ABSTRACT
Objective: To characterize myocardial injury and cardiovascular complications and their predictors in severe and critical COVID-19 patients admitted to the intensive care unit. Methods: This was an observational cohort study of severe and critical COVID-19 patients admitted to the intensive care unit. Myocardial injury was defined as blood levels of cardiac troponin above the 99th percentile upper reference limit. Cardiovascular events considered were the composite of deep vein thrombosis, pulmonary embolism, stroke, myocardial infarction, acute limb ischemia, mesenteric ischemia, heart failure and arrhythmia. Univariate and multivariate logistic regression or Cox proportional hazard models were used to determine predictors of myocardial injury. Results: Of 567 patients with severe and critical COVID-19 admitted to the intensive care unit, 273 (48.1%) had myocardial injury. Of the 374 patients with critical COVID-19, 86.1% had myocardial injury, and also showed more organ dysfunction and higher 28-day mortality (56.6% versus 27.1%, p < 0.001). Advanced age, arterial hypertension and immune modulator use were predictors of myocardial injury. Cardiovascular complications occurred in 19.9% of patients with severe and critical COVID-19 admitted to the intensive care unit, with most events occurring in patients with myocardial injury (28.2% versus 12.2%, p < 0.001). The occurrence of an early cardiovascular event during intensive care unit stay was associated with higher 28-day mortality compared with late or no events (57.1% versus 34% versus 41.8%, p = 0.01). Conclusion: Myocardial injury and cardiovascular complications were commonly found in patients with severe and critical forms of COVID-19 admitted to the intensive care unit, and both were associated with increased mortality in these patients. © 2023 Associacao de Medicina Intensiva Brasileira - AMIB. All rights reserved.
ABSTRACT
Background. SARS-CoV-2 induces endothelial damage and activates the complement system. In severe COVID-19 patients, complement split factor C5a is highly elevated leading to inflammation that contributes to multiorgan failure. The anti-C5a monoclonal antibody, Vilobelimab (Vilo), which preserves the membrane attack complex (MAC), was investigated in an adaptively designed, randomized doubleblind, placebo (P)-controlled Phase 3 international multicenter study for survival in critically ill COVID-19 patients (pts). Methods. COVID-19 pneumonia pts (N=368;Vilo n=177, P n=191), mechanically ventilated within 48 hrs before treatment, received up to 6, 800 mg infusions of Vilo or P on top of standard of care. The primary and main secondary endpoints were 28-day (d) and 60-d all-cause mortality. Results. Pts enrolled in the study were on corticosteroids (97%) and anticoagulants (98%) as standard of care. A smaller proportion (20%) were either continuing or had taken immunomodulators such as tocilizumab and baricitinib prior to receiving Vilo. The 28-d all-cause mortality was 31.7% with Vilo vs 41.6% with P (Kaplan-Meier estimates;Cox regression site-stratified, HR 0.73;95% CI:0.50-1.06;P=0.094), representing a 23.8% relative mortality reduction. In predefined primary outcome analysis without site stratification, however, Vilo significantly reduced mortality at 28 (HR 0.67;95% CI:0.48-0.96;P=0.027) and 60 days (HR 0.67;95% CI:0.48-0.92;P=0.016). Vilo also significantly reduced 28-d mortality in more severe pts with baseline WHO ordinal scale score of 7 (n=237, HR 0.62;95% CI:0.40-0.95;P=0.028), severe ARDS/PaO2/FiO2 <= 100 mmHg (n=98, HR 0.55;95% CI:0.30-0.98;P=0.044) and eGFR < 60 mL/min/1.73m2 (n=108, HR 0.55;95% CI:0.31-0.96;P=0.036). Treatment-emergent AEs were 90.9% Vilo vs 91.0% P. Infections were comparable: Vilo 62.9%, P 59.3%. Infection incidence per 100 Pt days were equal. No meningococcal infections were reported. Serious AEs were 58.9% Vilo, 63.5% P. Conclusion. Vilo significantly reduced mortality at 28 and 60 days in critically ill COVID-19 pts with no increase in infections suggesting the importance of targeting C5a while preserving MAC. Vilo targets inflammation which may represent an approach to treat sepsis and ARDS caused by other respiratory viruses. (Figure Presented).
