Down-regulation of KLF2 in lung fibroblasts is linked with COVID-19 immunofibrosis and restored by combined inhibition of NETs, JAK-1/2 and IL-6 signaling.

Kruppel-like factor 2 (KLF2) has been linked with fibrosis and neutrophil-associated thromboinflammation; however, its role in COVID-19 remains elusive. We investigated the effect of disease microenvironment on the fibrotic potential of human lung fibroblasts (LFs) and its association with KLF2 expression. LFs stimulated with plasma from severe COVID-19 patients down-regulated KLF2 expression at mRNA/protein and functional level acquiring a pre-fibrotic phenotype, as indicated by increased CCN2/collagen levels. Pre-incubation with the COMBI-treatment-agents (DNase I and JAKs/IL-6 inhibitors baricitinib/tocilizumab) restored KLF2 levels of LFs to normal abolishing their fibrotic activity. LFs stimulated with plasma from COMBI-treated patients at day-7 expressed lower CCN2 and higher KLF2 levels, compared to plasma prior-to-treatment, an effect not observed in standard-of-care treatment. In line with this, COMBI-treated patients had better outcome than standard-of-care group. These data link fibroblast KLF2 with NETosis and JAK/IL-6 signaling, suggesting the potential of combined therapeutic strategies in immunofibrotic diseases, such as COVID-19.

Complement C3 inhibition in severe COVID-19 using compstatin AMY-101.

Complement C3 activation contributes to COVID-19 pathology, and C3 targeting has emerged as a promising therapeutic strategy. We provide interim data from ITHACA, the first randomized trial evaluating a C3 inhibitor, AMY-101, in severe COVID-19 (PaO2/FiO2 ≤ 300 mmHg). Patients received AMY-101 (n = 16) or placebo (n = 15) in addition to standard of care. AMY-101 was safe and well tolerated. Compared to placebo (8 of 15, 53.3%), a higher, albeit nonsignificant, proportion of AMY-101-treated patients (13 of 16, 81.3%) were free of supplemental oxygen at day 14. Three nonresponders and two placebo-treated patients succumbed to disease-related complications. AMY-101 significantly reduced CRP and ferritin and restrained thrombin and NET generation. Complete and sustained C3 inhibition was observed in all responders. Residual C3 activity in the three nonresponders suggested the presence of a convertase-independent C3 activation pathway overriding the drug's inhibitory activity. These findings support the design of larger trials exploring the potential of C3-based inhibition in COVID-19 or other complement-mediated diseases.

Combined administration of inhaled DNase, baricitinib and tocilizumab as rescue treatment in COVID-19 patients with severe respiratory failure.

Aiming to reduce mortality in COVID-19 with severe respiratory failure we administered a combined rescue treatment (COMBI) on top of standard-of-care (SOC: dexamethasone/heparin) consisted of inhaled DNase to dissolve thrombogenic neutrophil extracellular traps, plus agents against cytokine-mediated hyperinflammation, namely anti-IL-6-receptor tocilizumab and JAK1/2 inhibitor baricitinib. Patients with PaO2/FiO2 < 100 mmHg were analysed. COMBI group (n = 22) was compared with similar groups that had received SOC alone (n = 26) or SOC plus monotherapy with either IL-1-receptor antagonist anakinra (n = 19) or tocilizumab (n = 11). COMBI was significantly associated with lower in-hospital mortality and intubation rate, shorter duration of hospitalization, and prolonged overall survival after a median follow-up of 110 days. In vitro, COVID-19 plasma induced tissue factor/thrombin pathway in primary lung fibroblasts. This effect was inhibited by the immunomodulatory agents of COMBI providing a mechanistic explanation for the clinical observations. These results support the conduct of randomized trials using combined immunomodulation in COVID-19 to target multiple interconnected pathways of immunothrombosis.

SARS-CoV-2 Vaccination Coverage and Key Public Health Indicators May Explain Disparities in COVID-19 Country-Specific Case Fatality Rate Within European Economic Area

