Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 27
Filter
1.
Hemasphere ; 4(6): e492, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-1234152

ABSTRACT

Iron metabolism might play a crucial role in cytokine release syndrome in COVID-19 patients. Therefore, we assessed iron metabolism markers in COVID-19 patients for their ability to predict disease severity. COVID-19 patients referred to the Heidelberg University Hospital were retrospectively analyzed. Patients were divided into outpatients (cohort A, n = 204), inpatients (cohort B, n = 81), and outpatients later admitted to hospital because of health deterioration (cohort C, n = 23). Iron metabolism parameters were severely altered in patients of cohort B and C compared to cohort A. In multivariate regression analysis including age, gender, CRP and iron-related parameters only serum iron and ferritin were significantly associated with hospitalization. ROC analysis revealed an AUC for serum iron of 0.894 and an iron concentration <6 µmol/l as the best cutoff-point predicting hospitalization with a sensitivity of 94.7% and a specificity of 67.9%. When stratifying inpatients in a low- and high oxygen demand group serum iron levels differed significantly between these two groups and showed a high negative correlation with the inflammatory parameters IL-6, procalcitonin, and CRP. Unexpectedly, serum iron levels poorly correlate with hepcidin. We conclude that measurement of serum iron can help predicting the severity of COVID-19. The differences in serum iron availability observed between the low and high oxygen demand group suggest that disturbed iron metabolism likely plays a causal role in the pathophysiology leading to lung injury.

2.
Front Immunol ; 11: 611318, 2020.
Article in English | MEDLINE | ID: covidwho-1082463

ABSTRACT

Autoimmune diseases and infections are often closely intertwined. Patients with autoimmune diseases are more susceptible to infections due to either active autoimmune disease or the medications used to treat them. Based on infections as environmental triggers of autoimmunity, an autoimmune response would also be expected in COVID-19. Although some studies have shown the occurance of autoantibodies and the possible development of autoimmune diseases after SARS-CoV-2 infection, current data suggest that the levels of autoantibodies following SARS-CoV-2 infection is comparable to that of some other known infections and that the autoantibodies might only be transient. The risk of SARS-CoV-2 infection in patients with a systemic autoimmune rheumatic disease (SARD) appears slightly higher compared to the general population and the course of COVID-19 disease does not seem to be very different, however, specific therapies such as glucocorticoids and anti-TNF might modulate the risk of hospitalization/death. Cytokine release syndrome is a severe complication in COVID-19. Many drugs used for the treatment of SARD are directly or indirectly targeting cytokines involved in the cytokine release syndrome, therefore it has been suggested that they could also be effective in COVID-19, but more evidence on the use of these medications for the treatment of COVID-19 is currently being collected.


Subject(s)
Autoimmune Diseases , COVID-19 , Rheumatic Diseases , Autoimmune Diseases/complications , Autoimmune Diseases/drug therapy , Autoimmune Diseases/immunology , COVID-19/complications , COVID-19/drug therapy , COVID-19/immunology , Humans , Rheumatic Diseases/complications , Rheumatic Diseases/drug therapy , Rheumatic Diseases/immunology , SARS-CoV-2
3.
J Glob Infect Dis ; 12(4): 221-224, 2020.
Article in English | MEDLINE | ID: covidwho-993888

ABSTRACT

Since the beginning of the COVID-19 pandemic, many therapeutic strategies have been tried, with mixed results, to prevent and treat adult multisystem inflammatory syndrome in COVID-19 (AMIS-COVID-19). The reason behind this may the complex web of highly intertwined pathophysiologic mechanisms involved in the SARS-CoV-2 infection and the corresponding human systemic response, leading to end-organ damage, disability, and death. Colchicine, high-dose aspirin, and montelukast are being investigated currently as potential modulators of AMIS-COVID-19 in patients who fail to improve with traditional therapeutic approaches. Here, we present a patient who presented with high fevers, extreme fatigue and dyspnea, and ongoing deterioration. As part of our clinical approach, we used the simultaneous combination of the three agents listed above, capitalizing on their different respective mechanisms of action against AMIS-COVID-19. Following the initiation of therapy, the patient showed symptomatic improvement within 24 h, with the ability to return to daily activities after 72 h of continued triple-agent approach. Based on this experience, we have reviewed the immunomodulatory basis of this regimen, including potential avenues in which it may prevent the development of cytokine release syndrome (CRS) and its clinical manifestation, AMIS-COVID-19. By blocking the early stages of an inflammatory response, via diverse mechanistic pathways, the regimen in question may prove effective in halting the escalation of CRS and AMIS-COVID-19 in acutely symptomatic, nonimproving COVID-19 patients.

