Search

Background: Tocilizumab, an interleukin-6 inhibitor is part of many international guidelines for the management of cytokine storm associated with severe coronavirus disease 2019 with observed improvements. However, this drug is not recommended during pregnancy owing to the lack of safety data. Restriction of such medication use makes the management of coronavirus disease 2019 in pregnant women more challenging. Pregnant women are more likely to deteriorate from respiratory infections because of the immunological changes during pregnancy and the hypoxic compromise. We report the use of tocilizumab in two pregnant patients who developed severe coronavirus disease 2019 with a successful outcome. To date, there have not been any published data on tocilizumab use in pregnancy for cytokine storm syndrome associated with coronavirus disease 2019.Case Presentations: In 2020, two pregnant women of Asian origin in the last trimester of pregnancy were admitted to our hospital with severe coronavirus disease 2019. Their clinical condition progressed rapidly despite maximum supportive treatments. Blood testing in the second week of illness showed rising ferritin and interleukin-6 levels, indicating the possibility of cytokine storm syndrome. Both developed respiratory failure necessitating mechanical ventilation. Due to their critical clinical condition and lack of response to supportive treatment, a decision was made to use intravenous tocilizumab therapy. Both were treated with one intravenous infusion of tocilizumab and had a successful outcome. They were extubated later and gradually weaned off supplemental oxygen. The first patient continued with her pregnancy during the hospital stay with normal fetal scans. The second patient needed an emergency cesarean section and delivered a healthy infant.Conclusion: In critical clinical situations, tocilizumab may have a role in managing coronavirus disease 2019 related cytokine storm during pregnancy. [ABSTRACT FROM AUTHOR]

Background: Due to the lack of proven therapies, we evaluated the effects of early administration of tocilizumab for COVID-19. By inhibition of the IL-6 receptor, tocilizumab may help to mitigate the hyperinflammatory response associated with progressive respiratory failure from SARS-CoV-2.Methods: A retrospective, observational study was conducted on hospitalized adults who received intravenous tocilizumab for COVID-19 between March 23, 2020 and April 10, 2020.Results: Most patients were male (66.7%), Hispanic (63.3%) or Black (23.3%), with a median age of 54 years. Tocilizumab was administered at a median of 8 days (range 1-21) after initial symptoms and 2 days (range 0-12) after hospital admission. Within 30 days from receiving tocilizumab, 36 patients (60.0%) demonstrated clinical improvement, 9 (15.0%) died, 33 (55.0%) were discharged alive, and 18 (30.0%) remained hospitalized. Successful extubation occurred in 13 out of 29 patients (44.8%). Infectious complications occurred in 16 patients (26.7%) at a median of 10.5 days. After tocilizumab was administered, there was a slight increase in PaO2/FiO2 and an initial reduction in CRP, but this effect was not sustained beyond day 10.Conclusions: Majority of patients demonstrated clinical improvement and were successfully discharged alive from the hospital after receiving tocilizumab. We observed a rebound effect with CRP, which may suggest the need for higher or subsequent doses to adequately manage cytokine storm. Based on our findings, we believe that tocilizumab may have a role in the early treatment of COVID-19, however larger randomized controlled studies are needed to confirm this. [ABSTRACT FROM AUTHOR]

