The impact of specific cytokine directed treatment on severe COVID-19

Reuken, Philipp; Rüthrich, Maria Madeleine; Hochhaus, Andreas; Hammersen, Johanna; Bauer, Michael; Rosée, Paul La; Rosée, F La; Stallmach, Andreas

doi:10.1038/s41375-021-01411-1

Cited by 3 publications

(3 citation statements)

References 10 publications

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“…▶ Change in the interleukin-6 (IL-6) concentration in blood from randomisation to day 7 (V 2 ) and day 14 (V 3 ) after randomisation ▶ Change in the ferritin concentration in blood from randomisation to day 7 (V 2 ) and day 14 (V 3 ) after randomisation ▶ Change in the lymphocyte count from randomisation to day 7 (V 2 ) and day 14 (V 3 ) after randomisation Assessment of the effect of infliximab in patients with severe COVID-19 on morbidity and prognosis ▶ Ventilation-free days until day 28 (V 4 ) after randomisation ▶ Renal replacement therapy-free days until day 28 (V 4 ) after randomisation ▶ Vasopressor-free days until day 28 (V 4 ) after randomisation ▶ Rate of occurrence of severe acute respiratory syndrome (ARDS) until day 28 (V 4 ) after randomisation (Berlin criteria and PaO 2 /FiO 2 ≤ 100 mmHg with PEEP ≥ 5 cmH 2 O [19]) ▶ WHO-COVID-19-Progression Scale on day 7 (V 2 ), 14 (V 3 ) and 28 (V 4 ) after randomisation ▶ Rate of admission to the intensive care unit after randomisation up to day 28 (V 4 ) after randomisation ▶ Length of hospital stay up to day 28 (V 4 ) after randomisation ▶ Length of intensive care unit stay up to day 28 (V 4 ) after randomisation ▶Mortality rates at day 14 (V 3 ) and day 90 (V 5 ) after randomisation ▶ EQ5D-3L (health-related quality of life): visual analogue scale value and sub-domain ratings at day 90 (V 5 ) after randomisation ▶ EQ5D-3L: index value at day 90 (V 5 ) after randomisation ▶ Frequencies of COVID-19 (long-term) sequelae (positive ratings in checklist) ▶ Incidence of cardiomyopathy at day 3 (V 1 ) and/or day 7 (V 2 ) after randomisation left-ventricular EF < 52 % in men and < 54 % in women, according to the American Society of Echocardiography [20] and the European Association of Cardiovascular Imaging or 10% reduction, if previously reduced [21][22][23][24] Sample size and statistical analysis Sample size planning was based on unpublished retrospective data from Jena University Hospital (April 2020-January 2021, part of the data set in [29]). In 31 patients, the 28-day mortality was 50% in SOC and 12.2% in patients with SOC + infliximab.…”

Section: Assessment Of the Effect Of Infliximab On An Excessive Immun...mentioning

confidence: 99%

Infliximab in the treatment of patients with severe COVID-19 (INFLIXCOVID): protocol for a randomised, controlled, multicentre, open-label phase II clinical study

Coldewey

Neu

Bloos

et al. 2022

Trials

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Background Despite the intense global research endeavour to improve the treatment of patients with COVID-19, the current therapy remains insufficient, resulting in persisting high mortality. Severe cases are characterised by a systemic inflammatory reaction driven by the release of pro-inflammatory cytokines such as IL-6 and tumour-necrosis-factor alpha (TNF-α). TNF-α-blocking therapies have proved beneficial in patients with chronic inflammatory diseases and could therefore pose a new treatment option in COVID-19. Hitherto, no results from randomised controlled trials assessing the effectiveness and safety of infliximab—a monoclonal antibody targeting TNF-α—in the treatment of COVID-19 have been published. Methods In this phase-2 clinical trial, patients with COVID-19 and clinical and laboratory signs of hyperinflammation will be randomised to receive either one dose of infliximab (5 mg/kg body weight) in addition to the standard of care or the standard of care alone. The primary endpoint is the difference in 28-day mortality. Further assessments concern the safety of infliximab therapy in COVID-19 and the influence of infliximab on morbidity and the course of the disease. For the supplementary scientific programme, blood and urine samples are collected to assess concomitant molecular changes. The Ethics Committee of the Friedrich Schiller University Jena (2021-2236-AMG-ff) and the Paul-Ehrlich-Institute (4513/01) approved the study. Discussion The results of this study could influence the therapy of patients with COVID-19 and affect the course of the disease worldwide, as infliximab is globally available and approved by several international drug agencies. Trial registration The trial was registered at clinicaltrials.gov (NCT04922827, 11 June 2021) and at EudraCT (2021-002098-25, 19 May 2021).