ABSTRACT
Background. Immune dysregulation associated with COVID-19 includes immune cell activation, inflammatory cytokine release, and neutrophil extracellular trap release (NETosis), which are mediated by spleen tyrosine kinase (SYK) (Fig 1). Fostamatinib, an oral spleen tyrosine kinase (SYK) inhibitor, was approved for immune thrombocytopenia (ITP) in 2018, and the Phase 3 trials showed a lower than expected rate of thrombosis.1 Clinical studies showed a reduction in IL-6 in patients with rheumatoid arthritis.2 The active metabolite of fostamatinib (R406) protected against LPS-induced acute lung injury and thrombosis in mice3,4 and reduced MUC1 in a mouse model of ALI.5 Fostamatinib demonstrated abrogation of the hyperimmune response caused by anti-spike IgG,6 including reduction in hyperactivation of platelets7 and NETosis in neutrophils8 in in vitro studies using plasma from patients with severe COVID-19. A phase 2 study (NCT04579393) evaluated fostamatinib vs. placebo (all received standard of care [SOC]) in 59 hospitalized patients with COVID-19 and demonstrated reduction in mortality, ordinal scale scores, and number of days in the intensive care unit (ICU) as well as meeting the primary endpoint of safety.9 A phase 3 clinical study (NCT04629703) of fostamatinib for the treatment of COVID-19 is underway. (Figure Presented) Methods. A Phase 3, randomized, double-blind, placebo-controlled, adaptive design, multi-center study (NCT04629703) is underway to evaluate fostamatinib in 308 adult patients hospitalized with COVID-19 and on oxygen without intubation (Fig 2). Patients will receive fostamatinib 150 mg BID or placebo for 14 days;both arms receive SOC. At baseline, the clinical status score (8-point ordinal scale) had to be 5 or 6. Patients >= 65 years had to have >= 1 risk factor for severe disease and adults < 65 had to have >= 3. The primary outcome is days on oxygen (Day 1 to 29). Other endpoints include change in clinical status score, days in the ICU, time to hospital discharge, all-cause mortality, oxygen-free status and safety. Fostamatinib is investigational for COVID-19. Results. Blinded data from this trial in progress are as of 2 December 2021. See Fig 3. Conclusion. Final results of this Phase 3 trial are anticipated in 2022.
ABSTRACT
Objective: Several therapies are being used or proposed for COVID-19, and many lack appropriate evaluations of their effectiveness and safety. The purpose of this document is to develop recommendations to support decisions regarding the pharmacological treatment of patients hospitalized with COVID-19 in Brazil. Methods: A group of 27 experts, including representatives of the Ministry of Health and methodologists, created this guideline. The method used for the rapid development of guidelines was based on the adoption and/or adaptation of existing international guidelines (GRADE ADOLOPMENT) and supported by the e-COVID-19 RecMap platform. The quality of the evidence and the preparation of the recommendations followed the GRADE method. Results: Sixteen recommendations were generated. They include strong recommendations for the use of corticosteroids in patients using supplemental oxygen, the use of anticoagulants at prophylactic doses to prevent thromboembolism and the nonuse of antibiotics in patients without suspected bacterial infection. It was not possible to make a recommendation regarding the use of tocilizumab in patients hospitalized with COVID-19 using oxygen due to uncertainties regarding the availability of and access to the drug. Strong recommendations against the use of hydroxychloroquine, convalescent plasma, colchicine, lopinavir + ritonavir and antibiotics in patients without suspected bacterial infection and also conditional recommendations against the use of casirivimab + imdevimab, ivermectin and rendesivir were made. Conclusion: To date, few therapies have proven effective in the treatment of hospitalized patients with COVID-19, and only corticosteroids and prophylaxis for thromboembolism are recommended. Several drugs were considered ineffective and should not be used to provide the best treatment according to the principles of evidence-based medicine and promote economical resource use. © 2022 Associacao de Medicina Intensiva Brasileira - AMIB. All rights reserved.
