ABSTRACT
The COVID-19 pandemic has affected people, healthcare systems and caregivers on a global scale causing bottlenecks in hospital resources and overload of healthcare systems. The presence of disease sequelae in patients hospitalized due to CO VID-19 warrants additional care and monitoring of these patients. Remote monitoring techniques have been implemented in several domains of healthcare such as cardiology, cardiac rehabilitation and nephrology. Monitoring of vital signs using these technologies has allowed the tracking of patients with more granularity, resulting in better clinical outcomes such as reduction in hospitalizations. Therefore, we hypothesize that remote monitoring is beneficial in managing CO VID-19 patients post-hospitalization, enabling home-based patient follow-up. In this study, we investigated the use of remote monitoring on a COVID-19 patient cohort discharged from a tertiary care center. A post-hoc division of patients into two groups (alert-generating patients and non-alert generating patients) was performed. The longitudinal progression of sensor and questionnaire data was studied using linear mixed-effect models. The measured heart rate values were statistically significant in terms of the intercept (p < 0.001), indicating a difference between the two patient groups at baseline immediately post-discharge. © 2022 Creative Commons.
ABSTRACT
Background/Introduction: Thromboinflammation in severe COVID-19 is associated with disease severity and outcome. The kallikrein pathway is suggested to mediate thromboinflammation in COVID-19 by activating inflammatory pathways and contactmediated coagulation. Purpose(s): The DAWn-antico study investigates if a multitarget modulation of the thromboinflammatory response improves outcomes in hospitalized patients with severe COVID-19. Method(s): In this multicenter open-label randomized clinical trial (EudraCT 2020-001739-28), patients hospitalized with COVID- 19 were 1:2 randomized to receive standard of care (SOC) or SOC plus study intervention. The intervention consisted of aprotinin (2,000,000 IE IV four times daily) combined with low-molecular-weight heparin (LMWH;SC 50 IU/kg twice daily at the ward, 75 IU/kg twice daily at intensive care). Additionally, patients with predefined hyperinflammation received the interleukin-1- receptor antagonist anakinra (100mg IV four times daily). The primary outcome was time to a sustained 2-point improvement on the 7-point WHO ordinal scale for clinical status, or discharge. The trial was funded by Life Sciences Research Partners, Research Foundation Flanders (G0G4720N), and KU Leuven COVID-19 fund. Result(s): Between 24 June 2020 and 01 February 2021, 105 patients were randomized, and 102 patients were included in the full analysis set (intervention N=67 vs. SOC N=35). Twenty-five patients from the intervention group (37%) received anakinra. The intervention did not affect the primary outcome (HR 0.77 [CI 0.50;1.19], p=0.24) or mortality (intervention n=3 (4.6%) vs. SOC n=2 (5.7%), HR 0.82, [CI 0.14;4.94], p=0.83). There was one treatment-related adverse event in the intervention group (hematuria, 1.49%). There was one thrombotic event in the intervention group (1.49%) and one in the SOC group (2.86%), but no major bleedings. Conclusion(s): In hospitalized COVID-19 patients, modulation of thromboinflammation with high-dose aprotinin and LMWH with or without anakinra did not improve outcome in patients with moderate to severe COVID-19. (Disclosure: this RCT was presented at ISTH 2022 in London and will be published in Research and Practise in Thrombosis and Haemostasis).
ABSTRACT
Background: Thromboinflammation in severe COVID-19 is associated with disease severity and inferior outcome. Evidence suggests that the kallikrein pathway potentially plays a vital role in COVID-19 associated thromboinflammation as it both activates downstream inflammatory pathways and contact-mediated coagulation. Aim(s): To investigate whether modulation of this pronounced thromboinflammatory response can improve outcomes in hospitalized patients with severe COVID-19. Method(s): This multicenter randomized clinical trial was approved by the ethics committee and supported by the KU Leuven COVID-19 fund and Research Foundation Flanders (FWO). After informed consent, eligible patients were 1:2 randomized to receive standard of care (SOC) or SOC plus study intervention (figure 1). The intervention consisted of off-label -kallikrein-inhibiting -aprotinin combined with low molecular weight heparin (LMWH). Additionally, patients with predefined hyperinflammation were treated with the interleukin-1 receptor antagonist anakinra. The primary endpoint was time to sustain a 2-point improvement in the WHO ordinal scale for clinical status. Result(s): Three hospitals in Belgium included 102 patients (35 SOC vs. 67 intervention). Twenty-five patients from the intervention group (37%) were treated with anakinra. Patients had elevated D-dimers (mean 1012.4 mug/L;SD 991.9 mug/L) and C-reactive protein (mean 81.4 mg/L;SD 59.6 mg/L) at admission confirming baseline activation of coagulation and inflammatory pathways. During hospitalization, 37% of patients were admitted to the ICU (29% SOC vs. 42% intervention), and 20% needed invasive ventilation (12% SOC vs. 25% intervention). The intervention did not affect the time to sustained clinical improvement or hospital discharge (figure 2), nor secondary clinical endpoints. Except for D-dimers at day 3, there was no significant C-reactive protein or D-dimer reductions. There were no differences in treatment-related adverse events. Conclusion(s): In hospitalized COVID-19 patients, additional modulation of thromboinflammation with high-dose aprotinin and LMWH with or without anakinra was feasible and safe but did not improve clinical nor biochemical outcomes.
