of thromboembolism and excess mortality. Difficulties with best anticoagulation practices and their implementation motivated the current analysis of COVID-19 patients who developed Venous Thromboembolism (VTE). Method This is a post-hoc analysis of a COVID-19 cohort, described in an economic study already published. The authors analyzed a subset of patients with confirmed VTE. We described the characteristics of the cohort, such as demographics, clinical status, and laboratory results. We tested differences amid two subgroups of patients, those with VTE or not, with the competitive risk Fine and Gray model. Results Out of 3186 adult patients with COVID-19, 245 (7.7%) were diagnosed with VTE, 174 (5.4%) of them during admission to the hospital. Four (2.3% of these 174) did not receive prophylactic anticoagulation and 19 (11%) discontinued anticoagulation for at least 3 days, resulting in 170 analyzed. During the first week of hospitalization, the laboratory most altered results were C-reactive protein and D-dimer. Patients with VTE were more critical, had a higher mortality rate, worse SOFA score, and, on average, 50% longer hospital stay. Conclusion Proven VTE incidence in this severe COVID-19 cohort was 7.7%, despite 87% of them complying completely with VTE prophylaxis. The clinician must be aware of the diagnosis of VTE in COVID-19, even in patients receiving proper prophylaxis.

Use and misuse of biomarkers and the role of D-dimer and C-reactive protein in the management of COVID-19: A post-hoc analysis of a prospective cohort study

OBJECTIVE: Coronavirus disease 2019 (COVID-19) is associated with high mortality among hospitalized patients and incurs high costs. Severe acute respiratory syndrome coronavirus 2 infection can trigger both inflammatory and thrombotic processes, and these complications can lead to a poorer prognosis. This study aimed to evaluate the association and temporal trends of D-dimer and C-reactive protein (CRP) levels with the incidence of venous thromboembolism (VTE), hospital mortality, and costs among inpatients with COVID-19. METHODS: Data were extracted from electronic patient records and laboratory databases. Crude and adjusted associations for age, sex, number of comorbidities, Sequential Organ Failure Assessment score at admission, and D-dimer or CRP logistic regression models were used to evaluate associations. RESULTS: Between March and June 2020, COVID-19 was documented in 3,254 inpatients. The D-dimer level ≥4,000 ng/mL fibrinogen equivalent unit (FEU) mortality odds ratio (OR) was 4.48 (adjusted OR: 1.97). The CRP level ≥220 mg/dL OR for death was 7.73 (adjusted OR: 3.93). The D-dimer level ≥4,000 ng/mL FEU VTE OR was 3.96 (adjusted OR: 3.26). The CRP level ≥220 mg/dL OR for VTE was 2.71 (adjusted OR: 1.92). All these analyses were statistically significant (p<0.001). Stratified hospital costs demonstrated a dose-response pattern. Adjusted D-dimer and CRP levels were associated with higher mortality and doubled hospital costs. In the first week, elevated D-dimer levels predicted VTE occurrence and systemic inflammatory harm, while CRP was a hospital mortality predictor. CONCLUSION: D-dimer and CRP levels were associated with higher hospital mortality and a higher incidence of VTE. D-dimer was more strongly associated with VTE, although its discriminative ability was poor, while CRP was a stronger predictor of hospital mortality. Their use outside the usual indications should not be modified and should be discouraged.

Mild and moderate Mannose Binding Lectin deficiency are associated with systemic lupus erythematosus and lupus nephritis in Brazilian patients / As deficiências leve e moderada de lectina ligadora de manose estão associadas ao lúpus eritematoso sistêmico e à nefrite lúpica em pacientes brasileiros

