Insights into the Role of Neutrophils and Neutrophil Extracellular Traps in Causing Cardiovascular Complications in Patients with COVID-19: A Systematic Review
Journal of clinical medicine. 2022;11(9)
BACKGROUND The coronavirus disease 2019 (COVID-19) pandemic caused by the SARS-CoV-2 virus has resulted in significant mortality and burdening of healthcare resources. While initially noted as a pulmonary pathology, subsequent studies later identified cardiovascular involvement with high mortalities reported in specific cohorts of patients. While cardiovascular comorbidities were identified early on, the exact manifestation and etiopathology of the infection remained elusive. This systematic review aims to investigate the role of inflammatory pathways, highlighting several culprits including neutrophil extracellular traps (NETs) which have since been extensively investigated. METHOD A search was conducted using three databases (MEDLINE; MEDLINE In-Process & Other Non-Indexed Citations and EMBASE). Data from randomized controlled trials (RCT), prospective series, meta-analyses, and unmatched observational studies were considered for the processing of the algorithm and treatment of inflammatory response during SARS-CoV-2 infection. Studies without the SARS-CoV-2 Infection period and case reports were excluded. RESULTS A total of 47 studies were included in this study. The role of the acute inflammatory response in the propagation of the systemic inflammatory sequelae of the disease plays a major part in determining outcomes. Some of the mechanisms of activation of these pathways have been highlighted in previous studies and are highlighted. CONCLUSION NETs play a pivotal role in the pathogenesis of the inflammatory response. Despite moving into the endemic phase of the disease in most countries, COVID-19 remains an entity that has not been fully understood with long-term effects remaining uncertain and requiring ongoing monitoring and research.
Atorvastatin versus placebo in patients with covid-19 in intensive care: randomized controlled trial
BMJ (Clinical research ed.). 2022;376:e068407
OBJECTIVE To assess the effect of statin treatment versus placebo on clinical outcomes in patients with covid-19 admitted to the intensive care unit (ICU). DESIGN INSPIRATION/INSPIRATION-S was a multicenter, randomized controlled trial with a 2×2 factorial design. Results for the anticoagulation randomization have been reported previously. Results for the double blind randomization to atorvastatin versus placebo are reported here. SETTING 11 hospitals in Iran. PARTICIPANTS Adults aged ≥18 years with covid-19 admitted to the ICU. INTERVENTION Atorvastatin 20 mg orally once daily versus placebo, to be continued for 30 days from randomization irrespective of hospital discharge status. MAIN OUTCOME MEASURES The primary efficacy outcome was a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or all cause mortality within 30 days from randomization. Prespecified safety outcomes included increase in liver enzyme levels more than three times the upper limit of normal and clinically diagnosed myopathy. A clinical events committee blinded to treatment assignment adjudicated the efficacy and safety outcomes. RESULTS Of 605 patients randomized between 29 July 2020 and 4 April 2021 for statin randomization in the INSPIRATION-S trial, 343 were co-randomized to intermediate dose versus standard dose prophylactic anticoagulation with heparin based regimens, whereas 262 were randomized after completion of the anticoagulation study. 587 of the 605 participants were included in the primary analysis of INSPIRATION-S, reported here: 290 were assigned to atorvastatin and 297 to placebo (median age 57 years (interquartile range 45-68 years); 256 (44%) women). The primary outcome occurred in 95 (33%) patients assigned to atorvastatin and 108 (36%) assigned to placebo (odds ratio 0.84, 95% confidence interval 0.58 to 1.21). Death occurred in 90 (31%) patients in the atorvastatin group and 103 (35%) in the placebo group (odds ratio 0.84, 95% confidence interval 0.58 to 1.22). Rates for venous thromboembolism were 2% (n=6) in the atorvastatin group and 3% (n=9) in the placebo group (odds ratio 0.71, 95% confidence interval 0.24 to 2.06). Myopathy was not clinically diagnosed in either group. Liver enzyme levels were increased in five (2%) patients assigned to atorvastatin and six (2%) assigned to placebo (odds ratio 0.85, 95% confidence interval 0.25 to 2.81). CONCLUSIONS In adults with covid-19 admitted to the ICU, atorvastatin was not associated with a significant reduction in the composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or all cause mortality compared with placebo. Treatment was, however, found to be safe. As the overall event rates were lower than expected, a clinically important treatment effect cannot be excluded. TRIAL REGISTRATION ClinicalTrials.gov NCT04486508.
