Andreas Barratt-Due

• Buanes, Eirik Alnes; Ghavidel, Fatemeh Zamanzad; Strand, Kristian; Haavind, Anniken; Mo, Skule & Kvåle, Reidar [Show all 8 contributors for this article] (2026). Hematologic Malignancies in Critical Care: A National Observational Comparison Between ICU and Non-ICU Patients. Acta Anaesthesiologica Scandinavica. ISSN 0001-5172. 70(5). doi: 10.1111/aas.70234. Full text in Research Archive
• Demoule, Alexandre; Decavèle, Maxens; Mehta, Sangeeta; Bauer, Philippe R.; Metaxa, Victoria & Pène, Frédéric [Show all 29 contributors for this article] (2026). Dyspnea as a marker of prognosis in immunocompromised patients with acute respiratory failure. Annals of Intensive Care. 16. doi: 10.1016/j.aicoj.2026.100091. Full text in Research Archive
• Gerogianni, Alexandra; Sørensen, Gro; Nilsen-Hoel, Tom; Ekholt, Karin; Schjalm, Camilla & Gude, Einar [Show all 13 contributors for this article] (2026). Implantation of a Continuous-Flow Left Ventricular Assist Device During Cardiopulmonary Bypass Is Associated with a Significant and Transient Acute Thromboinflammatory Response. International Journal of Molecular Sciences. ISSN 1661-6596. 27(10). doi: 10.3390/ijms27104594. Full text in Research Archive
• Mehta, Sangeeta; Azoulay, Elie; Munshi, Laveena; Demoule, Alexandre; Perner, Anders & Meyhoff, Tine Sylvest [Show all 40 contributors for this article] (2025). Sex-based differences in ICU management and outcomes of immunocompromised patients: A post hoc analysis of the prospective multicenter multinational Efraim cohort. Journal of Critical Care. ISSN 0883-9441. 89. doi: 10.1016/j.jcrc.2025.155149. Full text in Research Archive
• Russell, Lene; Azoulay, Elie; Anthon, Carl Thomas; Pène, Frédéric; Akella, Padmastuti & Mabrouki, Asma [Show all 26 contributors for this article] (2025). Platelet transfusion practice in the intensive care unit: the Nine-I international platelet transfusion survey. Annals of Intensive Care. 15(1). doi: 10.1186/s13613-025-01494-4. Full text in Research Archive
• Schellongowski, Peter; Buchtele, Nina; Staudinger, Thomas; Darmon, Michael; Lemiale, Virginie & Azoulay, Elie [Show all 44 contributors for this article] (2025). Acute respiratory distress syndrome in patients with cancer: the YELENNA prospective multinational observational cohort study. Intensive Care Medicine. ISSN 0342-4642. 51(10), p. 1809–1819. doi: 10.1007/s00134-025-08113-7. Full text in Research Archive Show summary

  Purpose Acute respiratory failure is the leading reason for intensive care unit (ICU) admission among critically ill patients with cancer. We aimed to describe the clinical characteristics, risk factors, and outcomes of patients with cancer and acute respiratory distress syndrome (ARDS) and to evaluate associations of venovenous extracorporeal membrane oxygenation (ECMO) with outcomes in the subgroup with severe ARDS. Methods We conducted a multinational, prospective, observational cohort study of patients with cancer and ARDS in 13 countries in Europe and North America. The primary endpoint was 90-day mortality. Results Among 715 included patients, 73.4% had hematologic malignancies and 26.6% solid tumors; 31.2% had undergone hematopoietic stem-cell transplantation (168 allogeneic). ICU, hospital, and 90-day mortality rates were 55.3%, 70.9%, and 73.2%, respectively. By multivariate analysis, independent predictors of higher 90-day mortality were older age, peripheral vascular disease, severe ARDS at inclusion, acute kidney injury, and ICU admission as a time-limited trial (vs. full code). Conversely, lymphoma was associated with lower 90-day mortality. Among the 322 patients (45.7%) with severe ARDS at inclusion, 90-day mortality was 82.2%; with no difference between patients who received ECMO (n = 58, 18%) and those who did not (82.6% vs. 80.7%, P = 0.89). This finding remained unchanged in a double-adjusted overlap- and propensity-weighted Cox mixed-effects model (adjusted hazard ratio, 1.12; 95% confidence interval 0.65–1.94; P = 0.69). Conclusion Patients with cancer and ARDS, particularly severe forms, experience high 90-day mortality, irrespective of ECMO use. These findings suggest a need for nuanced ICU goals-of-care discussions and raise concerns about the generalizability of ECMO guidelines to this population.

• Viermyr, Hans-Kittil; Halvorsen, Bente; Sagen, Ellen Lund; Michelsen, Annika Elisabet; Barratt-Due, Andreas & Kåsine, Trine [Show all 73 contributors for this article] (2024). High viral loads combined with inflammatory markers predict disease severity in hospitalized COVID-19 patients: Results from the NOR-Solidarity trial. Journal of Internal Medicine. ISSN 0954-6820. 296(3), p. 249–259. doi: 10.1111/joim.13820. Full text in Research Archive Show summary

  Objectives To investigate temporal changes in the association between SARS-CoV2 viral load (VL) and markers of inflammation during hospitalization, as well as the ability of these markers alone or in combination to predict severe outcomes. Methods Serial oropharyngeal and blood samples were obtained from hospitalized COVID-19 patients (n = 160). Levels of inflammatory markers and oropharyngeal VL were measured during hospitalization (admission, days 3–5, and days 7–10) and related to severe outcomes (respiratory failure/intensive care unit admission). Results Elevated admission levels of IL (interleukin)-6, IL-33, IL-8, monocyte chemoattractant protein-1 (MCP-1), interferon-γ-induced protein 10 (IP-10), IL-1β, and IL-1Ra were associated with severe outcomes during hospitalization. Although no inflammatory markers correlated with VL at baseline, there was a significant correlation between VL and levels of IP-10 and MCP-1 at days 3–5, accompanied by IL-8 and IL-6 at days 7–10. Finally, there was a seemingly additive effect of IP-10, MCP-1, and IL-6 in predicting severe outcomes when combined with high VL at baseline. Conclusions An increasing number of inflammatory markers were associated with VL during the first 10 days of hospitalization, and several of these markers were associated with severe outcomes, in particular when combined with elevated VL. Future studies should assess the potential for combining antiviral and immunomodulatory treatment, preferably guided by viral and inflammatory biomarkers, for the selection of high-risk patients.

• Fageräng, Beatrice Linnea Christina; Cyranka, Leon; Schjalm, Camilla; Ekholt, Karin; Larsen, Carina Sandem & Heinzelbecker, Julia [Show all 14 contributors for this article] (2024). The function of the complement system remains fully intact throughout the course of allogeneic stem cell transplantation. Frontiers in Immunology. 15. doi: 10.3389/fimmu.2024.1422370. Full text in Research Archive Show summary

  Introduction: Hematopoietic stem cell transplantation (HSCT) is associated with immune complications and endothelial dysfunction due to intricate donor-recipient interactions, conditioning regimens, and inflammatory responses. Methods: This study investigated the role of the complement system during HSCT and its interaction with the cytokine network. Seventeen acute myeloid leukemia patients undergoing HSCT were monitored, including blood sampling from the start of the conditioning regimen until four weeks post-transplant. Clinical follow-up was 200 days. Results: Total complement functional activity was measured by WIELISA and the degree of complement activation by ELISA measurement of sC5b-9. Cytokine release was measured using a 27-multiplex immuno-assay. At all time-points during HSCT complement functional activity remained comparable to healthy controls. Complement activation was continuously stable except for two patients demonstrating increased activation, consistent with severe endotheliopathy and infections. In vitro experiments with post-HSCT whole blood challenged with Escherichia coli, revealed a hyperinflammatory cytokine response with increased TNF, IL-1β, IL-6 and IL-8 formation. Complement C3 inhibition markedly reduced the cytokine response induced by Staphylococcus aureus, Aspergillus fumigatus, and cholesterol crystals. Discussion: In conclusion, HSCT patients generally retained a fully functional complement system, whereas activation occurred in patients with severe complications. The complement-cytokine interaction indicates the potential for new complement-targeting therapeutic strategies in HSCT.

• Barratt-Due, Andreas; Pettersen, Kristin; Dahl, Tuva Børresdatter; Holter, Jan Cato; Grønli, Renathe Henriksen & Dyrhol-Riise, Anne Ma [Show all 20 contributors for this article] (2024). Escalated complement activation during hospitalization is associated with higher risk of 60-day mortality in SARS-CoV-2-infected patients. Journal of Internal Medicine. ISSN 0954-6820. 296(1), p. 80–92. doi: 10.1111/joim.13783. Full text in Research Archive Show summary

  Background: The complement system, an upstream recognition system of innate immunity, is activated upon SARS-CoV-2 infection. To gain a deeper understanding of the extent and duration of this activation, we investigated complement activation profiles during the acute phase of COVID-19, its persistence post-recovery and dynamic changes in relation to disease severity. Methods: Serial blood samples were obtained from two cohorts of hospitalized COVID-19 patients (n = 457). Systemic complement activation products reflecting classical/lectin (C4d), alternative (C3bBbP), common (C3bc) and terminal pathway (TCC and C5a) were measured during hospitalization (admission, days 3–5 and days 7–10), at 3 months and after 1 year. Levels of activation and temporal profiles during hospitalization were related to disease severity defined as respiratory failure (PO2/FiO2 ratio <26.6 kPa) and/or admission to intensive care unit, 60-day total mortality and pulmonary pathology after 3 months. Findings: During hospitalization, TCC, C4d, C3bc, C3bBbP and C5a were significantly elevated compared to healthy controls. Severely ill patients had significantly higher levels of TCC and C4d (p < 0.001), compared to patients with moderate COVID-19. Escalated levels of TCC and C4d during hospitalization were associated with a higher risk of 60-day mortality (p < 0.001), and C4d levels were additionally associated with chest CT changes at 3 months (p < 0.001). At 3 months and 1 year, we observed consistently elevated levels of most complement activation products compared to controls. Conclusion: Hospitalized COVID-19 patients display prominent and long-lasting systemic complement activation. Optimal targeting of the system may be achieved through enhanced risk stratification and closer monitoring of in-hospital changes of complement activation products.

• Murphy, Sarah Louise Mikalsen; Balzer, Nora Reka; Ranheim, Trine; Sagen, Ellen Lund; Huse, Camilla & Bjerkeli, Vigdis [Show all 19 contributors for this article] (2024). Extracellular matrix remodelling pathway in peripheral blood mononuclear cells from severe COVID-19 patients: an explorative study. Frontiers in Immunology. 15. doi: 10.3389/fimmu.2024.1379570. Full text in Research Archive Show summary

  There is a reciprocal relationship between extracellular matrix (ECM) remodelling and inflammation that could be operating in the progression of severe COVID-19. To explore the immune-driven ECM remodelling in COVID-19, we in this explorative study analysed these interactions in hospitalised COVID-19 patients. RNA sequencing and flow analysis were performed on peripheral blood mononuclear cells. Inflammatory mediators in plasma were measured by ELISA and MSD, and clinical information from hospitalised COVID-19 patients (N=15) at admission was included in the analysis. Further, we reanalysed two publicly available datasets: (1) lung tissue RNA-sequencing dataset (N=5) and (2) proteomics dataset from PBCM. ECM remodelling pathways were enriched in PBMC from COVID-19 patients compared to healthy controls. Patients treated at the intensive care unit (ICU) expressed distinct ECM remodelling gene profiles compared to patients in the hospital ward. Several markers were strongly correlated to immune cell subsets, and the dysregulation in the ICU patients was positively associated with plasma levels of inflammatory cytokines and negatively associated with B-cell activating factors. Finally, our analysis of publicly accessible datasets revealed (i) an augmented ECM remodelling signature in inflamed lung tissue compared to non-inflamed tissue and (ii) proteomics analysis of PBMC from severe COVID-19 patients demonstrated an up-regulation in an ECM remodelling pathway. Our results may suggest the presence of an interaction between ECM remodelling, inflammation, and immune cells, potentially initiating or perpetuating pulmonary pathology in severe COVID-19.

