ABSTRACT
PURPOSE OF REVIEW: The COVID-19 pandemic is a global public health crisis with considerable mortality and morbidity. A role for cytokine storm and therapeutic immunomodulation in a subgroup of patients with severe COVID-19 was proposed early in the pandemic. The concept of cytokine storm in COVID-19 has been criticised, given the lack of clear definition and relatively modest cytokinaemia (which may be necessary for viral clearance) compared with acute respiratory distress syndrome and bacterial sepsis. Here we consider the arguments for and against the concept of cytokine storm in COVID-19. RECENT FINDINGS: Several criteria have been proposed to identify the subgroup of COVID-19 patients exhibiting a cytokine storm. The beneficial effects of corticosteroids and interleukin-6 inhibition suggest that inflammation is a modifiable pathogenic component of severe COVID-19. The presence of genetic polymorphisms and pathogenic auto-autoantibodies in severe COVID-19 also suggests a significant contribution of immune dysregulation to poor outcomes. SUMMARY: Hyperinflammation is a key component of severe COVID-19, residing underneath the cytokine storm umbrella term, associated with poor outcomes. Better understanding of the aetiopathogenesis, with identification of biomarkers to predict treatment responses and prognosis, will hopefully enable a stratified and ultimately precision medicine approach.
Subject(s)
COVID-19 , Cytokine Release Syndrome , Cytokines , Humans , Immunomodulation , Pandemics , SARS-CoV-2ABSTRACT
Idiopathic Multicentric Castleman Disease (iMCD) is a potentially life-threatening systemic disease whose complex symptomatology is due to cytokine dysregulation. We, herein, present a case of severe iMCD occurring in a previously healthy young man shortly after mRNA SARS-CoV-2 vaccination, responding to interleukin-6 blockade with siltuximab. Six months after the completion of siltuximab, the patient remained without any signs of iMCD or inflammation, indicating a temporal trigger of the disease. This case not only adds to the potential pathogenetic spectrum of MCD, but also extends the clinical picture of potential but rare adverse events following COVID-19 immunization.
Subject(s)
Castleman Disease , Leukopenia , Thrombocytopenia , Edema/etiology , Humans , Inflammation , Thrombocytopenia/etiologyABSTRACT
Background Dysregulated interleukin (IL)-6 production can be characterised by the levels present, the kinetics of its rise and its inappropriate location. Rapid, excessive IL-6 production can exacerbate tissue damage in vital organs. In this situation, therapy with an anti-IL-6 or anti-IL-6 receptor (IL-6R) monoclonal antibody, if inappropriately dosed, may be insufficient to fully block IL-6 signalling and normalise the immune response. Methods We analysed inhibition of C-reactive protein (CRP) – a biomarker for IL-6 activity – in patients with COVID-19 or idiopathic multicentric Castleman disease (iMCD) treated with tocilizumab (anti-IL-6R) or siltuximab (anti-IL-6), respectively. We used mathematical modelling to analyse how to optimise anti-IL-6 or anti-IL-6R blockade for the high levels of IL-6 observed in these diseases. Results IL-6 signalling was insufficiently inhibited in patients with COVID-19 or iMCD treated with standard doses of anti-IL-6 therapy. Patients whose disease worsened throughout therapy had only partial inhibition of CRP production. Our model demonstrated that, in a scenario representative of iMCD with persistent high IL-6 production not controlled by a single dose of anti-IL-6 therapy, repeated administration more effectively inhibited IL-6 activity. In a situation with rapid, high, dysregulated IL-6 production, such as severe COVID-19 or a cytokine storm, repeated daily administration of an anti-IL-6/anti-IL-6R agent, or alternating daily doses of anti-IL-6 and anti-IL-6R therapies, could neutralise IL-6 activity. Conclusion In clinical practice, IL-6 inhibition should be individualised based on pathophysiology to achieve full blockade of CRP production. Funding EUSA Pharma funded medical writing assistance and provided access to the phase II clinical data of siltuximab for analysis.