4.
Eur Cytokine Netw ; 2020 Dec 03.
Article in English | MEDLINE | ID: covidwho-955345

ABSTRACT

Coronavirus disease 19 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first identified in China and has spread worldwide with a significant rate of infection. Considering the elevated levels of proinflammatory cytokines in COVID-19, it is suggested that cytokine storms play a critical role in its pathogenesis, including acute respiratory distress syndrome (ARDS). However, there is no specific drug for preventing the cytokine release syndrome (CRS) caused by COVID-19. Indeed, interleukin 6 (IL-6) has been highlighted for its many biological functions, such as immune regulation, inflammatory response, and metabolism. Therapeutic blockade of the IL-6 signaling pathway is expected to reduce the excessive immune reponse observed in COVID-19. Currently, the IL-6 receptor antagonists tocilizumab and sarilumab, have been adopted for preventing CRS during the progression of COVID-19, and remarkable beneficial effects were observed by using these humanized monoclonal antibodies. Based on the pathogenesis of COVID-19, we reviewed the biological mechanism of IL-6 blockade in the treatment of SARS-CoV-2 infection and evaluated its clinical applications.

5.
Nanomaterials (Basel) ; 10(11)2020 Nov 20.
Article in English | MEDLINE | ID: covidwho-945889

ABSTRACT

Recent studies on coronavirus infectious disease 2019 (COVID-19) pathophysiology indicated the cytokine release syndrome induced by the virus as the main cause of mortality. Patients with severe COVID-19 infection present a systemic hyper inflammation that can lead to lung and multi-organ injuries. Among the most recent treatments, corticosteroids have been identified to be effective in mitigating these catastrophic effects. Our group has recently developed leukocyte-derived nanovesicles, termed leukosomes, able to target in vivo the inflamed vasculature associated with pathological conditions including cancer, cardiovascular diseases, and sepsis. Herein, to gain insights on the anti-inflammatory properties of leukosomes, we investigated their ability to reduce uncontrolled inflammation in a lethal model of lipopolysaccharide (LPS)-induced endotoxemia, recapitulating the cytokine storm syndrome observed in COVID-19 infection after encapsulating dexamethasone. Treated animals showed a significant survival advantage and an improved immune response resolution, as demonstrated by a cytokine array analysis of pro- and anti-inflammatory cytokines, chemokines, and other immune-relevant markers. Our results showed that leukosomes enhance the therapeutic activity of dexamethasone and better control the inflammatory response compared to the free drug. Such an approach could be useful for the development of personalized therapies in the treatment of hyperinflammation related to infectious diseases, including the ones caused by COVID-19.

6.
Trials ; 21(1): 934, 2020 Nov 19.
Article in English | MEDLINE | ID: covidwho-934298

ABSTRACT

OBJECTIVES: Zilucoplan (complement C5 inhibitor) has profound effects on inhibiting acute lung injury post COVID-19, and can promote lung repair mechanisms that lead to improvement in lung oxygenation parameters. The purpose of this study is to investigate the efficacy and safety of Zilucoplan in improving oxygenation and short- and long-term outcome of COVID-19 patients with acute hypoxic respiratory failure. TRIAL DESIGN: This is a phase 2 academic, prospective, 2:1 randomized, open-label, multi-center interventional study. PARTICIPANTS: Adult patients (≥18y old) will be recruited at specialized COVID-19 units and ICUs at 9 Belgian hospitals. The main eligibility criteria are as follows: 1) Inclusion criteria: a. Recent (≥6 days and ≤16 days) SARS-CoV-2 infection. b. Chest CT scan showing bilateral infiltrates within the last 2 days prior to randomisation. c. Acute hypoxia (defined as PaO2/FiO2 below 350 mmHg or SpO2 below 93% on minimal 2 L/min supplemental oxygen). d. Signs of cytokine release syndrome characterized by either high serum ferritin, or high D-dimers, or high LDH or deep lymphopenia or a combination of those. 2) Exclusion criteria: e. Mechanical ventilation for more than 24 hours prior to randomisation. f. Active bacterial or fungal infection. g. History of meningococcal disease (due to the known high predisposition to invasive, often recurrent meningococcal infections of individuals deficient in components of the alternative and terminal complement pathways). INTERVENTION AND COMPARATOR: Patients in the experimental arm will receive daily 32,4 mg Zilucoplan subcutaneously and a daily IV infusion of 2g of the antibiotic ceftriaxone for 14 days (or until hospital discharge, whichever comes first) in addition to standard of care. These patients will receive additional prophylactic antibiotics until 14 days after the last Zilucoplan dose: hospitalized patients will receive a daily IV infusion of 2g of ceftriaxone, discharged patients will switch to daily 500 mg of oral ciprofloxacin. The control group will receive standard of care and a daily IV infusion of 2g of ceftriaxone for 1 week (or until hospital discharge, whichever comes first), to control for the effects of antibiotics on the clinical course of COVID-19. MAIN OUTCOMES: The primary endpoint is the improvement of oxygenation as measured by mean and/or median change from pre-treatment (day 1) to post-treatment (day 6 and 15 or at discharge, whichever comes first) in PaO2/FiO2 ratio, P(A-a)O2 gradient and a/A PO2 ratio. (PAO2= Partial alveolar pressure of oxygen, PaO2=partial arterial pressure of oxygen, FiO2=Fraction of inspired oxygen). RANDOMISATION: Patients will be randomized in a 2:1 ratio (Zilucoplan: control). Randomization will be done using an Interactive Web Response System (REDCap). BLINDING (MASKING): In this open-label trial neither participants, caregivers, nor those assessing the outcomes will be blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 81 patients will be enrolled: 54 patients will be randomized to the experimental arm and 27 patients to the control arm. TRIAL STATUS: ZILU-COV protocol Version 4.0 (June 10 2020). Participant recruitment started on June 23 2020 and is ongoing. Given the uncertainty of the pandemic, it is difficult to predict the anticipated end date. TRIAL REGISTRATION: The trial was registered on Clinical Trials.gov on May 11th, 2020 (ClinicalTrials.gov Identifier: NCT04382755 ) and on EudraCT (Identifier: 2020-002130-33 ). FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Subject(s)
Complement C5/antagonists & inhibitors , Coronavirus Infections/complications , Hypoxia/drug therapy , Pneumonia, Viral/complications , Respiratory Insufficiency/drug therapy , Acute Disease , Adult , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/therapeutic use , Belgium/epidemiology , Betacoronavirus/isolation & purification , COVID-19 , Case-Control Studies , Ceftriaxone/administration & dosage , Ceftriaxone/therapeutic use , Coronavirus Infections/epidemiology , Coronavirus Infections/physiopathology , Coronavirus Infections/virology , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/drug therapy , Drug Therapy, Combination , Humans , Infusions, Intravenous , Injections, Subcutaneous , Oxygen/blood , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/physiopathology , Pneumonia, Viral/virology , Prospective Studies , SARS-CoV-2 , Safety , Treatment Outcome
7.
Pharmacol Rep ; 72(6): 1529-1537, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-915270

