Dataset Information

Transitions of blood immune endotypes and improved outcome by anakinra in COVID-19 pneumonia: an analysis of the SAVE-MORE randomized controlled trial.

ABSTRACT:

Background

Endotype classification may guide immunomodulatory management of patients with bacterial and viral sepsis. We aimed to identify immune endotypes and transitions associated with response to anakinra (human interleukin 1 receptor antagonist) in participants in the SAVE-MORE trial.

Methods

Adult patients hospitalized with radiological findings of PCR-confirmed severe pneumonia caused by SARS-CoV-2 and plasma-soluble urokinase plasminogen activator receptor levels of ≥ 6 ng/ml in the SAVE-MORE trial (NCT04680949) were characterized at baseline and days 4 and 7 of treatment using a previously defined 33-messenger RNA classifier to assign an immunological endotype in blood. Endpoints were changes in endotypes and progression to severe respiratory failure (SRF) associated with anakinra treatment.

Results

At baseline, 23.2% of 393 patients were designated as inflammopathic, 41.1% as adaptive, and 35.7% as coagulopathic. Only 23.9% were designated as the same endotype at days 4 and 7 compared to baseline, while all other patients transitioned between endotypes. Anakinra-treated patients were more likely to remain in the adaptive endotype during 7-day treatment (24.4% vs. 9.9%; p < 0.001). Anakinra also protected patients with coagulopathic endotype at day 7 against SRF compared to placebo (27.8% vs. 55.9%; p = 0.013).

Conclusion

We identify an association between endotypes defined using blood transcriptome and anakinra therapy for COVID-19 pneumonia, with anakinra-treated patients shifting toward endotypes associated with a better outcome, mainly the adaptive endotype. Trial registration ClinicalTrials.gov, NCT04680949, December 23, 2020.

SUBMITTER: Kyriazopoulou E

PROVIDER: S-EPMC10935809 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Publications

Transitions of blood immune endotypes and improved outcome by anakinra in COVID-19 pneumonia: an analysis of the SAVE-MORE randomized controlled trial.

Kyriazopoulou Evdoxia E Hasin-Brumshtein Yehudit Y Midic Uros U Poulakou Garyfallia G Milionis Haralampos H Metallidis Simeon S Astriti Myrto M Fragkou Archontoula A Rapti Aggeliki A Taddei Eleonora E Kalomenidis Ioannis I Chrysos Georgios G Angheben Andrea A Kainis Ilias I Alexiou Zoi Z Castelli Francesco F Serino Francesco Saverio FS Bakakos Petros P Nicastri Emanuele E Tzavara Vasiliki V Ioannou Sofia S Dagna Lorenzo L Dimakou Katerina K Tzatzagou Glykeria G Chini Maria M Bassetti Matteo M Kotsis Vasileios V Tsoukalas Dionysios G DG Selmi Carlo C Konstantinou Alexandra A Samarkos Michael M Doumas Michael M Masgala Aikaterini A Pagkratis Konstantinos K Argyraki Aikaterini A Akinosoglou Karolina K Symbardi Styliani S Netea Mihai G MG Panagopoulos Periklis P Dalekos George N GN Liesenfeld Oliver O Sweeney Timothy E TE Khatri Purvesh P Giamarellos-Bourboulis Evangelos J EJ

Critical care (London, England) 20240312 1

<h4>Background</h4>Endotype classification may guide immunomodulatory management of patients with bacterial and viral sepsis. We aimed to identify immune endotypes and transitions associated with response to anakinra (human interleukin 1 receptor antagonist) in participants in the SAVE-MORE trial.<h4>Methods</h4>Adult patients hospitalized with radiological findings of PCR-confirmed severe pneumonia caused by SARS-CoV-2 and plasma-soluble urokinase plasminogen activator receptor levels of ≥ 6 ng ...[more]

