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1.
International Journal of Molecular Sciences ; 23(9):4894, 2022.
Article in English | MDPI | ID: covidwho-1820290

ABSTRACT

The trajectory from moderate and severe COVID-19 into acute respiratory distress syndrome (ARDS) necessitating mechanical ventilation (MV) is a field of active research. We determined serum levels within 24 h of presentation of 20 different sets of mediators (calprotectin, pro- and anti-inflammatory cytokines, interferons) of patients with COVID-19 at different stages of severity (asymptomatic, moderate, severe and ARDS/MV). The primary endpoint was to define associations with critical illness, and the secondary endpoint was to identify the pathways associated with mortality. Results were validated in serial measurements of mediators among participants of the SAVE-MORE trial. Levels of the proinflammatory interleukin (IL)-8, IL-18, matrix metalloproteinase-9, platelet-derived growth factor (PDGF)-B and calprotectin (S100A8/A9) were significantly higher in patients with ARDS and MV. Levels of the anti-inflammatory IL-1ra and IL-33r were also increased;IL-38 was increased only in asymptomatic patients but significantly decreased in the more severe cases. Multivariate ordinal regression showed that pathways of IL-6, IL-33 and calprotectin were associated with significant probability for worse outcome. Calprotectin was serially increased from baseline among patients who progressed to ARDS and MV. Further research is needed to decipher the significance of these findings compared to other acute-phase reactants, such as C-reactive protein (CRP) or ferritin, for the prognosis and development of effective treatments.

2.
Viruses ; 14(4):767, 2022.
Article in English | MDPI | ID: covidwho-1786073

ABSTRACT

(1) Background: It is well-established that coronavirus disease-2019 (COVID-19) is highly pro-inflammatory, leading to activation of the coagulation cascade. COVID-19-induced hypercoagulability is associated with adverse outcomes and mortality. Current guidelines recommend that hospitalized COVID-19 patients should receive pharmacological prophylaxis against venous thromboembolism (VTE). (2) INTERACT is a retrospective, phase IV, observational cohort study aiming to evaluate the overall clinical effectiveness and safety of a higher than conventionally used prophylactic dose of anticoagulation with tinzaparin administered for VTE prevention in non-critically ill COVID-19 patients with moderate disease severity. (3) Results: A total of 705 patients from 13 hospitals in Greece participated in the study (55% men, median age 62 years). Anticoagulation with tinzaparin was initiated immediately after admission. A full therapeutic dose was received by 36.3% of the participants (mean ±SD 166 ±33 IU/Kgr/day) and the remaining patients (63.9%) received an intermediate dose (mean ±SD 114 ±22 IU/Kgr/day). The median treatment duration was 13 days (Q1–Q3: 8–20 days). During the study (April 2020 to November 2021), 14 thrombotic events (2.0%) were diagnosed (i.e., three cases of pulmonary embolism (PE) and 11 cases of deep venous thrombosis, DVT). Four bleeding events were recorded (0.6%). In-hospital death occurred in 12 patients (1.7%). Thrombosis was associated with increasing age (median: 74.5 years, Q1–Q3: 62–79, for patients with thrombosis vs. 61.9 years, Q1–Q3: 49–72, p = 0.0149), increased D-dimer levels for all three evaluation time points (at admission: 2490, Q1–Q3: 1580–6480 vs. 700, Q1–Q3: 400–1475, p < 0.0001), one week ±two days after admission (3510, Q1–Q3: 1458–9500 vs. 619, Q1–Q3: 352–1054.5, p < 0.0001), as well as upon discharge (1618.5, Q1–Q3: 1010–2255 vs. 500, Q1–Q3: 294–918, p < 0.0001). Clinical and laboratory improvement was affirmed by decreasing D-dimer and CRP levels, increasing platelet numbers and oxygen saturation measurements, and a drop in the World Health Organization (WHO) progression scale. (4) Conclusions: The findings of our study are in favor of prophylactic anticoagulation with an intermediate to full therapeutic dose of tinzaparin among non-critically ill patients hospitalized with COVID-19.