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Section: Assessment Of the Effect Of Infliximab On An Excessive Immun...mentioning

confidence: 99%

Infliximab in the treatment of patients with severe COVID-19 (INFLIXCOVID): protocol for a randomised, controlled, multicentre, open-label phase II clinical study

Coldewey

Neu

Bloos

et al. 2022

Trials

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“…So gibt es gute Evidenzen, die zeigen, dass durch eine immunsuppressive Medikation das Ausmaß der Hyperinflammation begrenzt wird und somit der Verlauf der Erkrankung abgemildert wird, wenn diese frühzeitig, d. h. bei ersten Hinweisen auf eine Hyperinflammation in der Therapie der COVID-19-Erkrankung eingesetzt werden. Der Einsatz von Dexamethason ist mittlerweile Standard in der Therapie [28], Tocilizumab als Interleukin-6-Rezeptor-Antagonist wird empfohlen [29] und TNF-Antikörper werden in randomisierten Studien aufgrund positiver Fallserien geprüft [30], [31]. Dieser scheinbare Widerspruch zwischen einem erhöhten Risiko für schwere Verläufe unter Therapie mit systemischen Steroiden auf der einen Seite und dem therapeutischen Einsatz von Immunsuppressiva auf der anderen Seite ist mit dem 2-phasigen Verlauf der COVID-19-Erkrankung auflösbar: Während am Beginn der Erkrankung die Virusreplikation im Vordergrund steht und daher in dieser Phase Immunsuppressiva ungünstige Effekte aufweisen, steht im späteren Verlauf die Entwicklung einer Hyperinflammation im Vordergrund.…”

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Chronisch-entzündliche Darmerkrankungen in der COVID-Pandemie: Manifestationen und Management

et al. 2022

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ZusammenfassungDie COVID-19-Pandemie beeinflusst das Leben von Patient*innen mit chronisch-entzündlichen Darmerkrankungen (CED) in erheblicher Weise. Betroffene und Angehörige haben zahlreiche Fragen zum Erkrankungsrisiko, zum Verlauf einer möglichen SARS-CoV-2-Infektion oder auch zum Einfluss der CED-spezifischen Therapie. Auch bestehen bei vielen CED-Patient*innen zusätzliche Fragen zu Sicherheit und Wirksamkeit einer Impfung gegen SARS-CoV-2. Ziel dieser Übersicht ist die Zusammenfassung der neusten Erkenntnisse zu COVID-19 und CED, aber auch die Diskussion zum Impfansprechen (humoral/zellulär), zum Einfluss laufender Therapie auf die Impfantwort sowie zur Häufigkeit von Nebenwirkungen und zur Bedeutung der Booster-Immunisierungen zu führen und für das Gespräch mit Patient*innen eine Evidenz-basierte Grundlage zu schaffen.

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“…Hyperinflammation describes a condition of imminent or actual organ failure caused by dysregulated release of inflammation mediators in response to SARS-CoV-2-infection leading to the severe clinical course of COVID-19 [ 11 , 12 ]. Affected patients frequently require anti-inflammatory treatment beyond glucocorticoids [ 13 – 15 ]. In this context, inhibition of the proinflammatory JAK/STAT pathway was considered a promising approach to be investigated [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

The JAK1/2 inhibitor ruxolitinib in patients with COVID-19 triggered hyperinflammation: the RuxCoFlam trial

Hammersen,

Birndt,

Döhner

et al. 2023

Leukemia

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Dysregulated hyperinflammatory response is key in the pathogenesis in patients with severe COVID-19 leading to acute respiratory distress syndrome and multiorgan failure. Whilst immunosuppression has been proven to be effective, potential biological targets and optimal timing of treatment are still conflicting. We sought to evaluate efficacy and safety of the Janus Kinase 1/2 inhibitor ruxolitinib, employing the previously developed COVID-19 Inflammation Score (CIS) in a prospective multicenter open label phase II trial (NCT04338958). Primary objective was reversal of hyperinflammation (CIS reduction of ≥25% at day 7 in ≥20% of patients). In 184 patients with a CIS of ≥10 (median 12) ruxolitinib was commenced at an initial dose of 10 mg twice daily and applied over a median of 14 days (range, 2–31). On day 7, median CIS declined to 6 (range, 1–13); 71% of patients (CI 64–77%) achieved a ≥25% CIS reduction accompanied by a reduction of markers of inflammation. Median cumulative dose was 272.5 mg/d. Treatment was well tolerated without any grade 3–5 adverse events related to ruxolitinib. Forty-four patients (23.9%) died, all without reported association to study drug. In conclusion, ruxolitinib proved to be safe and effective in a cohort of COVID-19 patients with defined hyperinflammation.

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The impact of specific cytokine directed treatment on severe COVID-19

Cited by 3 publications

References 10 publications

Infliximab in the treatment of patients with severe COVID-19 (INFLIXCOVID): protocol for a randomised, controlled, multicentre, open-label phase II clinical study

Infliximab in the treatment of patients with severe COVID-19 (INFLIXCOVID): protocol for a randomised, controlled, multicentre, open-label phase II clinical study

Chronisch-entzündliche Darmerkrankungen in der COVID-Pandemie: Manifestationen und Management

The JAK1/2 inhibitor ruxolitinib in patients with COVID-19 triggered hyperinflammation: the RuxCoFlam trial

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