ABSTRACT

BACKGROUND: This study was aimed to assess the efficacy and safety of tocilizumab (TCZ) and to investigate the factors related to the progress and mortality of patients with a secondary cytokine release syndrome caused by SARS-CoV-2. METHODS: A retrospective descriptive observational study of hospitalised patients with a positive polymerase chain reaction (PCR) result for SARS-CoV-2 and whose clinical evolution required the administration of one or more doses of TCZ was conducted. Demographic variables, clinical evolution, radiologic progress and analytical parameters were analysed on days 1, 3 and 5 after administration the first dose of TCZ. RESULTS: A total of 75 patients with a clinical history of Accurate Respiratory Distress Syndrome (ARDS) were analysed, among whom, 19 had mild ARDS (25.3%), 37 moderate ARDS (49.4%) and 19 severe ARDS (25.3%). Lymphocytopenia and high levels of PCR, D-Dimer and IL-6 were observed in almost all the patients (91.8%). Treatment with TCZ was associated with a reduction of lymphocytopenia, C-reactive protein (CRP) levels, severe ARDS cases and fever. Although a better evolution of PaO2/FiO2 was observed in patients who received two or more doses of TCZ (38/75), there was an increase in their mortality (47.4%) and ICU admission (86.8%). The 30-day mortality rate was 30.7% (20.5-42.4% CI) being hypertension, high initial D-dimer levels and ICU admission the only predictive factors found. CONCLUSION: Based on our results, treatment with TCZ was associated with a fever, swelling and ventilator support improvement. However, there is no evidence that the administration of two or more doses of TCZ was related to a mortality decrease.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/complications , Cytokine Release Syndrome/drug therapy , Intensive Care Units/statistics & numerical data , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/adverse effects , COVID-19/drug therapy , COVID-19/mortality , Cytokine Release Syndrome/mortality , Female , Humans , Male , Middle Aged , Polymerase Chain Reaction , Respiration, Artificial/statistics & numerical data , Retrospective Studies , SARS-CoV-2/isolation & purification , Severity of Illness Index , Treatment Outcome , Young Adult
8.
Semin Immunopathol ; 42(5): 619-634, 2020 10.
Article in English | MEDLINE | ID: covidwho-911894

ABSTRACT

The SARS-CoV-2 pandemic urgently calls for the development of effective preventive tools. COVID-19 hits greatly the elder and more fragile fraction of the population boosting the evergreen issue of the vaccination of older people. The development of a vaccine against SARS-CoV-2 tailored for the elderly population faces the challenge of the poor immune responsiveness of the older population due to immunosenescence, comorbidities, and pharmacological treatments. Moreover, it is likely that the inflammaging phenotype associated with age could both influence vaccination efficacy and exacerbate the risk of COVID-19-related "cytokine storm syndrome" with an overlap between the factors which impact vaccination effectiveness and those that boost virulence and worsen the prognosis of SARS-CoV-2 infection. The complex and still unclear immunopathological mechanisms of SARS-CoV-2 infection, together with the progressive age-related decline of immune responses, and the lack of clear correlates of protection, make the design of vaccination strategies for older people extremely challenging. In the ongoing effort in vaccine development, different SARS-CoV-2 vaccine candidates have been developed, tested in pre-clinical and clinical studies and are undergoing clinical testing, but only a small fraction of these are currently being tested in the older fraction of the population. Recent advances in systems biology integrating clinical, immunologic, and omics data can help to identify stable and robust markers of vaccine response and move towards a better understanding of SARS-CoV-2 vaccine responses in the elderly.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/prevention & control , Cytokine Release Syndrome/prevention & control , Immunosenescence/immunology , SARS-CoV-2/immunology , Aged , Aged, 80 and over , COVID-19/immunology , Frail Elderly , Humans , Vaccination
9.
Brain Behav Immun Health ; 9: 100173, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-898496