3.
Respirology ; 27(3): 246-247, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1723396
4.
Cell Reports Medicine ; : 100560, 2022.
Article in English | ScienceDirect | ID: covidwho-1706398

ABSTRACT

Summary Most patients infected with SARS-CoV-2 (COVID-19) experience mild, non-specific symptoms, but several develop severe symptoms associated with an excessive inflammatory response. Elevated plasma concentrations of soluble urokinase plasminogen activator receptor (suPAR) provide early warning of progression to severe respiratory failure (SRF) or death, but access to suPAR testing may be limited. The Severe COvid Prediction Estimate (SCOPE) score, derived from C-reactive protein, D-dimers, interleukin-6, and ferritin circulating concentrations among patients not receiving non-invasive or invasive mechanical ventilation during the SAVE-MORE study, offers comparable predictive accuracy for progression to SRF or death within 14 days as suPAR ≥6 ng/ml (area under receiver operator characteristic curve, 0.81 for both). SCOPE score is validated in two similar independent cohorts. SCOPE score 6 or more is an alternative to suPAR for predicting progression to SRF or death within 14 days of hospital admission for pneumonia, and it can be used to guide treatment decisions.

5.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-311148

ABSTRACT

Early recognition of risk and start of treatment may improve unfavorable outcome of COVID-19. In the SAVE-MORE double-blind randomized trial, 594 patients with pneumonia without respiratory dysfunction at risk as defined by plasma suPAR (soluble urokinase plasminogen activator receptor) ≥ 6 ng/ml were 1:2 randomized to subcutaneous placebo or 100 mg anakinra once daily for 10 days;85.9% were co-administered dexamethasone. After 28 days, anakinra-treated patients were distributed to lower strata of the 11-point World Health Organization ordinal Clinical Progression Scale (WHO-CPS) (adjusted odds ratio-OR 0.36;95%CI 0.26–0.50;P < 0.001);anakinra protected from severe disease or death (≥ 6 points of WHO-CPS) (OR: 0.46;P: 0.010). The median WHO-CPS decrease in the placebo and anakinra groups was 3 and 4 points (OR 0.40;P < 0.0001);the median 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) and hospital stay was shorter. (Sponsored by the Hellenic Institute for the Study of Sepsis ClinicalTrials.gov identifier, NCT04680949)

6.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-327237

ABSTRACT

Little is known on the key contributing factors towards progression into acute respiratory distress syndrome (ARDS) necessitating mechanical ventilation (MV) in COVID-19. We determined serum levels, within 24 hours of diagnosis, of alarmins, as well as pro- and anti-inflammatory molecules in asymptomatic, moderate, severe and intubated patients compared to non-infected comparators. Levels of the pro-inflammatory interleukin (IL)-8, IL-18, matrix metalloproteinase-9, platelet-derived growth factor (PDGF)-B and calprotectin (S100A8/A9) were specific drivers of ARDS. Levels of the anti-inflammatory IL-1ra and IL-33r were increased;IL-38 was increased only in asymptomatic patients, but significantly decreased in the more severe COVID-19 cases. Multivariate ordinal regression showed that pathways of IL-6, IL-33 and calprotectin gave significant probability for worse outcome. These results indicate a dysfunctional response to the presence of alarmins that may be used for prognosis and development of effective treatments.