A severe pneumonia-associated respiratory syndrome caused by a new coronavirus was identified in December 2019 (COVID-19), spread rapidly and has become a world-wide public health challenge. About 25% of COVID-19 patients experienced severe complications including acute respiratory distress syndrome (ARDS), and even progressed into an intensive care unit (ICU) admission and died. The exploration for the mortality causes and advancing novel therapeutic development of severe COVID-19 is crucial at the moment. The biopsy samples analysis at autopsy suggested that increased alveolar exudate caused by aberrant host immune response and inflammatory cytokine storm probably impedes alveolar gas exchange and contributes to the high mortality of severe COVID-19 patients. Our research has identified that pathogenic T cells and inflammatory monocytes incite inflammatory storm with large amount of interleukin 6, therefore monoclonal antibody that targets the IL-6 pathways may potentially curb inflammatory storm. Moreover, Tocilizumab treatment that blocking IL-6 receptors showed inspiring clinical results including temperature returned to normal quickly and respiratory function improved. Therefore, we suggest that Tocilizumab is an effective treatment in severe patients of COVID-19 to calm the inflammatory storm and reduce mortality. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study is to test the safety and effectiveness of individually or simultaneously blocking IL-6, IL-6 receptor and IL-1 versus standard of care on blood oxygenation and systemic cytokine release syndrome in patients with COVID-19 coronavirus infection and acute hypoxic respiratory failure and systemic cytokine release syndrome.Trial Design: A phase 3 prospective, multi-center, interventional, open label, 6-arm 2x2 factorial design study.Participants: Subjects will be recruited at the specialized COVID-19 wards and/or ICUs at 16 Belgian participating hospitals. Only adult (≥18y old) patients will be recruited with recent (≤16 days) COVID-19 infection and acute hypoxia (defined as PaO2/FiO2 below 350mmHg or PaO2/FiO2 below 280 on supplemental oxygen and immediately requiring high flow oxygen device or mechanical ventilation) and signs of systemic cytokine release syndrome characterized by high serum ferritin, or high D-dimers, or high LDH or deep lymphopenia or a combination of those, who have not been on mechanical ventilation for more than 24 hours before randomisation. Patients should have had a chest X-ray and/or CT scan showing bilateral infiltrates within the last 2 days before randomisation. Patients with active bacterial or fungal infection will be excluded.Intervention and Comparator: Patients will be randomized to 1 of 5 experimental arms versus usual care. The experimental arms consist of Anakinra alone (anti-IL-1 binding the IL-1 receptor), Siltuximab alone (anti-IL-6 chimeric antibody), a combination of Siltuximab and Anakinra, Tocilizumab alone (humanised anti-IL-6 receptor antibody) or a combination of Anakinra with Tocilizumab in addition to standard care. Patients treated with Anakinra will receive a daily subcutaneous injection of 100mg for a maximum of 28 days or until hospital discharge, whichever comes first. Siltuximab (11mg/kg) or Tocilizumab (8mg/kg, with a maximum dose of 800mg) are administered as a single intravenous injection immediately after randomization.Main Outcomes: The primary end point is the time to clinical improvement defined as the time from randomization to either an improvement of two points on a six-category ordinal scale measured daily till day 28 or discharge from the hospital or death. This ordinal scale is composed of (1) Death; (2) Hospitalized, on invasive mechanical ventilation or ECMO; (3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; (4) Hospitalized, requiring supplemental oxygen; (5) Hospitalized, not requiring supplemental oxygen; (6) Not hospitalized.Randomisation: Patients will be randomized using an Interactive Web Response System (REDCap). A 2x2 factorial design was selected with a 2:1 randomization regarding the IL-1 blockade (Anakinra) and a 1:2 randomization regarding the IL-6 blockade (Siltuximab and Tocilizumab).Blinding (masking): In this open-label trial neither participants, caregivers, nor those assessing the outcomes are blinded to group assignment.Numbers To Be Randomised (sample Size): A total of 342 participants will be enrolled: 76 patients will receive usual care, 76 patients will receive Siltuximab alone, 76 patients will receive Tocilizumab alone, 38 will receive Anakinra alone, 38 patients will receive Anakinra and Siltuximab and 38 patients will receive Anakinra and Tocilizumab.Trial Status: COV-AID protocol version 3.0 (15 Apr 2020). Participant recruitment is ongoing and started on April 4th 2020. Given the current decline of the COVID-19 pandemic in Belgium, it is difficult to anticipate the rate of participant recruitment.Trial Registration: The trial was registered on Clinical Trials.gov on April 1st, 2020 (ClinicalTrials.gov Identifier: NCT04330638) and on EudraCT on April 3rd 2020 (Identifier: 2020-001500-41).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. [ABSTRACT FROM AUTHOR]