• Anthon, Carl Thomas; Pène, Frédéric; Perner, Anders; Azoulay, Elie; Puxty, Kathryn & Louw, Andry Van De [Show all 47 contributors for this article] (2024). Platelet transfusions in adult ICU patients with thrombocytopenia: A sub-study of the PLOT-ICU inception cohort study. Acta Anaesthesiologica Scandinavica. ISSN 0001-5172. 68(8), p. 1018–1030. doi: 10.1111/aas.14467. Full text in Research Archive Show summary

  Background Platelet transfusions are frequently used in the intensive care unit (ICU), but current practices including used product types, volumes, doses and effects are unknown. Study design and methods Sub-study of the inception cohort study ‘Thrombocytopenia and Platelet Transfusions in the ICU (PLOT-ICU)’, including acutely admitted, adult ICU patients with thrombocytopenia (platelet count <150 × 109/L). The primary outcome was the number of patients receiving platelet transfusion in ICU by product type. Secondary outcomes included platelet transfusion details, platelet increments, bleeding, other transfusions and mortality. Results Amongst 504 patients with thrombocytopenia from 43 hospitals in 10 countries in Europe and the United States, 20.8% received 565 platelet transfusions; 61.0% received pooled products, 21.9% received apheresis products and 17.1% received both with a median of 2 (interquartile range 1–4) days from admission to first transfusion. The median volume per transfusion was 253 mL (180–308 mL) and pooled products accounted for 59.1% of transfusions, however, this varied across countries. Most centres (73.8%) used fixed dosing (medians ranging from 2.0 to 3.5 × 1011 platelets/transfusion) whilst some (mainly in France) used weight-based dosing (ranging from 0.5 to 0.7 × 1011 platelets per 10 kg body weight). The median platelet count increment for a single prophylactic platelet transfusion was 2 (−1 to 8) × 109/L. Outcomes of patients with thrombocytopenia who did and did not receive platelet transfusions varied. Conclusions Among acutely admitted, adult ICU patients with thrombocytopenia, 20.8% received platelet transfusions in ICU of whom most received pooled products, but considerable variation was observed in product type, volumes and doses across countries. Prophylactic platelet transfusions were associated with limited increases in platelet counts.

• Patrick-Brown, Thale Dawn; Barratt-Due, Andreas; Trøseid, Marius; Dyrhol-Riise, Anne Ma; Nezvalova-Henriksen, Katerina & Kåsine, Trine [Show all 8 contributors for this article] (2024). The effects of remdesivir on long-term symptoms in patients hospitalised for COVID-19: a pre-specified exploratory analysis. Communications Medicine. 4(231), p. 1–7. doi: 10.1038/s43856-024-00650-4. Full text in Research Archive Show summary

  Background There is an unmet need for treatment of long-term symptoms following COVID-19. Remdesivir is currently the only antiviral approved by the European Medicines Agency for hospitalised patients. Here, we report on the effect of remdesivir in addition to standard of care on long-term symptoms and quality of life in hospitalised patients with COVID-19 as part of the open-label randomised NOR-Solidarity trial (NCT04321616). Methods A total of 185 patients were included in the main trial, of which 118 (60%) were randomised to either remdesivir (n = 42; 36%) or a post-hoc defined control group composed of patients who received standard of care alone or standard of care with hydroxychloroquine (n = 76; 64%). Participants were given quality of life surveys to fill out to gauge their self-reported health over time (the COPD assessment test, the EQ-5D-5L and the RAND SF-36). Results Here we show that after three months, patients treated with remdesivir do not show significant improvements in stated health compared to those who were not. There are self-reported symptoms of fatigue [mean remdesivir group 2.6 (standard deviation 1.5) v control 2.1 (1.6), 95% confidence interval(CI) −1.17 to 0.15, p = 0.129], shortness of breath [3.0 (1.7) v 2.1 (1.8), 95% CI −1.53 to 0.16, p = 0.110] and coughing [1.8 (1.6) v 1.2 (1.5), 95% CI −1.3 to 0.33, p = 0.237] 3 months after randomisation assessed via the COPD Assessment Test. Conclusions Our findings indicate that treatment with remdesivir during hospitalisation does not provide any clinically relevant long-term benefit.

• Aslam, Tayyba Naz; Barratt-Due, Andreas; Fiane, Arnt Eltvedt; Friis, Camilla Margrethe; Hofsø, Kristin & Kåsine, Trine [Show all 8 contributors for this article] (2024). Gravide med akutt, alvorlig respirasjonssvikt utl⊘st av covid-19. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 144(1), p. 1–8. doi: 10.4045/tidsskr.23.0615. Full text in Research Archive Show summary

  Bakgrunn: Gravide med covid-19 har trolig økt risiko for alvorlig sykdom. Formålet med studien var å beskrive forløpet til gravide kvinner innlagt i intensivavdeling med akutt, alvorlig respirasjonssvikt utløst av covid-19. Materiale og metode: Gravide kvinner med covid-19 ble registrert ved innleggelse i Rikshospitalets intensivenheter i perioden mars 2020 til mai 2023. Vi gjennomgikk pasientenes journalopplysninger i ettertid og beskriver kliniske forløp, behandlingsparametere og laboratoriedata fra intensivoppholdet. Selvopplevd helse ble kartlagt 15 måneder etter intensivoppholdet. Resultater: 13 gravide var innlagt i perioden februar–desember 2021. Alle oppfylte kriterier for ARDS (acute respiratory distress syndrome / akutt lungesviktsyndrom) og fikk behandling i henhold til gjeldende retningslinjer med kortikosteroider og mekanisk ventilasjon. Ingen av pasientene var vaksinert mot covid-19. Ti pasienter ble oralintubert etter terapisvikt med non-invasiv mekanisk ventilasjon. Én pasient ble behandlet med ekstrakorporal membranoksygenering (ECMO). Alle gravide overlevde intensivoppholdet, men det var to tilfeller av intrauterin fosterdød. Nær halvparten av pasientene anga moderat til sterkt redusert egenopplevd helse og livskvalitet 15 måneder etter intensivoppholdet. Fortolkning: Samtlige gravide innlagt ved Rikshospitalets intensivenheter med ARDS utløst av covid-19 overlevde, men flere hadde plager lenge etter sykehusoppholdet.

• Amstutz, Alain; Speich, Benjamin; Mentré, France; Rüegg, Corina Silvia; Belhadi, Drifa & Assoumou, Lambert [Show all 35 contributors for this article] (2023). Effects of remdesivir in patients hospitalised with COVID-19: a systematic review and individual patient data meta-analysis of randomised controlled trials. The Lancet Respiratory Medicine. ISSN 2213-2600. 11(5), p. 453–464. doi: 10.1016/S2213-2600(22)00528-8. Full text in Research Archive
• Anthon, Carl Thomas; Pène, Frédéric; Perner, Anders; Azoulay, Elie; Puxty, Kathryn & Louw, Andry Van De [Show all 55 contributors for this article] (2023). Thrombocytopenia and platelet transfusions in ICU patients: an international inception cohort study (PLOT-ICU). Intensive Care Medicine. ISSN 0342-4642. 49(11), p. 1327–1338. doi: 10.1007/s00134-023-07225-2. Full text in Research Archive Show summary

  Purpose Thrombocytopenia (platelet count < 150 × 109/L) is common in intensive care unit (ICU) patients and is likely associated with worse outcomes. In this study we present international contemporary data on thrombocytopenia in ICU patients. Methods We conducted a prospective cohort study in adult ICU patients in 52 ICUs across 10 countries. We assessed frequencies of thrombocytopenia, use of platelet transfusions and clinical outcomes including mortality. We evaluated pre-selected potential risk factors for the development of thrombocytopenia during ICU stay and associations between thrombocytopenia at ICU admission and 90-day mortality using pre-specified logistic regression analyses. Results We analysed 1166 ICU patients; the median age was 63 years and 39.5% were female. Overall, 43.2% (95% confidence interval (CI) 40.4–46.1) had thrombocytopenia; 23.4% (20–26) had thrombocytopenia at ICU admission, and 19.8% (17.6–22.2) developed thrombocytopenia during their ICU stay. Absence of acquired immune deficiency syndrome (AIDS), non-cancer-related immune deficiency, liver failure, male sex, septic shock, and bleeding at ICU admission were associated with the development of thrombocytopenia during ICU stay. Among patients with thrombocytopenia, 22.6% received platelet transfusion(s), and 64.3% of in-ICU transfusions were prophylactic. Patients with thrombocytopenia had higher occurrences of bleeding and death, fewer days alive without the use of life-support, and fewer days alive and out of hospital. Thrombocytopenia at ICU admission was associated with 90-day mortality (adjusted odds ratio 1.7; 95% CI 1.19–2.42). Conclusion Thrombocytopenia occurred in 43% of critically ill patients and was associated with worse outcomes including increased mortality. Platelet transfusions were given to 23% of patients with thrombocytopenia and most were prophylactic.

• Cavaillon, Jean-Marc; Artigas, Antonio; Barratt-Due, Andreas; Giamarellos-Bourboulis, Evangelos J.; Gómez, Hernando & Hayem, Gilles [Show all 8 contributors for this article] (2023). SEVERE CORONAVIRUS DISEASE 2019: FROM PATHOGENESIS TO THERAPY. Shock. ISSN 1073-2322. 59(3), p. 10–15. doi: 10.1097/SHK.0000000000001956. Full text in Research Archive
• Bakkehaug, Jens Petter; Kåsine, Trine; Romundstad, Luis Georg; Narum, Jon; Laake, Jon Henrik & Svalebjørg, Morten [Show all 12 contributors for this article] (2023). Ekstrakorporal membranoksygenering ved akutt lungesviktsyndrom hos covid-19-pasienter. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 143(2). doi: 10.4045/tidsskr.22.0545. Full text in Research Archive
• Murphy, Sarah Louise Mikalsen; Halvorsen, Bente; Holter, Jan Cato; Huse, Camilla; Tveita, Anders & Trøseid, Marius [Show all 24 contributors for this article] (2023). Circulating markers of extracellular matrix remodelling in severe COVID-19 patients. Journal of Internal Medicine. ISSN 0954-6820. 294(6), p. 784–797. doi: 10.1111/joim.13725. Full text in Research Archive Show summary

  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.<p> <p>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. <p>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. <p>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.

• Ueland, Thor; Michelsen, Annika Elisabet; Tveita, Anders; Kåsine, Trine; Dahl, Tuva Børresdatter & Finbråten, Ane-Kristine [Show all 16 contributors for this article] (2023). Coagulopathy and adverse outcomes in hospitalized patients with COVID-19: results from the NOR-Solidarity trial. Research and Practice in Thrombosis and Haemostasis (RPTH). 8(1). doi: 10.1016/j.rpth.2023.102289. Full text in Research Archive Show summary

  Background - Several studies have examined parameters of increased thrombogenicity in COVID-19, but studies examining their association with long-term outcome and potential effects of antiviral agents in hospitalized patients with COVID-19 are scarce.<p> <p>Objectives - To evaluate plasma levels of hemostatic proteins during hospitalization in relation to disease severity, treatment modalities, and persistent pulmonary pathology after 3 months.<p> <p>Methods - In 165 patients with COVID-19 recruited into the NOR-Solidarity trial (NCT04321616) and randomized to treatment with hydroxychloroquine, remdesivir, or standard of care, we analyzed plasma levels of hemostatic proteins during the first 10 days of hospitalization (n = 160) and at 3 months of follow-up (n = 100) by enzyme immunoassay.<p> <p>Results - Our main findings were as follows: (i) tissue plasminogen activator (tPA) and tissue factor pathway inhibitor (TFPI) were increased in patients with severe disease (ie, the combined endpoint of respiratory failure [Po2-to-FiO2 ratio, <26.6 kPa] or need for treatment at an intensive care unit) during hospitalization. Compared to patients without severe disease, tPA levels were a median of 42% (P < .001), 29% (P = .002), and 36% (P = .015) higher at baseline, 3 to 5 days, and 7 to 10 days, respectively. For TFPI, median levels were 37% (P = .003), 25% (P < .001), and 10% (P = .13) higher in patients with severe disease at these time points, respectively. No changes in thrombin-antithrombin complex; alpha 2-antiplasmin; a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; or antithrombin were observed in relation to severe disease. (ii) Patients treated with remdesivir had lower levels of TFPI than those in patients treated with standard of care alone. (iii) TFPI levels during hospitalization, but not at 3 months of follow-up, were higher in those with persistent pathology on chest computed tomography imaging 3 months after hospital admission than in those without such pathology. No consistent changes in thrombin-antithrombin complex, alpha 2-antiplasmin, ADAMTS-13, tPA, or antithrombin were observed in relation to pulmonary pathology at 3 months of follow-up.<p> <p>Conclusion - TFPI and tPA are associated with severe disease in hospitalized patients with COVID-19. For TFPI, high levels measured during the first 10 days of hospitalization were also associated with persistent pulmonary pathology even 3 months after hospital admittance.

