RESUMO
COVID-19-related severe respiratory failure (SRF) leads to mechanical ventilation increasing the in-hospital mortality substantially. Abundancy of lung fibroblasts (LFs) in injured lung tissue has been associated with the progression of respiratory failure in COVID-19. Aiming to reduce mortality in patients with SRF (PaO2/FiO2<100 mmHg) and considering the multi-mechanistic nature of severe COVID-19 pathogenesis, we applied a combined rescue treatment (COMBI) on top of standard-of-care (SOC: dexamethasone and heparin) comprised inhaled DNase to dissolve thrombogenic neutrophil extracellular traps, plus agents against cytokine-mediated hyperinflammation, such as anti-IL-6 receptor tocilizumab and selective JAK1/2 inhibitor baricitinib. COMBI (n=22) was compared with SOC (n= 26), and with two previously and consecutively used therapeutic approaches, including either IL-1 receptor antagonist anakinra (ANA, n=19), or tocilizumab (TOCI, n=11), on top of SOC. In parallel, evaluation of immunothrombosis was assessed in vitro in human LFs, treated with the applied therapeutic agents upon stimulation with COVID-19 plasma. COMBI was associated with lower in-hospital mortality (p=0.014) and intubation rate (p=0.013), shorter duration of hospitalization (p=0.019), and prolonged overall survival after a median follow-up of 110{+/-}4 days (p=0.003). In vitro, COVID-19 plasma markedly induced tissue factor/thrombin pathway in LFs, while this effect was inhibited by the immunomodulatory agents of COMBI providing a mechanistic explanation for the clinical observations. These results suggest the design of randomized trials using combined immunomodulatory therapies in COVID-19-associated SRF targeting multiple interconnected pathways of immunothrombosis.
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PurposeLittle is known on the mortality rate in COVID-19 related acute metabolic emergencies, namely diabetic ketoacidosis (DKA), hyperglycaemic hyperosmolar state (HHS), combined DKA/HHS, and euglycaemic diabetic ketoacidosis (EDKA). MethodsA systematic literature review was conducted using EMBASE, PubMed/Medline, and Google Scholar from January 1, 2020 to January 9, 2021 to identify all case report series, cross-sectional studies, and meta-analyses of case reports describing mortality rate in DKA, HHS, and EDKA, in COVID-19 patients. The Joanna Briggs Institute critical appraisal checklist for case reports was used for quality assessment. ResultsFrom 313 identified publications, 4 fulfilled the inclusion criteria and analyzed qualitatively and quantitatively. A systematic review and meta-analysis with subgroup analyses examined mortality rate in a total of 152 COVID-19 patients who had developed DKA, HHS, combined DKA/HHS, or EDKA. Combined mortality rate and confidence intervals (CI) were estimated using random effects model. The study was registered to PROSPERO database (ID: 230737). ResultsCombined mortality rate was found to be 27.1% [95% CI: 11.2-46.9%]. Heterogeneity was considerable (I2=83%; 95% CI: 56-93%), corrected to 67% according to Von Hippel adjustment for small meta-analyses. Funnel plot presented no apparent asymmetry; Eggers and Beggs test yielded in P=0.44 and P=0.50, respectively. Sensitivity analysis failed to explain heterogeneity. ConclusionCOVID-19 related acute metabolic emergencies (DKA, HHS, and EDKA) are characterized by considerable mortality; thus, clinicians should be aware of timely detection and immediate treatment commencing.
RESUMO
IntroductionCOVID-19 is associated with DKA (Diabetic Ketoacidosis), HHS (Hyperglycaemic Hyperosmolar State) and EDKA (Euglycaemic DKA). High mortality has been observed in COVID-19-related diabetic ketoacidosis; however, evidence is scarce. Patients and MethodsA systematic literature review was conducted using EMBASE, PubMed/Medline, and Google Scholar from January to December 2020 to identify all case reports describing DKA, HHS, and EDKA, in COVID-19 patients. The Joanna Briggs Institute critical appraisal checklist for case reports was used for quality assessment. Univariate and multivariate analysis assessed correlations of study origin, combined DKA/HHS, age, BMI, HbA1c, administered antidiabetics, comorbidities, symptoms onset, disease status, CRP, ferritin, d-dimers, glucose, osmolarity, pH, bicarbonates, ketones, lactates, {beta}-hydroxybutyric acid, anion gap, and acute kidney injury (AKI) with outcome. ResultsFrom 312 identified publications, 41 including 71 cases analyzed qualitatively and quantitatively. Multivariate analysis demonstrated that COVID-19 disease status 4 (P<0.001), AKI (P<0.001), pH [≤]7.12 (P=0.032), and osmolarity [≥]324 (P=0.034), are all independently correlated with death. COVID-19 Disease Status 4 (P=3*10-8), combined DKA/HHS (P=0.021), and AKI (P=0.037) are independently correlated with death. ConclusionCOVID-19 intertwines with acute metabolic emergencies in diabetes leading to increased mortality; key determinants are critical COVID-19 illness, co-presence of ketoacidosis and hyperosmosis and AKI.
