High dose subcutaneous Anakinra to treat acute respiratory distress syndrome secondary to cytokine storm syndrome among severely ill COVID-19 patients

• Published in: Journal of autoimmunity Vol. 115; p. 102537
• Main Authors: Iglesias-Julián, Enrique, López-Veloso, María, de-la-Torre-Ferrera, Noelia, Barraza-Vengoechea, Julio Cesar, Delgado-López, Pedro David, Colazo-Burlato, María, Ubeira-Iglesias, Marta, Montero-Baladía, Miguel, Lorenzo-Martín, Andrés, Minguito-de-la-Iglesia, Javier, García-Muñoz, Juan Pablo, Sanllorente-Sebastián, Rodrigo, Vicente-González, Blanca, Alemán-Alemán, Ana, Buzón-Martín, Luis
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-12-2020
• Subjects: Acute respiratory distress syndrome; Adult; Aged; Aged, 80 and over; Anakinra; Antibodies, Monoclonal, Humanized - therapeutic use; Antirheumatic Agents - therapeutic use; Cohort Studies; COVID-19; COVID-19 Drug Treatment; Cytokine Release Syndrome - drug therapy; Cytokine storm syndrome; Disease Progression; Female; Humans; IL-1; Injections, Subcutaneous; Interleukin 1 Receptor Antagonist Protein - therapeutic use; Interleukin-1 - antagonists & inhibitors; Interleukin-6 - antagonists & inhibitors; Male; Middle Aged; Respiratory Distress Syndrome - drug therapy; SARS-CoV-2 - physiology; SARS-CoV2; Spain; Tocilizumab; Spain; COVID-19; Acute respiratory distress syndrome; SARS-CoV2; Cytokine storm syndrome; IL-1; Tocilizumab; Anakinra
• ISSN: 0896-8411; 1095-9157; 1095-9157
• DOI: 10.1016/j.jaut.2020.102537

Severely ill COVID-19 patients may end in acute respiratory distress syndrome (ARDS) and multi-organ failure. Some of them develop a systemic hyperinflammatory state produced by the massive release of inflammatory agents, known as cytokine storm syndrome (CSS). Inhibition of IL-1 by Anakinra (ANK) is a potential life-saving therapy for severe CSS cases. We propose a rationale for the use of subcutaneous ANK and review our initial experience in a small cohort of severe COVID-19 CSS patients.
Retrospective cohort study of COVID-19 patients developing ARDS (PaO2/FiO2 <300) and exhibiting signs of hyperinflammation (ferritin >1000 ng/mL and/or d-dimers > 1.5 μg/mL, plus IL-6 < 40 mg/mL) that received ANK. For comparison, a propensity score matched historical cohort of patients treated with IL-6 inhibitor Tocilizumab (TCZ) was used. Patients had previously received combinations of azithromycin, hydroxy-chloroquine, and methyl-prednisolone. Laboratory findings, respiratory function and adverse effects were monitored. Resolution of ARDS within the first 7 days of treatment was considered a favorable outcome.
Subcutaneous ANK (100 mg every 6 h) was given to 9 COVID-19 ARDS CSS patients (77.8% males). Median age was 62 years (range, 42 to 87). A TCZ cohort of 18 patients was selected by propensity score matching and treated with intravenous single dose of 600 mg for patients weighing >75 Kg, or 400 mg if < 75 Kg. Prior to treatment, median PaO2/FiO2 ratio of the ANK and TCZ cohorts were 193 and 249, respectively (p = 0.131). After 7 days of treatment, PaO2/FiO2 ratio improved in both groups to 279 (104–335) and 331 (140–476, p = 0.099) respectively. On day 7, there was significant reduction of ferritin (p = 0.046), CRP (p = 0.043), and IL-6 (p = 0.043) levels in the ANK cohort but only of CRP (p = 0.001) in the TCZ group. Favorable outcome was achieved in 55.6% and 88.9% of the ANK and TCZ cohorts, respectively (p = 0.281). Two patients that failed to respond to TCZ improved after ANK treatment. Aminotransferase levels significantly increased between day 1 and day 7 (p = 0.004) in the TCZ group. Mortality was the same in both groups (11%). There were not any opportunistic infection in the groups nor other adverse effects attributable to treatment.
Overall, 55.6% of COVID-19 ARDS CSS patients treated with ANK exhibited favorable outcome, not inferior to a TCZ treated matched cohort. ANK may be a potential alternative to TCZ for patients with elevated aminotransferases, and may be useful in non-responders to TCZ.
•A percentage of COVID-19 patients develop systemic hyperinflammation and cytokine storm syndrome (CSS).•COVID-19 related CSS may end up in acute respiratory distress syndrome (ARDS).•IL-1 plays a relevant role in such hyperinflammation state.•IL-1 inhibition by anakinra seems to be a promising treatment option for severely ill COVID-19 ARDS patients.