• Buanes, Eirik Alnes; Bruserud, Øyvind; Huroz, Sergio Carracedo; Barratt-Due, Andreas; Flaatten, Hans Kristian & Kvåle, Reidar (2023). External validation of SAPS II score reported to the Norwegian Intensive Care and Pandemic Registry (NIPaR). Norsk Epidemiologi. ISSN 0803-2491. 31(1-2), p. 99–104. doi: 10.5324/nje.v31i1-2.5618. Full text in Research Archive Show summary

  Background: Simplified Acute Physiology Score II (SAPS II) is a mortality prediction model widely used to compensate for differences between intensive care units (ICU) in benchmarking and research. Accuracy of SAPS II is sparsely documented. We investigate accuracy by comparing patient journal SAPS II values with registry SAPS II values in the Norwegian Intensive Care and Pandemic Registry (NIPaR). Method: NIPaR personnel collected data from the patient journal during visitations to ICUs in ten different hospitals between 2017 and 2022 while blinded for registry SAPS II data. The patient journal SAPS II values were subsequently compared with the registry SAPS II values. Results: Difference of means for SAPS II score between patient journal and registry data was 5.2 points (95% CI 2.8–7.6; p < 0.001). SAPS II score depended significantly on ICU (p < 0.001) and data origin (p = 0.006), whereas the interaction term for these two variables was not significant. Conclusion: We find low accuracy of SAPS II score in a registry setting.

• Tran, Trung; Vaage, Eline Benno; Mehta, Adi; Chopra, Adity; Tietze, Lisa & Kolderup, Heidi Anette [Show all 40 contributors for this article] (2022). Titers of antibodies against ancestral SARS-CoV-2 correlate with levels of neutralizing antibodies to multiple variants. npj Vaccines. 7(1). doi: 10.1038/s41541-022-00586-7. Full text in Research Archive Show summary

  Diagnostic assays currently used to monitor the efficacy of COVID-19 vaccines measure levels of antibodies to the receptor-binding domain of ancestral SARS-CoV-2 (RBDwt). However, the predictive value for protection against new variants of concern (VOCs) has not been firmly established. Here, we used bead-based arrays and flow cytometry to measure binding of antibodies to spike proteins and receptor-binding domains (RBDs) from VOCs in 12,000 serum samples. Effects of sera on RBD-ACE2 interactions were measured as a proxy for neutralizing antibodies. The samples were obtained from healthy individuals or patients on immunosuppressive therapy who had received two to four doses of COVID-19 vaccines and from COVID-19 convalescents. The results show that anti-RBDwt titers correlate with the levels of binding- and neutralizing antibodies against the Alpha, Beta, Gamma, Delta, Epsilon and Omicron variants. The benefit of multiplexed analysis lies in the ability to measure a wide range of anti-RBD titers using a single dilution of serum for each assay. The reactivity patterns also yield an internal reference for neutralizing activity and binding antibody units per milliliter (BAU/ml). Results obtained with sera from vaccinated healthy individuals and patients confirmed and extended results from previous studies on time-dependent waning of antibody levels and effects of immunosuppressive agents. We conclude that anti-RBDwt titers correlate with levels of neutralizing antibodies against VOCs and propose that our method may be implemented to enhance the precision and throughput of immunomonitoring.

• Søvik, Signe; Barratt-Due, Andreas; Kåsine, Trine; Olasveengen, Theresa M.; Strand, Marianne Wigernes & Tveita, Anders Aune [Show all 16 contributors for this article] (2022). Corticosteroids and superinfections in COVID-19 patients on invasive mechanical ventilation. Journal of Infection. ISSN 0163-4453. 85(1), p. 57–63. doi: 10.1016/j.jinf.2022.05.015. Full text in Research Archive Show summary

  Objectives To determine the incidence and characteristics of superinfections in mechanically ventilated COVID-19 patients, and the impact of dexamethasone as standard therapy. Methods This multicentre, observational, retrospective study included patients ≥ 18 years admitted from March 1st 2020 to January 31st 2021 with COVID-19 infection who received mechanical ventilation. Patient characteristics, clinical characteristics, therapy and survival were examined. Results 155/156 patients (115 men, mean age 62 years, range 26-84 years) were included. 67 patients (43%) had 90 superinfections, pneumonia dominated (78%). Superinfections were associated with receiving dexamethasone (66% vs 32%, p<0.0001), autoimmune disease (18% vs 5.7%, p<0.016) and with longer ICU stays (26 vs 17 days, p<0,001). Invasive fungal infections were reported exclusively in dexamethasone-treated patients [8/67 (12%) vs 0/88 (0%), p<0.0001]. Unadjusted 90-day survival did not differ between patients with or without superinfections (64% vs 73%, p=0.25), but was lower in patients receiving dexamethasone versus not (58% vs 78%, p=0.007). In multiple regression analysis, superinfection was associated with dexamethasone use [OR 3.7 (1.80–7.61), p<0.001], pre-existing autoimmune disease [OR 3.82 (1.13–12.9), p=0.031] and length of ICU stay [OR 1.05 p<0.001]. Conclusions In critically ill COVID-19 patients, dexamethasone as standard of care was strongly and independently associated with superinfections.

• Pan, Hongchao; Peto, Richard; Karim, Quarraisha Abdool; Alejandria, Marissa M.; Henao-Restrepo, Ana-Maria & Hernández-García, César [Show all 51 contributors for this article] (2022). Remdesivir and three other drugs for hospitalised patients with COVID-19: final results of the WHO Solidarity randomised trial and updated meta-analyses. The Lancet. ISSN 0140-6736. 399(10339), p. 1941–1953. doi: 10.1016/S0140-6736(22)00519-0. Full text in Research Archive Show summary

  Background The Solidarity trial among COVID-19 inpatients has previously reported interim mortality analyses for four repurposed antiviral drugs. Lopinavir, hydroxychloroquine, and interferon (IFN)-β1a were discontinued for futility but randomisation to remdesivir continued. Here, we report the final results of Solidarity and meta-analyses of mortality in all relevant trials to date. Methods Solidarity enrolled consenting adults (aged ≥18 years) recently hospitalised with, in the view of their doctor, definite COVID-19 and no contraindication to any of the study drugs, regardless of any other patient characteristics. Participants were randomly allocated, in equal proportions between the locally available options, to receive whichever of the four study drugs (lopinavir, hydroxychloroquine, IFN-β1a, or remdesivir) were locally available at that time or no study drug (controls). All patients also received the local standard of care. No placebos were given. The protocol-specified primary endpoint was in-hospital mortality, subdivided by disease severity. Secondary endpoints were progression to ventilation if not already ventilated, and time-to-discharge from hospital. Final log-rank and Kaplan-Meier analyses are presented for remdesivir, and are appended for all four study drugs. Meta-analyses give weighted averages of the mortality findings in this and all other randomised trials of these drugs among hospital inpatients. Solidarity is registered with ISRCTN, ISRCTN83971151, and ClinicalTrials.gov, NCT04315948. Findings Between March 22, 2020, and Jan 29, 2021, 14 304 potentially eligible patients were recruited from 454 hospitals in 35 countries in all six WHO regions. After the exclusion of 83 (0·6%) patients with a refuted COVID-19 diagnosis or encrypted consent not entered into the database, Solidarity enrolled 14 221 patients, including 8275 randomly allocated (1:1) either to remdesivir (ten daily infusions, unless discharged earlier) or to its control (allocated no study drug although remdesivir was locally available). Compliance was high in both groups. Overall, 602 (14·5%) of 4146 patients assigned to remdesivir died versus 643 (15·6%) of 4129 assigned to control (mortality rate ratio [RR] 0·91 [95% CI 0·82–1·02], p=0·12). Of those already ventilated, 151 (42·1%) of 359 assigned to remdesivir died versus 134 (38·6%) of 347 assigned to control (RR 1·13 [0·89–1·42], p=0·32). Of those not ventilated but on oxygen, 14·6% assigned to remdesivir died versus 16·3% assigned to control (RR 0·87 [0·76–0·99], p=0·03). Of 1730 not on oxygen initially, 2·9% assigned to remdesivir died versus 3·8% assigned to control (RR 0·76 [0·46–1·28], p=0·30). Combining all those not ventilated initially, 11·9% assigned to remdesivir died versus 13·5% assigned to control (RR 0·86 [0·76–0·98], p=0·02) and 14·1% versus 15·7% progressed to ventilation (RR 0·88 [0·77–1·00], p=0·04). The non-prespecified composite outcome of death or progression to ventilation occurred in 19·6% assigned to remdesivir versus 22·5% assigned to control (RR 0·84 [0·75–0·93], p=0·001). Allocation to daily remdesivir infusions (vs open-label control) delayed discharge by about 1 day during the 10-day treatment period. A meta-analysis of mortality in all randomised trials of remdesivir versus no remdesivir yielded similar findings. Interpretation Remdesivir has no significant effect on patients with COVID-19 who are already being ventilated. Among other hospitalised patients, it has a small effect against death or progression to ventilation (or both).

• Ueland, Thor; Sørvoll, Ingvild Hausberg; Mørtberg, Trude Victoria; Dahl, Tuva Børresdatter; Lerum, Tøri Vigeland & Michelsen, Annika Elisabet [Show all 16 contributors for this article] (2022). Anti-PF4/polyanion antibodies in COVID-19 patients are associated with disease severity and pulmonary pathology. Platelets. ISSN 0953-7104. 33(4), p. 640–644. doi: 10.1080/09537104.2022.2042238. Full text in Research Archive Show summary

  Thromboembolic events are frequent and associated with poor outcome in severe COVID-19 disease. Anti-PF4/polyanion antibodies are related to heparin-induced thrombocytopenia (HIT) and thrombus formation, but data on these antibodies in unselected COVID-19 populations are scarce. We assessed the presence of anti-PF4/polyanion antibodies in prospectively collected serum from an unselected cohort of hospitalized COVID-19 patients and evaluated if elevated levels could give prognostic information on ICU admission and respiratory failure (RF), were associated with markers of inflammation, endothelial activation, platelet activation, coagulation and fibrosis and were associated with long-term pulmonary CT changes. Five out of 65 patients had anti-PF4/polyanion reactivity with OD ≥0.200. These patients had more severe disease as reflected by ICU admission without any evidence of HIT. They also had signs of enhanced inflammation and fibrinogenesis as reflected by elevated ferritin and osteopontin, respectively, during the first 10 days of hospitalization. Increased ferritin and osteopontin persisted in these patients at 3 months follow-up, concomitant with pulmonary CT pathology. Our finding shows that the presence of anti-PF4/polyanion antibodies in unselected hospitalized COVID−19 patients was not related to HIT, but was associated with disease severity, inflammation, and pulmonary pathology after 3 months.