Background: Cytokine storm triggered by Severe Coronavirus Disease 2019 (COVID-19) is associated with high mortality. With high Interleukin -6 (IL-6) levels reported in COVID-19 related deaths in China, IL-6 is considered to be the key player in COVID-19 cytokine storm. Tocilizumab, a monoclonal antibody against IL-6 receptor, is used on compassionate grounds for treatment of COVID-19 cytokine storm. The aim of this study was to assess effect of tocilizumab on mortality due to COVID-19 cytokine storm.Method: This retrospective, observational study included patients of severe COVID-19 pneumonia with persistent hypoxia (defined as saturation 94% or less on supplemental Oxygen of 15 L per minute through non-rebreathing mask or PaO2/FiO2 ratio of less than 200) who were admitted to a tertiary care center in Mumbai, India, between 31st March to 5th July 2020. In addition to standard care, single Inj. Tocilizumab 400 mg was given intravenously to 151 consecutive COVID-19 patients with persistent hypoxia, from 13th May to 5th July 2020. These 151 patients were retrospectively analysed and compared with historic controls, ie consecutive COVID-19 patients with persistent hypoxia, defined as stated above (N = 118, from our first COVID-19 admission on 31st March to 12th May 2020 i.e., till tocilizumab was available in hospital). Univariate and multivariate Cox regression analysis was performed for identifying predictors of survival. Statistical analysis was performed using IBM SPSS version 26.Results: Out of 269 (151 in tocilizumab group and 118 historic controls) patients studied from 31st March to 5th July 2020, median survival in the tocilizumab group was significantly longer than in the control group; 18 days (95% CI, 11.3 to 24.7) versus 9 days (95% CI, 5.7 to 12.3); log rank p 0.007. On multivariate Cox regression analysis, independent predictors of survival were use of tocilizumab (HR 0.621, 95% CI 0.427-0.903, P 0.013) and higher oxygen saturation.Conclusion: Tocilizumab may improve survival in severe COVID-19 pneumonia with persistent hypoxia. Randomised controlled trials on use of tocilizumab as rescue therapy in patients of severe COVID-19 pneumonia with hypoxia (PaO2/FiO2 less than 200) due to hyperinflammatory state, are warranted. [ABSTRACT FROM AUTHOR]

We would like to comment on the article entitled "Association between cytokine profiles and lung injury in COVID-19 pneumonia" by Li-Da Chen and colleagues, with respect to emerging data regarding the immunopathogenesis of COVID-19. Chen et al. demonstrated the relevance of IL-2R, IL-6 and TNF-α in the cytokine storm and IL-6 as an independent predictor for COVID-19 severity. Del Valle et al. corroborated these findings with regard to IL-6 and disease severity, however, they also showed IL-8 to be of significance. This may be explained by the varying techniques used by the two studies to determine severity. Further studies including critically ill patients and the analysis of mortality rates in this patient cohort would greatly enhance the clinical relevance of these findings. As speculated by Chen et al., early studies on the use of tocilizumab in COVID-19 patients were promising, however, full results from ongoing trials are required to confirm a survival benefit in patients treated with tocilizumab. Moreover, investigating the roles of other pro-inflammatory cytokines and their impact on disease severity could potentially inform novel therapeutic targets. [ABSTRACT FROM AUTHOR]

Background: Coronavirus disease 2019 (COVID-19) is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2, previously named 2019-nCov), a novel coronavirus that emerged in China in December 2019 and was declared a global pandemic by World Health Organization by March 11th, 2020. Severe manifestations of COVID-19 are caused by a combination of direct tissue injury by viral replication and associated cytokine storm resulting in progressive organ damage. Discussion: We reviewed published literature between January 1st, 2000 and June 30th, 2020, excluding articles focusing on pediatric or obstetric population, with a focus on virus-host interactions and immunological mechanisms responsible for virus associated cytokine release syndrome (CRS). COVID-19 illness encompasses three main phases. In phase 1, SARS-CoV-2 binds with angiotensin converting enzyme (ACE)2 receptor on alveolar macrophages and epithelial cells, triggering toll like receptor (TLR) mediated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ƙB) signaling. It effectively blunts an early (IFN) response allowing unchecked viral replication. Phase 2 is characterized by hypoxia and innate immunity mediated pneumocyte damage as well as capillary leak. Some patients further progress to phase 3 characterized by cytokine storm with worsening respiratory symptoms, persistent fever, and hemodynamic instability. Important cytokines involved in this phase are interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α. This is typically followed by a recovery phase with production of antibodies against the virus. We summarize published data regarding virus-host interactions, key immunological mechanisms responsible for virus-associated CRS, and potential opportunities for therapeutic interventions. Conclusion: Evidence regarding SARS-CoV-2 epidemiology and pathogenesis is rapidly evolving. A better understanding of the pathophysiology and immune system dysregulation associated with CRS and acute respiratory distress syndrome in severe COVID-19 is imperative to identify novel drug targets and other therapeutic interventions. [ABSTRACT FROM AUTHOR]