ABSTRACT

Background: Depression appears to be a common complication in patients during and post-COVID-19 infection. Understanding the mechanism of action of cytokines such as interleukin-6, interleukin-10 and others in depression and in cytokine storm syndrome, the core component of COVID- 19, could shine a new light on future treatment options for both disorders. Objective: This review demonstrates the role of interleukins in COVID-19 pathogenesis and their role in depression. Results: We described cases we have treated as an example for the dual role interleukins have in COVID-19 infection and depression and reviewed approximately 70 articles focusing on the role of interleukins in cytokine storm syndrome and depression. Conclusion: This review highlights the key features of cytokines in both diseases. As the scientific community has more time to recover and process the effect of the current pandemic, we believe that additional research will pave the way to diverse pathways to treat depression in these patient and others.

10.
J Clin Med ; 9(9)2020 Sep 11.
Article in English | MEDLINE | ID: covidwho-892444

ABSTRACT

The ongoing coronavirus disease 2019 (COVID-19) pandemic has resulted in efforts to identify therapies to ameliorate adverse clinical outcomes. The recognition of the key role for increased inflammation in COVID-19 has led to a proliferation of clinical trials targeting inflammation. The purpose of this review is to characterize the current state of immunotherapy trials in COVID-19, and focuses on associated cardiotoxicities, given the importance of pharmacovigilance. The search terms related to COVID-19 were queried in ClinicalTrials.gov. A total of 1621 trials were identified and screened for interventional trials directed at inflammation. Trials (n = 226) were fully assessed for the use of a repurposed drug, identifying a total of 141 therapeutic trials using a repurposed drug to target inflammation in COVID-19 infection. Building on the results of the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial demonstrating the benefit of low dose dexamethasone in COVID-19, repurposed drugs targeting inflammation are promising. Repurposed drugs directed at inflammation in COVID-19 primarily have been drawn from cancer therapies and immunomodulatory therapies, specifically targeted anti-inflammatory, anti-complement, and anti-rejection agents. The proposed mechanisms for many cytokine-directed and anti-rejection drugs are focused on evidence of efficacy in cytokine release syndromes in humans or animal models. Anti-complement-based therapies have the potential to decrease both inflammation and microvascular thrombosis. Cancer therapies are hypothesized to decrease vascular permeability and inflammation. Few publications to date describe using these drugs in COVID-19. Early COVID-19 intervention trials have re-emphasized the subtle, but important cardiotoxic sequelae of potential therapies on outcomes. The volume of trials targeting the COVID-19 hyper-inflammatory phase continues to grow rapidly with the evaluation of repurposed drugs and late-stage investigational agents. Leveraging known clinical safety profiles and pharmacodynamics allows swift investigation in clinical trials for a novel indication. Physicians should remain vigilant for cardiotoxicity, often not fully appreciated in small trials or in short time frames.

11.
Med Hypotheses ; 145: 110352, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-885391

ABSTRACT

The Coronavirus Diseases-2019 (COVID-19) pandemic leads many researchers around the world to study the SARS-CoV-s2 infection and pathology to find a treatment for it. This generates a massive production of papers including pre-clinical, clinical and revisions but till now no specific treatment were identified. Meanwhile, like other coronavirus infections, COVID-19 leads to the cytokine storm syndrome resulting in hyperinflammation, exacerbated immune response and multiple organ dysfunctions indicating that drugs that modulate this response, as glucocorticoids could be a treatment option. However glucocorticoids have several side effects or usage limitations. In this sense a drug with anti-inflammatory effects and capable to reduce inflammation but with less after-effects could be a powerful tool to combat COVID-19. Thus the Ac2-26 Mimetic Peptide of Annexin A1 emerges as a possible therapy. The peptide has many anti-inflammatory effects described including the reduction of interleukin (IL)-6, one of the main mediators of cytokine storm syndrome. Therefore the hypothesis to use the Ac2-26 peptide to treat severe COVID-19 will be highlighted in this paper.