• Burghi, Gaston; Metaxa, Victoria; Pickkers, Peter; Soares, Marcio; Rello, Jordi & Bauer, Philippe R. [Show all 20 contributors for this article] (2022). End of life decisions in immunocompromised patients with acute respiratory failure. Journal of Critical Care. ISSN 0883-9441. 72. doi: 10.1016/j.jcrc.2022.154152. Full text in Research Archive
• Tveita, Anders Aune; Murphy, Sarah Louise Mikalsen; Holter, Jan Cato; Kildal, Anders Benjamin; Michelsen, Annika Elisabet & Lerum, Tøri Vigeland [Show all 28 contributors for this article] (2022). High Circulating Levels of the Homeostatic Chemokines CCL19 and CCL21 Predict Mortality and Disease Severity in COVID-19. Journal of Infectious Diseases. ISSN 0022-1899. 226(12), p. 2150–2160. doi: 10.1093/infdis/jiac313. Full text in Research Archive Show summary

  Background Immune dysregulation is a major factor in the development of severe coronavirus disease 2019 (COVID-19). The homeostatic chemokines CCL19 and CCL21 have been implicated as mediators of tissue inflammation, but data on their regulation in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is limited. We thus investigated the levels of these chemokines in COVID-19 patients. Methods Serial blood samples were obtained from patients hospitalized with COVID-19 (n = 414). Circulating CCL19 and CCL21 levels during hospitalization and 3-month follow-up were analyzed. In vitro assays and analysis of RNAseq data from public repositories were performed to further explore possible regulatory mechanisms. Results A consistent increase in circulating levels of CCL19 and CCL21 was observed, with high levels correlating with disease severity measures, including respiratory failure, need for intensive care, and 60-day all-cause mortality. High levels of CCL21 at admission were associated with persisting impairment of pulmonary function at the 3-month follow-up. Conclusions Our findings highlight CCL19 and CCL21 as markers of immune dysregulation in COVID-19. This may reflect aberrant regulation triggered by tissue inflammation, as observed in other chronic inflammatory and autoimmune conditions. Determination of the source and regulation of these chemokines and their effects on lung tissue is warranted to further clarify their role in COVID-19.

• Trøseid, Marius; Dahl, Tuva Børresdatter; Holter, Jan Cato; Kildal, Anders Benjamin; Murphy, Sarah Louise Mikalsen & Yang, Kuan [Show all 28 contributors for this article] (2022). Persistent T-cell exhaustion in relation to prolonged pulmonary pathology and death after severe COVID-19: Results from two Norwegian cohort studies. Journal of Internal Medicine. ISSN 0954-6820. 292(5), p. 816–828. doi: 10.1111/joim.13549. Full text in Research Archive Show summary

  Background: T-cell activation is associated with an adverse outcome in COVID-19, but whether T-cell activation and exhaustion relate to persistent respiratory dysfunction and death is unknown. Objectives: To investigate whether T-cell activation and exhaustion persist and are associated with prolonged respiratory dysfunction and death after hospitalization for COVID-19. Methods: Plasma and serum from two Norwegian cohorts of hospitalized patients with COVID-19 (n = 414) were analyzed for soluble (s) markers of T-cell activation (sCD25) and exhaustion (sTim-3) during hospitalization and follow-up. Results: Both markers were strongly associated with acute respiratory failure, but only sTim-3 was independently associated with 60-day mortality. Levels of sTim-3 remained elevated 3 and 12 months after hospitalization and were associated with pulmonary radiological pathology after 3 months. Conclusion: Our findings suggest prolonged T-cell exhaustion is an important immunological sequela, potentially related to long-term outcomes after severe COVID-19.

• Vestad, Beate; Ueland, Thor; Lerum, Tøri Vigeland; Dahl, Tuva Børresdatter; Holm, Kristian & Barratt-Due, Andreas [Show all 37 contributors for this article] (2022). Respiratory dysfunction three months after severe COVID-19 is associated with gut microbiota alterations. Journal of Internal Medicine. ISSN 0954-6820. 291(6), p. 801–812. doi: 10.1111/joim.13458. Full text in Research Archive Show summary

  Background: Although coronavirus disease 2019 (COVID-19) is primarily a respiratory infection, mounting evidence suggests that the gastrointestinal (GI) tract is involved in the disease, with gut barrier dysfunction and gut microbiota alterations being related to disease severity. Whether these alterations persist and are related to long-term respiratory dysfunction remains unknown. Methods: Plasma was collected during hospital admission and after three months from the NOR-Solidarity trial (n = 181) and analysed for markers of gut barrier dysfunction and inflammation. At the three-month follow-up, pulmonary function was assessed by measuring the diffusing capacity of the lungs for carbon monoxide (DLCO ). Rectal swabs for gut microbiota analyses were collected (n = 97) and analysed by sequencing the 16S rRNA gene. Results: Gut microbiota diversity was reduced in COVID-19 patients with respiratory dysfunction, defined as DLCO below the lower limit of normal three months after hospitalisation. These patients also had an altered global gut microbiota composition, with reduced relative abundance of 20 bacterial taxa and increased abundance of five taxa, including Veillonella, potentially linked to fibrosis. During hospitalisation, increased plasma levels of lipopolysaccharide-binding protein (LBP) were strongly associated with respiratory failure, defined as pO2 /fiO2 -(P/F ratio)

• Lerum, Tøri Vigeland; Maltzahn, Niklas; Aukrust, Pål; Trøseid, Marius; Nezvalova-Henriksen, Katerina & Kåsine, Trine [Show all 27 contributors for this article] (2021). Persistent pulmonary pathology after COVID-19 is associated with high viral load, weak antibody response, and high levels of matrix metalloproteinase-9. Scientific Reports. 11, p. 1–12. doi: 10.1038/s41598-021-02547-x. Full text in Research Archive Show summary

  The association between pulmonary sequelae and markers of disease severity, as well as pro-fibrotic mediators, were studied in 108 patients 3 months after hospital admission for COVID-19. The COPD assessment test (CAT-score), spirometry, diffusion capacity of the lungs (DLCO), and chest-CT were performed at 23 Norwegian hospitals included in the NOR-SOLIDARITY trial, an open-labelled, randomised clinical trial, investigating the efficacy of remdesivir and hydroxychloroquine (HCQ). Thirty-eight percent had a CAT-score ≥ 10. DLCO was below the lower limit of normal in 29.6%. Ground-glass opacities were present in 39.8% on chest-CT, parenchymal bands were found in 41.7%. At admission, low pO2/FiO2 ratio, ICU treatment, high viral load, and low antibody levels, were predictors of a poorer pulmonary outcome after 3 months. High levels of matrix metalloproteinase (MMP)-9 during hospitalisation and at 3 months were associated with persistent CT-findings. Except for a negative effect of remdesivir on CAT-score, we found no effect of remdesivir or HCQ on long-term pulmonary outcomes. Three months after hospital admission for COVID-19, a high prevalence of respiratory symptoms, reduced DLCO, and persistent CT-findings was observed. Low pO2/FiO2 ratio, ICU-admission, high viral load, low antibody levels, and high levels of MMP-9 were associated with a worse pulmonary outcome.

• Pascal, Furaha Nzanzu Blaise; Malisawa, Agnes; Barratt-Due, Andreas; Namboya, Felix & Pollach, Gregor (2021). General anaesthesia related mortality in a limited resource settings region: a retrospective study in two teaching hospitals of Butembo. BMC Anesthesiology. 21(1). doi: 10.1186/s12871-021-01280-2. Full text in Research Archive
• Kåsine, Trine; Riise, Anne Margarita Dyrhol; Barratt-Due, Andreas; Kildal, Anders Benjamin; Olsen, Inge Christoffer & Nezvalova-Henriksen, Katerina [Show all 39 contributors for this article] (2021). Neutrophil count predicts outcome in hospitalized COVID-19 patients. Results from the NOR-Solidarity trial. Journal of Internal Medicine. ISSN 0954-6820. 291(2), p. 241–243. doi: 10.1111/joim.13377. Full text in Research Archive Show summary

  Despite numerous studies on SARS-CoV-2-induced inflammation, we still lack markers for rapid disease progression with admission to intensive care unit (ICU) or respiratory failure(RF). Few studies have evaluated the prognostic value of routine diagnostic repertoire available at most hospitals. The NOR-Solidarity trial is an independent add-on study to the WHO Solidarity trial, evaluating hydroxychloroquine (HCQ)and remdesivir compared to standard of care in hospitalized COVID-19 patients [1]. We explored whether standard biomarkers in peripheral blood could give information on ICU admission and RFin hospitalized COVID-19 patients.

• Thomas, Anub Mathew; Chaban, Viktoriia; Pischke, Soeren; Orrem, Hilde Lang; Bosnes, Vidar & Sunde, Kjetil [Show all 13 contributors for this article] (2021). Complement ratios C3bc/C3 and sC5b-9/C5 do not increase the sensitivity of detecting acute complement activation systemically. Molecular Immunology. ISSN 0161-5890. 141, p. 273–279. doi: 10.1016/j.molimm.2021.11.016. Full text in Research Archive Show summary

  Background Complement activation plays an important pathogenic role in numerous diseases. The ratio between an activation product and its parent protein is suggested to be more sensitive to detect complement activation than the activation product itself. In the present study we explored whether the ratio between the activation product and the parent protein for C3 (C3bc/C3) and for C5 (sC5b-9/C5) increased the sensitivity to detect complement activation in acute clinical settings compared to the activation product alone. Materials and methods Samples from patients with acute heart failure following ST-elevated myocardial infarction (STEMI) and from patients with out-of-hospital cardiac arrest (OHCA) were used. C3, C3bc and C5, sC5b-9 were analysed in 629 and 672 patient samples, respectively. Healthy controls (n = 20) served to determine reference cut-off values for activation products and ratios, defined as two SD above the mean. Results Increased C3bc/C3- and sC5b-9/C5 ratios were vastly dependent on C3bc and sC5b-9. Thus, 99.5 % and 98.1 % of the increased C3bc/C3- and sC5b-9/C5 ratios were solely dependent on increased C3bc and sC5b-9, respectively. Significantly decreased C3 and C5 caused increased ratios in only 3/600 (0.5 %) and 4/319 (1.3 %) samples, respectively. Strong correlations between C3bc and C3bc/C3-ratio and between sC5b-9 and sC5b-9/C5-ratio were found in the STEMI- (r = 0.926 and r = 0.786, respectively) and the OHCA-population (r = 0.908 and r = 0.843, respectively; p < 0.0001 for all). Importantly, sC5b-9 identified worse outcome groups better than sC5b-9/C5-ratio. Conclusion C3bc and sC5b-9 were sensitive markers of complement activation. The ratios of C3bc/C3 and sC5b-9/C5 did not improve detection of complement activation systemically.

• Bjørkto, Magnus Holter; Barratt-Due, Andreas; Nordøy, Ingvild; Dörje, Christina; Galteland, Eivind & Lind, Andreas [Show all 9 contributors for this article] (2021). The use of eculizumab in Capnocytophaga canimorsus associated thrombotic microangiopathy: a case report. BMC Infectious Diseases. 21:137, p. 1–6. doi: 10.1186/s12879-021-05789-2. Full text in Research Archive
• Aamodt, Anne Hege; Høgestøl, Einar August; Popperud, Trine Haug; Holter, Jan Cato; Dyrhol-Riise, Anne Ma & Tonby, Kristian [Show all 15 contributors for this article] (2021). Blood neurofilament light concentration at admittance: a potential prognostic marker in COVID-19. Journal of Neurology. ISSN 0340-5354. doi: 10.1007/s00415-021-10517-6. Full text in Research Archive Show summary

  Objective To test the hypotheses that blood biomarkers for nervous system injury, serum concentrations of neurofilament light chain protein (NfL) and glial fibrillary acidic protein (GFAp) can serve as biomarkers for disease severity in COVID-19 patients. Methods Forty-seven inpatients with confirmed COVID-19 had blood samples drawn on admission for assessing serum biomarkers of CNS injury by Single molecule array (Simoa), NfL and GFAp. Concentrations of NfL and GFAp were analyzed in relation to symptoms, clinical signs, inflammatory biomarkers and clinical outcomes. We used multivariate linear models to test for differences in biomarker concentrations in the subgroups, accounting for confounding effects. Results In total, 21% (n = 10) of the patients were admitted to an intensive care unit, and the overall mortality rate was 13% (n = 6). Non-survivors had higher serum concentrations of NfL (p < 0.001) upon admission than patients who were discharged alive both in adjusted analyses (p = 2.6 × 10–7) and unadjusted analyses (p = 0.001). The concentrations of NfL in non-survivors increased over repeated measurements; whereas, the concentrations in survivors were stable. The GFAp concentration was also significantly higher in non-survivors than survivors (p = 0.02). Conclusion Increased concentrations of NfL and GFAp in COVID-19 patients on admission may indicate increased mortality risk. Measurement of blood biomarkers for nervous system injury can be useful to detect and monitor CNS injury in COVID-19.