Durable functional limitation in patients with coronavirus disease-2019 admitted to intensive care and the effect of intermediate-dose vs standard-dose anticoagulation on functional outcomes
European journal of internal medicine. 2022
INTRODUCTION Patients affected with severe forms of coronavirus disease 2019 (COVID-19) suffer from a wide range of sequelae, from limited airway diseases to multiple organ failure. These sequelae may create exercise limitation, impair the daily activity and thus impact the mental health and the social life. However, the extent of functional limitations and depressive symptoms are understudied especially in patients with COVID-19 after intensive care unit (ICU) hospitalization. METHODS The Intermediate versus Standard-dose Prophylactic anticoagulation In cRitically-ill pATIents with COVID-19: An opeN label randomized controlled trial (INSPIRATION) was a clinical trial that randomized ICU patients with COVID-19 to intermediate-dose vs standard-dose anticoagulation. In the current study, we assessed the interval change in 30-day and 90-day functional limitations based on the post-COVID-19 functional status scale (PCFS) and depressive symptoms based on the Patient Health Questionnaire-2 (PHQ-2) in the trial participants. We also assessed the effect of intermediate-dose vs standard-dose prophylactic anticoagulation on the functional outcomes and depressive symptoms. RESULTS Of 600 randomized patients in INSPIRATION, 375 (age: 62 years; 42% women) participated in the functional status study. 195 patients died during the 90-day follow up (191 by day 30). Among survivors, between day 30 and day 90, the proportion of patients with moderate-to-severe functional limitation (PCSF grade 3-or-4) decreased from 20.0% to 4.8% (P <0.001) and PHQ-2 ≥ 3 decreased from 25.5% to 16.6% (P = 0.05). The proportion of patients with no functional limitations (PCFS grade 0) increased (4.2% to 15.4%, P<0.001). Intermediate-dose compared with standard-dose prophylactic anticoagulation did not impact the 90-day proportion of patients with PCFS grade 3-or-4 (5.3% vs 4.2%; odds ratio (OR), 1.20, [95% CI, 0.46-3.11]; P = 0.80) or PHQ-2 ≥ 3 (17.9% vs 15.3%; OR, 1.14, [95% CI, 0.79-1.65]; P = 0.14), with similar results when accounting for study center. CONCLUSION In patients with COVID-19 admitted to the ICU, functional limitations and depressive symptoms were common at 30-day follow-up and had some improvement by 90-day follow-up among survivors. Intermediate-dose compared to standard-dose prophylactic anticoagulation did not improve functional outcomes.
Incidence and prognostic value of pulmonary embolism in COVID-19: A systematic review and meta-analysis
PloS one. 2022;17(3):e0263580
BACKGROUND Pulmonary embolisms are frequently and prognostically in individuals infected by coronavirus disease 2019 (COVID-19); the incidence of pulmonary embolisms is varied across numerous studies. This study aimed to assess the pooled incidence of pulmonary embolic events and the prognostic value of such events in intensive care unit (ICU) admissions of patients with COVID-19. METHODS The Cochrane Library, PubMed, and EmBase were systematically searched for eligible studies published on or before October 20, 2021. The pooled incidence of pulmonary embolism was calculated using the random-effects model. Moreover, the prognostic value was assessed by measuring the sensitivity, specificity, positive and negative likelihood ratio (PLR and NLR), diagnostic odds ratio (DOR), and the area under the receiver operating characteristic curve (AUC). RESULTS Thirty-six studies involving 10,367 COVID-19 patients were selected for the final meta-analysis. The cumulative incidence of pulmonary embolism in patients with COVID-19 was 21% (95% confidence interval [95%CI]: 18-24%; P<0.001), and the incidence of pulmonary embolism in ICU and non-ICU patients was 26% (95%CI: 22-31%; P<0.001) and 17% (95%CI: 14-20%; P<0.001), respectively. The predictive role of pulmonary embolism in ICU admission was also assessed, and the sensitivity, specificity, PLR, NLR, DOR, and AUC were 0.31 (95%CI: 0.21-0.42), 0.84 (95%CI: 0.75-0.90), 1.88 (95%CI: 1.45-2.45), 0.83 (95%CI: 0.75-0.91), 2.25 (95%CI: 1.64-3.08), and 0.61 (95%CI: 0.57-0.65), respectively. CONCLUSION This study found that the incidence of pulmonary embolism was relatively high in COVID-19 patients, and the incidence of pulmonary embolism in ICU patients was higher than that in non-ICU patients.