Abstract Objective The potential association of mannose binding lectin (MBL) deficiency and systemic lupus erythematosus (SLE) has been investigated in several studies, but results have been mixed. One explanation for the conflicting results could be differences in ethnic background of study subjects. In this study we investigated the association of MBL deficiency and SLE in a large cohort of Brazilian SLE patients and controls. Methods Serum MBL and Complement levels were determined for 286 Brazilian adult SLE patients and 301 healthy Brazilian adults as controls. MBL deficiency was classified as mild (<1000 and ≥500 µg/L), moderate (<500 and ≥100 µg/L) or severe (<100 µg/L). Results SLE patients presented higher frequency of mild and moderate MBL deficiency compared to controls. SLE patients with MBL deficiency presented higher frequency of lupus nephritis compared to those without MBL deficiency. MBL deficiency was not associated with any other clinical manifestation, use of immunosuppressant therapy, disease activity, disease severity serum or Complement levels. Conclusion This study shows that an association between MBL deficiency and SLE does exist in the Brazilian population. We also found an association between MBL deficiency and lupus nephritis. These findings support the hypothesis that MBL deficiency contributes to the development of SLE and lupus nephritis.

Resumo Objetivo Vários estudos já investigaram a potencial associação entre a deficiência de lectina de ligação a manose (LLM) e o lúpus eritematoso sistêmico (LES), mas os resultados obtidos são controversos. Uma explicação para esses resultados conflitantes poderia estar nas diferenças étnicas dos indivíduos estudados. Este estudo investigou a associação entre a deficiência de LLM e o LES em uma grande coorte de pacientes brasileiros com LES e controles. Métodos Determinaram-se os níveis séricos de LLM e complemento em 286 pacientes adultos brasileiros com LES e 301 adultos brasileiros saudáveis que atuaram como controles. A deficiência de LLM foi classificada como leve (< 1000 e ≥ 500 µg/L), moderada (< 500 e ≥ 100 µg/L) ou grave (< 100 µg/L). Resultados Os pacientes com LES apresentaram maior frequência de deficiências leve e moderada de LLM em relação aos controles. Os pacientes com LES com deficiência de LLM apresentaram maior frequência de nefrite lúpica em comparação com aqueles sem deficiência de LLM. A deficiência de LLM não esteve associada a qualquer outra manifestação clínica, uso de terapia imunossupressora, atividade da doença, gravidade da doença ou níveis séricos de complemento. Conclusão Este estudo mostra que há uma associação entre a deficiência de LLM e o LES na população brasileira. Encontrou-se também uma associação entre a deficiência de LLM e a nefrite lúpica. Esses resultados apoiam a hipótese de que a deficiência de LLM contribui para o desenvolvimento do LES e da nefrite lúpica.

Associação de imunodeficiência primária com lúpus eritematoso sistêmico: revisão da literatura e as lições aprendidas pela Divisão de Reumatologia de um hospital universitário terciário em São Paulo / Primary immunodeficiency association with systemic lupus erythematosus: review of literature and lessons learned by the Rheumatology Division of a tertiary university hospital at São Paulo, Brazil

Resumo As imunodeficiências primárias (IDP) representam um grupo heterogêneo de doenças resultantes de defeitos hereditários no desenvolvimento, na maturação e na função normal de células do sistema imunológico; assim, tornam os indivíduos suscetíveis a infecções recorrentes, alergia, autoimunidade e doenças malignas. Neste estudo retrospectivo descrevem-se doenças autoimunes (DAI), em especial o lúpus eritematoso sistêmico (LES), que surgiram associadas ao curso das IDP. Classicamente, a literatura descreve três grupos de IDP associadas ao LES: (1) deficiência de componentes da via do complemento, (2) defeitos na síntese de imunoglobulinas e (3) doença granulomatosa crônica (DGC). Na atualidade, outras IDP têm sido descritas como manifestações clínicas do LES, como a síndrome de Wiskott-Aldrich (WAS), a poliendocrinopatia autoimune-candidíase-distrofia ectodérmica (APECED), a síndrome linfoproliferativa autoimune (ALPS) e a linfocitopenia idiopática CD4+. Também são apresentados achados de uma coorte de adultos do ambulatório da Divisão de Reumatologia da Universidade Federal de São Paulo. As manifestações de IDP encontradas pelo nosso grupo de estudo foram consideradas leves em termos de gravidade de infecções e mortalidade no início da vida. Assim, é possível que alguns estados de imunodeficiência sejam compatíveis com a sobrevivência em relação à suscetibilidade infecciosa; no entanto, esses estados podem representar um fator de predisposição forte para o desenvolvimento de doenças imunológicas, como observado no LES.