7.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-314770

ABSTRACT

Background: Tocilizumab, an IL-6 inhibitor, has been repurposed against the “cytokine storm” in the setting of COVID-19. In this systematic review and meta-analysis, we evaluated the efficacy of tocilizumab in the management of hospitalised COVID-19.Methods: We searched MEDLINE, CENTRAL and medRxiv for studies of tocilizumab in hospitalised COVID-19 patients. Primary objective was the effectiveness of tocilizumab on mortality. Secondary objectives included the need for invasive mechanical ventilation (IMV), composite endpoints of mortality or IMV and intensive care unit (ICU) admission or IMV, length of hospitalisation and differences in mortality in ICU and non-ICU patients and in those receiving concomitantly corticosteroids.Findings: We included 52 studies (9 randomised controlled trials (RCTs) and 43 observational) with a total of 27,004 patients. In both RCTs and observational studies the use of tocilizumab was associated with a reduction in mortality;11% in RCTs (risk ratio, RR, 0.89, 95% CI 0.82 to 0.96;I 2 =0.3%) and 31% in observational studies (RR 0.69, 95% CI 0.58 to 0.83;I 2 =84.0%). The need for IMV was reduced by 19% in RCTs (RR 0.81, 95% CI 0.71 to 0.93), while a non-significant 19% reduction was observed in observational studies (RR 0.81, 95% CI 0.57 to 1.14). Both RCTs and observational studies showed a benefit from tocilizumab on the composite endpoint of mortality or IMV. Tocilizumab improved mortality both in ICU and non-ICU patients. Reduction in mortality was evident in observational studies regardless of the use of systemic corticosteroids, while there was a trend in favour of the concomitant use in the RCTs. We observed large heterogeneity in data from observational studies and small heterogeneity in RCTs.Interpretation: Tocilizumab was associated with lower mortality and other clinically relevant outcomes in hospitalised patients with moderate to critical COVID-19.Funding Statement: No funding was received for this study.Declaration of Interests: All authors declare no conflict of interest pertaining to this work.

8.
Comput Biol Med ; 141: 105176, 2022 02.
Article in English | MEDLINE | ID: covidwho-1664813

ABSTRACT

The coronavirus disease 2019 (COVID-19) which is caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is consistently causing profound wounds in the global healthcare system due to its increased transmissibility. Currently, there is an urgent unmet need to identify the underlying dynamic associations among COVID-19 patients and distinguish patient subgroups with common clinical profiles towards the development of robust classifiers for ICU admission and mortality. To address this need, we propose a four step pipeline which: (i) enhances the quality of multiple timeseries clinical data through an automated data curation workflow, (ii) deploys Dynamic Bayesian Networks (DBNs) for the detection of features with increased connectivity based on dynamic association analysis across multiple points, (iii) utilizes Self Organizing Maps (SOMs) and trajectory analysis for the early identification of COVID-19 patients with common clinical profiles, and (iv) trains robust multiple additive regression trees (MART) for ICU admission and mortality classification based on the extracted homogeneous clusters, to identify risk factors and biomarkers for disease progression. The contribution of the extracted clusters and the dynamically associated clinical data improved the classification performance for ICU admission to sensitivity 0.83 and specificity 0.83, and for mortality to sensitivity 0.74 and specificity 0.76. Additional information was included to enhance the performance of the classifiers yielding an increase by 4% in sensitivity and specificity for mortality. According to the risk factor analysis, the number of lymphocytes, SatO2, PO2/FiO2, and O2 supply type were highlighted as risk factors for ICU admission and the percentage of neutrophils and lymphocytes, PO2/FiO2, LDH, and ALP for mortality, among others. To our knowledge, this is the first study that combines dynamic modeling with clustering analysis to identify homogeneous groups of COVID-19 patients towards the development of robust classifiers for ICU admission and mortality.


Subject(s)
COVID-19 , Bayes Theorem , Hospitalization , Humans , Intensive Care Units , Retrospective Studies , SARS-CoV-2
9.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-294791

