Anakinra treatment in critically ill COVID-19 patients: a prospective cohort study.

Aged COVID-19 / physiopathology Cohort Studies Critical Illness / therapy Female Humans Interleukin 1 Receptor Antagonist Protein / adverse effects Male Middle Aged Pandemics / prevention & control Prospective Studies Receptors, Interleukin-1 / antagonists & inhibitors Statistics, Nonparametric COVID-19 Drug Treatment

Coronavirus disease 2019 Critical care Cytokines Immunity Interleukin-1 receptor antagonist protein SARS-CoV-2

Journal

Critical care (London, England)

ISSN: 1466-609X

Titre abrégé: Crit Care

Pays: England

ID NLM: 9801902

Informations de publication

Date de publication:
10 12 2020

Historique:

received: 09 09 2020

accepted: 29 10 2020

entrez: 11 12 2020

pubmed: 12 12 2020

medline: 1 1 2021

Statut: epublish

Résumé

A subset of critically ill COVID-19 patients develop a hyperinflammatory state. Anakinra, a recombinant interleukin-1 receptor antagonist, is known to be effective in several hyperinflammatory diseases. We investigated the effects of anakinra on inflammatory parameters and clinical outcomes in critically ill, mechanically ventilated COVID-19 patients with clinical features of hyperinflammation. In this prospective cohort study, 21 critically ill COVID-19 patients treated with anakinra were compared to a group of standard care. Serial data of clinical inflammatory parameters and concentrations of multiple circulating cytokines were determined and aligned on start day of anakinra in the treatment group, and median start day of anakinra in the control group. Analysis was performed for day - 10 to + 10 relative to alignment day. Clinical outcomes were analyzed during 28 days. Additionally, three sensitivity analyses were performed: (1) using propensity score-matched groups, (2) selecting patients who did not receive corticosteroids, and (3) using a subset of the control group aimed to match the criteria (fever, elevated ferritin) for starting anakinra treatment. Baseline patient characteristics and clinical parameters on ICU admission were similar between groups. As a consequence of bias by indication, plasma levels of aspartate aminotransferase (ASAT) (p = 0.0002), ferritin (p = 0.009), and temperature (p = 0.001) were significantly higher in the anakinra group on alignment day. Following treatment, no relevant differences in kinetics of circulating cytokines were observed between both groups. Decreases of clinical parameters, including temperature (p = 0.03), white blood cell counts (p = 0.02), and plasma levels of ferritin (p = 0.003), procalcitonin (p = 0.001), creatinine (p = 0.01), and bilirubin (p = 0.007), were more pronounced in the anakinra group. No differences in duration of mechanical ventilation or ICU length of stay were observed between groups. Sensitivity analyses confirmed these results. Anakinra is effective in reducing clinical signs of hyperinflammation in critically ill COVID-19 patients. A randomized controlled trial is warranted to draw conclusion about the effects of anakinra on clinical outcomes.

Sections du résumé

BACKGROUND

METHODS

In this prospective cohort study, 21 critically ill COVID-19 patients treated with anakinra were compared to a group of standard care. Serial data of clinical inflammatory parameters and concentrations of multiple circulating cytokines were determined and aligned on start day of anakinra in the treatment group, and median start day of anakinra in the control group. Analysis was performed for day - 10 to + 10 relative to alignment day. Clinical outcomes were analyzed during 28 days. Additionally, three sensitivity analyses were performed: (1) using propensity score-matched groups, (2) selecting patients who did not receive corticosteroids, and (3) using a subset of the control group aimed to match the criteria (fever, elevated ferritin) for starting anakinra treatment.

RESULTS

Baseline patient characteristics and clinical parameters on ICU admission were similar between groups. As a consequence of bias by indication, plasma levels of aspartate aminotransferase (ASAT) (p = 0.0002), ferritin (p = 0.009), and temperature (p = 0.001) were significantly higher in the anakinra group on alignment day. Following treatment, no relevant differences in kinetics of circulating cytokines were observed between both groups. Decreases of clinical parameters, including temperature (p = 0.03), white blood cell counts (p = 0.02), and plasma levels of ferritin (p = 0.003), procalcitonin (p = 0.001), creatinine (p = 0.01), and bilirubin (p = 0.007), were more pronounced in the anakinra group. No differences in duration of mechanical ventilation or ICU length of stay were observed between groups. Sensitivity analyses confirmed these results.

CONCLUSIONS

Anakinra is effective in reducing clinical signs of hyperinflammation in critically ill COVID-19 patients. A randomized controlled trial is warranted to draw conclusion about the effects of anakinra on clinical outcomes.

Identifiants

DOI: 10.1186/s13054-020-03364-w PMID: 33302991 PMC: PMC7726611

pubmed: 33302991

doi: 10.1186/s13054-020-03364-w

pii: 10.1186/s13054-020-03364-w

pmc: PMC7726611

doi:

Substances chimiques

Interleukin 1 Receptor Antagonist Protein 0

Receptors, Interleukin-1 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

688

Subventions

Organisme : H2020 European Research Council

ID : 833247

Pays : International

Investigateurs

Emma J Kooistra (EJ)

Nicole J B Waalders (NJB)

Inge Grondman (I)

Nico A F Janssen (NAF)

Aline H de Nooijer (AH)

Mihai G Netea (MG)

Frank L van de Veerdonk (FL)

Esther Ewalds (E)

Johannes G van der Hoeven (JG)

Matthijs Kox (M)

Peter Pickkers (P)

