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Anakinra combined with methylprednisolone in patients with severe COVID-19 pneumonia and hyperinflammation: An observational cohort study

Published:November 18, 2020DOI:https://doi.org/10.1016/j.jaci.2020.11.006

      Background

      Immunomodulants have been proposed to mitigate severe acute respiratory syndrome coronavirus 2–induced cytokine storm, which drives acute respiratory distress syndrome in coronavirus disease 2019 (COVID-19).

      Objective

      We sought to determine efficacy and safety of the association of IL-1 receptor antagonist anakinra plus methylprednisolone in severe COVID-19 pneumonia with hyperinflammation.

      Methods

      A secondary analysis of prospective observational cohort studies was carried out at an Italian tertiary health care facility. COVID-19 patients consecutively hospitalized (February 25, 2020, to March 30, 2020) with hyperinflammation (ferritin ≥1000 ng/mL and/or C-reactive protein >10 mg/dL) and respiratory failure (oxygen therapy from 0.4 FiO2 Venturi mask to invasive mechanical ventilation) were evaluated to investigate the effect of high-dose anakinra plus methylprednisolone on survival. Patients were followed from study inclusion to day 28 or death. Crude and adjusted (sex, age, baseline PaO2:FiO2 ratio, Charlson index, baseline mechanical ventilation, hospitalization to inclusion lapse) risks were calculated (Cox proportional regression model).

      Results

      A total of 120 COVID-19 patients with hyperinflammation (median age, 62 years; 80.0% males; median PaO2:FiO2 ratio, 151; 32.5% on mechanical ventilation) were evaluated. Of these, 65 were treated with anakinra and methylprednisolone and 55 were untreated historical controls. At 28 days, mortality was 13.9% in treated patients and 35.6% in controls (Kaplan-Meier plots, P = .005). Unadjusted and adjusted risk of death was significantly lower for treated patients compared with controls (hazard ratio, 0.33, 95% CI, 0.15-0.74, P = .007, and HR, 0.18, 95% CI, 0.07-0.50, P = .001, respectively). No significant differences in bloodstream infections or laboratory alterations were registered.

      Conclusions

      Treatment with anakinra plus methylprednisolone may be a valid therapeutic option in COVID-19 patients with hyperinflammation and respiratory failure, also on mechanical ventilation. Randomized controlled trials including the use of either agent alone are needed to confirm these results.

      Key words

      Abbreviations used:

      CCI (Charlson comorbidity index), COVID-19 (Coronavirus disease 2019), CRP (C-reactive protein), MPD (Methylprednisolone), MV (Mechanical ventilation), SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2), SOC (Standard of care)

      Introduction

      As of November 2020, the ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affected 46 million people worldwide, resulting in more than 1.2 million deaths.
      Johns Hopkins University
      The Center for Systems Science and Engineering.
      High levels of proinflammatory cytokines, C-reactive protein (CRP), and ferritin correlate with worse outcomes in patients with severe COVID-19.
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      IL-1–receptor antagonist anakinra is one of the cytokine-blocking agents used for COVID-19 treatment.
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      single-center experiences have reported encouraging findings.
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      • et al.
      Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study.
      • Huet T.
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      • Jouveshomme S.
      • Dauriat G.
      • Lazareth I.
      • et al.
      Anakinra for severe forms of COVID-19: a cohort study.
      The short half-life of anakinra enables to rapidly discontinue its action in case of adverse reactions or secondary infections, making its use suitable for critically ill patients also.
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      • Mangioni D.
      • Tagliabue P.
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      • Costantino G.
      • Minoia F.
      • et al.
      Use of anakinra in severe COVID-19: a case report.
      ,
      • Huet T.
      • Beaussier H.
      • Voisin O.
      • Jouveshomme S.
      • Dauriat G.
      • Lazareth I.
      • et al.
      Anakinra for severe forms of COVID-19: a cohort study.
      IL-1 inhibition is also associated with reduction in endothelial dysfunction and microvascular alteration,
      • Fearon W.F.
      • Fearon D.T.
      Inflammation and cardiovascular disease.
      which seem crucial in COVID-19–related thromboembolic events.
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      • et al.
      COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options.
      Corticosteroid treatment is a cornerstone in the management of noninfectious hyperinflammatory conditions, namely cytokine storm syndromes.
      • Mehta P.
      • Cron R.Q.
      • Hartwell J.
      • Manson J.J.
      • Tattersall R.S.
      Silencing the cytokine storm: the use of intravenous anakinra in haemophagocytic lymphohistiocytosis or macrophage activation syndrome.
      Favorable data have recently emerged in support of the use of corticosteroids in patients with severe COVID-19, especially in those receiving invasive MV.

      RECOVERY Collaborative Group; Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, et al. Dexamethasone in hospitalized patients with Covid-19 – preliminary report [published online ahead of print July 17, 2020]. N Engl J Med. https://doi.org/10.1056/NEJMoa2021436.