ABSTRACT

Most patients infected with SARS-CoV-2 (COVID-19) experience mild, non-specific symptoms, but several develop severe symptoms associated with an excessive inflammatory response. Elevated plasma concentrations of soluble urokinase plasminogen activator receptor (suPAR) provide early warning of progression to severe respiratory failure (SRF) or death, but access to suPAR testing may be limited. The Severe COvid Prediction Estimate (SCOPE) score, derived from C-reactive protein, D-dimer, interleukin-6, and ferritin circulating concentrations at hospitalization during the SAVE-MORE study, offers comparable predictive accuracy for progression to SRF or death within 14 days as suPAR ≥6 ng/ml (area under receiver operator characteristic curve, 0.81 for both). SCOPE score was validated against an independent dataset from the SAVE study. The SCOPE score is an alternative to suPAR for predicting progression to SRF or death within 14 days of hospital admission for pneumonia, and it can be used to guide treatment decisions.<br><br>Funding: The study was funded in part by the Hellenic Institute for the Study of Sepsis and by Swedish Orphan Biovitrum. The Hellenic Institute for the Study of Sepsis is the Sponsor of the SAVE and SAVE-MORE studies.<br><br>Declaration of Interests:E. J. Giamarellos-Bourboulis has received honoraria from Abbott CH, bioMérieux, Brahms GmbH, GSK, InflaRx GmbH, Sobi and XBiotech Inc;independent educational grants from Abbott CH, AxisShield, bioMérieux Inc, InflaRx GmbH, Johnson & Johnson, MSD, Sobi and XBiotech Inc.;and funding from the Horizon2020 Marie-Curie Project European Sepsis Academy (granted to the National and Kapodistrian University of Athens), and the Horizon 2020 European Grants ImmunoSep and RISKinCOVID (granted to the Hellenic Institute for the Study of Sepsis). G. Poulakou has received independent educational grants from Pfizer, MSD, Angelini, and Biorad. H. Milionis reports receiving honoraria, consulting fees and non-financial support from healthcare companies, including Amgen, Angelini, Bayer, Mylan, MSD, Pfizer, and Servier. L. Dagna had received consultation honoraria from SOBI. M. Bassetti has received funds for research grants and/or advisor/consultant and/or speaker/chairman from Angelini, Astellas, Bayer, Biomerieux, Cidara, Cipla, Gilead, Menarini, MSD, Pfizer, Roche, Shionogi and Nabriva. P. Panagopoulos has received honoraria from GILEAD Sciences, Janssen, and MSD. G. N. Dalekos is an advisor or lecturer for Ipsen, Pfizer, Genkyotex, Novartis, Sobi, received research grants from Abbvie, Gilead and has served as PI in studies for Abbvie, Novartis, Gilead, Novo Nordisk, Genkyotex, Regulus Therapeutics Inc, Tiziana Life Sciences, Bayer, Astellas, Pfizer, Amyndas Pharmaceuticals, CymaBay Therapeutics Inc., Sobi and Intercept Pharmaceuticals. M. G. Netea is supported by an ERC Advanced Grant (#833247) and a Spinoza grant of the Netherlands Organization for Scientific Research. Hes is a scientific founder of TTxD and he has received independent educational grants from TTxD, GSK, Ono Pharma and ViiV HealthCare. The other authors do not have any competing interest to declare.<br><br>Ethics Approval Statement: The SAVE protocol was approved by the National Ethics Committee of Greece (approval 38/20) and National Organization for Medicines approval (ISO 28/20). The SAVE-MORE protocol was approved by the National Ethics Committee of Greece (approval 161/20) and by the Ethics Committee of the National Institute for Infectious Diseases Lazzaro Spallanzani, IRCCS, in Rome (1 February 2021).<br><br>Trial Registration: The SAVE study was prospectively registered prior to enrolling the first patient (EudraCT number 2020-001466-11;ClinicalTrials.gov identifier NCT04357366). The SAVE-MORE study was prospectively registered (EudraCT no. 2020-005828-11;ClinicalTrials.gov identifier NCT04680949). Written informed consent was provided by all patients prior to enrollment.

