Eculizumab-C5 complexes express a C5a neoepitope in vivo: Consequences for interpretation of patient complement analyses

Contains fulltext : 177337.pdf (Publisher’s version ) (Open Access)The complement system has obtained renewed clinical focus due to increasing number of patients treated with eculizumab, a monoclonal antibody inhibiting cleavage of C5 into C5a and C5b. The FDA approved indications are paroxysmal nocturnal haemoglobinuria and atypical haemolytic uremic syndrome, but many other diseases are candidates for complement inhibition. It has been postulated that eculizumab does not inhibit C5a formation in vivo, in contrast to what would be expected since it blocks C5 cleavage. We recently revealed that this finding was due to a false positive reaction in a C5a assay. In the present study, we identified expression of a neoepitope which was exposed on C5 after binding to eculizumab in vivo. By size exclusion chromatography of patient serum obtained before and after infusion of eculizumab, we document that the neoepitope was exposed in the fractions containing the eculizumab-C5 complexes, being positive in this actual C5a assay and negative in others. Furthermore, we confirmed that it was the eculizumab-C5 complexes that were detected in the C5a assay by adding an anti-IgG4 antibody as detection antibody. Competitive inhibition by anti-C5 antibodies localized the epitope to the C5a moiety of C5. Finally, acidification of C5, known to alter C5 conformation, induced a neoepitope reacting identical to the one we explored, in the C5a assays. These data are important for interpretation of complement analyses in patients treated with eculizumab

UPSCALE: Upscaling Sustainable Collaborative Consumption Using Public Libraries

UPSCALE is an international collaboration of universities, research institutes, public libraries, and non-governmental organisations (NGOs) that explore the preconditions for and possible upscaling of collaborative consumption using public libraries. UPSCALE runs until autumn 2024, and results will be published continuously in journals dealing with library and information studies, climate research, and sustainability. In this research note, we introduce ongoing research from the UPSCALE research group by presenting several case studies that show how public libraries act as change agents in different ways regarding sustainable development. This might be by facilitating, promoting the lending, and sharing alternative collections in the library or by building collaborations, partnerships, and networks with local community actors, NGOs, and other local and national partners

Double blockade of CD14 and complement C5 abolishes the cytokine storm and improves morbidity and survival in polymicrobial sepsis in mice

Sepsis and septic shock, caused by an excessive systemic host-inflammatory response, are associated with high morbidity and mortality. The complement system and TLRs provide important pattern recognition receptors initiating the cytokine storm by extensive cross-talk. We hypothesized that double blockade of complement C5 and the TLR coreceptor CD14 could improve survival of experimental polymicrobial sepsis. Mice undergoing cecal ligation and puncture (CLP)–induced sepsis were treated with neutralizing anti-CD14 Ab biG 53, complement C5 inhibitor coversin (Ornithodoros moubata C inhibitor), or a combination thereof. The inflammatory study (24-h observation) revealed statistically significant increases in 22 of 24 measured plasma biomarkers in the untreated CLP group, comprising 14 pro- and anti-inflammatory cytokines and 8 chemokines, growth factors, and granulocyte activation markers. Single CD14 or C5 blockade significantly inhibited 20 and 19 of the 22 biomarkers, respectively. Combined CD14 and C5 inhibition significantly reduced all 22 biomarkers (mean reduction 85%; range 54–95%) compared with the untreated CLP group. Double blockade was more potent than single treatment and was required to significantly inhibit IL-6 and CXCL1. Combined inhibition significantly reduced morbidity (motility and eyelid movement) and mortality measured over 10 d. In the positive control CLP group, median survival was 36 h (range 24–48 h). Combined treatment increased median survival to 96 h (range 24–240 h) (p = 0.001), whereas survival in the single-treatment groups was not significantly increased (median and range for anti-CD14 and anti-C5 treatment were 36 h [24–48 h] and 48 h [24–96 h]). Combined with standard intervention therapy, specific blockade of CD14 and C5 might represent a promising new therapeutic strategy for treatment of polymicrobial sepsis