      • Tomazini B.M.
      • Maia I.S.
      • Cavalcanti A.B.
      • Berwanger O.
      • Rosa R.G.
      • Veiga V.C.
      • et al.
      Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19.
      • Fadel R.
      • Morrison A.R.
      • Vahia A.
      • Smith Z.R.
      • Chaudhry Z.
      • Bhargava P.
      • et al.
      Early short-course corticosteroids in hospitalized patients with COVID-19.
      • Ramiro S.
      • Mostard R.L.M.
      • Magro-Checa C.
      • van Dongen C.M.P.
      • 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.
      In a recent meta-analysis of prospective, randomized clinical trials on critically ill patients with COVID-19, use of corticosteroids compared with placebo or standard of care (SOC) resulted in a significantly lower 28-day mortality.
      • Sterne J.A.C.
      • Murthy S.
      • Diaz J.V.
      • Slutsky A.S.
      • Villar J.
      • et al.
      Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19.
      With this study, we aimed at investigating the efficacy and safety of combined treatment with anakinra and methylprednisolone (anti–IL-1 + MPD) in COVID-19 patients with hyperinflammation and respiratory failure.

      Results and discussion

      Of 476 COVID-19 patients admitted at our hospital between February 25 and March 30, 2020, a total of 120 (25.2%) patients with hyperinflammation and respiratory failure were included according to inclusion/exclusion criteria (see this article’s Methods section in the Online Repository at www.jacionline.org). Of these, 65 were treated with anti–IL-1 + MPD and 55 were untreated historical controls.
      Median age of the study population was 62 years (interquartile range, 54.5-70 years), 80.0% (96 of 120) were males, and median Charlson comorbidity index (CCI) was 0 (interquartile range, 0-1). At inclusion, median PaO2:FiO2 ratio was 151 (105-204.5), 32.5% (39 of 120) were on mechanical ventilation (MV), median ferritin was 1555 μg/L (1239-2679 μg/L), and median CRP was 15.2 mg/dL (10.8-23.1 mg/dL). Compared with historical controls, patients treated with anti–IL-1 + MPD had less frequently CCI less than or equal to 1 (25% vs 45.4%; P = .017), longer duration of hospitalization before inclusion (3 vs 1 median days; P < .0001), lower baseline PaO2:FiO2 ratio (median of 142 vs 173; P = .049), reduced proportion of lopinavir/ritonavir treatment (30.8% vs 70.9%; P < .0001), and higher proportion of anticoagulant therapy (63.1% vs 38.9%; P = .009). The 2 groups did not differ by age, sex, number of patients on MV at inclusion, baseline ferritin, CRP, lymphocyte and platelet counts, hemoglobin and liver enzyme levels, and use of remdesivir and hydroxichloroquine during hospitalization (Table I).
      Table ISummarization of the study population characteristics according to treatment with anakinra and MPD
      CharacteristicNTreatedNNot treatedP value
      Demographic
      Age (y)6560 (54-69)5563 (55-76).339
      Sex: male6552 (80)5544 (80)1.000
      CCI650 (0-0)550 (0-1).037
      CCI ≥16416 (25)5525 (45.4).017
      Days between hospitalization and inclusion653 (1-6)551 (0-2)<.0001
      Respiratory function at inclusion
      PaO2:FiO2 ratio
       <1006219 (30.7)507 (14.0).049
       100-2006232 (51.6)5024 (48.0)
       200-300629 (14.5)5014 (28.0)
       300-400622 (3.2)505 (10.0)
      MV6518 (27.7)5521 (37.5).222
      Laboratory markers at inclusion
      Ferritin (ng/mL)
       <20006335 (56.45)3827 (71.0).144
       >20006327 (43.55)3811 (29.0)
      Lymphocyte count (103/L)630.7 (0.5-0.9)550.8 (0.5-1.1).458
      CRP (mg/dL)6514.8 (9.0-24.5)5115.6 (11.5-21.9).969
      Hemoglobin (g/dL)6512.9 (10.6-14.1)5512.5 (10.9-14.1).912
      Platelet count (103/L)65244 (177-326)55230 (189-304).436
      Alanine transaminase (U/L)6241 (28-56)5138.0 (25.0-73.0).899
      Gamma-glutamyl transferase (U/L)4159.0 (34.4-110.8)4153.0 (26.6-95.0).792
      d-dimer (μg/L)561220 (855-2906)471271 (1059-1854).944
      Concomitant medications
      Remdesivir658 (12.3)5511 (20.0).250
      Hydroxychloroquine6565 (100)5552 (94.6).057
      Lopinavir/ritonavir6520 (30.8)5539 (70.9)<.0001
      Anticoagulant therapy6541 (63.1)5421 (38.9).009
      Continuous variables are presented as median (interquartile range), and categorical variables are reported as absolute number (percentage). P values < .05 are indicated in boldface.
