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1.
Clin Immunol ; 238: 109016, 2022 05.
Article in English | MEDLINE | ID: covidwho-1797060

ABSTRACT

Aiming to reduce mortality in COVID-19 with severe respiratory failure we administered a combined rescue treatment (COMBI) on top of standard-of-care (SOC: dexamethasone/heparin) consisted of inhaled DNase to dissolve thrombogenic neutrophil extracellular traps, plus agents against cytokine-mediated hyperinflammation, namely anti-IL-6-receptor tocilizumab and JAK1/2 inhibitor baricitinib. Patients with PaO2/FiO2 < 100 mmHg were analysed. COMBI group (n = 22) was compared with similar groups that had received SOC alone (n = 26) or SOC plus monotherapy with either IL-1-receptor antagonist anakinra (n = 19) or tocilizumab (n = 11). COMBI was significantly associated with lower in-hospital mortality and intubation rate, shorter duration of hospitalization, and prolonged overall survival after a median follow-up of 110 days. In vitro, COVID-19 plasma induced tissue factor/thrombin pathway in primary lung fibroblasts. This effect was inhibited by the immunomodulatory agents of COMBI providing a mechanistic explanation for the clinical observations. These results support the conduct of randomized trials using combined immunomodulation in COVID-19 to target multiple interconnected pathways of immunothrombosis.


Subject(s)
Antibodies, Monoclonal, Humanized , COVID-19 , Deoxyribonucleases , Respiratory Insufficiency , Antibodies, Monoclonal, Humanized/therapeutic use , Azetidines/therapeutic use , COVID-19/drug therapy , Deoxyribonucleases/therapeutic use , Humans , Purines/therapeutic use , Pyrazoles/therapeutic use , Respiratory Insufficiency/drug therapy , Respiratory Insufficiency/virology , SARS-CoV-2 , Sulfonamides/therapeutic use , Treatment Outcome
2.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-330140

ABSTRACT

COVID-19-related severe respiratory failure (SRF) leads to mechanical ventilation increasing the in-hospital mortality substantially. Abundancy of lung fibroblasts (LFs) in injured lung tissue has been associated with the progression of respiratory failure in COVID-19. Aiming to reduce mortality in patients with SRF (PaO2/FiO2<100 mmHg) and considering the multi-mechanistic nature of severe COVID-19 pathogenesis, we applied a combined rescue treatment (COMBI) on top of standard-of-care (SOC: dexamethasone and heparin) comprised inhaled DNase to dissolve thrombogenic neutrophil extracellular traps, plus agents against cytokine-mediated hyperinflammation, such as anti-IL-6 receptor tocilizumab and selective JAK1/2 inhibitor baricitinib. COMBI (n=22) was compared with SOC (n= 26), and with two previously and consecutively used therapeutic approaches, including either IL-1 receptor antagonist anakinra (ANA, n=19), or tocilizumab (TOCI, n=11), on top of SOC. In parallel, evaluation of immunothrombosis was assessed in vitro in human LFs, treated with the applied therapeutic agents upon stimulation with COVID-19 plasma. COMBI was associated with lower in-hospital mortality (p=0.014) and intubation rate (p=0.013), shorter duration of hospitalization (p=0.019), and prolonged overall survival after a median follow-up of 110+/-4 days (p=0.003). In vitro, COVID-19 plasma markedly induced tissue factor/thrombin pathway in LFs, while this effect was inhibited by the immunomodulatory agents of COMBI providing a mechanistic explanation for the clinical observations. These results suggest the design of randomized trials using combined immunomodulatory therapies in COVID-19-associated SRF targeting multiple interconnected pathways of immunothrombosis.

3.
J Clin Invest ; 130(11): 6151-6157, 2020 11 02.
Article in English | MEDLINE | ID: covidwho-1435146

ABSTRACT

Emerging data indicate that complement and neutrophils contribute to the maladaptive immune response that fuels hyperinflammation and thrombotic microangiopathy, thereby increasing coronavirus 2019 (COVID-19) mortality. Here, we investigated how complement interacts with the platelet/neutrophil extracellular traps (NETs)/thrombin axis, using COVID-19 specimens, cell-based inhibition studies, and NET/human aortic endothelial cell (HAEC) cocultures. Increased plasma levels of NETs, tissue factor (TF) activity, and sC5b-9 were detected in patients. Neutrophils of patients yielded high TF expression and released NETs carrying active TF. Treatment of control neutrophils with COVID-19 platelet-rich plasma generated TF-bearing NETs that induced thrombotic activity of HAECs. Thrombin or NETosis inhibition or C5aR1 blockade attenuated platelet-mediated NET-driven thrombogenicity. COVID-19 serum induced complement activation in vitro, consistent with high complement activity in clinical samples. Complement C3 inhibition with compstatin Cp40 disrupted TF expression in neutrophils. In conclusion, we provide a mechanistic basis for a pivotal role of complement and NETs in COVID-19 immunothrombosis. This study supports strategies against severe acute respiratory syndrome coronavirus 2 that exploit complement or NETosis inhibition.