ABSTRACT
Introduction In acute respiratory distress syndrome (ARDS) patients with irreversible lung damage, lung transplantation from a ventilator and/or extracorporeal membrane oxygenation support (ECMO) is feasible. Recently, selection criteria for lung transplant candidates with a COVID-19 associated ARDS have been published. Here, we report the efficacy of high dose corticosteroids as ultimate salvage therapy, despite Meduri scheme attempts, in a patient listed for transplantation. Case Report A 50-year-old female with a medical history of Multiple Sclerosis (relapsing-remitting type under treatment with anti-alpha4 -integrin therapy), was tested positive for COVID-19. She deteriorated and was admitted to the hospital. High flow oxygen and dexamethasone (six milligram daily), were started but unfortunately, she developed a severe ARDS with need for mechanical ventilation and ECMO support. Corticosteroids according to the Meduri scheme and ciprofloxacin were started. Weaning trials were initiated but failed and CT-thorax showed consolidation and presumed fibrosis. After 37 days on ECMO, she was evaluated and listed for bilateral lung transplantation. A corticosteroid pulse therapy of 1000 mg of methylprednisolone IV for three days during antibiotic coverage with piperacillin/tazobactam was started and within three days the clinical condition of the patient improved and she could be weaned from ECMO (51 days of ECMO) and delisted from the lung transplantation waiting list. Nowadays, patient does not require oxygen, is at home and revalidating. Summary Here, we report the efficacy of a regimen with high dose corticosteroids as ultimate salvage therapy, despite Meduri scheme attempts, in a patient listed for transplantation. Corticosteroids are beneficial for immunomodulation and may reduce hyperinflammation. Our trial with administration of high dose corticosteroids pulse therapy in COVID-19 ARDS patients refractory to corticosteroids according to “classical schemes” has been successful and is informative. Further studies, will hopefully further elucidate responders and non-responders to high dose corticosteroid pulse therapy and preferably answer the question if prophylactic use of antibiotics and antifungals (in view of possible complications such as pulmonary aspergillosis and mucormycosis) is prudent in this vulnerable group.
ABSTRACT
BACKGROUND: The peak of the global COVID-19 pandemic has not yet been reached, and many countries face the prospect of a second wave of infections before effective vaccinations will be available. After an initial phase of viral replication, some patients develop a second illness phase in which the host thrombotic and inflammatory responses seem to drive complications. Severe COVID-19 disease is linked to high mortality, hyperinflammation, and a remarkably high incidence of thrombotic events. We hypothesize a crucial pathophysiological role for the contact pathway of coagulation and the kallikrein-bradykinin pathway. Therefore, drugs that modulate this excessive thromboinflammatory response should be investigated in severe COVID-19. METHODS: In this adaptive, open-label multicenter randomized clinical trial, we compare low molecular weight heparins at 50 IU anti-Xa/kg twice daily-or 75 IU anti-Xa twice daily for intensive care (ICU) patients-in combination with aprotinin to standard thromboprophylaxis in hospitalized COVID-19 patients. In the case of hyperinflammation, the interleukin-1 receptor antagonist anakinra will be added on top of the drugs in the interventional arm. In a pilot phase, the effect of the intervention on thrombotic markers (D-dimer) will be assessed. In the full trial, the primary outcome is defined as the effect of the interventional drugs on clinical status as defined by the WHO ordinal scale for clinical improvement. DISCUSSION: In this trial, we target the thromboinflammatory response at multiple levels. We intensify the dose of low molecular weight heparins to reduce thrombotic complications. Aprotinin is a potent kallikrein pathway inhibitor that reduces fibrinolysis, activation of the contact pathway of coagulation, and local inflammatory response. Additionally, aprotinin has shown in vitro inhibitory effects on SARS-CoV-2 cellular entry. Because the excessive thromboinflammatory response is one of the most adverse prognostic factors in COVID-19, we will add anakinra, a recombinant interleukin-1 receptor antagonist, to the regimen in case of severely increased inflammatory parameters. This way, we hope to modulate the systemic response to SARS-CoV-2 and avoid disease progressions with a potentially fatal outcome. TRIAL REGISTRATION: The EU Clinical Trials Register 2020-001739-28 . Registered on April 10, 2020.