      Within the 28-day follow-up, 28 of 120 (23%) patients died, 9 of 65 (13.9%) in the anti–IL-1 + MPD group compared with 19 of 55 (35.6%) controls (Kaplan-Meier curves, P = .004; Fig 1, A). Among patients without MV, mortality rate was 6 of 47 (12.8%) in the anti–IL-1 + MPD group compared with 10 of 34 (29.4%) in controls (P = .04; Fig 1, B). Among those with MV, it was 3 of 18 (16.7%) in the anti–IL-1 + MPD group and 9 of 21 (42.8%) in controls (P = .076; Fig 1, C). Overall cumulative risk of death at 28 days was significantly lower for the anti–IL-1 + MDP group compared with controls (hazard ratio, 0.33; 95% CI, 0.15-0.74; P = .007). Other factors significantly associated with survival were age less than 65 years, baseline PaO2:FiO2 ratio more than 100, and CCI 0 compared with 1 or more. No association to survival was found for antiviral treatment or for anticoagulant therapy (see Tables E1 and E2 in this article’s Online Repository at www.jacionline.org). At multivariable analysis, treatment with anti–IL-1 + MPD was found to be independently associated with survival when adjusted by sex, age, baseline PaO2:FiO2 ratio, CCI, MV at inclusion, and days between hospitalization and inclusion (hazard ratio, 0.18; 95% CI, 0.07-0.50; P = .001) (see Table E3 in this article’s Online Repository at www.jacionline.org).
      Figure thumbnail gr1
      Fig 1Survival according to treatment with anakinra and MPD (anti–IL-1 + MPD). Both treated patients and controls were characterized by hyperinflammation and respiratory failure and fulfilled inclusion/exclusion criteria (see this article’s section in the Online Repository). A, Survival of all individuals exposed to combined treatment is shown in the red color, dotted line; survival of the control group is shown in the blue color, continuous line. B and C, Survival of individuals exposed to combined treatment compared with controls in patients without and with MV at inclusion, respectively.
      Treated patients experienced consistent improvements in respiratory function and a rapid lowering of serum CRP levels during treatment (Fig 2).
      Figure thumbnail gr2
      Fig 2Daily changes in serum CRP from inclusion to day 14 (overall duration of the treatment with anakinra and MPD) for treated (A) and untreated (B) patients.
      Overall, anti–IL-1 + MPD treatment was well tolerated. Grade 3 or greater gamma-glutamyl transferase increase (27.7%), anemia (24.6%), alanine transaminase increase (6.2%), and granulocytopenia (1.5%) were observed in treated patients. However, a comparable proportion of these adverse events was observed within controls. No differences in adverse events were reported between intravenous and subcutaneous routes of administration. Nine bloodstream infections (13.8%) were observed in the anti–IL-1 + MDP group and 4 (7.3%) in controls (P = .23).
      To our knowledge, this is the largest observational study evaluating the efficacy of anakinra associated with MPD in COVID-19 patients with hyperinflammation and respiratory failure.
      Several clinical trials are currently in progress to evaluate the benefits of anakinra treatment in COVID-19.
      • King A.
      • Vail A.
      • O’Leary C.
      • Hannan C.
      • Brough D.
      • Patel H.
      • et al.
      Anakinra in COVID-19: important considerations for clinical trials.
      In a retrospective study of COVID-19 patients with respiratory failure outside the intensive care unit, Cavalli et al
      • 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.
      found a survival benefit in high-dose anakinra (5 mg/kg twice a day intravenously) use compared with SOC (90% vs 56% at day 21). A significant reduction in a composite outcome of mortality and/or intensive care unit admission was also observed in a French cohort treated with subcutaneous anakinra (100 mg twice a day for 72 hours, then 100 mg daily for 7 days) compared with historical controls (25% vs 73% at day 20).
      • Huet T.
      • Beaussier H.
      • Voisin O.
      • Jouveshomme S.
      • Dauriat G.
      • Lazareth I.
      • et al.
      Anakinra for severe forms of COVID-19: a cohort study.
      In contrast to these studies, our analysis encompassed almost one-third of patients (32.5%) who were on MV at inclusion. Moreover, combined treatment with high-dose anakinra and MPD was chosen on the basis of widely approved treatment regimens used in severe cytokine storm syndromes.
      • Mehta P.
      • Cron R.Q.
      • Hartwell J.
      • Manson J.J.
      • Tattersall R.S.
      Silencing the cytokine storm: the use of intravenous anakinra in haemophagocytic lymphohistiocytosis or macrophage activation syndrome.
      Of note, corticosteroids such as dexamethasone

      RECOVERY Collaborative Group; Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, et al. Dexamethasone in hospitalized patients with Covid-19 – preliminary report [published online ahead of print July 17, 2020]. N Engl J Med. https://doi.org/10.1056/NEJMoa2021436.