10.
J Innate Immun ; : 1-11, 2021 Dec 01.
Article in English | MEDLINE | ID: covidwho-1546612

ABSTRACT

BACKGROUND: Macrophage activation-like syndrome (MALS) and complex immune dysregulation (CID) often underlie acute respiratory distress (ARDS) in COVID-19. We aimed to investigate the effect of personalized immunotherapy on clinical improvement of critical COVID-19. METHODS: In this open-label prospective trial, 102 patients with ARDS by SARS-CoV-2 were screened for MALS (ferritin >4,420 ng/mL) and CID (ferritin ≤4,420 ng/mL and low human leukocyte antigen (HLA)-DR expression on CD14-monocytes). Patients with MALS or CID with increased aminotransferases received intravenous anakinra; those with CID and normal aminotransferases received tocilizumab. The primary outcome was ≥25% decrease in the Sequential Organ Failure Assessment (SOFA) score and/or 50% increase in the respiratory ratio by day 8; 28-day mortality, change of SOFA score by day 28, serum biomarkers, and cytokine production by mononuclear cells were secondary endpoints. RESULTS: The primary study endpoint was met in 58.3% of anakinra-treated patients and in 33.3% of tocilizumab-treated patients (p: 0.01). Most patients in both groups received dexamethasone as standard of care. No differences were found in secondary outcomes, mortality, and SOFA score changes. Ferritin decreased among anakinra-treated patients; interleukin-6, soluble urokinase plasminogen activator receptor, and HLA-DR expression increased among tocilizumab-treated patients. Survivors by day 28 who received anakinra were distributed to lower severity levels of the WHO clinical progression scale. Greater incidence of secondary infections was found with tocilizumab treatment. CONCLUSION: Immune assessment resulted in favorable anakinra responses among critically ill patients with COVID-19 and features of MALS.

11.
J Clin Med ; 10(22)2021 Nov 18.
Article in English | MEDLINE | ID: covidwho-1524043

ABSTRACT

BACKGROUND: We aimed to investigate the potential beneficial effect of immunomodulation therapy on the thromboembolic risk in hospitalized COVID-19 patients. METHODS: We searched PubMed and Scopus for randomized trials reporting the outcomes of venous thromboembolism (VTE), ischemic stroke or systemic embolism, myocardial infarction, any thromboembolic event, and all-cause mortality in COVID-19 patients treated with immunomodulatory agents. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using the Mantel-Haenszel random effects method. RESULTS: Among 8499 patients hospitalized with COVID-19, 4638 were treated with an immunomodulatory agent, 3861-with usual care only. Among the patients prescribed immunomodulatory agents, there were 1.77 VTEs per 100 patient-months compared to 2.30 among those treated with usual care (OR: 0.84, 95% CI: 0.61-1.16; I2: 0%). Among the patients who received an interleukin 6 (IL-6) antagonist, VTEs were reported in 12 among the 1075 patients compared to 20 among the 848 receiving the usual care (OR: 0.52, 95% CI: 0.22-1.20; I2: 6%). Immunomodulators as an add-on to usual care did not reduce the risk of stroke or systemic embolism (OR: 1.10, 95% CI: 0.50-2.40; I2: 0%) or of myocardial infarction (OR: 1.06, 95% CI: 0.47-2.39; I2: 0%) and there was a nonsignificant reduction in any thromboembolic event (OR: 0.86, 95% CI: 0.65-1.14; I2: 0%). CONCLUSIONS: We did not identify a statistically significant effect of immunomodulation on prevention of thromboembolic events in COVID-19. However, given the large effect estimate for VTE prevention, especially in the patients treated with IL-6 antagonists, we cannot exclude a potential effect of immunomodulation.

14.
Respirology ; 26(11): 1027-1040, 2021 11.
Article in English | MEDLINE | ID: covidwho-1450576

ABSTRACT

Tocilizumab has been repurposed against the 'cytokine storm' in the setting of coronavirus disease 2019 (COVID-19). Our aim was to evaluate the efficacy of tocilizumab in the management of hospitalized COVID-19 patients. We searched MEDLINE, CENTRAL and medRxiv for studies of tocilizumab in hospitalized COVID-19 patients. Primary objective was the effectiveness of tocilizumab on mortality. Secondary objectives included the need for invasive mechanical ventilation (IMV), composite endpoints of mortality or IMV and intensive care unit (ICU) admission or IMV, length of hospitalization and differences in mortality in subgroups (ICU and non-ICU patients and patients receiving or not receiving concomitant corticosteroids). We included 52 studies (nine randomized controlled trials [RCTs] and 43 observational) with a total of 27,004 patients. In both RCTs and observational studies, the use of tocilizumab was associated with a reduction in mortality; 11% in RCTs (risk ratio [RR] 0.89, 95% CI 0.82 to 0.96) and 31% in observational studies (RR 0.69, 95% CI 0.58 to 0.83). The need for IMV was reduced by 19% in RCTs (RR 0.81, 95% CI 0.71 to 0.93), while no significant reduction was observed in observational studies. Both RCTs and observational studies showed a benefit from tocilizumab on the composite endpoint of mortality or IMV. Tocilizumab improved mortality both in ICU and non-ICU patients. Reduction in mortality was evident in observational studies regardless of the use of systemic corticosteroids, while that was not the case in the RCTs. Tocilizumab was associated with lower mortality and other clinically relevant outcomes in hospitalized patients with moderate-to-critical COVID-19.


Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , COVID-19/drug therapy , Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/diagnosis , COVID-19/mortality , Hospital Mortality , Humans , Respiration, Artificial , SARS-CoV-2
15.
Nat Med ; 27(10): 1752-1760, 2021 10.
Article in English | MEDLINE | ID: covidwho-1392877

ABSTRACT

Early increase of soluble urokinase plasminogen activator receptor (suPAR) serum levels is indicative of increased risk of progression of coronavirus disease 2019 (COVID-19) to respiratory failure. The SAVE-MORE double-blind, randomized controlled trial evaluated the efficacy and safety of anakinra, an IL-1α/ß inhibitor, in 594 patients with COVID-19 at risk of progressing to respiratory failure as identified by plasma suPAR ≥6 ng ml-1, 85.9% (n = 510) of whom were receiving dexamethasone. At day 28, the adjusted proportional odds of having a worse clinical status (assessed by the 11-point World Health Organization Clinical Progression Scale (WHO-CPS)) with anakinra, as compared to placebo, was 0.36 (95% confidence interval 0.26-0.50). The median WHO-CPS decrease on day 28 from baseline in the placebo and anakinra groups was 3 and 4 points, respectively (odds ratio (OR) = 0.40, P < 0.0001); the respective median decrease of Sequential Organ Failure Assessment (SOFA) score on day 7 from baseline was 0 and 1 points (OR = 0.63, P = 0.004). Twenty-eight-day mortality decreased (hazard ratio = 0.45, P = 0.045), and hospital stay was shorter.


Subject(s)
COVID-19/drug therapy , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Receptors, Urokinase Plasminogen Activator/blood , Aged , COVID-19/virology , Double-Blind Method , Female , Humans , Interleukin 1 Receptor Antagonist Protein/adverse effects , Male , Middle Aged , Placebos , SARS-CoV-2/isolation & purification
16.
Infect Dis Ther ; 10(4): 2333-2351, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1345213

ABSTRACT

INTRODUCTION: The anti-inflammatory effect of macrolides prompted the study of oral clarithromycin in moderate COVID-19. METHODS: An open-label non-randomized trial in 90 patients with COVID-19 of moderate severity was conducted between May and October 2020. The primary endpoint was defined at the end of treatment (EOT) as no need for hospital re-admission and no progression into lower respiratory tract infection (LRTI) for patients with upper respiratory tract infection and as at least 50% decrease of the respiratory symptoms score without progression into severe respiratory failure (SRF) for patients with LRTI. Viral load, biomarkers, the function of mononuclear cells and safety were assessed. RESULTS: The primary endpoint was attained in 86.7% of patients treated with clarithromycin (95% CIs 78.1-92.2%); this was 91.7% and 81.4% among patients starting clarithromycin the first 5 days from symptoms onset or later (odds ratio after multivariate analysis 6.62; p 0.030). The responses were better for patients infected by non-B1.1 variants. Clarithromycin use was associated with decreases in circulating C-reactive protein, tumour necrosis factor-alpha and interleukin (IL)-6; by increase of production of interferon-gamma and decrease of production of interleukin-6 by mononuclear cells; and by suppression of SARS-CoV-2 viral load. No safety concerns were reported. CONCLUSIONS: Early clarithromycin treatment provides most of the clinical improvement in moderate COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04398004.