• Tangen, Jorun; Aukrust, Pål; Barratt-Due, Andreas; Skulstad, Helge & Edvardsen, Thor (2021). Reduced cardiac function by echocardiography in a minority of COVID-19 patients three months after hospitalization. Journal of the American Society of Echocardiography. ISSN 0894-7317. doi: 10.1016/j.echo.2021.10.014. Full text in Research Archive
• Diallo, Alpha; Trøseid, Marius; Simensen, Victoria C; Boston, Anaïs; Demotes, Jacques & Olsen, Inge Christoffer [Show all 28 contributors for this article] (2021). Accelerating clinical trial implementation in the context of the COVID-19 pandemic: challenges, lessons learned and recommendations from DisCoVeRy and the EU-SolidAct EU response group. Clinical Microbiology and Infection (CMI). ISSN 1198-743X. 28(1), p. 1–6. doi: 10.1016/j.cmi.2021.10.011. Full text in Research Archive
• Barratt-Due, Andreas; Olsen, Inge Christoffer; Nezvalova-Henriksen, Katerina; Kåsine, Trine; Lund-Johansen, Fridtjof & Hoel, Hedda Benedicte [Show all 43 contributors for this article] (2021). Evaluation of the Effects of Remdesivir and Hydroxychloroquine on Viral Clearance in COVID-19 : A Randomized Trial. Annals of Internal Medicine. ISSN 0003-4819. 174(9), p. 1261–1269. doi: 10.7326/M21-0653. Full text in Research Archive Show summary

  Background: New treatment modalities are urgently needed for patients with COVID-19. The World Health Organization (WHO) Solidarity trial showed no effect of remdesivir or hydroxychloroquine (HCQ) on mortality, but the antiviral effects of these drugs are not known. Objective: To evaluate the effects of remdesivir and HCQ on all-cause, in-hospital mortality; the degree of respiratory failure and inflammation; and viral clearance in the oropharynx. Design: NOR-Solidarity is an independent, add-on, randomized controlled trial to the WHO Solidarity trial that included biobanking and 3 months of clinical follow-up (ClinicalTrials.gov: NCT04321616). Setting: 23 hospitals in Norway. Patients: Eligible patients were adults hospitalized with confirmed SARS-CoV-2 infection. Intervention: Between 28 March and 4 October 2020, a total of 185 patients were randomly assigned and 181 were included in the full analysis set. Patients received remdesivir (n = 42), HCQ (n = 52), or standard of care (SoC) (n = 87). Measurements: In addition to the primary end point of WHO Solidarity, study-specific outcomes were viral clearance in oropharyngeal specimens, the degree of respiratory failure, and inflammatory variables. Results: No significant differences were seen between treatment groups in mortality during hospitalization. There was a marked decrease in SARS-CoV-2 load in the oropharynx during the first week overall, with similar decreases and 10-day viral loads among the remdesivir, HCQ, and SoC groups. Remdesivir and HCQ did not affect the degree of respiratory failure or inflammatory variables in plasma or serum. The lack of antiviral effect was not associated with symptom duration, level of viral load, degree of inflammation, or presence of antibodies against SARS-CoV-2 at hospital admittance. Limitation: The trial had no placebo group. Conclusion: Neither remdesivir nor HCQ affected viral clearance in hospitalized patients with COVID-19.

• Louw, Andry van de; Rello, Jordi; Martin-Loeches, Ignacio; Mokart, Djamel; Metaxa, Victoria & Benoit, Dominique D. [Show all 19 contributors for this article] (2021). Bacteremia in critically ill immunocompromised patients with acute hypoxic respiratory failure: A post-hoc analysis of a prospective multicenter multinational cohort. Journal of Critical Care. ISSN 0883-9441. 64, p. 114–119. doi: 10.1016/j.jcrc.2021.03.014. Full text in Research Archive
• Medeiros, Pedro Miguel Coelho; Schjalm, Camilla; Christiansen, Dorte; Sokolova, Marina; Pischke, Soeren Erik & Würzner, Reinhard [Show all 8 contributors for this article] (2021). Vitamin C, Hydrocortisone, and the Combination Thereof Significantly Inhibited Two of Nine Inflammatory Markers Induced by Escherichia Coli But Not by Staphylococcus Aureus - When Incubated in Human Whole Blood. Shock. ISSN 1073-2322. 57(1), p. 72–80. doi: 10.1097/SHK.0000000000001834. Full text in Research Archive Show summary

  Vitamin C combined with hydrocortisone is increasingly being used to treat septic patients, even though this treatment regimen is based on questionable evidence. When used, a marked effect on key players of innate immunity would be expected, as sepsis is featured by a dysregulated immune response. Here, we explored the effect of vitamin C and hydrocortisone alone and combined, in an ex vivo human whole-blood model of Escherichia coli- or Staphylococcus aureus-induced inflammation. Inflammatory markers for activation of complement (terminal C5b-9 complement complex [TCC]), granulocytes (myeloperoxidase), platelets (β-thromboglobulin), cytokines (tumor necrosis factor [TNF], IL-1β, IL6, and IL-8), and leukocytes (CD11b and oxidative burst) were quantified, by enzyme-linked immunosorbent assay, multiplex technology, and flow cytometry. In E. coli- and S. aureus-stimulated whole blood, a broad dose-titration of vitamin C and hydrocortisone alone did not lead to dose–response effects for the central innate immune mediators TCC and IL-6. Hence, the clinically relevant doses were used further. Compared to the untreated control sample, two of the nine biomarkers induced by E. coli were reduced by hydrocortisone and/or vitamin C. TNF was reduced by hydrocortisone alone (19%, P = 0.01) and by the combination (31%, P = 0.01). The oxidative burst of monocytes and granulocytes was reduced for both drugs alone and their combination, (ranging 8–19%, P < 0.05). Using S. aureus, neither of the drugs, alone nor in combination, had any effects on the nine biomarkers. In conclusion, despite the limitation of the ex vivo model, the effect of vitamin C and hydrocortisone on bacteria-induced inflammatory response in human whole blood is limited and following the clinical data.

• Messika, Jonathan; Darmon, Michael; Mal, Hervé; Pickkers, Peter; Soares, Marcio & Canet, Emmanuel [Show all 30 contributors for this article] (2020). Etiologies and Outcomes of Acute Respiratory Failure in Solid Organ Transplant Recipients: Insight Into the EFRAIM Multicenter Cohort. Transplantation Proceedings. ISSN 0041-1345. 52(10), p. 2980–2987. doi: 10.1016/j.transproceed.2020.02.170. Full text in Research Archive
• Kayambankadzanja, Raphael Kazidule; Lihaka, Moses; Barratt-Due, Andreas; Kachingwe, Mtisunge; Kumwenda, Wezzie & Lester, Rebecca [Show all 9 contributors for this article] (2020). The use of antibiotics in the intensive care unit of a tertiary hospital in Malawi. BMC Infectious Diseases. 20(1), p. 1–7. doi: 10.1186/s12879-020-05505-6. Full text in Research Archive
• Munshi, Laveena; Darmon, Michael; Soares, Marcio; Pickkers, Peter; Bauer, Philippe R. & Meert, Anne-Pascale [Show all 18 contributors for this article] (2020). Acute Respiratory Failure Outcomes in Patients with Hematologic Malignancies and Hematopoietic Cell Transplant: A Secondary Analysis of the EFRAIM Study. Biology of Blood and Marrow Transplantation. ISSN 1083-8791. doi: 10.1016/j.bbmt.2020.09.035. Full text in Research Archive Show summary

  Patients with allogeneic hematopoietic cell transplantation (HCT) who develop acute respiratory failure (ARF) are perceived to have worse outcomes than autologous HCT recipients and non-transplant patients with hematologic malignancy (HM). Within a large international prospective cohort, we evaluated clinical outcomes in these 3 populations. We conducted a secondary analysis of the EFRAIM study, a multicenter observational study of immunocompromised adults with ARF admitted to 62 intensive care units (ICUs) in 16 countries. We described characteristics and compared outcomes of patients with HM who did not undergo transplantation and patients who underwent autologous or allogeneic HCT using multivariable logistic regression and propensity score-matched analyses. A total of 801 patients were included: 570 who did not undergo transplantation, 86 autologous HCT recipients and 145 allogeneic HCT recipients. Acute myelogenous leukemia (171 of 570; 30%) was the most common HM and most common indication for allogeneic HCT (76 of 145; 52%). Compared with the patients who did not undergo HCT and autologous HCT recipients, allogeneic HCT recipients were younger, had fewer comorbid conditions, and were more likely to undergo diagnostic bronchoscopy in the ICU. Unadjusted ICU and hospital mortality were 35% and 45%, respectively, across the entire cohort. In multivariable regression analysis, autologous HCT (odds ratio [OR], 1.07; 95% confidence interval [CI], .57 to 2.03; P = .82) and allogeneic HCT (OR, .99; 95% CI, .60 to 1.66; P = .98) were not associated with higher hospital mortality compared with the no-HCT cohort, adjusting for demographic, functional, clinical, malignancy, and ARF characteristics. The results were similar when analyzed using propensity score-matching techniques. Our findings indicate that autologous and allogeneic HCT recipients who develop ARF and require ICU admission have similar hospital mortality as patients with HM not treated with HCT.

• Martin-Loeches, Ignacio; Darmon, Michael; Demoule, Alexandre; Antonelli, Massimo; Schellongowski, Peter & Pickkers, Peter [Show all 23 contributors for this article] (2020). ICU-acquired pneumonia in immunosuppressed patients with acute hypoxemic respiratory failure: A post-hoc analysis of a prospective international cohort study. Journal of Critical Care. ISSN 0883-9441. p. 1–3. doi: 10.1016/j.jcrc.2020.09.027. Full text in Research Archive
• Pischke, Soeren; Hødnebø, Stina; Wester, Torjus; Haugaa, Håkon; Kvernebo, Knut & Barratt-Due, Andreas [Show all 7 contributors for this article] (2020). Intraperitoneal microdialysis detects intestinal leakage earlier than hemodynamic surveillance and systemic inflammation in a pig model. Scandinavian Journal of Gastroenterology. ISSN 0036-5521. 56(2), p. 219–227. doi: 10.1080/00365521.2020.1863459. Full text in Research Archive Show summary

  Objective Anastomotic leakage is a common complication following large abdominal surgery, often developing to life-threatening abdominal sepsis due to late diagnosis. Currently, diagnostics rely on systemic hemodynamic and infection monitoring. We hypothesized that intraperitoneal microdialysis allows detection of peritonitis prior to changes in standard clinical parameters in a pig model. Materials and Methods We included six pigs; five underwent intraperitoneal fecal contamination, one had sham surgery for a total of 10 h. Microdialysis was established in four intraabdominal quadrants and two hepatic lobes. All pigs were hemodynamically monitored with pulmonary artery and femoral artery catheters. Blood samples were assessed for inflammatory markers, terminal complement complex (TCC), interleukin (IL)-6, IL-10, and plasminogen activator inhibitor-1 (PAI-1). Results Microdialysis showed intraperitoneal lactate increase during the first two hours after fecal contamination, which remained elevated throughout the observation time with concurrent decrease of glucose. Arterial lactate remained within reference range (<1,6mM). Systemic inflammatory markers TCC, IL-6, IL-10 and PAI-1 increased significantly after minimum four hours. Mean arterial pressure, stroke volume variation and cardiac output were not compromised the first five hours. Sham surgery did not influence any of the parameters. Conclusion Intraperitoneal fecal contamination leads to a rapid and pronounced intraperitoneal increase in lactate, decrease in glucose while pyruvate and glycerol levels remain unchanged. This distinct metabolic pattern of peritoneal inflammation can be easily detected by microdialysis. Observation of this pattern may minimize time to safe diagnosis of intestinal perforations after intraperitoneal fecal contamination.