      ,
      • Tomazini B.M.
      • Maia I.S.
      • Cavalcanti A.B.
      • Berwanger O.
      • Rosa R.G.
      • Veiga V.C.
      • et al.
      Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19.
      and MPD
      • Fadel R.
      • Morrison A.R.
      • Vahia A.
      • Smith Z.R.
      • Chaudhry Z.
      • Bhargava P.
      • et al.
      Early short-course corticosteroids in hospitalized patients with COVID-19.
      ,
      • Ramiro S.
      • Mostard R.L.M.
      • Magro-Checa C.
      • van Dongen C.M.P.
      • 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.
      have recently been shown to be beneficial in COVID-19 patients with respiratory failure. In the Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial, the addition of short-course dexamethasone (6 mg every 24 hours for 10 days or less) to SOC resulted in lower 28-day mortality compared with SOC alone among hospitalized COVID-19 patients (22.9% vs 25.7%, respectively).

      RECOVERY Collaborative Group; Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, et al. Dexamethasone in hospitalized patients with Covid-19 – preliminary report [published online ahead of print July 17, 2020]. N Engl J Med. https://doi.org/10.1056/NEJMoa2021436.

      Interestingly, the highest beneficial effect was obtained in patients on invasive MV (29.3% mortality in the dexamethasone group compared with 41.4% mortality in the SOC group at day 28), whereas no difference was seen among those receiving no respiratory support. No treatment with anakinra was reported in any of the study arms. Conversely, in the COVID-19 Dexamethasone (CoDEX) trial, the addition of intravenous dexamethasone (20 mg every 24 hours for 5 days, followed by 10 mg every 24 hours for an additional 5 days) to SOC compared with SOC alone in mechanically ventilated COVID-19 patients with moderate to severe acute respiratory distress syndrome (ARDS) resulted in a significant benefit in the number of ventilator-free days (6.6 vs 4.0 days) but not in all-cause 28-day mortality (56.3% vs 61.5%, respectively).
      • Tomazini B.M.
      • Maia I.S.
      • Cavalcanti A.B.
      • Berwanger O.
      • Rosa R.G.
      • Veiga V.C.
      • et al.
      Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19.
      In their multicenter quasi-experimental study, Fadel et al
      • Fadel R.
      • Morrison A.R.
      • Vahia A.
      • Smith Z.R.
      • Chaudhry Z.
      • Bhargava P.
      • et al.
      Early short-course corticosteroids in hospitalized patients with COVID-19.
      compared mortality and/or intensive care unit admission of patients with moderate to severe COVID-19 either on early, short-course MPD (0.5-1 mg/kg/d for 3 days) or SOC.
      • Fadel R.
      • Morrison A.R.
      • Vahia A.
      • Smith Z.R.
      • Chaudhry Z.
      • Bhargava P.
      • et al.
      Early short-course corticosteroids in hospitalized patients with COVID-19.
      The composite end point occurred at a lower rate in the MPD group (34.9% vs 54.3% at day 14). Again, no patient was treated with anakinra. Ramiro et al
      • Ramiro S.
      • Mostard R.L.M.
      • Magro-Checa C.
      • van Dongen C.M.P.
      • 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.
      prospectively investigated the effect of high-dose intravenous MPD (250 mg on day 1 followed by 80 mg on days 2-5) on the outcome of patients with severe COVID-19–associated cytokine storm syndromes and respiratory failure. In 43% of cases, anti–IL-6 tocilizumab was added as escalation of immunosuppressive treatment, whereas no patients received anakinra. Compared with matched historical controls, hospital mortality was 65% lower and the need of MV was 71% lower in the treatment group. Table II summarizes the major clinical studies that have used either anakinra alone or steroids alone for the treatment of severe COVID-19 so far.
      Table IISummarization of major clinical studies that have used either anakinra alone or steroids alone for the treatment of severe COVID-19
      ReferenceInvestigated drugStudy designStudy populationTreatment/interventionOutcomes
      Cavalli et al,
      • 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
      AnakinraMonocentric retrospective case-control study (Italy)
      • Hyperinflammation (CRP ≥100 mg/L and/or ferritin ≥900 ng/mL)
      • Bilateral pneumonia
      • PaO2:FiO2 ≤200 mm Hg on noninvasive ventilation
      • No mechanically ventilated patients
      IV anakinra 5 mg/kg twice a day (no. 29) vs SOT (no. 16, historical controls)
      • 21-d survival: 90% in the anakinra group vs 56% the in SOT group (P = .009)
      • MV-free survival: 72% in the anakinra group vs 50% in the SOT group (P = .15)
      Huet et al,
      • 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
      AnakinraMonocentric case-control study (prospective cohort with historical controls) (France)
      • Bilateral pneumonia
      • Oxygen saturation of ≤93% under oxygen 6 L/min or more, or saturation ≤93% under oxygen 3 L/min with a loss of 3% in 24 h
      • No mechanically ventilated patients
      SC anakinra 100 mg twice daily for 72 h followed by 100 mg daily for 7 d (no. 52) vs SOT (no. 44, historical controls)
      • Need for invasive MV or death: 25% in the anakinra group vs 73% in the SOT group (95% CI, 0.10-0.49; P = .00021)
      Cauchois et al, PNAS 2020AnakinraMulticenter retrospective case-control study (France)
      • Hyperinflammation (CRP ≥110 mg/L)
      • Bilateral pneumonia
      • Increase of more than 4 L/min in the previous 12 h in oxygen requirement
      • Mechanically ventilated patients included (2 in the anakinra group vs 4 in the SOT group)
      IV anakinra 300 mg daily for 5 d tapered to 200 mg daily for 2 d and 100 mg for 1 d (no. 12) vs SOT (no. 10)
      • Mortality: 0% in the anakinra group vs 10% in the SOT group (P = .45)
      • Ventilator-free days during the first 20 d (number of days alive and free from MV): 20 in the anakinra group vs 17 in the SOT group (P = .06)
      • Number of days with oxygen requirement <3 L/min: 15.5 in the anakinra group vs 8 in the SOT group (P < .05)
      Horby et al,

