ABSTRACT
Introduction: A subgroup of patients with severe COVID-19 presents with progressive hyperinfammation governed by proinfammatory cy-tokine release. Ruxolitinib (rux), an inhibitor of the Janus kinases 1/2, approved for myelofbrosis and polycythemia vera, is highly active in the cytokine storm disorders hemophagocytic lymphohistiocytosis (HLH) and graf versus host disease (GvHD). As mortality of severe COVID-19 in the literature reached 50% depending on age and comorbidities, of-label individual rux treatment to overcome the deadly cytokine storm was ofered to patients with systemic hyperinfammation. Method(s): Monocentric retrospective cohort analysis of stratifed treatment intervention. Systemic infammation was determined and assessed via a newly developed COVID-infammation score (CIS). Patients reaching >=10 out of 16 points (bipulmonary infltrates in CT/XRay (3);CRP > 20 ULN (2), ferritin > 2 ULN (2), triglycerides > 1.5 ULN (1), interleu-kin-6 > 3 ULN (1), fbrinogen > ULN (1), leukocytes > ULN (1), lym-phopenia < 1.1/nl (2), fever >= 38.5degreeC (2), coagulation disorder (D-Dimer > ULN, PTT > ULN) (1) were ofered treatment with rux up to 28 days. First patient treated was on March 30th, 2020. Data cut-of was June 3rd, 2020. Rux was initiated at 7.5mg bid and dose adapted with optional dose increase up to 20mg bid. Result(s): A total of 196 patients were treated at the Schwarzwald-Baar Klinikum. The interdisciplinary Covid-board allocated 19 of 196 patients to rux treatment based on CIS, adequate organ function and informed consent. 68% (13/19) of treated patients were male. Median age was 65 (55-83) years. Mortality was 17% (3/19). Seven patients were treated on ICU. Median hospitalization length was 20 days. Median CIS-Score at baseline was 12. The prespecifed efficacy threshold of 25% CIS-r eduction by day 5, 7 and 15 afer start of rux treatment was achieved (42% (15-70), 54% (15-77) and 60% (15-80) with consistent clinical improvement as assessed by the WHO ordinal scale and the NEWS2-scale. SARS-CoV2-PCR follow-up status was assessed in 9/19 patients at recovery and returned negative. One patient tested for seroconversion revealed high IgG/IgM test result (titer > 10). Conclusion(s): The JAK1/2-Inhibitor rux efectively controls infammation in patients with severe COVID-19 without signals of unexpected toxici-ty or impaired infection control. A prospective controlled trial has been initiated (NCT04338958).
ABSTRACT
BACKGROUND: Patients with severe COVID-19 develop hyperferritinemic inflammation, a rare sepsis-like immune dysregulation syndrome. METHODS: Stratified treatment decisions in a cross-location telemedical interdisciplinary case conference were assessed in this retrospective cohort study. A standardized treatment algorithm including continuous positive airway pressure and noninvasive ventilation was implemented. A locally developed COVID inflammation score (CIS) defined patients at risk for severe disease. Patients with life-threatening inflammation were offered off-label treatment with the immune modulator ruxolitinib. RESULTS: Between 4 March 2020 and 26 June 2020 COVID-19 patients (nâ¯= 196) were treated. Median patient age (70 years) and comorbidity were high in interstudy comparison. Mortality in all patients was 17.3%. However, advance care planning statements and physician directives limited treatment intensity in 50% of the deceased patients. CIS monitoring of ruxolitinib-treated high-risk patients (nâ¯= 20) on days 5, 7, and15 resulted in suppression of inflammation by 42% (15-70), 54% (15-77) and 60% (15-80). Here, mortality was 20% (4/20). Adjusted for patients with a maximum care directive including ICU, total mortality was 8.7% (17/196). CONCLUSION: Severe COVID-19 pneumonia with hyperferritinemic inflammation is related to macrophage activation syndrome-like sepsis. An interdisciplinary intensive care teleconference as a quality tool for ICUs is proposed to detect patients with rare sepsis-like syndromes.
Subject(s)
COVID-19 , SARS-CoV-2 , Aged , Critical Care , Humans , Inflammation , Retrospective StudiesABSTRACT
A subgroup of patients with severe COVID-19 suffers from progression to acute respiratory distress syndrome and multiorgan failure. These patients present with progressive hyperinflammation governed by proinflammatory cytokines. An interdisciplinary COVID-19 work flow was established to detect patients with imminent or full blown hyperinflammation. Using a newly developed COVID-19 Inflammation Score (CIS), patients were prospectively stratified for targeted inhibition of cytokine signalling by the Janus Kinase 1/2 inhibitor ruxolitinib (Rux). Patients were treated with efficacy/toxicity guided step up dosing up to 14 days. Retrospective analysis of CIS reduction and clinical outcome was performed. Out of 105 patients treated between March 30th and April 15th, 2020, 14 patients with a CIS ≥ 10 out of 16 points received Rux over a median of 9 days with a median cumulative dose of 135 mg. A total of 12/14 patients achieved significant reduction of CIS by ≥25% on day 7 with sustained clinical improvement in 11/14 patients without short term red flag warnings of Rux-induced toxicity. Rux treatment for COVID-19 in patients with hyperinflammation is shown to be safe with signals of efficacy in this pilot case series for CRS-intervention to prevent or overcome multiorgan failure. A multicenter phase-II clinical trial has been initiated (NCT04338958).