Subject(s)
Betacoronavirus , Complement Membrane Attack Complex , Coronavirus Infections , Extracellular Traps , Neutrophils , Pandemics , Pneumonia, Viral , Thromboplastin , Thrombosis , Aged , Betacoronavirus/immunology , Betacoronavirus/metabolism , COVID-19 , Complement Activation/drug effects , Complement Membrane Attack Complex/immunology , Complement Membrane Attack Complex/metabolism , Coronavirus Infections/blood , Coronavirus Infections/immunology , Extracellular Traps/immunology , Extracellular Traps/metabolism , Female , Humans , Male , Middle Aged , Neutrophils/immunology , Neutrophils/metabolism , Peptides, Cyclic/pharmacology , Pneumonia, Viral/blood , Pneumonia, Viral/immunology , Receptor, Anaphylatoxin C5a/antagonists & inhibitors , Receptor, Anaphylatoxin C5a/blood , Receptor, Anaphylatoxin C5a/immunology , Respiratory Distress Syndrome/blood , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/virology , SARS-CoV-2 , Thrombin/immunology , Thrombin/metabolism , Thromboplastin/immunology , Thromboplastin/metabolism , Thrombosis/blood , Thrombosis/immunology , Thrombosis/virology
4.
Cell Death Differ ; 28(11): 3125-3139, 2021 11.
Article in English | MEDLINE | ID: covidwho-1241944

ABSTRACT

SARS-CoV-2 infection poses a major threat to the lungs and multiple other organs, occasionally causing death. Until effective vaccines are developed to curb the pandemic, it is paramount to define the mechanisms and develop protective therapies to prevent organ dysfunction in patients with COVID-19. Individuals that develop severe manifestations have signs of dysregulated innate and adaptive immune responses. Emerging evidence implicates neutrophils and the disbalance between neutrophil extracellular trap (NET) formation and degradation plays a central role in the pathophysiology of inflammation, coagulopathy, organ damage, and immunothrombosis that characterize severe cases of COVID-19. Here, we discuss the evidence supporting a role for NETs in COVID-19 manifestations and present putative mechanisms, by which NETs promote tissue injury and immunothrombosis. We present therapeutic strategies, which have been successful in the treatment of immunο-inflammatory disorders and which target dysregulated NET formation or degradation, as potential approaches that may benefit patients with severe COVID-19.


Subject(s)
COVID-19/pathology , Extracellular Traps/metabolism , Neutrophils/immunology , COVID-19/complications , COVID-19/immunology , Citrullination , Complement Activation , Humans , Neutrophils/metabolism , Platelet Activation , SARS-CoV-2/isolation & purification , Severity of Illness Index , Thrombosis/etiology
5.
Clin Immunol ; 220: 108598, 2020 11.
Article in English | MEDLINE | ID: covidwho-778645

ABSTRACT

Growing clinical evidence has implicated complement as a pivotal driver of COVID-19 immunopathology. Deregulated complement activation may fuel cytokine-driven hyper-inflammation, thrombotic microangiopathy and NET-driven immunothrombosis, thereby leading to multi-organ failure. Complement therapeutics have gained traction as candidate drugs for countering the detrimental consequences of SARS-CoV-2 infection. Whether blockade of terminal complement effectors (C5, C5a, or C5aR1) may elicit similar outcomes to upstream intervention at the level of C3 remains debated. Here we compare the efficacy of the C5-targeting monoclonal antibody eculizumab with that of the compstatin-based C3-targeted drug candidate AMY-101 in small independent cohorts of severe COVID-19 patients. Our exploratory study indicates that therapeutic complement inhibition abrogates COVID-19 hyper-inflammation. Both C3 and C5 inhibitors elicit a robust anti-inflammatory response, reflected by a steep decline in C-reactive protein and IL-6 levels, marked lung function improvement, and resolution of SARS-CoV-2-associated acute respiratory distress syndrome (ARDS). C3 inhibition afforded broader therapeutic control in COVID-19 patients by attenuating both C3a and sC5b-9 generation and preventing FB consumption. This broader inhibitory profile was associated with a more robust decline of neutrophil counts, attenuated neutrophil extracellular trap (NET) release, faster serum LDH decline, and more prominent lymphocyte recovery. These early clinical results offer important insights into the differential mechanistic basis and underlying biology of C3 and C5 inhibition in COVID-19 and point to a broader pathogenic involvement of C3-mediated pathways in thromboinflammation. They also support the evaluation of these complement-targeting agents as COVID-19 therapeutics in large prospective trials.


Subject(s)
Betacoronavirus/pathogenicity , Complement C3/antagonists & inhibitors , Complement C5/antagonists & inhibitors , Complement Inactivating Agents/therapeutic use , Coronavirus Infections/drug therapy , Immunologic Factors/therapeutic use , Pneumonia, Viral/drug therapy , Respiratory Distress Syndrome/drug therapy , Antibodies, Monoclonal, Humanized/therapeutic use , Biomarkers/blood , C-Reactive Protein/metabolism , COVID-19 , Cohort Studies , Complement Activation/drug effects , Complement C3/genetics , Complement C3/immunology , Complement C5/genetics , Complement C5/immunology , Coronavirus Infections/complications , Coronavirus Infections/immunology , Coronavirus Infections/virology , Extracellular Traps/drug effects , Female , Gene Expression , Humans , Interleukin-6/metabolism , Male , Middle Aged , Neutrophils/drug effects , Neutrophils/immunology , Neutrophils/virology , Pandemics , Peptides, Cyclic/therapeutic use , Pneumonia, Viral/complications , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Respiratory Distress Syndrome/complications , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/virology , SARS-CoV-2 , Severity of Illness Index
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