      RECOVERY Collaborative Group; Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, et al. Dexamethasone in hospitalized patients with Covid-19 – preliminary report [published online ahead of print July 17, 2020]. N Engl J Med. https://doi.org/10.1056/NEJMoa2021436.

      N Engl J Med 2020
      DexamethasoneMulticenter randomized open-label trial (United Kingdom)
      • Hospitalized patients with SARS-CoV-2 infection
      • Mechanically ventilated patients included
      SOT + oral or IV dexamethasone 6 mg once daily for up to 10 d (no. 2104) vs SOT (no. 4321)
      • Overall 28-d mortality: 22.9% in the dexamethasone group vs 25.7% in the SOT group (95% CI, 0.75-0.93); 29.3% vs 41.4% in mechanically ventilated patients (95% CI, 0.51-0.81); 23.3% vs 26.2% in patients with oxygen requirement (95% CI, 0.72-0.94); 17.8% vs 14.0% in patients with no respiratory support (95% CI, 0.91-1.55)
      Tomazini et al,
      • Tomazini B.M.
      • Maia I.S.
      • Cavalcanti A.B.
      • Berwanger O.
      • Rosa R.G.
      • Veiga V.C.
      • et al.
      Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19.
      JAMA 2020
      DexamethasoneMulticenter randomized open-label trial (Brazil)
      • Mechanically ventilated patients only
      • MV for <48 h
      • Moderate to severe ARDS (PaO2:FiO2 ≤200 mm Hg)
      • No corticosteroid use in the previous 15 d
      SOT + IV dexamethasone 20 mg daily for 5 d followed by 10 mg daily for an additional 5 d or until ICU discharge (no. 151) vs SOT (no. 148)
      • Ventilator-free days during the first 28 d: 6.6 in the dexamethasone group vs 4.0 in the SOT group (P = .04)
      • 28-d mortality: 56.3% in the dexamethasone group vs 61.5% in the SOT group (P = .85)
      Fadel et al,
      • Fadel R.
      • Morrison A.R.
      • Vahia A.
      • Smith Z.R.
      • Chaudhry Z.
      • Bhargava P.
      • et al.
      Early short-course corticosteroids in hospitalized patients with COVID-19.
      Clin Infect Dis 2020
      MPDMulticenter quasi-experimental study (United States)
      • Bilateral pneumonia
      • Oxygen requirement of 4 L/min or more, or escalating oxygen requirement from baseline
      • Mechanically ventilated patients included
      IV MPD 0.5-1 mg/kg/d for 3 d (up to 7 d in ICU patients) (no. 132) vs SOT (no. 81, historical controls)
      • Mortality: 13.6% in the MPD group vs 26.3% in the SOT group (P = .024)
      • Need for MV: 21.7% in the MPD group vs 36.6% in the SOT group (P = .025)
      • ICU admission during hospitalization: 27.3% in the MPD group vs 44.3% in the SOT group (P = .017)
      • Composite outcome (all 3 above): 34.9% in the MPD group vs 54.3% in the SOT group (P = .005)
      Ramiro et al,
      • Ramiro S.
      • Mostard R.L.M.
      • Magro-Checa C.
      • van Dongen C.M.P.
      • 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
      MPDMonocentric case-control study (prospective cohort with historical controls) (the Netherlands)
      • Hyperinflammation (at least 2: CRP ≥100 mg/L, ferritin ≥900 ng/mL, D-dimer >1500 μg/L)
      • Bilateral pneumonia
      • Oxygen saturation of ≤94% in ambient air or tachypnea >30/min
      • Mechanically ventilated patients included (1 in the MPD group vs 13 in the SOT group)
      IV MPD 250 mg on day 1 followed by 80 mg daily for 2-7 d with possible escalation with TCZ (single dose 8 mg/kg) at day 2-5 if worsening in clinical or respiratory status (no. 86) vs SOT (no. 86, historical controls)
      • Clinical improvement (2 points in the WHO 7-point ordinal scale): 74.4% in the MPD group vs 51.2% in the SOT group (P = .0025)
      • Mortality: 16.3% in the MPD group vs 47.7% in the SOT group (P = .0004)
      • Need for MV: 11.6% in the MPD group vs 27.9% in the SOT group (P = .0003)
      ICU, Intensive care unit, IV, intravenous; SC, subcutaneous; SOT, standard of therapy; TCZ, tocilizumab (humanized mAb against the IL-6 receptor); WHO, World Health Organization.
      In our study, patients treated with the combination of anakinra plus MPD experienced lower mortality than controls (13.9% vs 35.6% at day 28; P = .004). Notably, mortality in treated patients who were on MV at baseline was as low as 16.7%, yet only a trend toward significance emerged compared with the SOC group, possibly due to limited sample size. The outcomes of this population can be compared with the results of MV patients in the RECOVERY trial (no comparison can be made for non-MV patients due to different disease severity between studies).

