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Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study.
Cavalli, Giulio; De Luca, Giacomo; Campochiaro, Corrado; Della-Torre, Emanuel; Ripa, Marco; Canetti, Diana; Oltolini, Chiara; Castiglioni, Barbara; Tassan Din, Chiara; Boffini, Nicola; Tomelleri, Alessandro; Farina, Nicola; Ruggeri, Annalisa; Rovere-Querini, Patrizia; Di Lucca, Giuseppe; Martinenghi, Sabina; Scotti, Raffaella; Tresoldi, Moreno; Ciceri, Fabio; Landoni, Giovanni; Zangrillo, Alberto; Scarpellini, Paolo; Dagna, Lorenzo.
  • Cavalli G; Vita-Salute San Raffaele University, Milan, Italy.
  • De Luca G; Unit of Immunology, Rheumatology, Allergy, and Rare Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • Campochiaro C; Unit of Immunology, Rheumatology, Allergy, and Rare Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • Della-Torre E; Unit of Immunology, Rheumatology, Allergy, and Rare Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • Ripa M; Unit of Immunology, Rheumatology, Allergy, and Rare Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • Canetti D; Vita-Salute San Raffaele University, Milan, Italy.
  • Oltolini C; Department of Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • Castiglioni B; Department of Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • Tassan Din C; Department of Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • Boffini N; Department of Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • Tomelleri A; Department of Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • Farina N; Unit of Immunology, Rheumatology, Allergy, and Rare Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • Ruggeri A; Unit of Immunology, Rheumatology, Allergy, and Rare Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • Rovere-Querini P; Unit of Immunology, Rheumatology, Allergy, and Rare Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • Di Lucca G; Hematology and Bone Marrow Transplant Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • Martinenghi S; Vita-Salute San Raffaele University, Milan, Italy.
  • Scotti R; Internal Medicine, Diabetes, and Endocrinology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • Tresoldi M; General Medicine and Advanced Care Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • Ciceri F; General Medicine and Advanced Care Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • Landoni G; General Medicine and Advanced Care Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • Zangrillo A; General Medicine and Advanced Care Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • Scarpellini P; Vita-Salute San Raffaele University, Milan, Italy.
  • Dagna L; Hematology and Bone Marrow Transplant Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Lancet Rheumatol ; 2(6): e325-e331, 2020 Jun.
Article in English | MEDLINE | ID: covidwho-197737
Semantic information from SemMedBD (by NLM)
1. anakinra TREATS COVID-19
Subject
anakinra
Predicate
TREATS
Object
COVID-19
2. anakinra TREATS Patients
Subject
anakinra
Predicate
TREATS
Object
Patients
3. COVID-19 PROCESS_OF Patients
Subject
COVID-19
Predicate
PROCESS_OF
Object
Patients
4. anakinra INHIBITS Interleukin-1
Subject
anakinra
Predicate
INHIBITS
Object
Interleukin-1
5. Inflammation PROCESS_OF Patients
Subject
Inflammation
Predicate
PROCESS_OF
Object
Patients
6. Respiratory Distress Syndrom PROCESS_OF C0030705
Subject
Respiratory Distress Syndrom
Predicate
PROCESS_OF
Object
C0030705
7. Noninvasive Ventilation ADMINISTERED_TO Persons
Subject
Noninvasive Ventilation
Predicate
ADMINISTERED_TO
Object
Persons
8. Hospitals LOCATION_OF Retrospective Cohort Study
Subject
Hospitals
Predicate
LOCATION_OF
Object
Retrospective Cohort Study
9. Serum LOCATION_OF C-reactive protein
Subject
Serum
Predicate
LOCATION_OF
Object
C-reactive protein
10. Standard Treatment ADMINISTERED_TO Patients
Subject
Standard Treatment
Predicate
ADMINISTERED_TO
Object
Patients
11. Noninvasive Ventilation TREATS Severe Acute Respiratory Syndrome
Subject
Noninvasive Ventilation
Predicate
TREATS
Object
Severe Acute Respiratory Syndrome
12. anakinra NEG_ADMINISTERED_TO Patients
Subject
anakinra
Predicate
NEG_ADMINISTERED_TO