Upscale: Upscaling Sustainable Collaborative Consumption Using Public Libraries

UPSCALE is an international collaboration of universities, research institutes, public libraries, and non-governmental organisations (NGOs) that explore the preconditions for and possible upscaling of collaborative consumption using public libraries. UPSCALE runs until autumn 2024, and results will be published continuously in journals dealing with library and information studies, climate research,and sustainability. In this research note, we introduce ongoing research from the UPSCALE research group by presenting several case studies that show how public libraries act as change agents in different ways regarding sustainable development. This might be by facilitating, promoting the lending, and sharing alternative collections in the library or by building collaborations, partnerships, and networks with local community actors, NGOs, and other local and national partners

The use of antibiotics in the intensive care unit of a tertiary hospital in Malawi

Background Antibiotic resistance is on the rise. A contributing factor to antibiotic resistance is the misuse of antibiotics in hospitals. The current use of antibiotics in ICUs in Malawi is not well documented and there are no national guidelines for the use of antibiotics in ICUs. The aim of the study was to describe the use of antibiotics in a Malawian ICU. Methods A retrospective review of medical records of all admissions to the main ICU in Queen Elizabeth Central Hospital in Blantyre, Malawi, between January 2017 and April 2019. Data were extracted from the ICU patient register on clinical parameters on admission, diagnoses, demographics and antibiotics both prescribed and given for all patients admitted to the ICU. Usage of antibiotics in the ICU and bacterial culture results from samples taken in the ICU and in the peri-ICU period, (from 5 days before ICU admission to 5 days after ICU discharge), were described. Results Six hundred-and-forty patients had data available on prescribed and received medications and were included in the analyses. Of these, 577 (90.2%) were prescribed, and 522 (81.6%) received an antibiotic in ICU. The most commonly used antibiotics were ceftriaxone, given to 470 (73.4%) of the patients and metronidazole to 354 (55.3%). Three-hundred-and-thirty-three (52.0%) of the patients received more than one type of antibiotic concurrently – ceftriaxone and metronidazole was the most common combination, given to 317 patients. Forty five patients (7.0%) were given different antibiotics sequentially. One-hundred-and-thirty-seven patients (21.4%) had a blood culture done in the peri-ICU period, of which 70 (11.0% of the patients) were done in the ICU. Twenty-five (18.3%) of the peri-ICU cultures were positive and eleven different types of bacteria were grown in the cultures, of which 17.2% were sensitive to ceftriaxone. Conclusion We have found a substantial usage of antibiotics in an ICU in Malawi. Ceftriaxone, the last-line antibiotic in the national treatment guidelines, is commonly used, and bacteria appear to show high levels of resistance to it, although blood culture testing is infrequently used. Structured antibiotic stewardship programs may be useful in all ICUs

Combined inhibition of C5 and CD14 efficiently attenuated the inflammatory response in a porcine model of meningococcal sepsis

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ICU-acquired pneumonia in immunosuppressed patients with acute hypoxemic respiratory failure: A post-hoc analysis of a prospective international cohort study

Objective: Intensive Care Units (ICU) acquired Pneumonia (ICU-AP) is one of the most frequent nosocomial infections in critically ill patients. Our aim was to determine the effects of having an ICU-AP in immunosuppressed patients with acute hypoxemic respiratory failure. Design: Post-hoc analysis of a multinational, prospective cohort study in 16 countries. Settings: ICU. Patients: Immunosuppressed patients with acute hypoxemic respiratory failure. Intervention: None. Measurements and main results: The original cohort had 1611 and in this post-hoc analysis a total of 1512 patients with available data on hospital mortality and occurrence of ICU-AP were included. ICU-AP occurred in 158 patients (10.4%). Hospital mortality was higher in patients with ICU-AP (14.8% vs. 7.1% p < 0.001). After adjustment for confounders and centre effect, use of vasopressors (Odds Ratio (OR) 2.22; 95%CI 1.46-.39) and invasive me-chanical ventilation at day 1 (OR 2.12 vs. high flow oxygen; 95%CI 1.07-4.20) were associated with increased risk of ICU-AP while female gender (OR 0.63; 95%CI 0.43-94) and chronic kidney disease (OR 0.43; 95%CI 0.22-0.88) were associated with decreased risk of ICU-AP. After adjustment for confounders and centre effect, ICU-AP was independently associated with mortality (Hazard Ratio 1.48; 95%CI 14.-1.91; P = 0.003). Conclusions: The attributable mortality of ICU-AP has been repetitively questioned in immunosuppressed pa-tients with acute respiratory failure. This manuscript found that ICU-AP represents an independent risk factor for hospital mortality.(c) 2020 Elsevier Inc. All rights reserved.Peer reviewe