• Pascal, Furaha Nzanzu Blaise; Musavuli, Paulin Kambale; Ketha, Joel Kambale; Sikakulya, Franck Katembo; Barratt-Due, Andreas & Castner, Thomas [Show all 7 contributors for this article] (2020). Practice of standard monitoring during anaesthesia in hospitals of North Kivu: A survey of health facilities of the health antenna of Butembo. BMC Health Services Research. 20:262, p. 1–8. doi: 10.1186/s12913-020-05076-x. Full text in Research Archive
• Aamodt, Anne Hege; Harbo, Hanne Flinstad; Eldøen, Guttorm; Barratt-Due, Andreas & Aukrust, Pål (2020). Hvordan påvirkes hjernen ved covid-19? Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 140(10), p. 968–969. doi: 10.4045/tidsskr.20.0444. Full text in Research Archive
• Ueland, Thor; Heggelund, Lars; Lind, Andreas; Holten, Aleksander Rygh; Tonby, Kristian & Michelsen, Annika [Show all 26 contributors for this article] (2020). Elevated plasma sTIM-3 levels in patients with severe COVID-19. Journal of Allergy and Clinical Immunology. ISSN 0091-6749. 147(1), p. 92–98. doi: 10.1016/j.jaci.2020.09.007. Full text in Research Archive Show summary

  Background The pathogenesis of coronavirus disease 2019 (COVID-19) is still incompletely understood, but it seems to involve immune activation and immune dysregulation. Objective We examined the parameters of activation of different leukocyte subsets in COVID-19–infected patients in relation to disease severity. Methods We analyzed plasma levels of myeloperoxidase (a marker of neutrophil activation), soluble (s) CD25 (sCD25) and soluble T-cell immunoglobulin mucin domain-3 (sTIM-3) (markers of T-cell activation and exhaustion), and sCD14 and sCD163 (markers of monocyte/macrophage activation) in 39 COVID-19–infected patients at hospital admission and 2 additional times during the first 10 days in relation to their need for intensive care unit (ICU) treatment. Results Our major findings were as follows: (1) severe clinical outcome (ICU treatment) was associated with high plasma levels of sTIM-3 and myeloperoxidase, suggesting activated and potentially exhausted T cells and activated neutrophils, respectively; (2) in contrast, sCD14 and sCD163 showed no association with need for ICU treatment; and (3) levels of sCD25, sTIM-3, and myeloperoxidase were inversely correlated with degree of respiratory failure, as assessed by the ratio of Pao2 to fraction of inspired oxygen, and were positively correlated with the cardiac marker N-terminal pro-B–type natriuretic peptide. Conclusion Our findings suggest that neutrophil activation and, in particular, activated T cells may play an important role in the pathogenesis of COVID-19 infection, suggesting that T-cell–targeted treatment options and downregulation of neutrophil activation could be of importance in this disorder.

• Mokart, Djamel; Darmon, Michael; Schellongowski, Peter; Pickkers, Peter; Soares, Marcio & Rello, Jordi [Show all 28 contributors for this article] (2020). Acute respiratory failure in immunocompromised patients: outcome and clinical features according to neutropenia status. Annals of Intensive Care. 10:146, p. 1–9. doi: 10.1186/s13613-020-00764-7. Full text in Research Archive
• Demoule, Alexandre; Antonelli, Massimo; Schellongowski, Peter; Pickkers, Peter; Soares, Marcio & Meyhoff, Tine Sylvest [Show all 25 contributors for this article] (2020). Respiratory Mechanics and Outcomes in Immunocompromised Patients With ARDS: A Secondary Analysis of the EFRAIM Study. Chest. ISSN 0012-3692. 158(5), p. 1947–1957. doi: 10.1016/j.chest.2020.05.602. Full text in Research Archive
• Pan, Hongchao; Peto, Richard; Henao-Restrepo, Ana Maria; Preziosi, Marie-Pierre; Sathiyamoorthy, Vasee & Karim, Quarraisha Abdool [Show all 74 contributors for this article] (2020). Repurposed Antiviral Drugs for Covid-19 — Interim WHO Solidarity Trial Results. New England Journal of Medicine. ISSN 0028-4793. 384(6), p. 497–511. doi: 10.1056/NEJMoa2023184. Full text in Research Archive
• Holter, Jan Cato; Pischke, Soeren; Boer, Eline de; Lind, Andreas; Jenum, Synne & Holten, Aleksander Rygh [Show all 32 contributors for this article] (2020). Systemic complement activation is associated with respiratory failure in COVID-19 hospitalized patients. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 117(40), p. 25018–25025. doi: 10.1073/pnas.2010540117. Full text in Research Archive Show summary

  Respiratory failure in the acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is hypothesized to be driven by an overreacting innate immune response, where the complement system is a key player. In this prospective cohort study of 39 hospitalized coronavirus disease COVID-19 patients, we describe systemic complement activation and its association with development of respiratory failure. Clinical data and biological samples were obtained at admission, days 3 to 5, and days 7 to 10. Respiratory failure was defined as PO2/FiO2 ratio of ≤40 kPa. Complement activation products covering the classical/lectin (C4d), alternative (C3bBbP) and common pathway (C3bc, C5a, and sC5b-9), the lectin pathway recognition molecule MBL, and antibody serology were analyzed by enzyme-immunoassays; viral load by PCR. Controls comprised healthy blood donors. Consistently increased systemic complement activation was observed in the majority of COVID-19 patients during hospital stay. At admission, sC5b-9 and C4d were significantly higher in patients with than without respiratory failure (P = 0.008 and P = 0.034). Logistic regression showed increasing odds of respiratory failure with sC5b-9 (odds ratio 31.9, 95% CI 1.4 to 746, P = 0.03) and need for oxygen therapy with C4d (11.7, 1.1 to 130, P = 0.045). Admission sC5b-9 and C4d correlated significantly to ferritin (r = 0.64, P < 0.001; r = 0.69, P < 0.001). C4d, sC5b-9, and C5a correlated with antiviral antibodies, but not with viral load. Systemic complement activation is associated with respiratory failure in COVID-19 patients and provides a rationale for investigating complement inhibitors in future clinical trials.

• Martin-Loeches, Ignacio; Lemiale, Virginie; Geoghegan, Pierce; McMahon, Mary Aisling; Pickkers, Peter & Soares, Marcio [Show all 40 contributors for this article] (2019). Influenza and associated co-infections in critically ill immunosuppressed patients. Critical Care. ISSN 1364-8535. 23:152, p. 1–10. doi: 10.1186/s13054-019-2425-6. Full text in Research Archive Show summary

  Background It is unclear whether influenza infection and associated co-infection are associated with patient-important outcomes in critically ill immunocompromised patients with acute respiratory failure. Methods Preplanned secondary analysis of EFRAIM, a prospective cohort study of 68 hospitals in 16 countries. We included 1611 patients aged 18 years or older with non-AIDS-related immunocompromise, who were admitted to the ICU with acute hypoxemic respiratory failure. The main exposure of interest was influenza infection status. The primary outcome of interest was all-cause hospital mortality, and secondary outcomes ICU length of stay (LOS) and 90-day mortality. Results Influenza infection status was categorized into four groups: patients with influenza alone (n = 95, 5.8%), patients with influenza plus pulmonary co-infection (n = 58, 3.6%), patients with non-influenza pulmonary infection (n = 820, 50.9%), and patients without pulmonary infection (n = 638, 39.6%). Influenza infection status was associated with a requirement for intubation and with LOS in ICU (P < 0.001). Patients with influenza plus co-infection had the highest rates of intubation and longest ICU LOS. On crude analysis, influenza infection status was associated with ICU mortality (P < 0.001) but not hospital mortality (P = 0.09). Patients with influenza plus co-infection and patients with non-influenza infection alone had similar ICU mortality (41% and 37% respectively) that was higher than patients with influenza alone or those without infection (33% and 26% respectively). A propensity score-matched analysis did not show a difference in hospital mortality attributable to influenza infection (OR = 1.01, 95%CI 0.90–1.13, P = 0.85). Age, severity scores, ARDS, and performance status were all associated with ICU, hospital, and 90-day mortality. Conclusions Category of infectious etiology of respiratory failure (influenza, non-influenza, influenza plus co-infection, and non-infectious) was associated with ICU but not hospital mortality. In a propensity score-matched analysis, influenza infection was not associated with the primary outcome of hospital mortality. Overall, influenza infection alone may not be an independent risk factor for hospital mortality in immunosuppressed patients.

• Azoulay, Elie; Bauer, Philippe R.; Mariotte, Eric; Russell, Lene; Knoebl, Paul & Martín-Loeches, Ignacio [Show all 20 contributors for this article] (2019). Expert statement on the ICU management of patients with thrombotic thrombocytopenic purpura. Intensive Care Medicine. ISSN 0342-4642. 45(11), p. 1518–1539. doi: 10.1007/s00134-019-05736-5. Full text in Research Archive
• Thorgersen, Ebbe Billmann; Barratt-Due, Andreas; Haugaa, Håkon; Harboe, Morten; Pischke, Søren & Nilsson, Per [Show all 7 contributors for this article] (2019). The role of complement in liver injury, regeneration, and transplantation. Hepatology. ISSN 0270-9139. 70(2), p. 725–736. doi: 10.1002/hep.30508. Full text in Research Archive Show summary

  The liver is both an immunologically complex and a privileged organ. The innate immune system is a central player, in which the complement system emerges as a pivotal part of liver homeostasis, immune responses, and crosstalk with other effector systems in both innate and adaptive immunity. The liver produces the majority of the complement proteins and is the home of important immune cells such as Kupffer cells. Liver immune responses are delicately tuned between tolerance to many antigens flowing in from the alimentary tract, a tolerance that likely makes the liver less prone to rejection than other solid organ transplants, and reaction to local injury, systemic inflammation, and regeneration. Notably, complement is a double‐edged sword as activation is detrimental by inducing inflammatory tissue damage in, for example, ischemia–reperfusion injury and transplant rejection yet is beneficial for liver tissue regeneration. Therapeutic complement inhibition is rapidly developing for routine clinical treatment of several diseases. In the liver, targeted inhibition of damaged tissue may be a rational and promising approach to avoid further tissue destruction and simultaneously preserve beneficial effects of complement in areas of proliferation. Here, we argue that complement is a key system to manipulate in the liver in several clinical settings, including liver injury and regeneration after major surgery and preservation of the organ during transplantation.

