Modulation of thromboinflammation in hospitalized COVID-19 patients with aprotinin, low molecular weight heparin, and anakinra: the DAwn- AntiCo study

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).

Satisfaction of the Use of Telehealth and Access to Care for Veterans During the COVID-19 Pandemic.

Background: While many health care providers have shifted toward telehealth services in response to the COVID-19 pandemic, little is known about the perception and acceptance of such services, particularly among vulnerable populations. Veterans, who are at increased risk of physical and mental health needs, may benefit from the use and availability of telehealth services. Materials and Methods: Cross sectional survey data related to telehealth use, satisfaction, and access were collected through an online survey. Participants from previous research studies and veterans receiving care at a national veteran behavioral health organization were invited to participate. Results: A total of 404 veterans participated. Before the pandemic, many veterans had never used telehealth for physical (72%) or mental (76%) health care. Since the start of the pandemic, 62% of participants reported they received some care through telehealth services. Most participants found telehealth valuable and helpful (82%), indicated the technology was well explained (77%), and felt that issues were resolved quickly and easily (67%). Access to care was limited among participants who utilize massage therapy (64%), dental care (53%), routine checkups (50%), acupuncture (50%), and physical therapy (48%). Discussion: These findings showed an increase in the use of telehealth services and overwhelming satisfaction among veterans. Despite this, some veterans indicated barriers to receiving physical and mental health care. Conclusions: This provides an opportunity to expand the use of telehealth services to meet the health care needs of veterans. Barriers to care should be addressed to minimize the impact on the well-being of veterans.

Monocyte-driven atypical cytokine storm and aberrant neutrophil activation as key mediators of COVID-19 disease severity.

Epidemiological and clinical reports indicate that SARS-CoV-2 virulence hinges upon the triggering of an aberrant host immune response, more so than on direct virus-induced cellular damage. To elucidate the immunopathology underlying COVID-19 severity, we perform cytokine and multiplex immune profiling in COVID-19 patients. We show that hypercytokinemia in COVID-19 differs from the interferon-gamma-driven cytokine storm in macrophage activation syndrome, and is more pronounced in critical versus mild-moderate COVID-19. Systems modelling of cytokine levels paired with deep-immune profiling shows that classical monocytes drive this hyper-inflammatory phenotype and that a reduction in T-lymphocytes correlates with disease severity, with CD8+ cells being disproportionately affected. Antigen presenting machinery expression is also reduced in critical disease. Furthermore, we report that neutrophils contribute to disease severity and local tissue damage by amplification of hypercytokinemia and the formation of neutrophil extracellular traps. Together our findings suggest a myeloid-driven immunopathology, in which hyperactivated neutrophils and an ineffective adaptive immune system act as mediators of COVID-19 disease severity.

Manifestaciones pulmonares y radiológicas del Sars-Cov2 en pediatría

Las infecciones respiratorias agudas son causa de alta morbi-mortalidad a nivel mundial. El Coronavirus descubierto en Wuhan, China en el 2019 es de interés mundial por las diferentes manifestaciones clínicas que pueden aparecer en niños. Nuestro objetivo principal es revisar las manifestaciones del COVID-19 en el aparato respiratorio y los hallazgos a nivel radiológicos en pediatría. Se estiman que solo el 5,7% de los niños han sido hospitalizados, siendo los niños con comorbilidades y menores de 1 año los que suponen un riesgo mayor para enfermedad grave. A nivel global la mediana de edad de presentación de los casos es alrededor de 7 años, detectándose más casos a mayor edad, pero siendo la gravedad inversamente proporcional a la edad. La forma asintomática o leve son las presentaciones más comunes reportadas en niños, siendo de hasta en el 90% de los niños infectados. Los estudios de laboratorio pueden ser normales o presentar leucocitos alterados en un 69,2% y a nivel radiológico se ha observado en niños que en un 69% presentan opacidades bilaterales en vidrio despulido. En este momento, cualquier infección respiratoria aguda hay que descartar COVID-19, para poder evitar complicaciones en el paciente...(AU)

Manifestaciones pulmonares y radiológicas del Sars-Cov2 en pediatría

Las infecciones respiratorias agudas son causa de alta morbi-mortalidad a nivel mundial. El Coronavirus descubierto en Wuhan, China en el 2019 es de interés mundial por las diferentes manifestaciones clínicas que pueden aparecer en niños. Nuestro objetivo principal es revisar las manifestaciones del COVID-19 en el aparato respiratorio y los hallazgos a nivel radiológicos en pediatría. Se estiman que solo el 5,7% de los niños han sido hospitalizados, siendo los niños con comorbilidades y menores de 1 año los que suponen un riesgo mayor para enfermedad grave. A nivel global la mediana de edad de presentación de los casos es alrededor de 7 años, detectándose más casos a mayor edad, pero siendo la gravedad inversamente proporcional a la edad. La forma asintomática o leve son las presentaciones más comunes reportadas en niños, siendo de hasta en el 90% de los niños infectados. Los estudios de laboratorio pueden ser normales o presentar leucocitos alterados en un 69,2% y a nivel radiológico se ha observado en niños que en un 69% presentan opacidades bilaterales en vidrio despulido. En este momento, cualquier infección respiratoria aguda hay que descartar COVID-19, para poder evitar complicaciones en el paciente...(AU)

A randomized, open-label, adaptive, proof-of-concept clinical trial of modulation of host thromboinflammatory response in patients with COVID-19: the DAWn-Antico study.

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.

Anticoagulant therapy in COVID-19 critically ill: Should we go for more?

Critically ill COVID-19 patients often develop a severe pro-thrombotic milieu, as reflected by the markedly increased d-dimer levels. Several cohort studies have reported high rates of thrombotic complications, including deep venous thrombosis (DVT) and pulmonary embolism (PE), myocardial infarction, stroke and microvascular thrombosis. Accordingly, COVID-19 patients who are hospitalized either at a normal, non-intensive care unit (ICU) or at the ICU need to receive appropriate dosages of anticoagulant therapy to prevent or treat these thrombotic complications. This manuscript summarizes the institutional guidance for the antithrombotic prophylaxis and treatment of VTE as outlined by a multidisciplinary team of experts during the first weeks of the COVID-19 pandemic in Europe. Controlled studies are needed to verify the optimal anticoagulation for both prophylaxis and treatment.