Subject(s)
Annexin A1/chemistry , COVID-19/drug therapy , COVID-19/immunology , COVID-19/therapy , Peptides/chemistry , Anti-Inflammatory Agents/chemistry , Cytokines/metabolism , Humans , Inflammation , Interleukin-6/metabolism , Models, Theoretical , Protein Binding
12.
Int J Biol Sci ; 16(15): 3028-3036, 2020.
Article in English | MEDLINE | ID: covidwho-874840

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2, with acute respiratory failure as the most significant symptom, has led to a global pandemic. Angiotensin-converting enzyme 2 (ACE2) is considered as the most important receptor of SARS-CoV-2 and wildly expressed in human tissues. Whereas, the extremely low expression of ACE2 in lung could hardly interpret the severe symptom of pneumonia in COVID-19 patients. Here we profiled two SARS-CoV-2 infection related genes, the transmembrane serine protease 2 (TMPRSS2) and the interferon-inducible transmembrane protein 3 (IFITM3), in human tissues and organs. Consistent with the expression and distribution of ACE2, TMPRSS2 was also highly expressed in digestive, urinary and reproductive systems, but low expressed in lung. Notably, the anti-virus protein IFITM3 also expressed much lower in lung than other tissues, which might be related to the severe lung symptoms of COVID-19. In addition, the low expression of IFITM3 in immune cells suggested that SARS-CoV-2 might attack lymphocytes and induce the cytokine release syndrome (CRS). Furthermore, cancer patients were considered as more susceptible to SARS-CoV-2 infection. Our data supposed that fourteen types of tumors might have different susceptibility to the virus according to ACE2, TMPRSS2 and IFITM3 expression patterns. Interestingly the prognosis of six types of cancers including breast carcinoma (BRCA), lung adenocarcinoma (LUAD), uterine corpus endometrial carcinoma (UCEC), renal clear cell carcinoma (KIRC), prostate adenocarcinoma (PRAD), and hepatocellular carcinoma (LIHC) were closely related to these gene expressions. Our study explored the expression and distribution profiles of two potential novel molecules that might participate in SARS-CoV-2 infection and involved in immunity, which may provide a functional basis for preventing infection of SARS-CoV-2.


Subject(s)
Gene Expression Regulation, Neoplastic , Membrane Proteins/physiology , Neoplasms/metabolism , RNA-Binding Proteins/physiology , Receptors, Virus/physiology , Serine Endopeptidases/physiology , Angiotensin-Converting Enzyme 2 , Betacoronavirus , COVID-19 , Coronavirus Infections/genetics , Coronavirus Infections/metabolism , DNA Mutational Analysis , Gene Expression Regulation , Healthy Volunteers , Humans , Membrane Proteins/genetics , Neoplasms/diagnosis , Neoplasms/genetics , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/genetics , Pneumonia, Viral/metabolism , Prognosis , RNA-Binding Proteins/genetics , Receptors, Virus/genetics , SARS-CoV-2 , Serine Endopeptidases/genetics , Tissue Distribution
13.
J Infect Dis ; 222(9): 1444-1451, 2020 10 01.
Article in English | MEDLINE | ID: covidwho-851783

ABSTRACT

Corona virus disease 2019 (COVID-19) patients with severe immune abnormalities are at risk of cytokine release syndrome (CRS). The definition, prevention, and treatment of symptoms of CRS in critically ill patients with COVID-19 are important problems. We report a single-center case series of 11 COVID-19 patients with acute respiratory distress syndrome from The First Affiliated Hospital of Guangzhou Medical University in China from 26 January 2020 to 18 February 2020. The termination date of follow-up was 19 February 2020. Eight patients were determined to have characteristics of CRS, including pulmonary inflammation, fever, and dysfunction of nonpulmonary organs. An increase in interleukin-6 in peripheral blood was the highest risk factor and an early indicator of CRS in COVID-19.


Subject(s)
Coronavirus Infections/immunology , Cytokine Release Syndrome/blood , Interleukin-6/blood , Leukocytes, Mononuclear , Pneumonia, Viral/blood , Aged , Betacoronavirus , Biomarkers/blood , COVID-19 , Coronavirus Infections/blood , Coronavirus Infections/complications , Critical Illness , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/virology , Female , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Prognosis , Risk Factors , SARS-CoV-2
14.
BioDrugs ; 34(6): 705-711, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-848562