• Bauer, Philippe R.; Chevret, Sylvie; Yadav, Hemang; Mehta, Sangeeta; Pickkers, Peter & Bukan, Ramin Brandt [Show all 35 contributors for this article] (2019). Diagnosis and outcome of acute respiratory failure in immunocompromised patients after bronchoscopy. European Respiratory Journal. ISSN 0903-1936. 54:1802442, p. 1–11. doi: 10.1183/13993003.02442-2018. Full text in Research Archive
• Thomas, Anub Mathew; Gerogianni, Alexandra; McAdam, Martin Berner; Fløisand, Yngvar; Lau, Corinna & Espevik, Terje [Show all 9 contributors for this article] (2019). Complement component C5 and TLR molecule CD14 mediate heme-induced thromboinflammation in human blood. Journal of Immunology. ISSN 0022-1767. 203(6), p. 1571–1578. doi: 10.4049/jimmunol.1900047. Full text in Research Archive Show summary

  Heme is a critical danger molecule liberated from hemeproteins in various conditions, including from hemoglobin in hemolytic diseases. Heme may cause thromboinflammatory damage by activating inflammatory and hemostatic pathways, such as complement, the TLRs, coagulation, and platelets. In this study, we explored the effect of single and dual inhibition of complement component C5 and TLR coreceptor CD14 on heme-induced thromboinflammation in an ex vivo human whole blood model. Heme induced a dose-dependent activation of complement via the alternative pathway. Single inhibition of C5 by eculizumab attenuated the release of IL-6, IL-8, TNF, MCP-1, MIP-1α, IFN-γ, LTB-4, MMP-8 and -9, and IL-1Ra with more than 60% (p < 0.05 for all) reduced the upregulation of CD11b on granulocytes and monocytes by 59 and 40%, respectively (p < 0.05), and attenuated monocytic tissue factor expression by 33% (p < 0.001). Blocking CD14 attenuated IL-6 and TNF by more than 50% (p < 0.05). In contrast to single inhibition, combined C5 and CD14 was required for a significantly attenuated prothrombin cleavage (72%, p < 0.05). Markers of thromboinflammation were also quantified in two patients admitted to the hospital with sickle cell disease (SCD) crisis. Both SCD patients had pronounced hemolysis and depleted plasma hemopexin and haptoglobin. Plasma heme and complement activation was markedly increased in one patient, a coinciding observation as demonstrated ex vivo. In conclusion, heme-induced thromboinflammation was largely attenuated by C5 inhibition alone, with a beneficial effect of adding a CD14 inhibitor to attenuate prothrombin activation. Targeting C5 has the potential to reduce thromboinflammation in SCD crisis patients.

• Thomas, Anub Mathew; Schjalm, Camilla; Nilsson, Per; Lindenskov, Paal Helge H.; Rørtveit, Runa & Solberg, Rønnaug [Show all 15 contributors for this article] (2018). Combined Inhibition of C5 and CD14 Attenuates Systemic Inflammation in a Piglet Model of Meconium Aspiration Syndrome. Neonatology. ISSN 1661-7800. 113(4), p. 322–330. doi: 10.1159/000486542. Full text in Research Archive Show summary

  Background: Meconium aspiration syndrome (MAS) is a severe lung condition affecting newborns and it can lead to a systemic inflammatory response. We previously documented complement activation and cytokine release in a piglet MAS model. Additionally, we showed ex vivo that meconium-induced inflammation was dependent on complement and Toll-like receptors. Objectives: To assess the efficacy of the combined inhibition of complement (C5) and CD14 on systemic inflammation induced in a forceful piglet MAS model. Methods: Thirty piglets were randomly allocated to a treatment group receiving the C5-inhibitor SOBI002 and anti-CD14 (n = 15) and a nontreated control group (n = 15). MAS was induced by intratracheal meconium instillation, and the piglets were observed for 5 h. Complement, cytokines, and myeloperoxidase (MPO) were measured by ELISA. Results: SOBI002 ablated C5 activity and the formation of the terminal complement complex in vivo. The combined inhibition attenuated the inflammasome cytokines IL-1β and IL-6 by 60 (p = 0.029) and 44% (p = 0.01), respectively, and also MPO activity in the bronchoalveolar fluid by 42% (p = 0.017). Ex vivo experiments in human blood revealed that the combined regimen attenuated meconium-induced MPO release by 64% (p = 0.008), but there was only a negligible effect with single inhibition, indicating a synergic cross-talk between the key molecules C5 and CD14. Conclusion: Combined inhibition of C5 and CD14 attenuates meconium-induced inflammation in vivo and this could become a future therapeutic regimen for MAS.

• Orrem, Hilde Lang; Nilsson, Per; Pischke, Søren Erik; Kleveland, Ola; Yndestad, Arne & Ekholt, Karin [Show all 18 contributors for this article] (2018). IL-6 receptor inhibition by tocilizumab attenuated expression of C5a receptor 1 and 2 in non-ST-elevation myocardial infarction. Frontiers in Immunology. 9. doi: 10.3389/fimmu.2018.02035. Full text in Research Archive Show summary

  Background: Elevated interleukin-6 (IL-6) and complement activation are associated with detrimental effects of inflammation in coronary artery disease (CAD). The complement anaphylatoxins C5a and C3a interact with their receptors; the highly inflammatory C5aR1, and the C5aR2 and C3aR. We evaluated the effect of the IL-6 receptor (IL-6R)-antagonist tocilizumab on the expression of the anaphylatoxin receptors in whole blood from non-ST-elevation myocardial infarction (NSTEMI) patients. Separately, anaphylatoxin receptor expression in peripheral blood mononuclear cells (PBMC) from patients with different entities of CAD was investigated. Materials and Methods: NSTEMI patients were randomized to one dose of tocilizumab (n = 28) or placebo (n = 32) and observed for 6 months. Whole blood samples drawn at inclusion, at day 2, 3 and after 6 months were used for mRNA isolation. Plasma was prepared for analysis of complement activation measured as sC5b-9 by ELISA. Furthermore, patients with different CAD entities comprising stable angina pectoris (SAP, n = 22), non-ST-elevation acute coronary syndrome (NSTE-ACS, n = 21) and ST-elevation myocardial infarction (STEMI, n = 20) were included. PBMC was isolated from blood samples obtained at admission to hospital and mRNA isolated. Anaphylatoxin-receptor-expression was analyzed with qPCR using mRNA from whole blood and PBMC, respectively. Results: Our main findings were (i) Tocilizumab decreased C5aR1 and C5aR2 mRNA expression significantly (p < 0.001) and substantially (>50%) at day 2 and 3, whereas C3aR expression was unaffected. (ii) Tocilizumab did not affect complement activation. (iii) In analyzes of different CAD entities, C5aR1 expression was significantly increased in all CAD subgroups compared to controls with the highest level in the STEMI patients (p < 0.001). For C5aR2 and C3aR the expression compared to controls were more moderate with increased expression of C5aR2 in the STEMI group (p < 0.05) and C3aR in the NSTE-ACS group (p < 0.05). Conclusion: Expression of C5aR1 and C5aR2 in whole blood was significantly attenuated by IL-6R-inhibition in NSTEMI patients. These receptors were significantly upregulated in PBMC CAD patients with particularly high levels of C5aR1 in STEMI patients.

• Buanes, Eirik Alnes; Barratt-Due, Andreas; Kvåle, Reidar; Leistad, Lillian & Konstante, Rita (2018). Viktig å skilje intermediærpasientar frå intensivpasientar. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. Full text in Research Archive
• Orrem, Hilde Lang; Nilsson, Per; Pischke, Søren Erik; Grindheim, Guro; Garred, Peter & Seljeflot, Ingebjørg [Show all 12 contributors for this article] (2018). Acute heart failure following myocardial infarction: complement activation correlates with the severity of heart failure in patients developing cardiogenic shock. ESC Heart Failure. 5(3), p. 292–301. doi: 10.1002/ehf2.12266. Full text in Research Archive Show summary

  Aims Heart failure (HF) is an impending complication to myocardial infarction. We hypothesized that the degree of complement activation reflects severity of HF following acute myocardial infarction. Methods and results The LEAF trial (LEvosimendan in Acute heart Failure following myocardial infarction) evaluating 61 patients developing HF within 48 h after percutaneous coronary intervention‐treated ST‐elevation myocardial infarction herein underwent a post hoc analysis. Blood samples were drawn from inclusion to Day 5 and at 42 day follow‐up, and biomarkers were measured with enzyme immunoassays. Regional myocardial contractility was measured by echocardiography as wall motion score index (WMSI). The cardiogenic shock group (n = 9) was compared with the non‐shock group (n = 52). Controls (n = 44) were age‐matched and sex‐matched healthy individuals. C4bc, C3bc, C3bBbP, and sC5b‐9 were elevated in patients at inclusion compared with controls (P < 0.01). The shock group had higher levels compared with the non‐shock group for all activation products except C3bBbP (P < 0.05). At Day 42, all products were higher in the shock group (P < 0.05). In the shock group, sC5b‐9 correlated significantly with WMSI at baseline (r = 0.68; P = 0.045) and at Day 42 (r = 0.84; P = 0.036). Peak sC5b‐9 level correlated strongly with WMSI at Day 42 (r = 0.98; P = 0.005). Circulating endothelial cell activation markers sICAM‐1 and sVCAM‐1 were higher in the shock group during the acute phase (P < 0.01), and their peak levels correlated with sC5b‐9 peak level in the whole HF population (r = 0.32; P = 0.014 and r = 0.30; P = 0.022, respectively). Conclusions Complement activation discriminated cardiogenic shock from non‐shock in acute ST‐elevation myocardial infarction complicated by HF and correlated with regional contractility and endothelial cell activation, suggesting a pathogenic role of complement in this condition.

• Azoulay, Elie; Pickkers, Peter; Soares, Marcio; Perner, Anders; Rello, Jordi & Bauer, Philippe R. [Show all 37 contributors for this article] (2017). Acute hypoxemic respiratory failure in immunocompromised patients: the Efraim multinational prospective cohort study. Intensive Care Medicine. ISSN 0342-4642. 43(12), p. 1808–1819. doi: 10.1007/s00134-017-4947-1. Full text in Research Archive
• Pischke, Søren Erik; Gustavsen, Alice; Orrem, Hilde Lang; Egge, Kjetil Hagene; Courivaud, Fredric A A & Fontenelle, Hugues [Show all 15 contributors for this article] (2017). Complement factor 5 blockade reduces porcine myocardial infarction size and improves immediate cardiac function. Basic Research in Cardiology. ISSN 0300-8428. 112:20(3). doi: 10.1007/s00395-017-0610-9. Full text in Research Archive Show summary

  Inhibition of complement factor 5 (C5) reduced myocardial infarction in animal studies, while no benefit was found in clinical studies. Due to lack of cross-reactivity of clinically used C5 antibodies, different inhibitors were used in animal and clinical studies. Coversin (Ornithodoros moubata complement inhibitor, OmCI) blocks C5 cleavage and binds leukotriene B4 in humans and pigs. We hypothesized that inhibition of C5 before reperfusion will decrease infarct size and improve ventricular function in a porcine model of myocardial infarction. In pigs (Sus scrofa), the left anterior descending coronary artery was occluded (40 min) and reperfused (240 min). Coversin or placebo was infused 20 min after occlusion and throughout reperfusion in 16 blindly randomized pigs. Coversin significantly reduced myocardial infarction in the area at risk by 39% (p = 0.03, triphenyl tetrazolium chloride staining) and by 19% (p = 0.02) using magnetic resonance imaging. The methods correlated significantly (R = 0.92, p < 0.01). Tissue Doppler echocardiography showed increased systolic displacement (31%, p < 0.01) and increased systolic velocity (29%, p = 0.01) in coversin treated pigs. Interleukin-1β in myocardial microdialysis fluid was significantly reduced (31%, p < 0.05) and tissue E-selectin expression was significantly reduced (p = 0.01) in the non-infarcted area at risk by coversin treatment. Coversin ablated plasma C5 activation throughout the reperfusion period and decreased myocardial C5b-9 deposition, while neither plasma nor myocardial LTB4 were significantly reduced. Coversin substantially reduced the size of infarction, improved ventricular function, and attenuated interleukin-1β and E-selectin in this porcine model by inhibiting C5. We conclude that inhibition of C5 in myocardial infarction should be reconsidered.

