CFO Jonathan Cartu Claims - Interleukin-1 blockade with high-dose anakinra in patients with C... - Jonathan Cartu Family Medical Clinic & Patient Care Center
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CFO Jonathan Cartu Claims – Interleukin-1 blockade with high-dose anakinra in patients with C…

NIP Web Desk Team

CFO Jonathan Cartu Claims – Interleukin-1 blockade with high-dose anakinra in patients with C…


Summary

Background

Mortality of patients with coronavirus disease 2019 (COVID-19), acute respiratory distress syndrome (ARDS), and systemic inflammation is high. In areas of pandemic outbreak, the number of patients can exceed maximum capacity of intensive care units (ICUs), and, thus, these individuals often receive non-invasive ventilation outside of the ICU. Effective treatments for this population are needed urgently. Anakinra is a recombinant interleukin-1 receptor antagonist that might be beneficial in this patient population.

Methods

We conducted a retrospective cohort study at the San Raffaele Hospital in Milan, Italy. We included consecutive patients (aged ≥18 years) with COVID-19, moderate-to-severe ARDS, and hyperinflammation (defined as serum C-reactive protein ≥100 mg/L, ferritin ≥900 ng/mL, or both) who were managed with non-invasive ventilation outside of the ICU and who received standard treatment of 200 mg hydroxychloroquine twice a day orally and 400 mg lopinavir with 100 mg ritonavir twice a day orally. We compared survival, mechanical ventilation-free survival, changes in C-reactive protein, respiratory function, and clinical status in a cohort of patients who received additional treatment with anakinra (either 5 mg/kg twice a day intravenously [high dose] or 100 mg twice a day subcutaneously [low dose]) with a retrospective cohort of patients who did not receive anakinra (referred to as the standard treatment group). All outcomes were assessed at 21 days. This study is part of the COVID-19 Biobank study, which is registered with ClinicalTrials.gov, NCT04318366.

Findings

Between March 17 and March 27, 2020, 29 patients received high-dose intravenous anakinra, non-invasive ventilation, and standard treatment. Between March 10 and March 17, 2020, 16 patients received non-invasive ventilation and standard treatment only and comprised the comparison group for this study. A further seven patients received low-dose subcutaneous anakinra in addition to non-invasive ventilation and standard treatment; however, anakinra treatment was interrupted after 7 days because of a paucity of effects on serum C-reactive protein and clinical status. At 21 days, treatment with high-dose anakinra was associated with reductions in serum C-reactive protein and progressive improvements in respiratory function in 21 (72%) of 29 patients; five (17%) patients were on mechanical ventilation and three (10%) died. In the standard treatment group, eight (50%) of 16 patients showed respiratory improvement at 21 days; one (6%) patient was on mechanical ventilation and seven (44%) died. At 21 days, survival was 90% in the high-dose anakinra group and 56% in the standard treatment group (p=0·009). Mechanical ventilation-free survival was 72% in the anakinra group versus 50% in the standard treatment group (p=0·15). Bacteraemia occurred in four (14%) of 29 patients receiving high-dose anakinra and two (13%) of 16 patients receiving standard treatment. Discontinuation of anakinra was not followed by inflammatory relapses.

Interpretation

In this retrospective cohort study of patients with COVID-19 and ARDS managed with non-invasive ventilation outside of the ICU, treatment with high-dose anakinra was safe and associated with clinical improvement in 72% of patients. Confirmation of efficacy will require controlled trials.

Funding

None.

Introduction

As of April 29, 2020, the coronavirus disease 2019 (COVID-19) pandemic has affected 3 018 681 people worldwide, causing the death of 207 973.

WHO
Coronavirus disease 2019 (COVID-19): situation report—100.

Current management of COVID-19 is supportive, and respiratory failure from acute respiratory distress syndrome (ARDS) is the main cause of death.

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.

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Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China.

Mortality in patients with COVID-19 and ARDS who are admitted to the intensive care unit (ICU) is high: a study of 24 patients reported that 50% had died at 14 days,

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whereas mortality in other reports ranges from 28% to 78%.

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Mortality is increased in patients with pronounced systemic inflammation.

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.

  • Ruan Q
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  • Jiang L
  • Song J

Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China.

In areas where the COVID-19 pandemic is overwhelming, the number of patients with COVID-19 and ARDS can exceed the maximum capacity of ICUs.

COVID-19 and Italy: what next?.

As a shortage of ICU beds has emerged, with an unsettling element of overall lethality,

COVID-19 and Italy: what next?.

many patients with COVID-19 and ARDS have received maximum supportive treatment, including non-invasive ventilation in medical wards, while awaiting access to the ICU and further therapeutic approaches. Treatments are needed to effectively reduce mortality and prevent ICU admission in this population.

Research in context

Evidence before this study

Since the coronavirus disease 2019 (COVID-19) outbreak, evidence has emerged that some patients develop acute lung injury and respiratory insufficiency as a result of an excessive, maladaptive host inflammatory response to severe acute respiratory syndrome coronavirus 2. Published work has delineated a similarity between this subgroup of patients with COVID-19 and those with hyperinflammatory syndromes (eg, resembling the cytokine storm that develops in patients with macrophage activation syndrome or after chimeric antigen receptor T-cell treatment). On this basis, use of cytokine-blocking agents has been proposed for treatment of patients with COVID-19; however, data are scarce for the efficacy and safety of these treatments in this population. In particular, no published study has assessed interleukin-1 (IL-1) blockade with anakinra, despite previous evidence of efficacy and safety of this treatment for patients with hyperinflammatory syndromes.

Added value of this study

Our retrospective cohort study is, as far as we know, the first to describe IL-1 blockade with high-dose intravenous anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation.

Implications of all the available evidence

Our study, together with pre-existing evidence of the efficacy and safety of anakinra in patients with hyperinflammatory syndromes, suggests that this agent deserves consideration and controlled testing for the treatment of COVID-19.

Anakinra is an interleukin (IL)-1 receptor antagonist that blocks activity of the proinflammatory cytokines IL-1α and IL-1β and is used to treat autoinflammatory disorders (eg, adult-onset Still’s disease, systemic-onset juvenile idiopathic arthritis, and familial Mediterranean fever) at a daily dose of 100 mg subcutaneously in adult patients.

Treating rheumatological diseases and co-morbidities with interleukin-1 blocking therapies.

A subgroup of patients with COVID-19 show hyperinflammatory symptoms that resemble the cytokine storm after chimeric antigen receptor T-cell treatment or in patients with macrophage activation syndrome, with release of IL-1, IL-6, IL-18, and interferon γ.

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COVID-19: consider cytokine storm syndromes and immunosuppression.

Cytokine-blocking agents, including high-dose anakinra, are effective treatments for these disorders.

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CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade.

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Benefit of anakinra in treating pediatric secondary hemophagocytic lymphohistiocytosis.

However, compared with other cytokine-blocking agents, anakinra has a remarkable record of safety and a…

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