Circulating markers of extracellular matrix remodelling in severe COVID-19 patients

Background Abnormal remodelling of the extracellular matrix (ECM) has generally been linked to pulmonary inflammation and fibrosis and may also play a role in the pathogenesis of severe COVID-19. To further elucidate the role of ECM remodelling and excessive fibrogenesis in severe COVID-19, we examined circulating levels of mediators involved in various aspects of these processes in COVID-19 patients. Methods Serial blood samples were obtained from two cohorts of hospitalised COVID-19 patients (n = 414). Circulating levels of ECM remodelling mediators were quantified by enzyme immunoassays in samples collected during hospitalisation and at 3-month follow-up. Samples were related to disease severity (respiratory failure and/or treatment at the intensive care unit), 60-day total mortality and pulmonary pathology after 3-months. We also evaluated the direct effect of inactivated SARS-CoV-2 on the release of the different ECM mediators in relevant cell lines. Results Several of the measured markers were associated with adverse outcomes, notably osteopontin (OPN), S100 calcium-binding protein A12 and YKL-40 were associated with disease severity and mortality. High levels of ECM mediators during hospitalisation were associated with computed tomography thorax pathology after 3-months. Some markers (i.e. growth differential factor 15, galectin 3 and matrix metalloproteinase 9) were released from various relevant cell lines (i.e. macrophages and lung cell lines) in vitro after exposure to inactivated SARS-CoV-2 suggesting a direct link between these mediators and the causal agent of COVID-19. Conclusion Our findings highlight changes to ECM remodelling and particularly a possible role of OPN, S100A12 and YKL-40 in the pathogenesis of severe COVID-19

Acute respiratory failure in immunocompromised patients : outcome and clinical features according to neutropenia status

Abstract Background The impact of neutropenia in critically ill immunocompromised patients admitted in a context of acute respiratory failure (ARF) remains uncertain. The primary objective was to assess the prognostic impact of neutropenia on outcomes of these patients. Secondary objective was to assess etiology of ARF according to neutropenia. Methods We performed a post hoc analysis of a prospective multicenter multinational study from 23 ICUs belonging to the Nine-I network. Between November 2015 and July 2016, all adult immunocompromised patients with ARF admitted to the ICU were included in the study. Adjusted analyses included: (1) a hierarchical model with center as random effect; (2) propensity score (PS) matched cohort; and (3) adjusted analysis in the matched cohort. Results Overall, 1481 patients were included in this study of which 165 had neutropenia at ICU admission (11%). ARF etiologies distribution was significantly different between neutropenic and non-neutropenic patients, main etiologies being bacterial pneumonia (48% vs 27% in neutropenic and non-neutropenic patients, respectively). Initial oxygenation strategy was standard supplemental oxygen in 755 patients (51%), high-flow nasal oxygen in 165 (11%), non-invasive ventilation in 202 (14%) and invasive mechanical ventilation in 359 (24%). Before adjustment, hospital mortality was significantly higher in neutropenic patients (54% vs 42%; p = 0.006). After adjustment for confounder and center effect, neutropenia was no longer associated with outcome (OR 1.40, 95% CI 0.93–2.11). Similar results were observed after matching (52% vs 46%, respectively; p = 0.35) and after adjustment in the matched cohort (OR 1.04; 95% CI 0.63–1.72). Conclusion Neutropenia at ICU admission is not associated with hospital mortality in this cohort of critically ill immunocompromised patients admitted for ARF. In neutropenic patients, main ARF etiologies are bacterial and fungal infections