ABSTRACT
Background: Patients with cancer, both active and previously treated, are at a higher risk of developing severe outcomes from COVID-19. During the pandemic, health care systems (HCS) have adapted the delivery of care, and disparities between private and public systems became even more striking. In Brazil, where 70% of the population depends on the public system, ICU demands largely exceed the capacity in most public centers, whereas in private centers the situation is less challenging. Herein we compare outcomes of patients with cancer and COVID-19 treated in the public and private HCS in Brazil. Methods: We used data from adult patients with solid malignancies who tested positive for COVID-19 and were admitted to two tertiary centers in the state of São Paulo. Patients who tested positive for SARS-CoV2 RNA real-time polymerase chain reaction (RT-PCR) were included. We collected data on baseline clinical conditions, cancer and treatment. Patients were classified by HCS: public system (public) versus (vs) private insurance coverage (private). The co-primary endpoints were all-cause mortality and a composite endpoint consisting of intensive-care-unit (ICU) admission, mechanical ventilation or death (ICU-MV-D). Chi-square, Fisher's exact test and Mann-Whitney U test were used when appropriate. We assessed the association between outcomes and HCS using logistic regression analyses, adjusting for age, sex, current anticancer treatment and comorbidities. Results: From March 16 to October 20 2020, 124 patients were identified. Of those, 90 (72%) were from the public and 34 (28%) from the private HCS. There were no statistical differences in sex, smoking, primary tumor siteand staging between patients from both HCS. Conversely, patients treated in the private system were older [66 (SD 13.8) vs 74 (SD 15.1), p=0.004], had more comorbidities (64.7% vs 37.8% p=0.009), and were on anticancer treatment more frequently (64.7% vs 34.4% p=0.004) compared to public patients. There were no differences in all-cause mortality (public 40% vs private 44.1% p=0.69) between patients treated at the different HCS. Nevertheless, in the composite outcome, private system was significantly associated with increased risk of ICU-MV-D compared to the public system (79.4% and 57.8% p=0.030, respectively). The median time from COVID-19 diagnosis to ICU-MV-D was 13 vs 8 days (p=0.031) and to death was 25 vs 24 days (p=0.24), respectively for public and private HCS patients. In the multivariable logistic regression, HCS was not associated with death [adjusted odds ratio (aOR)=1.16 p=0.75] or ICU-MV-D (aOR=0.55, p=0.27). Conclusion: While patients in the private system were older and had more comorbidities, there were no differences in inpatients all-cause mortality between private and public systems. However, private patients were associated with increased ICU-MV-D. We hypothesize that these findings may reflect disparities in ICU availability, known to be higher in the private system. Further studies investigating this hypothesis are warranted. EDR and DVA co-senior authors.
ABSTRACT
Background. Key pathologies in severe COVID-19 include immune cell activation, inflammatory cytokine release, and neutrophil extracellular trap release (NETosis), which are mediated by spleen tyrosine kinase (SYK) (Figure 1). Fostamatinib, an oral SYK inhibitor approved for chronic immune thrombocytopenia, has shown activity in vitro using plasma from patients with severe COVID-19, by abrogating the hyperimmune response triggered by anti-spike IgG;1 inhibiting hyperactivation in platelets;2 and blocking NETosis in neutrophils.3 R406, active metabolite of fostamatinib, protected against LPS-induced acute lung injury and thrombosis in mice.4,5 In clinical studies, fostamatinib reduced IL-6 in patients with rheumatoid arthritis.6 Therefore, a phase 2 study (NCT04579393) evaluated fostamatinib vs. placebo plus standard of care (SOC) in 59 hospitalized COVID-19 patients (manuscript pending). We initiated a phase 3 clinical study (NCT04629703) of fostamatinib for the treatment of COVID-19. Methods. A double-blind, randomized, placebo-controlled, adaptive design, multi-center, Phase 3 study (NCT04629703) is underway to evaluate the safety and efficacy of fostamatinib in 308 adult patients with COVID-19 (Figure 2). Hospitalized patients without respiratory failure (with or without supplemental oxygen) were included. Patients with ARDS or using extracorporeal membrane oxygenation (ECMO) were excluded. Patients will receive fostamatinib 150 mg BID or placebo for 14 days;both arms receive SOC. The primary outcome will be progression to severe/critical disease (worsening in clinical status score on the 8-point ordinal scale) within 29 days of the first dose of study drug. Fostamatinib is investigational for COVID-19. Results. Blinded update of trial in progress as of 28 April 2021. 12 patients have been randomized in North and South America. The clinical status score at Baseline was 5 (Hospitalized, requiring supplemental oxygen) in all 12 patients. Five patients had 8 adverse events (AE) (Fig 3). One AE (PE) was serious and is resolving. No deaths have been reported. At least two patients have been discharged (Day 5, Day 13) with continued dosing at home. Conclusion. Fostamatinib has the potential to provide a treatment option for the hyperimmune complications of COVID-19.