17.
Eur J Neurol ; 28(11): 3826-3836, 2021 11.
Article in English | MEDLINE | ID: covidwho-1316884

ABSTRACT

Since the onset of the COVID-19 pandemic, a substantial proportion of COVID-19 patients had documented thrombotic complications and ischemic stroke. Several mechanisms related to immune-mediated thrombosis, the renin angiotensin system and the effect of SARS-CoV-2 in cardiac and brain tissue may contribute to the pathogenesis of ischemic stroke in patients with COVID-19. Simultaneously, significant strains on global healthcare delivery, including ischemic stroke management, have made treatment of stroke in the setting of COVID-19 particularly challenging. In this review, we summarize the current knowledge on epidemiology, clinical manifestation, and pathophysiology of ischemic stroke in patients with COVID-19 to bridge the gap from bench to bedside and clinical practice during the most challenging global health crisis of the last decades.


Subject(s)
Brain Ischemia , COVID-19 , Ischemic Stroke , Stroke , Brain Ischemia/complications , Brain Ischemia/epidemiology , Humans , Pandemics , SARS-CoV-2 , Stroke/epidemiology , Stroke/therapy
18.
Rheumatology (Oxford) ; 60(12): 5527-5537, 2021 12 01.
Article in English | MEDLINE | ID: covidwho-1231045

ABSTRACT

OBJECTIVES: Acute respiratory distress syndrome and cytokine release syndrome are the major complications of coronavirus disease 2019 (COVID-19) associated with increased mortality risk. We performed a meta-analysis to assess the efficacy and safety of anakinra in adult hospitalized non-intubated patients with COVID-19. METHODS: Relevant trials were identified by searching literature until 24 April 2021 using the following terms: anakinra, IL-1, coronavirus, COVID-19, SARS-CoV-2. Trials evaluating the effect of anakinra on the need for invasive mechanical ventilation and mortality in hospitalized non-intubated patients with COVID-19 were included. RESULTS: Nine studies (n = 1119) were eligible for inclusion in the present meta-analysis. Their bias risk with reference to the assessed parameters was high. In pooled analyses, anakinra reduced the need for invasive mechanical ventilation (odds ratio (OR): 0.38, 95% CI: 0.17-0.85, P = 0.02, I2 = 67%; six studies, n = 587) and mortality risk (OR: 0.32, 95% CI: 0.23-0.45, P < 0.00001, I2 = 0%; nine studies, n = 1119) compared with standard of care therapy. There were no differences regarding the risk of adverse events, including liver dysfunction (OR: 0.75, 95% CI: 0.48-1.16, P > 0.05, I2 = 28%; five studies, n = 591) and bacteraemia (OR: 1.07, 95% CI: 0.42-2.73, P > 0.05, I2 = 71%; six studies, n = 727). CONCLUSIONS: Available evidence shows that treatment with anakinra reduces both the need for invasive mechanical ventilation and mortality risk of hospitalized non-intubated patients with COVID-19 without increasing the risk of adverse events. Confirmation of efficacy and safety requires randomized placebo-controlled trials.


Subject(s)
COVID-19/drug therapy , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Receptors, Interleukin-1/antagonists & inhibitors , Humans , Treatment Outcome
19.
Elife ; 102021 03 08.
Article in English | MEDLINE | ID: covidwho-1121691

ABSTRACT

Background: It was studied if early suPAR-guided anakinra treatment can prevent severe respiratory failure (SRF) of COVID-19. Methods: A total of 130 patients with suPAR ≥6 ng/ml were assigned to subcutaneous anakinra 100 mg once daily for 10 days. Primary outcome was SRF incidence by day 14 defined as any respiratory ratio below 150 mmHg necessitating mechanical or non-invasive ventilation. Main secondary outcomes were 30-day mortality and inflammatory mediators; 28-day WHO-CPS was explored. Propensity-matched standard-of care comparators were studied. Results: 22.3% with anakinra treatment and 59.2% comparators (hazard ratio, 0.30; 95% CI, 0.20-0.46) progressed into SRF; 30-day mortality was 11.5% and 22.3% respectively (hazard ratio 0.49; 95% CI 0.25-0.97). Anakinra was associated with decrease in circulating interleukin (IL)-6, sCD163 and sIL2-R; IL-10/IL-6 ratio on day 7 was inversely associated with SOFA score; patients were allocated to less severe WHO-CPS strata. Conclusions: Early suPAR-guided anakinra decreased SRF and restored the pro-/anti-inflammatory balance. Funding: This study was funded by the Hellenic Institute for the Study of Sepsis, Technomar Shipping Inc, Swedish Orphan Biovitrum, and the Horizon 2020 Framework Programme. Clinical trial number: NCT04357366.