Pleun Hemelaar (P)

Remi Beunders (R)

Niklas Bruse (N)

Tim Frenzel (T)

Jeroen Schouten (J)

Hugo Touw (H)

Sjef van der Velde (S)

Hetty van der Eng (H)

Noortje Roovers (N)

Margreet Klop-Riehl (M)

Jelle Gerretsen (J)

Wout Claassen (W)

Hidde Heesakkers (H)

Tirsa van Schaik (T)

Leonie Buijsse (L)

Leo Joosten (L)

Quirijn de Mast (Q)

Martin Jaeger (M)

Ilse Kouijzer (I)

Helga Dijkstra (H)

Heidi Lemmers (H)

Reinout van Crevel (R)

Josephine van de Maat (J)

Gerine Nijman (G)

Simone Moorlag (S)

Esther Taks (E)

Priya Debisarun (P)

Heiman Wertheim (H)

Joost Hopman (J)

Janette Rahamat-Langendoen (J)

Chantal Bleeker-Rovers (C)

Hans Koenen (H)

Esther Fasse (E)

Esther van Rijssen (E)

Manon Kolkman (M)

Bram van Cranenbroek (B)

Ruben Smeets (R)

Irma Joosten (I)

Commentaires et corrections

Type : CommentIn

Références

Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan. China Lancet. 2020;395(10223):497–506.

doi: 10.1016/S0140-6736(20)30183-5

Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan. China Intensive Care Med. 2020;46:846–8.

doi: 10.1007/s00134-020-05991-x

Henry BM, de Oliveira MHS, Benoit S, Plebani M, Lippi G. Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis. Clin Chem Lab Med. 2020;58(7):1021–8.

doi: 10.1515/cclm-2020-0369

Schulert GS, Grom AA. Pathogenesis of macrophage activation syndrome and potential for cytokine-directed therapies. Annu Rev Med. 2015;66:145–59.

doi: 10.1146/annurev-med-061813-012806

Zhang C, Wu Z, Li JW, Zhao H, Wang GQ. Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality. Int J Antimicrob Agents. 2020;55(5):105954.

doi: 10.1016/j.ijantimicag.2020.105954

Giamarellos-Bourboulis EJ, Netea MG, Rovina N, Akinosoglou K, Antoniadou A, Antonakos N, et al. Complex immune dysregulation in COVID-19 patients with severe respiratory failure. Cell Host Microbe. 2020;27(6):992.e3-1000.e3.

doi: 10.1016/j.chom.2020.04.009

Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033–4.

doi: 10.1016/S0140-6736(20)30628-0

Shakoory B, Carcillo JA, Chatham WW, Amdur RL, Zhao H, Dinarello CA, et al. Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: reanalysis of a prior phase III trial. Crit Care Med. 2016;44(2):275–81.

doi: 10.1097/CCM.0000000000001402

Cavalli G, De Luca G, Campochiaro C, Della-Torre E, Ripa M, Canetti D, 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(6):e325–31.

doi: 10.1016/S2665-9913(20)30127-2

Dimopoulos G, de Mast Q, Markou N, Theodorakopoulou M, Komnos A, Mouktaroudi M, et al. Favorable anakinra responses in severe COVID-19 patients with secondary hemophagocytic lymphohistiocytosis. Cell Host Microbe. 2020;28:117.e1-123.e1.

doi: 10.1016/j.chom.2020.05.007

Huet T, Beaussier H, Voisin O, Jouveshomme S, Dauriat G, Lazareth I, et al. Anakinra for severe forms of COVID-19: a cohort study. Lancet Rheumatol. 2020;2:e393–400.

doi: 10.1016/S2665-9913(20)30164-8

Navarro-Millán I, Sattui SE, Lakhanpal A, Zisa D, Siegel CH, Crow MK. Use of anakinra to prevent mechanical ventilation in severe COVID-19: a case series. Arthritis Rheumatol. 2020. https://doi.org/10.1002/art.41422 .

doi: 10.1002/art.41422 pubmed: 32602262 pmcid: 7537257

Aouba A, Baldolli A, Geffray L, Verdon R, Bergot E, Martin-Silva N, et al. Targeting the inflammatory cascade with anakinra in moderate to severe COVID-19 pneumonia: case series. Ann Rheum Dis. 2020;79:1381–2.

doi: 10.1136/annrheumdis-2020-217706

Lopez-Castejon G, Brough D. Understanding the mechanism of IL-1β secretion. Cytokine Growth Factor Rev. 2011;22(4):189–95.

doi: 10.1016/j.cytogfr.2011.10.001

Kyriazopoulou E, Leventogiannis K, Norrby-Teglund A, Dimopoulos G, Pantazi A, Orfanos SE, et al. Macrophage activation-like syndrome: an immunological entity associated with rapid progression to death in sepsis. BMC Med. 2017;15(1):172.

doi: 10.1186/s12916-017-0930-5

Ramiro S, Mostard RLM, Magro-Checa C, van Dongen CMP, Dormans T, Buijs J, et al. Historically controlled comparison of glucocorticoids with or without tocilizumab versus supportive care only in patients with COVID-19-associated cytokine storm syndrome: results of the CHIC study. Ann Rheum Dis. 2020;79:annrheumdis-2020-218479.

Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, et al. Dexamethasone in hospitalized patients with Covid-19—preliminary report. N Engl J Med. 2020. https://doi.org/10.1056/NEJMoa2021436 .

doi: 10.1056/NEJMoa2021436 pubmed: 7490833 pmcid: 7490833