ABSTRACT

Itolizumab is a first-in-class anti-CD6 monoclonal antibody that was initially developed for various cancers and was later developed and approved in India for treatment of moderate to severe chronic plaque psoriasis in 2013. This drug is now being re-purposed for COVID-19. The potential utility of itolizumab in COVID-19, based on its unique mechanism of action in ameliorating cytokine release syndrome (CRS), was proposed first in Cuba with approval of a single-arm clinical trial and expanded access use. Subsequently, a phase II, open-label, randomized, placebo-controlled trial has been conducted in 30 COVID-19 patients in India after receiving regulatory permission. Based on the results, the Indian drug regulatory agency recently approved itolizumab in July 2020 for 'restricted emergency use' for the treatment of CRS in moderate to severe acute respiratory distress syndrome (ARDS) due to COVID-19. This has drawn sharp criticism within the scientific community, with the approval being granted on the basis of a relatively small phase II trial, without conduct of a conventional phase III trial, and lacking availability of the claimed supportive real-world evidence in the public domain to date. In a global scenario where finding a successful treatment for COVID-19 is of utmost priority, a biologic agent has been re-purposed and approved with a successfully completed RCT, in a country where cases and mortality due to COVID-19 are growing exponentially. However, instead of welcoming the approval with open arms, many doubts are being raised. This is an issue that needs to be considered and dealt with sensitively, as well as scientifically.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Coronavirus Infections/drug therapy , Drug Approval , Pneumonia, Viral/drug therapy , Antibodies, Monoclonal, Humanized/pharmacology , COVID-19 , Drug Repositioning , Humans , India , Pandemics
15.
Dig Liver Dis ; 52(12): 1383-1389, 2020 12.
Article in English | MEDLINE | ID: covidwho-834313

ABSTRACT

The microbiota-gut-liver-lung axis plays a bidirectional role in the pathophysiology of a number of infectious diseases. During the course of severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and 2 (SARS-CoV-2) infection, this pathway is unbalanced due to intestinal involvement and systemic inflammatory response. Moreover, there is convincing preliminary evidence linking microbiota-gut-liver axis perturbations, proinflammatory status, and endothelial damage in noncommunicable preventable diseases with coronavirus disease 2019 (Covid-19) severity. Intestinal damage due to SARS-CoV-2 infection, systemic inflammation-induced dysfunction, and IL-6-mediated diffuse vascular damage may increase intestinal permeability and precipitate bacterial translocation. The systemic release of damage- and pathogen-associated molecular patterns (e.g. lipopolysaccharides) and consequent immune-activation may in turn auto-fuel vicious cycles of systemic inflammation and tissue damage. Thus, intestinal bacterial translocation may play an additive/synergistic role in the cytokine release syndrome in Covid-19. This review provides evidence on gut-liver axis involvement in Covid-19 as well as insights into the hypothesis that intestinal endotheliitis and permeability changes with bacterial translocation are key pathophysiologic events modulating systemic inflammatory response. Moreover, it presents an overview of readily applicable measures for the modulation of the gut-liver axis and microbiota in clinical practice.


Subject(s)
Bacterial Translocation/immunology , COVID-19/immunology , Cytokine Release Syndrome/immunology , Gastrointestinal Microbiome/immunology , Intestinal Mucosa/metabolism , Lipopolysaccharides/metabolism , Liver/metabolism , Permeability , Alarmins/immunology , Alarmins/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Cytokine Release Syndrome/metabolism , Disease Progression , Humans , Immunity/immunology , Inflammation , Interleukin-6/immunology , Lipopolysaccharides/immunology , Liver/immunology , Lung/immunology , Lung/metabolism , Microbiota/immunology , Pathogen-Associated Molecular Pattern Molecules/immunology , Pathogen-Associated Molecular Pattern Molecules/metabolism , SARS-CoV-2/metabolism , Serine Endopeptidases/metabolism
16.
Intern Med ; 59(22): 2945-2949, 2020 Nov 15.
Article in English | MEDLINE | ID: covidwho-789033

ABSTRACT

Treatment with tocilizumab (TCZ) to block interleukin-6 (IL-6) signalling is predicted to mitigate cytokine release syndrome (CRS) caused by coronavirus disease 2019 (COVID-19). However, the adverse effects of TCZ on patients with COVID-19 remain unclear. We herein report a patient with COVID-19 treated with TCZ who developed acute hypertriglyceridaemia. Despite favipiravir treatment, acute respiratory distress syndrome developed in a 45-year-old patient with COVID-19; thus, TCZ was initiated. The triglyceride levels greatly increased after TCZ administration. Physicians should consider the negative impact of TCZ on the lipid profile in patients with COVID-19, although COVID-19-induced CRS itself may be an aggravating factor.


Subject(s)
Antibodies, Monoclonal, Humanized/adverse effects , Betacoronavirus , Coronavirus Infections/drug therapy , Hypertriglyceridemia/chemically induced , Pneumonia, Viral/drug therapy , Acute Disease , Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19 , Coronavirus Infections/blood , Coronavirus Infections/epidemiology , Humans , Hypertriglyceridemia/blood , Interleukin-6/blood , Male , Middle Aged , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/epidemiology , Retrospective Studies , SARS-CoV-2 , Triglycerides/blood
17.
Med Hypotheses ; 144: 110242, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-739959

ABSTRACT

The outbreak of coronavirus disease 2019 (COVID-19) requires urgent need for effective treatment. Severe COVID-19 is characterized by a cytokine storm syndrome with subsequent multiple organ failure (MOF) and acute respiratory distress syndrome (ARDS), which may lead to intensive care unit and increased risk of death. While awaiting a vaccine, targeting COVID-19-induced cytokine storm syndrome appears currently as the efficient strategy to reduce the mortality of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The stress-responsive enzyme, heme oxygenase-1 (HO-1) is largely known to protect against inflammatory response in animal models. HO-1 is induced by hemin, a well-tolerated molecule, used for decades in the treatment of acute intermittent porphyria. Experimental studies showed that hemin-induced HO-1 mitigates cytokine storm and lung injury in mouse models of sepsis and renal ischemia-reperfusion injury. Furthermore, HO-1 may also control numerous viral infections by inhibiting virus replication. In this context, we suggest the hypothesis that HO-1 cytoprotective pathway might be a promising target to control SARS-CoV-2 infection and mitigate COVID-19-induced cytokine storm and subsequent ARDS.