Abstract Primary immunodeficiency disorders (PID) represent a heterogeneous group of diseases resulting from inherited defects in the development, maturation and normal function of immune cells; thus, turning individuals susceptible to recurrent infections, allergy, autoimmunity, and malignancies. In this retrospective study, autoimmune diseases (AIDs), in special systemic lupus erythematosus (SLE) which arose associated to the course of PID, are described. Classically, the literature describes three groups of PID associated with SLE: (1) deficiency of Complement pathway components, (2) defects in immunoglobulin synthesis, and (3) chronic granulomatous disease (CGD). Currently, other PID have been described with clinical manifestation of SLE, such as Wiskott–Aldrich syndrome (WAS), autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), autoimmune lymphoproliferative syndrome (ALPS) and idiopathic CD4+ lymphocytopenia. Also we present findings from an adult cohort from the outpatient clinic of the Rheumatology Division of Universidade Federal de São Paulo. The PID manifestations found by our study group were considered mild in terms of severity of infections and mortality in early life. Thus, it is possible that some immunodeficiency states are compatible with survival regarding infectious susceptibility; however these states might represent a strong predisposing factor for the development of immune disorders like those observed in SLE.

Global DNA methylation pattern and correlation with complement system proteins in Brazilian patients with systemic lupus erythematosus / Padrão global de metilação do DNA e correlação com proteínas do sistema complemento em pacientes brasileiros com lúpus eritematoso sistêmico

Introduction: Nucleic acid methylation may have major effects on gene expression patterns and, by consequence, on the development of autoimmunity, like Systemic Lupus Erythematosus (SLE). Objective: To investigate the pattern of global DNA methylation in SLE patients and compare this pattern with laboratory parameters. Methods: Genomic DNA was isolated from SLE patients with non-active disease (SLEDAI<6), SLE patients with active disease (SLEDAI>6), and healthy individuals. Global DNA methylation was evaluated by digestion of genomic DNA with Hpa II and Msp I and compared with laboratory parameters. Results and conclusion: A statistical difference in DNA global methylation was observed when SLE patients were compared to healthy individuals. A positive correlation was observed between the frequency of global methylation and C3 and C4 serum levels for SLE patients with SLEDAI<6. These results suggest that the relative amount of DNA methylation is increased in SLE patients, and differential methylation of genes related to the complement pathway alters gene expression involved in autoimmune response in SLE patients.

Introdução: Metilação do ácido nucleico pode alterar a expressão gênica e favorecer o desenvolvimento de autoimunidade, como lúpus eritematoso sistêmico (LES). Objetivo: Investigar o padrão de metilação global do DNA em pacientes com LES e comparar com parâmetros laboratoriais. Métodos: DNA genômico foi isolado de pacientes com LES com doença não ativa (SLEDAI <6), pacientes com doença ativa (SLEDAI> 6) e indivíduos saudáveis. Metilação do DNA global foi avaliada por digestão do DNA genômico com Hpall e MspI e comparados com parâmetros laboratoriais. Resultados e conclusão: Foi observada diferença estatística na metilação global do DNA em pacientes com LES. Verificou-se correlação positiva entre a frequência de metilação global e níveis séricos C3 e C4 em pacientes com SLEDAI <6. Estes resultados sugerem que a quantidade relativa de metilação do DNA está aumentada em pacientes com LES, e a metilação de diferentes genes relacionados com o sistema complemento podem alterar a expressão de genes envolvidos no LES.