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BackgroundIn a previous open-label trial, early anakinra treatment guided by elevated soluble urokinase plasminogen activator receptor (suPAR) prevented progression of COVID-19 pneumonia into respiratory failure. MethodsIn the SAVE-MORE multicenter trial, 594 hospitalized patients with moderate and severe COVID-19 pneumonia and plasma suPAR 6 ng/ml or more and receiving standard-of-care were 1:2 randomized to subcutaneous treatment with placebo or 100 mg anakinra once daily for 10 days. The primary endpoint was the overall clinical status of the 11-point World Health Organization ordinal Clinical Progression Scale (WHO-CPS) at day 28. The changes of the WHO-CPS and of the sequential organ failure assessment (SOFA) score were the main secondary endpoints. ResultsAnakinra-treated patients were distributed to lower strata of WHO-CPS by day 28 (adjusted odds ratio-OR 0.36; 95%CI 0.26-0.50; P<0.001); anakinra protected from severe disease or death (6 or more points of WHO-CPS) (OR: 0.46; P: 0.010). The median absolute decrease of WHO-CPS in the placebo and anakinra groups from baseline was 3 and 4 points respectively at day 28 (OR 0.40; P<0.0001); and 2 and 3 points at day 14 (OR 0.63; P: 0.003); the absolute decrease of SOFA score was 0 and 1 points (OR 0.63; P: 0.004). 28-day mortality decreased (hazard ratio: 0.45; P: 0.045). Hospital stay was shorter. ConclusionsEarly start of anakinra treatment guided by suPAR provides 2.78 times better improvement of overall clinical status in moderate and severe COVID-19 pneumonia. (Sponsored by the Hellenic Institute for the Study of Sepsis ClinicalTrials.gov identifier, NCT04680949)
ABSTRACT
BackgroundAnakinra may represent an important therapy to improve the prognosis of COVID-19 patients. This meta-analysis using individual patient data was designed to assess the efficacy and safety of anakinra treatment in patients with COVID-19. MethodsBased on a pre-specified protocol (PROSPERO: CRD42020221491), a systematic literature search was performed in MEDLINE (PubMed), Cochrane, medRxiv.org, bioRxiv.org and clinicaltrials.gov databases for trials in COVID-19 comparing administration of anakinra with standard-of-care and/or placebo. Individual patient data from eligible trials were requested. The primary endpoint was the mortality rate and the secondary endpoint was safety. FindingsLiterature search yielded 209 articles, of which 178 articles fulfilled screening criteria and were full-text assessed. Aggregate data on 1185 patients from 9 studies were analyzed and individual patient data on 895 patients from 6 studies were collected. Most studies used historical controls. Mortality was significantly lower in anakinra-treated patients (38/342 [11{middle dot}1%]) as compared with 137/553 (24{middle dot}8%) observed in patients receiving standard-of-care and/or placebo on top of standard-of-care (137/553 [24{middle dot}8%]); adjusted odds ratio (OR), 0{middle dot}32; 95% CI, 0{middle dot}20 to 0{middle dot}51; p <0{middle dot}001. The mortality benefit was similar across subgroups regardless of diabetes mellitus, ferritin concentrations, or baseline P/F ratio. The effect was more profound in patients exhibiting CRP levels >100 mg/L (OR 0{middle dot}28,95%CI 0{middle dot}27-1{middle dot}47). Safety issues, such as increase of secondary infections, did not emerge. InterpretationAnakinra may be a safe anti-inflammatory treatment option in patients hospitalized with moderate-to-severe COVID-19 pneumonia to reduce mortality, especially in the presence of hyperinflammation signs such as CRP>100mg /L. FundingSobi. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSSince the emergence of the COVID-19 pandemic, numerous drugs have been tried in an effort to prevent major detrimental consequences, such as respiratory and multiorgan failure and death. Early during the pandemic, it was realized that drugs aiming to regulate the immune host reaction may play an important role in the treatment of COVID-19. Evidence from a small number of patients with moderate or severe COVID-19 treated with anakinra, and interleukin-1 receptor antagonist, has suggested therapeutic efficacy. We systematically searched all available literature and aimed to present cumulative evidence of anakinra treatment in COVID-19 and the related effect on mortality. Added value of this studyThis is the first patient-level analysis on the effect of anakinra treatment in COVID-19 patients, which, on the one hand, suggests a significant benefit in the reduction of mortality and on the other hand, reassures safety of the treatment. Most importantly, the current study identifies a subgroup of patients with CRP>100mg/L, that may benefit most from treatment with anakinra. Confirmation of these effects in larger randomized clinical trials (RCTs) is urgently needed. Implications of all the available evidenceAnakinra may be an effective and safe immunomodulatory treatment in moderate-to-severe cases of pneumonia due to COVID-19 to prevent unfavorable outcomes. Anakinra may be helpful to avoid adverse events, such as breakthrough infections observed often with dexamethasone use, and may be considered an alternative in specific subgroups of patients e.g. diabetics. Larger trials, summarized in the Table, are ongoing and their results are urgently needed to investigate anakinras best place in the treatment of COVID-19. O_TBL View this table: org.highwire.dtl.DTLVardef@37134borg.highwire.dtl.DTLVardef@1d3ca11org.highwire.dtl.DTLVardef@1774b08org.highwire.dtl.DTLVardef@df281borg.highwire.dtl.DTLVardef@c2188d_HPS_FORMAT_FIGEXP M_TBL C_TBL