PMID: 38475786

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Project description:BackgroundThe SAVE-MORE trial demonstrated that anakinra treatment in COVID-19 pneumonia with plasma soluble urokinase plasminogen activator (suPAR) levels of 6 ng/mL or more was associated with 0.36 odds for a worse outcome compared to placebo when expressed by the WHO-Clinical Progression Scale (CPS) at day 28. Herein, we report the results of subgroup analyses and long-term outcomes.MethodsThis prospective, double-blind, randomised clinical trial, recruited patients with a confirmed SARS-CoV-2 infection, in need of hospitalisation, lower respiratory tract infection and plasma suPAR ≥6 ng/mL from 37 academic and community hospitals in Greece and Italy. Patients were 1:2 randomised to subcutaneous treatment with placebo or anakinra (100 mg) once daily for 10 days. Pre-defined subgroups of Charlson's comorbidity index (CCI), sex, age, level of suPAR, and time from symptom onset were analysed for the primary endpoint (overall comparison of distribution of frequencies of the scores from the WHO-CPS between treatments on day 28), by multivariable ordinal regression analysis in the intention to treat (ITT) population. This trial is registered with the EU Clinical Trials Register (2020-005828-11) and ClinicalTrials.gov (NCT04680949).FindingsPatients were enrolled between 23 December 2020 and 31 March 2021; 189 patients in the placebo arm and 405 patients in the anakinra arm were the ITT population. Multivariable analysis showed that anakinra treatment was accompanied by significantly lower odds for worse outcome compared to placebo at day 28 for all studied subgroups (CCI ≥ 2, OR: 0.34, 95% confidence intervals [CI] 0.22-0.50; CCI < 2, OR: 0.38, 95% CI 0.21-0.68; suPAR > 9 ng/mL, OR: 0.35, 95% CI 0.19-0.66; suPAR 6-9 ng/mL, OR: 0.35, 95% CI 0.24-0.52; patients ≥65 years, OR: 0.41, 95% CI 0.25-0.66; and patients <65 years, OR: 0.29, 95% CI 0.19-0.45). The benefit was uniform, irrespective of the time from start of symptoms until the start of the study drug. At days 60 and 90, anakinra treatment had odds of 0.40 (95% CI 0.28-0.57) and 0.46 (95% CI 0.32-0.67) respectively, for a worse outcome compared to placebo. The costs of general ward stay, ICU stay, and drugs were lower with anakinra treatment.InterpretationAnakinra represents an important therapeutic tool in the management of COVID-19 that may be administered in all subgroups of patients; benefits are maintained until day 90.FundingHellenic Institute for the Study of Sepsis; Swedish Orphan Biovitrum AB.

Project description:The purpose of this study was to characterize acute changes in inflammatory pathways in the mouse eye after blast-mediated traumatic brain injury (bTBI) and to determine whether modulation of these pathways could protect the structure and function of retinal ganglion cells (RGC). The bTBI was induced in C57BL/6J male mice by exposure to three 20 psi blast waves directed toward the head with the body shielded, with an inter-blast interval of one hour. Acute cytokine expression in retinal tissue was measured through reverse transcription-quantitative polymerase chain reaction (RT-qPCR) four hours post-blast. Increased retinal expression of interleukin (lL)-1β, IL-1α, IL-6, and tumor necrosis factor (TNF)α was observed in bTBI mice exposed to blast when compared with shams, which was associated with activation of microglia and macroglia reactivity, assessed via immunohistochemistry with ionized calcium binding adaptor molecule 1 and glial fibrillary acidic protein, respectively, one week post-blast. Blockade of the IL-1 pathway was accomplished using anakinra, an IL-1RI antagonist, administered intra-peritoneally for one week before injury and continuing for three weeks post-injury. Retinal function and RGC layer thickness were evaluated four weeks post-injury using pattern electroretinogram (PERG) and optical coherence tomography (OCT), respectively. After bTBI, anakinra treatment resulted in a preservation of RGC function and RGC structure when compared with saline treated bTBI mice. Optic nerve integrity analysis demonstrated a trend of decreased damage suggesting that IL-1 blockade also prevents axonal damage after blast. Blast exposure results in increased retinal inflammation including upregulation of pro-inflammatory cytokines and activation of resident microglia and macroglia. This may explain partially the RGC loss we observed in this model, as blockade of the acute inflammatory response after injury with the IL-1R1 antagonist anakinra resulted in preservation of RGC function and RGC layer thickness.