      RECOVERY Collaborative Group; Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, et al. Dexamethasone in hospitalized patients with Covid-19 – preliminary report [published online ahead of print July 17, 2020]. N Engl J Med. https://doi.org/10.1056/NEJMoa2021436.

      Although the 28-day mortality is similar between MV patients in control groups (42.8% vs 41.4%), our cohort of patients treated with anti–IL-1 + MPD seemed to have experienced a better outcome than patients in the dexamethasone arm of the RECOVERY trial (16.7% vs 29.3% mortality at day 28, respectively). The use of anakinra as add-on therapy to corticosteroids may provide meaningful clinical benefits in this setting and warrants further consideration. The impact of combined treatment was confirmed after adjusting by age, comorbidities, respiratory dysfunction, and length of hospitalization before inclusion, with a 18% reduction in mortality. Combined treatment was overall well tolerated, with no significant differences in adverse event compared with controls. Frequencies of bloodstream infections and laboratory alterations of patients treated with anakinra plus MPD were similar to those reported in studies investigating anakinra as a single agent.
      • Pontali E.
      • Volpi S.
      • Antonucci G.
      • Castellaneta M.
      • Buzzi D.
      • Tricerri F.
      • et al.
      Safety and efficacy of early high-dose IV anakinra in severe COVID-19 lung disease.
      • 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.
      • Huet T.
      • Beaussier H.
      • Voisin O.
      • Jouveshomme S.
      • Dauriat G.
      • Lazareth I.
      • et al.
      Anakinra for severe forms of COVID-19: a cohort study.
      Our work has limitations. First, the monocentric nature of the study might affect the generalizability of our results. Second, although controls have been recruited in the same setting, their number is lower than the cases, mainly because the association of anti–IL-1 + MPD has been implemented relatively early during the pandemic. Third, because no groups treated either with anakinra alone or MPD alone have been included in the analysis, no definitive conclusions could be drawn on the single or synergistic effect of the 2 drugs. Moreover, SOC consisted of evolving combinations of antivirals and anticoagulant therapy, which, although not significantly associated with survival, represent a potential bias. Lastly, no primary hard end point other than 28-day mortality was considered: intermediate end points may help better evaluating treatment efficacy in patients with different severity and length of disease.
      In conclusion, combined treatment with anakinra and MPD may be a valid therapeutic option in COVID-19 patients with hyperinflammation and respiratory failure, and also in mechanically ventilated patients. Randomized controlled trials that include arms for steroids and anti–IL-1 therapy alone are needed to confirm these results.
      For detailed methods, please see the Methods section in this article’s Online Repository at www.jacionline.org.
      Clinical implications
      In the search for an optimal support treatment, combination of high-dose anakinra plus MPD may be beneficial in COVID-19 severe pneumonia with hyperinflammation. This combined treatment is candidate for further investigation.
      We thank the health care workers of our hospital for their professional and indefatigable commitment to COVID-19 patients’ care, in these difficult times.
      We thank Dr Liliane Chatenoud for her endless patience in statistical analysis support.
      We are grateful to Chiara Abbruzzese, Nicola Bottino, and Paola Tagliabue for their active participation to study conduction; and to Marcello Macchia, Gisella Beatrice Beretta, and all the data managers and study coordinators involved in data collection.
      “COVID-19 NETWORK” Working Group: Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico. Scientific Direction: Silvano Bosari, Luigia Scudeller, Giuliana Fusetti, Laura Rusconi, and Silvia Dell’Orto; Department of Transfusion Medicine and Biobank: Daniele Prati, Luca Valenti, Giuseppe Lamorte, Maria Manunta, Guido Baselli, and Luigi Santoro; Infectious Diseases Unit: Andrea Gori, Alessandra Bandera, Antonio Muscatello, Davide Mangioni, Laura Alagna, Giorgio Bozzi, Andrea Lombardi, Riccardo Ungaro, Teresa Itri, Valentina Ferroni, Valeria Pastore, Roberta Massafra, and Ilaria Rondolini; Internal Medicine, Hemophilia and Thrombosis Center and Fondazione Luigi Villa: Flora Peyvandi, Roberta Gualtierotti, Barbara Ferrari, Raffaella Rossio, Elisabetta Corona, Nicolò Rampi, and Costanza Massimo; Internal Medicine, Immunology and Allergology: Nicola Montano, Barbara Vigone, Chiara Bellocchi, Elisa Fiorelli, Valerie Melli, and Eleonora Tobaldini; Respiratory Unit and Cystic Fibrosis Adult Center: Francesco Blasi, Stefano Aliberti, Maura Spotti, Edoardo Simonetta, Leonardo Terranova, Francesco Amati, Carmen Miele, Sofia Misuraca, Alice D’Adda, Silvia Della Fiore, Marta Di Pasquale, Marco Mantero Martina Contarini, Margherita Ori, Letizia Morlacchi, Valeria Rossetti, Andrea Gramegna, Maria Pappalettera, Mirta Cavallini, and Annalisa Vigni; Cardiology Unit: Marco Vicenzi and Irena Rota. Emergency Medicine: Giorgio Costantino, Monica Solbiati, Ludovico Furlan, Marta Mancarella, Giulia Colombo, Giorgio Colombo, and Alice Fanin; Acute Internal Medicine: Valter Monzani, Angelo Rovellini, Laura Barbetta, Filippo Billi, and Christian Folli; Internal Medicine: Marina Baldini, Irena Motta, and Natalia Scaramellini; Internal Medicine and Metabolic Diseases: Anna Ludovica Fracanzani, Rosa Lombardi, and Federica Iuculano; Geriatric Unit: Matteo Cesari, Marco Proietti, and Laura Calcaterra. Istituto di Ricerche Farmacologiche Mario Negri IRCCS: Alessandro Nobili, Mauro Tettamanti, and Igor Monti.