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ImportanceCOVID-19 is a heterogenous disease most frequently causing respiratory tract infection but in its severe forms, respiratory failure and multiple organ dysfunction syndrome may occur, resembling sepsis. The prevalence of viral sepsis among COVID-19 patients is still unclear. ObjectiveWe aimed to describe this in a systematic review. Data sourcesMEDLINE(PubMed), Cochrane and Google Scholar databases were searched for studies reporting on patients hospitalized with confirmed COVID-19, diagnosed with sepsis or infection-related organ dysfunctions or receiving organ replacement therapy. Study selectionEligible were full-text English articles of randomized and non-randomized clinical trials and observational studies reporting on patients with confirmed COVID-19, who are diagnosed with sepsis or have infection-related organ dysfunctions. Systematic reviews, editorials, conference abstracts, animal studies, case reports, articles neither in English nor full-text, and studies with fewer than 30 participants were excluded. Data extraction and synthesisAll eligible studies were included in a narrative synthesis of results and after reviewing all included studies a meta-analysis was conducted. Separate sensitivity analyses were conducted per adult vs pediatric populations and per Intensive Care Unit (ICU) vs non-ICU populations. Main outcomes and measuresPrimary endpoint was the prevalence of sepsis using Sepsis-3 criteria among patients with COVID-19 and among secondary, new onset of infection-related organ dysfunction. Outcomes were expressed as proportions with respective 95% confidence interval (CI). ResultsOf 1,903 articles, 104 were analyzed. The prevalence of sepsis in COVID-19 was 39.9% (95% CI, 35.9-44.1; I2, 99%). In sensitivity analysis, sepsis was present in 25.1% (95% CI, 21.8-28.9; I2 99%) of adult patients hospitalized in non-Intensive-Care-Unit (ICU) wards (40 studies) and in 83.8 (95% CI, 78.1-88.2; I2,91%) of adult patients hospitalized in the ICU (31 studies). Sepsis in children hospitalized with COVID-19 was as high as 7.8% (95% CI, 0.4-64.9; I2, 97%). Acute Respiratory Distress Syndrome was the most common organ dysfunction in adult patients in non-ICU (27.6; 95% CI, 21.6-34.5; I2, 99%) and ICU (88.3%; 95% CI, 79.7-93.5; I2, 97%) Conclusions and relevanceDespite the high heterogeneity in reported results, sepsis frequently complicates COVID-19 among hospitalized patients and is significantly higher among those in the ICU. PROSPERO registration number: CRD42020202018. No funding. KEY POINTSO_ST_ABSQuestionC_ST_ABSWhat is the prevalence of viral sepsis by Sepsis-3 definition among hospitalized patients with COVID-19? FindingsIn this systematic review and meta-analysis, we systematically reviewed published literature for evidence of organ failure in COVID-19, to estimate the prevalence of viral sepsis in this setting, by means of SOFA score calculation. The prevalence of sepsis in COVID-19 was 39.9% (95% CI, 35.9-44.1; I2, 99%). MeaningThis is the first study to address the burden of viral sepsis in hospitalized patients with COVID-19, a highly heterogenous infection ranging from asymptomatic cases to severe disease leading to death, as reflected in the high heterogeneity of this study.
ABSTRACT
IntroductionThe management of pneumonia caused by SARS-CoV-2 should rely on early recognition of the risk for progression to severe respiratory failure (SRF) and its prevention. We investigated if early suPAR (soluble urokinase plasminogen activator receptor)-guided anakinra treatment could prevent COVID-19-assocated SRF. MethodsIn this open-label prospective trial, 130 patients admitted with SARS-CoV-2 pneumonia SARS-CoV-2 and suPAR levels [≥]6 g/l were assigned to subcutaneous anakinra 100mg once daily for 10 days. The primary outcome was the incidence of SRF at day 14. Secondary outcomes were 30-day mortality, changes in sequential organ failure assessment (SOFA) score, of cytokine-stimulation pattern and of circulating inflammatory mediators. Equal number of propensity score-matched comparators for comorbidities, severity on admission and standard-of care (SOC) were studied. ResultsThe incidence of SRF was 22.3% (95% CI, 16.0-30.2%) among anakinra-treated patients and 59.2% (95% CI, 50.6-67.3%; P: 4.6 x 10-8) among SOC comparators (hazard ratio, 0.30; 95%CI, 0.20-0.46). 30-day mortality was 11.5% (95% CI, 7.1-18.2%) and 22.3% (95% CI, 16.0-30.2%) respectively (hazard ratio 0.49; 95% CI 0.25-0.97%; P: 0.041). Anakinra treatment was associated with decrease in SOFA score and in circulating interleukin (IL)-6, sCD163 and sIL2-R; the serum IL-10/IL-6 ratio on day 7 was inversely associated with the change in SOFA score. Duration of stay at the intensive care unit and at hospital was shortened compared to the SOC group; the cost of hospitalization was decreased. ConclusionsEarly suPAR-guided anakinra treatment is associated with decrease of the risk for SRF and restoration of the pro- /anti-inflammatory balance. Trial RegistrationClinicalTrials.gov, NCT04357366