Project description:The commonly used techniques for systolic blood pressure (SBP) and diastolic blood pressure (DBP) measurement are the auscultatory Korotkoff-based sphygmomanometry and oscillometry. The former technique is relatively accurate but is limited to a physician's office because its automatic variant is subject to noise artifacts. Consequently, the Korotkoff-based measurement overestimates the blood pressure in some patients due to white coat effect, and because it is a single measurement, it cannot properly represent the variable blood pressure. Automatic oscillometry can be used at home by the patient and is preferred even in clinics. However, the technique's accuracy is low and errors of 10-15 mmHg are common. Recently, we have developed an automatic technique for SBP measurement, based on an arm pressure cuff and a finger photoplethysmographic probe. The technique was found to be significantly more accurate than oscillometry, and comparable to the Korotkoff-based technique, the reference-standard for non-invasive blood pressure measurements. The measurement of SBP is a mainstay for the diagnosis and follow-up of hypertension, which is a major risk factor for several adverse events, mainly cardiovascular. Lowering blood pressure evidently reduces the risk, but excessive lowering can result in hypotension and consequently hypoperfusion to vital organs, since blood pressure is the driving force for blood flow. Erroneous measurement by 10 mmHg can lead to a similar unintended reduction of SBP and may adversely affect patients treated to an SBP of 120-130 mmHg. In particular, in elderly patients, unintended excessive reduction of blood pressure due to inaccurate SBP measurement can result in cerebral hypoperfusion and consequent cognitive decline. By using a more accurate technique for automatic SBP measurement (such as the photoplethysmographic-based technique), the optimal blood pressure target can be achieved with lower risk for hypotension and its adverse events.

Project description:ObjectiveTo assess the clinical outcome (death and/or Intensive Care Unit (ICU) admission) based on the time from hospital admission to the administration of anakinra and the possible usefulness of a "simplified" SCOPE score to stratify the risk of worse prognosis in our cohort of patients with moderate/severe SARS-CoV-2 pneumonia, both vaccinated and unvaccinated, that received anakinra and corticosteroids. In addition, the clinical, analytical, and imaging characteristics of patients at admission are described.MethodsRetrospective cohort study of 312 patients admitted to Hospital Clínico San Cecilio in Granada for moderate/severe pneumonia caused by SARS-CoV-2 that received anakinra and corticosteroids between March 2020 and January 2022. Clinical and analytical data were collected as well as the patient outcome at 30 and 60 days after admission. Three treatment groups were established according to the time from hospital admission to administration of anakinra: early (1st-2nd day), intermediate (3rd-5th day), and late (after the 5th day).ResultsThe median age was 67.4 years (IQR 22-97 years) and 204 (65.4%) were male. The most common comorbidity was hypertension (58%). The median time from the start of symptoms to anakinra administration was 6 days (IQR 5-10) and the SaFi (SaO2/FiO2) was 228 (IQR 71-471). The cure rate was higher in the early-onset anakinra group versus the late-onset group (73% vs 56.6%). The latter had a higher percentage of deaths (27.4%) and a greater number of patients remained hospitalized for a month (16%). On admission, the patients had elevated C-reactive protein (CRP), ferritin, and D-dimer values and decreased total lymphocytes. Analytical improvement was observed at both 72 hours and one month after treatment. 42 (13.5%) required ICU admission, and 23 (7.3%) orotracheal intubation. At 60 days, 221 (70.8%) were discharged, 87 (27.8%) had died and 4 (1.4%) remained hospitalized. The mean dose of anakinra was 1000 mg (100-2600 mg) with differences found between the dose administered and the clinical outcome. There were no differences in the primary outcome based on vaccination. A simplified SCOPE score at the start of anakinra administration was lower in patients with better clinical evolution.ConclusionsEarly treatment with anakinra and corticosteroids was associated with a better outcome regardless of vaccination status. A simplified SCOPE was found to be a good prognostic tool.

Dataset Information

Transitions of blood immune endotypes and improved outcome by anakinra in COVID-19 pneumonia: an analysis of the SAVE-MORE randomized controlled trial.

Background

Methods

Results

Conclusion

Publications

Transitions of blood immune endotypes and improved outcome by anakinra in COVID-19 pneumonia: an analysis of the SAVE-MORE randomized controlled trial.

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