      Methods

      A secondary analysis of prospective, observational cohort studies (COVID-19_Network; nCOV-2019_ICU Study) was performed at Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy (Institutional Review Board #241_2020; #236_2020). All patients with COVID-19 who fulfilled the following inclusion criteria were analyzed: age more than 18 years; evidence of pneumonia; ferritin greater than or equal to 1000 ng/mL and/or CRP greater than 10 mg/dL (see Qin et al,
      • Qin C.
      • Zhou L.
      • Hu Z.
      • Zhang S.
      • Yang S.
      • Tao Y.
      • et al.
      Dysregulation of immune response in patients with coronavirus 2019 (COVID-19) in Wuhan, China.
      Zhou et al,
      • Zhou F.
      • Yu T.
      • Du R.
      • Fan G.
      • Liu Y.
      • Liu Z.
      • et al.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      Chen et al,
      • Chen G.
      • Wu D.
      • Guo W.
      • Cao Y.
      • Huang D.
      • Wang H.
      • et al.
      Clinical and immunological features of severe and moderate coronavirus disease 2019.
      and King et al
      • King A.
      • Vail A.
      • O’Leary C.
      • Hannan C.
      • Brough D.
      • Patel H.
      • et al.
      Anakinra in COVID-19: important considerations for clinical trials.
      ); respiratory failure with need of supplemental oxygen (oxygen therapy from 0.4 FiO2 Venturi mask to invasive MV). Exclusion criteria were data available for less than 48 hours or death within 48 hours from inclusion; symptoms for less than 7 days; uncontrolled bacterial infections (ie, sepsis/septic shock); treatment with anti–IL-1 or MPD alone.
      From March 5, 2020, patients were treated off-label with anti–IL-1 + MPD according to local standard operating procedures. Treatment was implemented at a different time in distinct settings (ie, COVID-19 intensive care unit [ICU], sub–ICU, internal medicine), starting from the ICU. Written informed consent for off-label use was obtained from all patients (except those on MV). The control group included patients with COVID-19 admitted and followed from February 25, 2020, to the time of anti–IL-1 + MPD introduction. Patients who retrospectively fulfilled all the inclusion and exclusion criteria for treatment were consecutively included in the control group.
      Anakinra (Swedish Orphan Biovitrum AB, Stockholm, Sweden) was administered subcutaneously at 200 mg every 8 hours for 3 days, then 100 mg every 8 hours up to day 14.
      • Mehta P.
      • Cron R.Q.
      • Hartwell J.
      • Manson J.J.
      • Tattersall R.S.
      Silencing the cytokine storm: the use of intravenous anakinra in haemophagocytic lymphohistiocytosis or macrophage activation syndrome.
      Patients on MV were treated with off-label intravenous administration (3-hour infusion time).
      • Mehta P.
      • Cron R.Q.
      • Hartwell J.
      • Manson J.J.
      • Tattersall R.S.
      Silencing the cytokine storm: the use of intravenous anakinra in haemophagocytic lymphohistiocytosis or macrophage activation syndrome.
      • Pontali E.
      • Volpi S.
      • Antonucci G.
      • Castellaneta M.
      • Buzzi D.
      • Tricerri F.
      • et al.
      Safety and efficacy of early high-dose IV anakinra in severe COVID-19 lung disease.
      • 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.
      • Huet T.
      • Beaussier H.
      • Voisin O.
      • Jouveshomme S.
      • Dauriat G.
      • Lazareth I.
      • et al.
      Anakinra for severe forms of COVID-19: a cohort study.
      The intravenous route was chosen in view of the pharmacokinetic alterations of critically ill patients in the ICU (ie, high volume of distribution, massive generalized cutaneous edema consequent to water retention, and low albumin). Also, because patients on MV were on anticoagulant therapy, subcutaneous administration could lead to hematomas or infectious complications.
      MPD was administered at 1 mg/kg loading dose, then 1 mg/kg/d (fractioned, 2 doses) for 5 days, then 0.5 mg/kg/d (fractioned, 2 doses) for 5 days, followed by 0.25 mg/kg/d (every 24 hours or fractioned) up to day 14.