Patients infected with COVID-19 (36 studies, n= 10,367).
Systematic review and meta-analysis assessing the pooled incidence of pulmonary embolic events and the prognostic value of such events in intensive and non-intensive care.
The cumulative incidence of pulmonary embolism in patients with COVID-19 was 21%, and the incidence of pulmonary embolism in intensive care unit (ICU) and non-ICU patients was 26% and 17%, respectively. The predictive role of pulmonary embolism in ICU admission was also assessed, (sensitivity: 0.31, specificity: 0.84, positive likelihood ratio: 1.88, negative likelihood ratio: 0.83, diagnostic odds ratio: 2.25, and the area under the receiver operating characteristic curve: 0.61).
Elucidating the Correlation of D-Dimer Levels with COVID-19 Severity: A Scoping Review
AIMS: The review explores the findings of previous studies to elucidate the association between levels of D-dimer and COVID-19 severity and prognosis. In addition, we assessed the efficiency of anticoagulant therapies in reducing COVID-19 severity and improving the prognosis of the patients. MATERIALS AND METHODS A comprehensive literature review was conducted using MEDLINE/PubMed databases, Scopus, and Web of Science with the help of keywords "COVID-19," "D-Dimer," "Thrombosis," "Fibrin network," "Anticoagulant therapy," "Inflammation," and "disease severity." Based on all these articles and clinical experience, a scoping review was constructed and the full texts of the articles that were retrieved were accessed. RESULTS A D-dimer is a complex protein molecule that is formed during plasmin-mediated degradation of the fibrin network. Thus, it serves as a marker of thrombotic activity. On the other hand, in addition to severe respiratory distress and reduction in pulmonary gas exchange, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) also triggers prothrombotic changes in the infected individuals. The levels of D-dimer have been postulated to be positively associated with the degree of disease severity among COVID-19 patients. CONCLUSIONS It has been postulated that D-dimer could potentially be used as a biomarker to predict the prognosis and outcome of COVID-19 patients at the time of admission to hospitals and facilitate more personalized and efficient clinical management that could significantly reduce the mortality rate of such patients and allow more rapid recovery.
Coronary Stent Thrombosis in COVID-19 Patients: A Systematic Review of Cases Reported Worldwide
Approximately 5 million percutaneous coronary interventions are performed worldwide annually. Therefore, stent-related complications pose a serious public health concern. Stent thrombosis, although rare, is usually catastrophic, often associated with extensive myocardial infarction or death. Because little progress has been made in outcomes following stent thrombosis, ongoing research is focusing on further understanding the predictors as well as frequency and timing in various patient subgroups. Coronavirus disease-2019 (COVID-19), a viral illness caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), activates inflammatory mechanisms that potentially create a prothrombotic environment and increases the risk of local micro thromboembolism and all types of stent thrombosis. In-stent thrombosis occurrence increased during the COVID-19 pandemic, however, there is still lack of comprehensive studies describing this population. This review and worldwide analysis of coronary stent thrombosis cases related to COVID-19 summarizes all available data.