People infected with the SARS-CoV-2 virus, which causes COVID-19, can develop severe respiratory failure and require a ventilator to keep breathing, but this does not happen to every infected individual. Measuring a blood protein called suPAR (soluble urokinase plasminogen activator receptor) may help identify patients at the greatest risk of developing severe respiratory failure and requiring a ventilator. Previous investigations have suggested that measuring suPAR can identify pneumonia patients at highest risk for developing respiratory failure. The protein can be measured by taking a blood sample, and its levels provide a snapshot of how the body's immune system is reacting to infection, and of how it may respond to treatment. Anakinra is a drug that forms part of a class of medications called interleukin antagonists. It is commonly prescribed alone or in combination with other medications to reduce pain and swelling associated with rheumatoid arthritis. Kyriazopoulou et al. investigated whether treating COVID-19 patients who had developed pneumonia with anakinra could prevent the use of a ventilator and lower the risk of death. The findings show that treating COVID-19 patients with an injection of 100 milligrams of anakinra for ten days may be an effective approach because the drug combats inflammation. Kyriazopoulou et al. examined various markers of the immune response and discovered that anakinra was able to improve immune function, protecting a significant number of patients from going on a ventilator. The drug was also found to be safe and cause no significant adverse side effects. Administering anakinra decreased of the risk of progression into severe respiratory failure by 70%, and reduced death rates significantly. These results suggest that it may be beneficial to use suPAR as an early biomarker for identifying those individuals at highest risk for severe respiratory failure, and then treat them with anakinra. While the findings are promising, they must be validated in larger studies.


Subject(s)
Anti-Inflammatory Agents/administration & dosage , COVID-19/drug therapy , Interleukin 1 Receptor Antagonist Protein/administration & dosage , Respiratory Insufficiency/prevention & control , Aged , Aged, 80 and over , Antigens, CD/blood , Antigens, Differentiation, Myelomonocytic/blood , COVID-19/mortality , Female , Humans , Incidence , Injections, Subcutaneous , Interleukin-10/blood , Interleukin-6/blood , Male , Middle Aged , Receptors, Cell Surface/blood , Receptors, Urokinase Plasminogen Activator/blood , Receptors, Urokinase Plasminogen Activator/metabolism , Respiration, Artificial , Respiratory Insufficiency/epidemiology , SARS-CoV-2 , Standard of Care , Treatment Outcome
20.
J Cardiovasc Dev Dis ; 8(2)2021 Feb 12.
Article in English | MEDLINE | ID: covidwho-1085069

ABSTRACT

BACKGROUND: Although remdesivir treatment is widely used during the pandemic coronavirus disease 2019 (COVID-19), there is scarce evidence regarding its cardiac side effects. CASE PRESENTATION: We report the case of a 36-year-old male hospitalized due to severe COVID-19 symptoms. He presented with a 10-day history of fever (up to 39.7 °C), productive cough, hemoptysis, fatigue, myalgias and hypoxemia. The patient received supplemental oxygen, dexamethasone, remdesivir and empirical antibiotic treatment according to protocol. Asymptomatic sinus bradycardia developed on hospital day 3 (namely, heart rate 39/min compared to 92/min on admission). Secondary causes of bradycardia were excluded based on the absence of relevant evidence from laboratory work-up and echocardiographic examination. The patient's rhythm restored to normal 9 days after the discontinuation of remdesivir. CONCLUSIONS: Considering the frequent use of remdesivir in patients with COVID-19, physicians should be aware of this possible adverse event.

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