      All subjects received the treatment that was considered SOC at time of the study, which includes hydroxychloroquine in most cases and lopinavir/ritonavir in some. Some patients were also subjected to the use of experimental antiviral remdesivir through compassionate use (Table I). According to the hospital internal guidelines, all patients received antithrombotic prophylaxis/treatment with enoxaparin sodium during hospitalization. Specifically, until mid-March 2020, hospital guidelines recommended prophylaxis with 100 U/kg every 24 hours for patients weighing 80 kg and 5000 U every 12 hours for patients weighing 80 kg (if normal renal function), irrespective of the severity of the disease. From mid-March, based on increased observations of thromboembolic events in patients with severe COVID-19, dosage was increased and stratified according to the severity of the disease (and the corresponding risk of thromboembolic events): 100 U/kg every 24 hours in COVID-19 internal medicine (70 U/kg every 12 hours for obese patients), 70 U/kg every 12 hours in COVID-19 sub-ICUs, and 100 U/kg every 12 hours in COVID-19 ICU. This latter scheme was considered in evaluating the percentages of anticoagulant therapy reported in Table I.
      The primary outcome was 28-days survival rate. Adverse events were graded according to CTCAE_v4.0. Differences between groups were assessed using 2-sample t test or Wilcoxon rank-sum test for parametric and nonparametric continuous variables and Fisher exact test for categorical variables. Study inclusion (t0) started at anti–IL-1 + MPD initiation (cases) or when ferritin/CRP levels above thresholds were registered (controls). Kaplan-Meier plots were used for survival data. Patients were followed from t0 to day 28 or death. If discharged earlier than day 28, patient status was assessed by postdischarge follow-up phone calls. Unadjusted and adjusted Cox proportional regression models were used after controlling for proportional hazards assumption. Factors associated with mortality at univariate analysis and hospitalization setting (days elapsed from hospitalization to t0, MV at inclusion) were considered as covariates. Statistical significance was set at α less than 0.05. Analyses were performed using SAS software v.9.4 (SAS Institute Inc, Cary, NC).
      Table E1Sensitivity analysis of the impact of anticoagulant therapy on the clinical outcome of treated and control patients
      CharacteristicRangesNo. of patientsDeathsP value
      Anti–IL-1 + MPD
       Anticoagulant therapyNo242 (8.3).466
      Yes417 (17.1)
      No anti–IL-1 + MPD
       Anticoagulant therapyNo3310 (30.3).554
      Yes218 (38.1)
      Variables are reported as absolute number (percentage).
      Table E2Sensitivity analysis of the impact of antiviral therapy (lopinavir/ritonavir + hydroxychloroquine) on the clinical outcome of treated and control patients
      CharacteristicRangesNo. of patientsDeathsP value
      Anti–IL-1 + MPD
       Antiviral therapyNo458 (17.8).169
      Yes201 (5.0)
      No anti–IL-1 + MPD
       Antiviral therapyNo133 (23.1).488
      Yes3913 (33.3)
      Variables are reported as absolute number (percentage). Three patients in the control group who were treated with lopinavir/ritonavir alone were excluded.
      Table E3Crude and adjusted Cox proportional regression models of the treatment with anakinra and MPD
      Hazard ratio95% CIP value
      Crude0.330.15-0.77.007
      Adjusted
      Adjusted Cox proportional regression model by sex, age, PaO2/FiO2 at baseline, CCI, MV at inclusion, and days elapsed from hospitalization to inclusion.
      0.180.07-0.50.001
      The proportional hazards assumption was checked by using a transform of the Schoenfeld residuals and performing a supremum test of the null hypothesis that the observed pattern of martingale residuals was not different from the expected pattern (https://stats.idre.ucla.edu/sas/seminars/sas-survival/).
      Adjusted Cox proportional regression model by sex, age, PaO2/FiO2 at baseline, CCI, MV at inclusion, and days elapsed from hospitalization to inclusion.

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