Aortic Thrombosis following COVID-19: A Systematic Review
The Thoracic and cardiovascular surgeon. 2022
BACKGROUND Arterial and venous thromboses associated with the coronavirus disease 2019 (COVID-19) have been well described. These events are caused by a hypercoagulable state due to endotheliopathy and infection-driven coagulopathy. There has been an ever-increasing number of documented cases of aortic thrombosis (AoT) in COVID-19 patients. We conducted a systematic review of current scientific literature to identify and consolidate evidence of AoT in COVID-19 patients. METHODS A systematic review of literature was conducted between March 15, 2020, and May 1, 2021, on PubMed and Cochrane databases. Additionally, a case from our facility was included. RESULTS A total of 38 studies (12 case series and 26 case reports) and a case from our facility describing AoT in 56 COVID-19 patients were included. Patients were aged 64.8 ± 10.5 years, were predominantly male (75%), and had several comorbidities. AoT was symptomatic in 82,14% of patients; however, when D dimers were reported, they were significantly elevated even in otherwise asymptomatic patients. Most patients had no previous history of aortic disease. Thrombosis was described in all parts of the aorta, with several cases reporting multiple locations. The median reported time until development of AoT was 10 days. Peripheral thrombosis occurred in 73.21% of cases, most commonly causing lower limb ischemia. Mortality rate was 30.4%. CONCLUSIONS AoT can occur with no clinical symptoms or as a primary symptom in otherwise asymptomatic COVID-19 patients. D dimers are a highly sensitive diagnostic tool. Diagnosis of this condition prior to development of complications could be instrumental in saving many lives.
Efficacy of different anticoagulant doses for patients with COVID-19: a systematic review and network meta-analysis
PURPOSE As no reported randomized control trials (RCTs) directly compare the three administration doses of anticoagulants (prophylactic dose, treatment dose, and no treatment), the most recommended dose to be administered to patients with coronavirus disease 2019 (COVID-19) remains unclear. The purpose of this study was to examine the effects of anticoagulant doses administered to patients with COVID-19, using a network meta-analysis (NMA) including high-quality studies. METHODS All eligible trials from the Cochrane Central Register of Controlled Trials, MEDLINE, and Clinicaltrials.gov were included. We included RCTs and observational studies adjusted for covariates for patients aged ≥ 18 years and hospitalized due to objectively confirmed COVID-19. The main study outcome was mortality. RESULTS In patients with moderate COVID-19, the prophylactic (relative risk (RR) 0.64 [95% confidence interval (CI) 0.52-0.80]) and treatment dose (RR 0.57 [95% CI 0.45-0.72] were associated with a lower risk of short-term mortality than that with no anticoagulant treatment. However, the prophylactic and treatment dose groups were not significantly different. The hierarchy for efficacy in reducing short-term mortality was treatment dose (P score 92.4) > prophylactic dose (57.6) > no treatment (0.0). In patients with severe COVID-19, due to the absence of trials with the no-treatment group, NMA could not be conducted. However, pairwise comparison did not show a significant difference between the prophylactic and treatment dose groups. CONCLUSIONS Treatment and prophylactic doses of anticoagulants showed similar effects on mortality; however, the treatment dose is preferred over the prophylactic dose for patients with both moderate and severe COVID-19. TRIAL REGISTRATION NUMBER AND REGISTRATION DATES PROSPERO (registration number: CRD42021245308, 05/21/2021).
