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1.
J Clin Med ; 11(4)2022 Feb 19.
Article in English | MEDLINE | ID: covidwho-1715434

ABSTRACT

Correlation between risk of graft-versus-host disease (GvHD) and CD3+ counts within the peripheral blood stem cell graft has recently been reported in the setting of post-transplant cyclophosphamide (PT-Cy). We aimed to investigate the benefit of the addition of a single dose of anti-T lymphocyte globulin (ATLG 5 mg/kg) to PT-Cy in this setting. Starting in 2019, all patients receiving PBSC transplant containing CD3+ counts above 300 × 106/kg (study group) received a post-transplant dose of ATLG in addition to standard PT-Cy. The study was designed as a real-life analysis and included all consecutive Hematopoietic Stem Cell Transplantation (HSCT) recipients according to the above-mentioned inclusion criterion (n = 21), excluding cord blood and bone marrow donors. Using a 1:2 matched-pair analysis, we compared the outcomes with a historical population who received PT-Cy only (control group). We found a delayed platelet engraftment (29% vs. 45% at 30 days, p = 0.03) and a non-significant trend toward higher risk of poor graft function (29% vs. 19%, p = 0.52). The addition of ATLG impacted long-term immune reconstitution on the CD4+ subsets, but this did not translate into higher rate of relapse or viral infection. Acute GvHD was not significantly impacted, but 1-year cumulative incidence of chronic GvHD was significantly lower in the study group (15% vs. 41%, p = 0.04). Survival outcomes were comparable. In conclusion PT-Cy and ATLG was overall safe and translated into a low rate of chronic GvHD incidence.

4.
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
5.
Clin Immunol ; 215: 108450, 2020 06.
Article in English | MEDLINE | ID: covidwho-172295

ABSTRACT

Acute respiratory distress syndrome (ARDS) is a devastating clinical manifestation of COVID-19 pneumonia and is mainly based on an immune-driven pathology. Mounting evidence suggests that COVID-19 is fueled by a maladaptive host inflammatory response that involves excessive activation of innate immune pathways. While a "cytokine storm" involving IL-6 and other cytokines has been documented, complement C3 activation has been implicated as an initial effector mechanism that exacerbates lung injury in preclinical models of SARS-CoV infection. C3-targeted intervention may provide broader therapeutic control of complement-mediated inflammatory damage in COVID-19 patients. Herein, we report the clinical course of a patient with severe ARDS due to COVID-19 pneumonia who was safely and successfully treated with the compstatin-based complement C3 inhibitor AMY-101.


Subject(s)
Betacoronavirus/drug effects , Complement Activation/drug effects , Complement C3/antagonists & inhibitors , Complement Inactivating Agents/therapeutic use , Coronavirus Infections/drug therapy , Peptides, Cyclic/therapeutic use , Pneumonia, Viral/drug therapy , Aged , Antiviral Agents/therapeutic use , Atrial Fibrillation/drug therapy , Atrial Fibrillation/immunology , Atrial Fibrillation/pathology , Atrial Fibrillation/virology , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Coronavirus Infections/virology , Humans , Hypercholesterolemia/drug therapy , Hypercholesterolemia/immunology , Hypercholesterolemia/pathology , Hypercholesterolemia/virology , Hypertension/drug therapy , Hypertension/immunology , Hypertension/pathology , Hypertension/virology , Lung/drug effects , Lung/immunology , Lung/pathology , Lung/virology , Male , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , SARS-CoV-2 , Treatment Outcome
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