Aim To investigate the reasons for disparity regarding the country-specific COVID-19-related case fatality rate (CFR) within the 30 countries of the European Economic Area (EEA). Materials and methods Data regarding population, area, COVID-19-associated infections/deaths, vaccination, life expectancy, elderly population, infant mortality, gender disparity, urbanization, gross domestic product (GDP), income per capita, health spending per capita, physicians, nursing personnel, hospital beds, ICU beds, hypertension, diabetes, obesity, and smoking from all EEA countries were collected from official sources on January 16, 2022. Correlation coefficients were computed, and optimal scaling using ridge regression was used to reach the most parsimonious multivariate model assessing any potential independent correlation of public health parameters with COVID-19 CFR. Results COVID-19 CFR ranges from 0.1% (Iceland) to 4.0% (Bulgaria). All parameters but population density, GDP, total health spending (% of GDP), ICU beds, diabetes, and obesity were correlated with COVID-19 CFR. In the most parsimonious multivariate model, elderly population rate (P = 0.018), males/total ratio (P = 0.013), nurses/hospital beds (P = 0.001), physicians/hospital beds (P = 0.026), public health spending (P = 0.013), smoking rate (P = 0.013), and unvaccinated population rate (P = 0.00005) were demonstrated to present independent correlation with COVID-19 CFR. In detail, the COVID-19 CFR is estimated to increase by 1.24 times in countries with vaccination rate of <0.34, 1.11 times in countries with an elderly population rate of ≥0.20, 1.14 times in countries with male ratio values ≥0.493, 1.12 times in countries spending <2,000$ annually per capita for public health, 1.14 and 1.10 times in countries with <2.30 nurses and <0.88 physicians per hospital bed, respectively, and 1.12 in countries with smoking ratio ≥0.22, while holding all other independent variables of the model constant. Conclusion COVID-19 CFR varies substantially among EEA countries and is independently linked with low vaccination rates, increased elderly population rate, diminished public health spending per capita, insufficient physicians and nursing personnel per hospital bed, and prevalent smoking habits. Therefore, public health authorities are awaited to consider these parameters in prioritizing actions to manage the SARS-CoV-2 pandemic.

Diabetes-related acute metabolic emergencies in COVID-19 patients: a systematic review and meta-analysis.

AIMS: COVID-19 is associated with diabetic ketoacidosis (DKA), hyperglycaemic hyperosmolar state (HHS) and euglycaemic DKA (EDKA); however, evidence regarding parameters affecting outcome and mortality rates is scarce. METHODS: A systematic literature review was conducted using EMBASE, PubMed/Medline, and Google Scholar from January 2020 to 7 January 2021 to identify all studies describing clinical profile, outcome and mortality rates regarding DKA, HHS, DKA/HHS and EDKA cases in COVID-19 patients. The appropriate Joanna Briggs Institute tools were used for quality assessment; quality of evidence was approached using GRADE. Univariate and multivariate analyses were used to assess correlations between clinical characteristics and outcome based on case reports. Combined mortality rates (CMR) were estimated from data reported in case report series, cross-sectional studies, and meta-analyses. The protocol was submitted to PROSPERO (ID: 229356/230737). RESULTS: From 312 identified publications, 44 were qualitatively and quantitatively analyzed. Critical COVID-19 necessitating ICU (P = 3 × 10-8), DKA/HHS presence (P = 0.021), and AKI (P = 0.037) were independently correlated with death. Increased COVID-19 severity (P = 0.003), elevated lactates (P < 0.001), augmented anion gap (P < 0.001), and AKI (P = 0.002) were associated with DKA/HHS. SGLT-2i were linked with EDKA (P = 0.004) and negatively associated with AKI (P = 0.023). CMR was 27.1% (95% CI 11.2-46.9%) with considerable heterogeneity (I 2 = 67%). CONCLUSION: Acute diabetes-related metabolic emergencies in COVID-19 patients lead to increased mortality; key determinants are critical COVID-19 illness, coexistence of DKA/HHS and AKI. Previous SGLT-2i treatment, though associated with EDKA, might preserve renal function in COVID-19 patients. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13340-021-00502-9.

The Activin/Follistatin Axis Is Severely Deregulated in COVID-19 and Independently Associated With In-Hospital Mortality.

BACKGROUND: Activins are members of the transforming growth factor-ß superfamily implicated in the pathogenesis of several immunoinflammatory disorders. Based on our previous studies demonstrating that overexpression of activin-A in murine lung causes pathology sharing key features of coronavirus disease 2019 (COVID-19), we hypothesized that activins and their natural inhibitor follistatin might be particularly relevant to COVID-19 pathophysiology. METHODS: Activin-A, activin-B, and follistatin were retrospectively analyzed in 574 serum samples from 263 COVID-19 patients hospitalized in 3 independent centers, and compared with demographic, clinical, and laboratory parameters. Optimal scaling with ridge regression was used to screen variables and establish a prediction model. RESULT: The activin/follistatin axis was significantly deregulated during the course of COVID-19, correlated with severity and independently associated with mortality. FACT-CLINYCoD, a scoring system incorporating follistatin, activin-A, activin-B, C-reactive protein, lactate dehydrogenase, intensive care unit admission, neutrophil/lymphocyte ratio, age, comorbidities, and D-dimers, efficiently predicted fatal outcome (area under the curve [AUC], 0.951; 95% confidence interval, .919-.983; P <10-6). Two validation cohorts indicated similar AUC values. CONCLUSIONS: This study demonstrates a link between activin/follistatin axis and COVID-19 mortality and introduces FACT-CLINYCoD, a novel pathophysiology-based tool that allows dynamic prediction of disease outcome, supporting clinical decision making.