The anti-C5a antibody vilobelimab efficiently inhibits C5a in patients with severe COVID-19
Clinical and translational science. 2022
Recently, we reported the phase II portion of the adaptive phase II/III PANAMO trial exploring potential benefit and safety of selectively blocking C5a with the monoclonal antibody vilobelimab (IFX-1) in patients with severe coronavirus disease 2019 (COVID-19). The potent anaphylatoxin C5a attracts neutrophils and monocytes to the infection site, causes tissue damage by oxidative radical formation and enzyme releases, and leads to activation of the coagulation system. Results demonstrated that C5a inhibition with vilobelimab was safe and secondary outcomes appeared in favor of vilobelimab. We now report the pharmacokinetic/pharmacodynamic (PK/PD) analysis of the phase II study. Between March 31 and April 24, 2020, 30 patients with severe COVID-19 pneumonia confirmed by real-time polymerase chain reaction were randomly assigned 1:1 to receive vilobelimab plus best supportive care or best supportive care only. Samples for measurement of vilobelimab, C3a and C5a blood concentrations were taken. Vilobelimab predose (trough) drug concentrations in plasma ranged from 84,846 to 248,592 ng/ml (571 to 1674 nM) with a geometric mean of 151,702 ng/ml (1022 nM) on day 2 and from 80,060 to 200,746 ng/ml (539 to 1352 nM) with a geometric mean of 139,503 ng/ml (939 nM) on day 8. After the first vilobelimab infusion, C5a concentrations were suppressed in the vilobelimab group (median 39.70 ng/ml 4.8 nM, IQR 33.20-45.55) as compared to the control group (median 158.53 ng/ml 19.1 nM, IQR 60.03-200.89, p = 0.0006). The suppression was maintained on day 8 (p = 0.001). The current PK/PD analysis shows that vilobelimab efficiently inhibits C5a in patients with severe COVID-19.
Study of Alteplase for Respiratory Failure in SARS-CoV-2 COVID-19: A Vanguard Multicenter, Rapidly Adaptive, Pragmatic, Randomized Controlled Trial
BACKGROUND Pulmonary vascular microthrombi are a proposed mechanism of COVID-19 respiratory failure. We hypothesized that early administration of tissue plasminogen activator (tPA) followed by therapeutic heparin would improve pulmonary function in these patients. RESEARCH QUESTION Does tPA improve pulmonary function in severe COVID-19 respiratory failure, and is it safe? STUDY DESIGN AND METHODS Adults with COVID-19-induced respiratory failure were randomized from May14, 2020 through March 3, 2021, in two phases. Phase 1 (n = 36) comprised a control group (standard-of-care treatment) vs a tPA bolus (50-mg tPA IV bolus followed by 7 days of heparin; goal activated partial thromboplastin time [aPTT], 60-80 s) group. Phase 2 (n = 14) comprised a control group vs a tPA drip (50-mg tPA IV bolus, followed by tPA drip 2 mg/h plus heparin 500 units/h over 24 h, then heparin to maintain aPTT of 60-80 s for 7 days) group. Patients were excluded from enrollment if they had not undergone a neurologic examination or cross-sectional brain imaging within the previous 4.5 h to rule out stroke and potential for hemorrhagic conversion. The primary outcome was Pao(2) to Fio(2) ratio improvement from baseline at 48 h after randomization. Secondary outcomes included Pao(2) to Fio(2) ratio improvement of > 50% or Pao(2) to Fio(2) ratio of ≥ 200 at 48 h (composite outcome), ventilator-free days (VFD), and mortality. RESULTS Fifty patients were randomized: 17 in the control group and 19 in the tPA bolus group in phase 1 and eight in the control group and six in the tPA drip group in phase 2. No severe bleeding events occurred. In the tPA bolus group, the Pao(2) to Fio(2) ratio values were significantly (P < .017) higher than baseline at 6 through 168 h after randomization; the control group showed no significant improvements. Among patients receiving a tPA bolus, the percent change of Pao(2) to Fio(2) ratio at 48 h (16.9% control [interquartile range (IQR), -8.3% to 36.8%] vs 29.8% tPA bolus [IQR, 4.5%-88.7%]; P = .11), the composite outcome (11.8% vs 47.4%; P = .03), VFD (0.0 [IQR, 0.0-9.0] vs 12.0 [IQR, 0.0-19.0]; P = .11), and in-hospital mortality (41.2% vs 21.1%; P = .19) did not reach statistically significant differences when compared with those of control participants. The patients who received a tPA drip did not experience benefit. INTERPRETATION The combination of tPA bolus plus heparin is safe in severe COVID-19 respiratory failure. A phase 3 study is warranted given the improvements in oxygenation and promising observations in VFD and mortality. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT04357730; URL: www. CLINICALTRIALS gov.