Object
Patients
13. Respiration PROCESS_OF Cohort
Subject
Respiration
Predicate
PROCESS_OF
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Cohort
14. C-reactive protein compared_with anakinra
Subject
C-reactive protein
Predicate
compared_with
Object
anakinra
15. anakinra ADMINISTERED_TO Patients
Subject
anakinra
Predicate
ADMINISTERED_TO
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Patients
16. Noninvasive Ventilation ADMINISTERED_TO Patients
Subject
Noninvasive Ventilation
Predicate
ADMINISTERED_TO
Object
Patients
17. anakinra INTERACTS_WITH C-reactive protein
Subject
anakinra
Predicate
INTERACTS_WITH
Object
C-reactive protein
18. anakinra INHIBITS C-reactive protein
Subject
anakinra
Predicate
INHIBITS
Object
C-reactive protein
19. anakinra TREATS Respiratory Distress Syndrom
Subject
anakinra
Predicate
TREATS
Object
Respiratory Distress Syndrom
20. Noninvasive Ventilation TREATS Respiratory Distress Syndrom
Subject
Noninvasive Ventilation
Predicate
TREATS
Object
Respiratory Distress Syndrom
21. Noninvasive Ventilation TREATS COVID-19
Subject
Noninvasive Ventilation
Predicate
TREATS
Object
COVID-19
22. anakinra TREATS COVID-19
Subject
anakinra
Predicate
TREATS
Object
COVID-19
23. anakinra TREATS Patients
Subject
anakinra
Predicate
TREATS
Object
Patients
24. COVID-19 PROCESS_OF Patients
Subject
COVID-19
Predicate
PROCESS_OF
Object
Patients
25. anakinra INHIBITS Interleukin-1
Subject
anakinra
Predicate
INHIBITS
Object
Interleukin-1
26. Inflammation PROCESS_OF Patients
Subject
Inflammation
Predicate
PROCESS_OF
Object
Patients
27. Respiratory Distress Syndrome, Adult PROCESS_OF Patients
Subject
Respiratory Distress Syndrome, Adult
Predicate
PROCESS_OF
Object
Patients
28. Noninvasive Ventilation ADMINISTERED_TO Persons
Subject
Noninvasive Ventilation
Predicate
ADMINISTERED_TO
Object
Persons
29. Hospitals LOCATION_OF Retrospective Cohort Study
Subject
Hospitals
Predicate
LOCATION_OF
Object
Retrospective Cohort Study
30. Serum LOCATION_OF C-reactive protein
Subject
Serum
Predicate
LOCATION_OF
Object
C-reactive protein
31. Standard Treatment ADMINISTERED_TO Patients
Subject
Standard Treatment
Predicate
ADMINISTERED_TO
Object
Patients
32. Noninvasive Ventilation TREATS Severe Acute Respiratory Syndrome
Subject
Noninvasive Ventilation
Predicate
TREATS
Object
Severe Acute Respiratory Syndrome
33. anakinra NEG_ADMINISTERED_TO Patients
Subject
anakinra
Predicate
NEG_ADMINISTERED_TO
Object
Patients
34. Respiration PROCESS_OF Cohort
Subject
Respiration
Predicate
PROCESS_OF
Object
Cohort
35. C-reactive protein compared_with anakinra
Subject
C-reactive protein
Predicate
compared_with
Object
anakinra
36. anakinra ADMINISTERED_TO Patients
Subject
anakinra
Predicate
ADMINISTERED_TO
Object
Patients
37. Noninvasive Ventilation ADMINISTERED_TO Patients
Subject
Noninvasive Ventilation
Predicate
ADMINISTERED_TO
Object
Patients
38. anakinra INTERACTS_WITH C-reactive protein
Subject
anakinra
Predicate
INTERACTS_WITH
Object
C-reactive protein
39. anakinra INHIBITS C-reactive protein
Subject
anakinra
Predicate
INHIBITS
Object
C-reactive protein
40. anakinra TREATS Respiratory Distress Syndrome, Adult
Subject
anakinra
Predicate
TREATS
Object
Respiratory Distress Syndrome, Adult
41. Noninvasive Ventilation TREATS Respiratory Distress Syndrome, Adult
Subject
Noninvasive Ventilation
Predicate
TREATS
Object
Respiratory Distress Syndrome, Adult
42. Noninvasive Ventilation TREATS COVID-19
Subject
Noninvasive Ventilation
Predicate
TREATS
Object
COVID-19
ABSTRACT

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.

Full text: Available Collection: International databases Database: MEDLINE Type of study: Controlled clinical trial / Etiology study / Observational study / Risk factors Language: English Journal: Lancet Rheumatol Year: 2020 Document Type: Article Affiliation country: S2665-9913(20)30127-2

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Full text: Available Collection: International databases Database: MEDLINE Type of study: Controlled clinical trial / Etiology study / Observational study / Risk factors Language: English Journal: Lancet Rheumatol Year: 2020 Document Type: Article Affiliation country: S2665-9913(20)30127-2