ABSTRACT
COVID-19 ranges from asymptomatic through to respiratory failure and death. Although specific pre-existing conditions such as age and male sex have been associated with poor outcomes, we remain largely ignorant of the mechanisms predisposing to severe disease. In this study, the authors discovered that approximately 10% of 987 patients with life-threatening COVID-19 harbored neutralizing antibodies to Type I interferons (IFNs)1. They demonstrated that these antibodies could neutralize high concentrations of the corresponding IFN and could rescue SARS-CoV-2 infection from inhibition by IFN in vitro. Importantly, anti-IFN antibodies were associated with low levels of serum IFN. These observations suggest that disease severity in these individuals results from a failure to control SARS-CoV-2 replication because of antibody-mediated IFN inhibition. The study suggests specific treatments and diagnostics for this class of severe COVID-19.
ABSTRACT
Drug repurposing provides a way to identify effective treatments more quickly and economically. To speed up the search for antiviral treatment of COVID-19, a new platform provides a range of computational models to identify drugs with potential anti-COVID-19 effects.
Subject(s)
COVID-19/complications , Cytokine Release Syndrome/physiopathology , Cytokines/physiology , Autoimmune Diseases/complications , Bacterial Infections/complications , Blood Proteins/physiology , Chemokines/physiology , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/therapy , Cytokines/immunology , Humans , Interleukins/physiology , Virus Diseases/complicationsSubject(s)
Abdominal Pain/etiology , Adrenal Gland Diseases/pathology , Castleman Disease/diagnosis , Edema/pathology , Fever/etiology , Abdominal Pain/diagnosis , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/therapeutic use , Antineoplastic Agents, Hormonal/administration & dosage , Antineoplastic Agents, Hormonal/therapeutic use , Azetidines/administration & dosage , Azetidines/therapeutic use , Bone Marrow/metabolism , Bone Marrow/pathology , Bortezomib/administration & dosage , Bortezomib/therapeutic use , Castleman Disease/drug therapy , Castleman Disease/pathology , Cyclosporine/administration & dosage , Cyclosporine/therapeutic use , Dexamethasone/administration & dosage , Dexamethasone/therapeutic use , Drug Therapy, Combination , Fever/diagnosis , Humans , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/therapeutic use , Janus Kinase Inhibitors/administration & dosage , Janus Kinase Inhibitors/therapeutic use , Male , Middle Aged , Purines/administration & dosage , Purines/therapeutic use , Pyrazoles/administration & dosage , Pyrazoles/therapeutic use , Renal Insufficiency/etiology , Reticulin , Sulfonamides/administration & dosage , Sulfonamides/therapeutic use , Thrombocytopenia/etiologyABSTRACT
The COVID-19 pandemic has driven unprecedented efforts to identify existing treatments that can be quickly and effectively repurposed to reduce morbidity and mortality. In this issue of Cell Metabolism, Zhang et al. (2020) report an association between statin use and improved outcomes in a large observational study of hospitalized COVID-19 patients. Given the widespread availability, low cost, and safety of statins, this promising result should be further investigated in randomized controlled trials.
Subject(s)
Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Drug Repositioning/methods , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Pneumonia, Viral/drug therapy , COVID-19 , Cytokine Release Syndrome/drug therapy , Humans , Observational Studies as Topic , Pandemics , SARS-CoV-2ABSTRACT
The emergence of SARS-CoV-2/2019 novel coronavirus (COVID-19) has created a global pandemic with no approved treatments or vaccines. Many treatments have already been administered to COVID-19 patients but have not been systematically evaluated. We performed a systematic literature review to identify all treatments reported to be administered to COVID-19 patients and to assess time to clinically meaningful response for treatments with sufficient data. We searched PubMed, BioRxiv, MedRxiv, and ChinaXiv for articles reporting treatments for COVID-19 patients published between 1 December 2019 and 27 March 2020. Data were analyzed descriptively. Of the 2706 articles identified, 155 studies met the inclusion criteria, comprising 9152 patients. The cohort was 45.4% female and 98.3% hospitalized, and mean (SD) age was 44.4 years (SD 21.0). The most frequently administered drug classes were antivirals, antibiotics, and corticosteroids, and of the 115 reported drugs, the most frequently administered was combination lopinavir/ritonavir, which was associated with a time to clinically meaningful response (complete symptom resolution or hospital discharge) of 11.7 (1.09) days. There were insufficient data to compare across treatments. Many treatments have been administered to the first 9152 reported cases of COVID-19. These data serve as the basis for an open-source registry of all reported treatments given to COVID-19 patients at www.CDCN.org/CORONA . Further work is needed to prioritize drugs for investigation in well-controlled clinical trials and treatment protocols.