Abstract: The Article published by Giulio Cavalli and colleagues in The Lancet Rheumatology,1Cavalli G De Luca G Campochiaro C et al.Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study.Lancet Rheumatol. 2020; 2: 325-331Summary Full Text Full Text PDF PubMed Scopus (769) Google Scholar in combination with our case series of nine patients,2Aouba A Baldolli A Geffray L et al.Targeting the inflammatory cascade with anakinra in moderate to severe COVID-19 pneumonia: case series.Ann Rheum Dis. 2020; (published online May 6.)DOI:10.1136/annrheumdis-2020-217706Crossref PubMed Scopus (180) Google Scholar supports the targeting of the IL-1 pathway as a safe and promising approach in the various types of lung involvement in patients with COVID-19. These complementary studies that cover the entire spectrum of severity of lung involvement in hospitalised patients with COVID-19, provide the first efficacy and safety data for anakinra, depending on the doses used and the stage of lung injury. The study by Cavalli and colleagues focused on moderate-to-severe acute respiratory distress syndrome (ARDS) associated with COVID-19, for which low-dose anakinra was ineffective, prompting a significant increase in anakinra dosage that yielded better outcomes.1Cavalli G De Luca G Campochiaro C et al.Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study.Lancet Rheumatol. 2020; 2: 325-331Summary Full Text Full Text PDF PubMed Scopus (769) Google Scholar However, in our study,2Aouba A Baldolli A Geffray L et al.Targeting the inflammatory cascade with anakinra in moderate to severe COVID-19 pneumonia: case series.Ann Rheum Dis. 2020; (published online May 6.)DOI:10.1136/annrheumdis-2020-217706Crossref PubMed Scopus (180) Google Scholar a low-dose regimen, similar to that proposed by Cavalli and colleagues,1Cavalli G De Luca G Campochiaro C et al.Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study.Lancet Rheumatol. 2020; 2: 325-331Summary Full Text Full Text PDF PubMed Scopus (769) Google Scholar was associated with good outcomes in patients with moderate-to-severe COVID-19 and oxygen-dependent pneumonia with a high risk of worsening (due to comorbidities, intense inflammatory syndrome, or both). In a longitudinal transcriptomic cytokine analysis, Ong and colleagues3Ong EZ Chan YFZ Leong WY et al.A dynamic immune response shapes COVID-19 progression.Cell Host Microbe. 2020; (published online April 30.)DOI: 10.1016/j.chom.2020.03.021Summary Full Text Full Text PDF Scopus (212) Google Scholar showed that peak expression of IL-1α and IL-β preceded the nadir of respiratory function in patients with severe COVID-19 pneumonia. Therefore, the early use of anakinra during COVID-associated lung injury might prevent the progression to ARDS and mechanic ventilation. Because of safety concerns, Cavalli and colleagues chose to stop anakinra as soon as liver transaminases exceeded the upper normal limit by more than three times.1Cavalli G De Luca G Campochiaro C et al.Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study.Lancet Rheumatol. 2020; 2: 325-331Summary Full Text Full Text PDF PubMed Scopus (769) Google Scholar However, such an increase in liver transaminases is common in patients COVID-19.4Cai Q Huang D Yu H et al.COVID-19: abnormal liver function tests.J Hepatol. 2020; (published online April 13.)DOI:10.1016/j.jhep.2020.04.006Google Scholar We noticed in patients treated with low-dose anakinra, as well as in untreated patients (data not shown), that concentrations of liver transaminases and triglycerides increase, even when C-reactive protein concentrations decreased. Therefore, the increase in triglyceride levels, which is not a classic anakinra side-effect, and in liver transaminases could correspond to haemophagocytic lymphohistiocytosis-like manifestations of COVID-19. Of note, increased liver transaminases might also have been a side-effect of lopinavir–ritonavir treatment in the study by Cavalli and colleagues.1Cavalli G De Luca G Campochiaro C et al.Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study.Lancet Rheumatol. 2020; 2: 325-331Summary Full Text Full Text PDF PubMed Scopus (769) Google Scholar, 4Cai Q Huang D Yu H et al.COVID-19: abnormal liver function tests.J Hepatol. 2020; (published online April 13.)DOI:10.1016/j.jhep.2020.04.006Google Scholar Moreover, liver injury and increased liver transaminases are associated with COVID-19 severity.4Cai Q Huang D Yu H et al.COVID-19: abnormal liver function tests.J Hepatol. 2020; (published online April 13.)DOI:10.1016/j.jhep.2020.04.006Google Scholar, 5Parohan M Yaghoubi S Seraj A Liver injury is associated with severe coronavirus disease 2019 (COVID-19) infection: a systematic review and meta-analysis of retrospective studies.Hepatol Res. 2020; (published online May 9.)DOI:10.1111/hepr.13510Crossref PubMed Scopus (112) Google Scholar Discontinuation of anti-IL-1 therapy due to increased liver transaminases could result in a lost opportunity for patients to receive anakinra who need it most, although the withdrawal of anakinra did not shorten the median duration of treatment in the study by Cavalli and colleagues.1Cavalli G De Luca G Campochiaro C et al.Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study.Lancet Rheumatol. 2020; 2: 325-331Summary Full Text Full Text PDF PubMed Scopus (769) Google Scholar Thus, we believe that only stronger and continuous increases in liver transaminases, mostly those that appeared after the onset of anakinra, should be considered to avoid premature discontinuation of therapy. We hope that the ongoing randomised controlled trials will confirm these promising results and provide answers to the outstanding questions. We declare no competing interests. Anakinra for patients with COVID-19We read with interest the Article by Giulio Cavalli and colleagues1 in The Lancet Rheumatology about the use of anakinra for patients with acute respiratory distress syndrome (ARDS) related to COVID-19. Although the study by Cavalli and colleagues was not performed in intensive care units (ICUs), the semantics used by the authors derive from critical care practice and need some precision. First, the definition of ARDS necessitates a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (PaO2:FiO2) of less than 200 mm Hg for a diagnosis of moderate ARDS and of less than 100 mm Hg for severe ARDS, assessed on invasive mechanical ventilation with a positive end-expiratory pressure of more than 5 cm H2O. Full-Text PDF Anakinra for patients with COVID-19In The Lancet Rheumatology, Giulio Cavalli and colleagues1 report potential beneficial effects of the IL-1 receptor antagonist anakinra in patients with COVID-19, acute respiratory distress syndrome (ARDS), and hyperinflammation. In the study protocol, anakinra was given in combination with a 4-aminoquinoline and, although promising, we suggest that this combination cannot be fully synergistic in the presence of cytokine release syndrome. Full-Text PDF Anakinra for patients with COVID-19 – Authors' replyWe thank Xavier Valette and Damien du Cheyron, Nicolas Martin-Silva and colleagues, and Omar Maoujoud and colleagues for their interest in our Article on treatment of patients with COVID-19 and acute respiratory distress syndrome (ARDS) with the IL-1 receptor antagonist anakinra, published in The Lancet Rheumatology.1 Full-Text PDF Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort studyIn 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. Full-Text PDF