Subject(s)
COVID-19/drug therapy , COVID-19/metabolism , Cytokine Release Syndrome/drug therapy , Heme Oxygenase-1/metabolism , Respiratory Distress Syndrome/physiopathology , Animals , Anti-Inflammatory Agents/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19 Vaccines , Critical Care , Cytokine Release Syndrome/prevention & control , Cytokines/metabolism , Hemin/metabolism , Humans , Inflammation , Interleukin-6/metabolism , Models, Theoretical , Polymorphism, Genetic , Respiratory Distress Syndrome/virology
18.
Proc Natl Acad Sci U S A ; 117(36): 22351-22356, 2020 09 08.
Article in English | MEDLINE | ID: covidwho-724752

ABSTRACT

Cytokine release syndrome (CRS) is a life-threatening complication induced by systemic inflammatory responses to infections, including bacteria and chimeric antigen receptor T cell therapy. There are currently no immunotherapies with proven clinical efficacy and understanding of the molecular mechanisms of CRS pathogenesis is limited. Here, we found that patients diagnosed with CRS from sepsis, acute respiratory distress syndrome (ARDS), or burns showed common manifestations: strikingly elevated levels of the four proinflammatory cytokines interleukin (IL)-6, IL-8, monocyte chemotactic protein-1 (MCP-1), and IL-10 and the coagulation cascade activator plasminogen activator inhibitor-1 (PAI-1). Our in vitro data indicate that endothelial IL-6 trans-signaling formed an inflammation circuit for robust IL-6, IL-8, and MCP-1 production and promoted PAI-1 production; additionally, an IL-6 signaling blockade by the human monoclonal antibody tocilizumab blunted endothelial cell activation. Plasma from severe COVID-19 patients similarly exhibited increased IL-6, IL-10, and MCP-1 levels, but these levels were not as high as those in patients with CRS from other causes. In contrast, the PAI-1 levels in COVID-19 patients were as highly elevated as those in patients with bacterial sepsis or ARDS. Tocilizumab treatment decreased the PAI-1 levels and alleviated critical illness in severe COVID-19 patients. Our findings suggest that distinct levels of cytokine production are associated with CRS induced by bacterial infection and COVID-19, but both CRS types are accompanied by endotheliopathy through IL-6 trans-signaling. Thus, the present study highlights the crucial role of IL-6 signaling in endothelial dysfunction during bacterial infection and COVID-19.


Subject(s)
Cytokine Release Syndrome/metabolism , Endothelial Cells/metabolism , Interleukin-6/metabolism , Plasminogen Activator Inhibitor 1/metabolism , Signal Transduction , Adult , Aged , Antibodies, Monoclonal, Humanized/therapeutic use , Betacoronavirus , Burns/metabolism , Burns/pathology , COVID-19 , Cells, Cultured , Coronavirus Infections/drug therapy , Coronavirus Infections/metabolism , Coronavirus Infections/pathology , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/pathology , Cytokines/blood , Cytokines/metabolism , Endothelial Cells/drug effects , Female , Humans , Inflammation , Interleukin-6/blood , Male , Middle Aged , Pandemics , Plasminogen Activator Inhibitor 1/blood , Pneumonia, Viral/drug therapy , Pneumonia, Viral/metabolism , Pneumonia, Viral/pathology , Receptors, Interleukin-6/antagonists & inhibitors , Receptors, Interleukin-6/metabolism , Respiratory Distress Syndrome/metabolism , Respiratory Distress Syndrome/pathology , SARS-CoV-2 , Sepsis/metabolism , Sepsis/pathology
19.
Front Immunol ; 11: 1311, 2020.
Article in English | MEDLINE | ID: covidwho-646534

ABSTRACT

Chimeric antigen receptor T cell (CART) therapy, administration of certain T cell-agonistic antibodies, immune check point inhibitors, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) and Toxic shock syndrome (TSS) caused by streptococcal as well as staphylococcal superantigens share one common complication, that is T cell-driven cytokine release syndrome (CRS) accompanied by multiple organ dysfunction (MOD). It is not understood whether the failure of a particular organ contributes more significantly to the severity of CRS. Also not known is whether a specific cytokine or signaling pathway plays a more pathogenic role in precipitating MOD compared to others. As a result, there is no specific treatment available to date for CRS, and it is managed only symptomatically to support the deteriorating organ functions and maintain the blood pressure. Therefore, we used the superantigen-induced CRS model in HLA-DR3 transgenic mice, that closely mimics human CRS, to delineate the immunopathogenesis of CRS as well as to validate a novel treatment for CRS. Using this model, we demonstrate that (i) CRS is characterized by a rapid rise in systemic levels of several Th1/Th2/Th17/Th22 type cytokines within a few hours, followed by a quick decline. (ii) Even though multiple organs are affected, small intestinal immunopathology is the major contributor to mortality in CRS. (iii) IFN-γ deficiency significantly protected from lethal CRS by attenuating small bowel pathology, whereas IL-17A deficiency significantly increased mortality by augmenting small bowel pathology. (iv) RNA sequencing of small intestinal tissues indicated that IFN-γ-STAT1-driven inflammatory pathways combined with enhanced expression of pro-apoptotic molecules as well as extracellular matrix degradation contributed to small bowel pathology in CRS. These pathways were further enhanced by IL-17A deficiency and significantly down-regulated in mice lacking IFN-γ. (v) Ruxolitinib, a selective JAK-1/2 inhibitor, attenuated SAg-induced T cell activation, cytokine production, and small bowel pathology, thereby completely protecting from lethal CRS in both WT and IL-17A deficient HLA-DR3 mice. Overall, IFN-γ-JAK-STAT-driven pathways contribute to lethal small intestinal immunopathology in T cell-driven CRS.


Subject(s)
Coronavirus Infections/pathology , Cytokine Release Syndrome/drug therapy , Interferon-gamma/genetics , Interleukin-17/genetics , Janus Kinase Inhibitors/therapeutic use , Pneumonia, Viral/pathology , Pyrazoles/therapeutic use , Animals , COVID-19 , Cells, Cultured , Coronavirus Infections/drug therapy , Cytokine Release Syndrome/pathology , Cytokine Release Syndrome/prevention & control , Cytokines/blood , Cytokines/immunology , HLA-DR3 Antigen/genetics , Intestine, Small/immunology , Intestine, Small/pathology , Lymphocyte Activation/drug effects , Mice , Mice, Knockout , Nitriles , Pandemics , Pneumonia, Viral/drug therapy , Pyrimidines , T-Lymphocytes, Helper-Inducer/immunology
20.
Shock ; 54(4): 438-450, 2020 10.
Article in English | MEDLINE | ID: covidwho-639941

ABSTRACT

The world is currently embroiled in a pandemic of coronavirus disease 2019 (COVID-19), a respiratory illness caused by the novel betacoronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The severity of COVID-19 disease ranges from asymptomatic to fatal acute respiratory distress syndrome. In few patients, the disease undergoes phenotypic differentiation between 7 and 14 days of acute illness, either resulting in full recovery or symptom escalation. However, the mechanism of such variation is not clear, but the facts suggest that patient's immune status, comorbidities, and the systemic effects of the viral infection (potentially depending on the SARS-CoV-2 strain involved) play a key role. Subsequently, patients with the most severe symptoms tend to have poor outcomes, manifest severe hypoxia, and possess elevated levels of pro-inflammatory cytokines (including IL-1ß, IL-6, IFN-γ, and TNF-α) along with elevated levels of the anti-inflammatory cytokine IL-10, marked lymphopenia, and elevated neutrophil-to-lymphocyte ratios. Based on the available evidence, we propose a mechanism wherein SARS-CoV-2 infection induces direct organ damage while also fueling an IL-6-mediated cytokine release syndrome (CRS) and hypoxia, resulting in escalating systemic inflammation, multi-organ damage, and end-organ failure. Elevated IL-6 and hypoxia together predisposes patients to pulmonary hypertension, and the presence of asymptomatic hypoxia in COVID-19 further compounds this problem. Due to the similar downstream mediators, we discuss the potential synergistic effects and systemic ramifications of SARS-CoV-2 and influenza virus during co-infection, a phenomenon we have termed "COVI-Flu." Additionally, the differences between CRS and cytokine storm are highlighted. Finally, novel management approaches, clinical trials, and therapeutic strategies toward both SARS-CoV-2 and COVI-Flu infection are discussed, highlighting host response optimization and systemic inflammation reduction.


Subject(s)
Betacoronavirus , Coinfection/therapy , Coronavirus Infections/complications , Hypoxia/therapy , Immunotherapy , Influenza, Human/complications , Pneumonia, Viral/complications , COVID-19 , Coinfection/diagnosis , Coinfection/virology , Coronavirus Infections/diagnosis , Coronavirus Infections/drug therapy , Coronavirus Infections/therapy , Humans , Hypoxia/virology , Influenza, Human/diagnosis , Influenza, Human/therapy , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/therapy , SARS-CoV-2
SELECTION OF CITATIONS
SEARCH DETAIL
...