• Barratt-Due, Andreas; Pischke, Søren Erik; Nilsson, Per; Espevik, Terje & Mollnes, Tom Eirik (2017). Dual inhibition of complement and Toll-like receptors as a novel approach to treat inflammatory diseases-C3 or C5 emerge together with CD14 as promising targets. Journal of Leukocyte Biology. ISSN 0741-5400. 101(1), p. 193–204. doi: 10.1189/jlb.3VMR0316-132R. Full text in Research Archive Show summary

  The host is protected by pattern recognition systems, including complement and TLRs, which are closely cross-talking. If improperly activated, these systems might induce tissue damage and disease. Inhibition of single downstream proinflammatory cytokines, such as TNF, IL-1β, and IL-6, have failed in clinical sepsis trials, which might not be unexpected, given the substantial amounts of mediators involved in the pathogenesis of this condition. Instead, we have put forward a hypothesis of inhibition at the recognition phase by “dual blockade” of bottleneck molecules of complement and TLRs. By acting upstream and broadly, the dual blockade could be beneficial in conditions with improper or uncontrolled innate immune activation threatening the host. Key bottleneck molecules in these systems that could be targets for inhibition are the central complement molecules C3 and C5 and the important CD14 molecule, which is a coreceptor for several TLRs, including TLR4 and TLR2. This review summarizes current knowledge of inhibition of complement and TLRs alone and in combination, in both sterile and nonsterile inflammatory processes, where activation of these systems is of crucial importance for tissue damage and disease. Thus, dual blockade might provide a general, broad-acting therapeutic regimen against a number of diseases where innate immunity is improperly activated.

• Hellerud, Bernt C; Orrem, Hilde Lang; Dybwik, Knut Gustav; Pischke, Søren Erik; Barratt-Due, Andreas & Castellheim, Albert [Show all 15 contributors for this article] (2017). Combined inhibition of C5 and CD14 efficiently attenuated the inflammatory response in a porcine model of meningococcal sepsis. Journal of Intensive Care. ISSN 2052-0492. 5:21, p. 1–9. doi: 10.1186/s40560-017-0217-0. Full text in Research Archive Show summary

  Background Fulminant meningococcal sepsis, characterized by overwhelming innate immune activation, mostly affects young people and causes high mortality. This study aimed to investigate the effect of targeting two key molecules of innate immunity, complement component C5, and co-receptor CD14 in the Toll-like receptor system, on the inflammatory response in meningococcal sepsis. Methods Meningococcal sepsis was simulated by continuous intravenous infusion of an escalating dose of heat-inactivated Neisseria meningitidis administered over 3 h. The piglets were randomized, blinded to the investigators, to a positive control group (n = 12) receiving saline and to an interventional group (n = 12) receiving a recombinant anti-CD14 monoclonal antibody together with the C5 inhibitor coversin. Results A substantial increase in plasma complement activation in the untreated group was completely abolished in the treatment group (p = 0.006). The following inflammatory mediators were substantially reduced in plasma in the treatment group: Interferon-γ by 75% (p = 0.0001), tumor necrosis factor by 50% (p = 0.01), Interleukin (IL)-8 by 50% (p = 0.03), IL-10 by 40% (p = 0.04), IL-12p40 by 50% (p = 0.03), and granulocyte CD11b (CR3) expression by 20% (p = 0.01). Conclusion Inhibition of C5 and CD14 may be beneficial in attenuating the detrimental effects of complement activation and modulating the cytokine storm in patients with fulminant meningococcal sepsis.

• Ricklin, Daniel; Barratt-Due, Andreas & Mollnes, Tom Eirik (2017). Complement in clinical medicine: Clinical trials, case reports and therapy monitoring. Molecular Immunology. ISSN 0161-5890. 89, p. 10–21. doi: 10.1016/j.molimm.2017.05.013. Full text in Research Archive Show summary

  Research during past decades made it evident that complement is involved in more tasks than fighting infections, but has important roles in other immune surveillance and housekeeping functions. If the balance between complement activation and regulation is out of tune, however, complement can quickly turn against the host and contribute to adverse processes that result in various clinical conditions. Whereas clinical awareness was initially focused on complement deficiencies, excessive activation and insufficient regulation are frequently the dominant factors in complement-related disorders. The individual complement profile of a patient often determines the course and severity of the disease, and the pathophysiological involvement of complement may be highly diverse. As a consequence, complement assays have evolved as essential tools not only in initial diagnosis but also for following disease progression and for monitoring complement-targeted therapies, which become increasingly available in routine clinical use. We herein review the current state of complement-directed drug candidates in clinical evaluation and provide an overview of extended indications considered for the FDA-approved inhibitor eculizumab. Furthermore we review the literature describing cases reports and case series where eculizumab has been used “off-label”. Finally, we give a summary of the currently available tests to measure complement profiles and discuss their suitability in diagnostics and treatment monitoring. With complement finally entering the clinical arena, there are intriguing opportunities for treating complement-mediated diseases. However, this progress also requires a new awareness about complement pathophysiology, adequate diagnostic tools and suitable treatment options among clinicians treating patients with such disorders.

• Nilsson, Per; Thomas, Anub Mathew; Bergseth, Grete; Gustavsen, Alice; Volokhina, Elena B. & Heuvel, Lambertus P. van den [Show all 8 contributors for this article] (2017). Eculizumab-C5 complexes express a C5a neoepitope in vivo: Consequences for interpretation of patient complement analyses. Molecular Immunology. ISSN 0161-5890. 89, p. 111–114. doi: 10.1016/j.molimm.2017.05.021. Full text in Research Archive Show summary

  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.

• Gustavsen, Alice; Skattum, Lillemor; Bergseth, Grete; Lorentzen, Bjørg; Fløisand, Yngvar & Bosnes, Vidar [Show all 8 contributors for this article] (2017). Effect on mother and child of eculizumab given before caesarean section in a patient with severe antiphospholipid syndrome. Medicine. ISSN 0025-7974. 96(11). doi: 10.1097/MD.0000000000006338. Full text in Research Archive Show summary

  Rationale: Antiphospholipid syndrome (APS) in pregnancy may trigger the life-threatening catastrophic antiphospholipid syndrome (CAPS). Complement activation is implicated in the pathogenesis, and inhibition of complement factor C5 is suggested as an additional treatment option. Patient concerns, diagnosis and interventions: We present a pregnant patient treated with the C5-inhibitor eculizumab due to high risk of developing devastating APS-related complications. The complement inhibitory effects of the treatment were examined both in the patient and the premature infant. Outcomes: Complement activity in the mother recovered considerably faster than anticipated; however, no new thrombosis or CAPS developed during the last week of pregnancy or postpartum. Blood sampling from the umbilical vein and artery, and from the infant after delivery showed low complement activity; however, only 0.3% of the eculizumab concentration detected in the mother, consistent with low placental passage of eculizumab. Lessons: The data underscore the importance of close monitoring of complement inhibition and individualizing dosage regimens in pregnant patients receiving eculizumab. We document how traditional functional complement activity tests cannot assess the effect of eculizumab in premature infants due to the very low levels of complement factors detected in this infant born in gestational week 33. Only trace amounts of eculizumab passed the placenta. In conclusion, complement C5 inhibition might be a safe candidate treatment option for APS during pregnancy and delivery, and additionally, enables prolongation of pregnancy with important weeks. Abbreviations: APS = antiphospholipid syndrome, CAPS = catastrophic antiphospholipid syndrome, E-C5 = eculizumab-C5, EDTA = ethylenediaminetetraacetic acid, IgG = immunoglobulin G.

• Barratt-Due, Andreas; Fløisand, Yngvar; Lang, Hilde Elisabeth; Kvam, Ann Kristin; Holme, Pål Andre & Bergseth, Grete [Show all 8 contributors for this article] (2016). Complement activation is a crucial pathogenic factor in catastrophic antiphospholipid syndrome. Rheumatology. ISSN 1462-0324. doi: 10.1093/rheumatology/kew040. Full text in Research Archive Show summary

  Catastrophic antiphospholipid syndrome is associated with excessive complement activation explaining the clinical efficacy of complement inhibitory treatment.

• Egge, Kjetil Hagene; Barratt-Due, Andreas; Nymo, Stig Haugset; Lindstad, Julie Katrine; Pharo, Anne Margrethe & Lau, Corinna [Show all 9 contributors for this article] (2015). The anti-inflammatory effect of combined complement and CD14 inhibition is preserved during escalating bacterial load. Clinical and Experimental Immunology. ISSN 0009-9104. 181(3), p. 457–467. doi: 10.1111/cei.12645. Full text in Research Archive Show summary

  Combined inhibition of complement and CD14 is known to attenuate bacterial-induced inflammation, but the dependency of the bacterial load on this effect is unknown. Thus, we investigated whether the effect of such combined inhibition on Escherichia coli- and Staphylococcus aureus-induced inflammation was preserved during increasing bacterial concentrations. Human whole blood was preincubated with anti-CD14, eculizumab (C5-inhibitor) or compstatin (C3-inhibitor), or combinations thereof. Then heat-inactivated bacteria were added at final concentrations of 5 × 104−1 × 108/ml (E. coli) or 5 × 107−4 × 108/ml (S. aureus). Inflammatory markers were measured using enzyme-linked immunosorbent assay (ELISA), multiplex technology and flow cytometry. Combined inhibition of complement and CD14 significantly (P < 0.05) reduced E. coli-induced interleukin (IL)-6 by 40–92% at all bacterial concentrations. IL-1β, IL-8 and macrophage inflammatory protein (MIP)-1α were significantly (P < 0.05) inhibited by 53–100%, and the effect was lost only at the highest bacterial concentration. Tumour necrosis factor (TNF) and MIP-1β were significantly (P < 0.05) reduced by 80–97% at the lowest bacterial concentration. Monocyte and granulocyte CD11b were significantly (P < 0.05) reduced by 63–91% at all bacterial doses. Lactoferrin was significantly (P < 0.05) attenuated to the level of background activity at the lowest bacterial concentration. Similar effects were observed for S. aureus, but the attenuation was, in general, less pronounced. Compared to E. coli, much higher concentrations of S. aureus were required to induce the same cytokine responses. This study demonstrates generally preserved effects of combined complement and CD14 inhibition on Gram-negative and Gram-positive bacterial-induced inflammation during escalating bacterial load. The implications of these findings for future therapy of sepsis are discussed.

• Jensen, L.L.; Barratt-Due, Andreas; Englund, P.N.; Harju, Jarkko A.; Sigursson, Theodor Skuli & Liberg, John-Petter (2015). Paediatric ventilation treatment of acute lung injury in Nordic intensive care units. Acta Anaesthesiologica Scandinavica. ISSN 0001-5172. 59(5), p. 568–575. doi: 10.1111/aas.12500. Full text in Research Archive
• Egge, Kjetil Hagene; Thorgersen, Ebbe Billmann; Pischke, Søren Erik; Lindstad, Julie Katrine; Pharo, Anne Margrethe & Bongoni, Anjan K. [Show all 10 contributors for this article] (2015). Organ inflammation in porcine Escherichia coli sepsis is markedly attenuated by combined inhibition of C5 and CD14. Immunobiology. ISSN 0171-2985. 220(8), p. 999–1005. doi: 10.1016/j.imbio.2015.04.002. Full text in Research Archive
• Skjeflo, Espen Waage; Sagatun, Caroline; Dybwik, Knut; Aam, Sturla; Urving, Sven Haakon & Nunn, Miles A. [Show all 14 contributors for this article] (2015). Combined inhibition of complement and CD14 improved outcome in porcine polymicrobial sepsis. Critical Care. ISSN 1364-8535. 19:415(1). doi: 10.1186/s13054-015-1129-9. Full text in Research Archive Show summary

  Introduction Sepsis is an exaggerated and dysfunctional immune response to infection. Activation of innate immunity recognition systems including complement and the Toll-like receptor family initiate this disproportionate inflammatory response. The aim of this study was to explore the effect of combined inhibition of the complement component C5 and the Toll-like receptor co-factor CD14 on survival, hemodynamic parameters and systemic inflammation including complement activation in a clinically relevant porcine model of polymicrobial sepsis. Methods Norwegian landrace piglets (4 ± 0.5 kg) were blindly randomized to a treatment group (n = 12) receiving the C5 inhibitor coversin (OmCI) and anti-CD14 or to a positive control group (n = 12) receiving saline. Under anesthesia, sepsis was induced by a 2 cm cecal incision and the piglets were monitored in standard intensive care for 8 hours. Three sham piglets had a laparotomy without cecal incision or treatment. Complement activation was measured as sC5b-9 using enzyme immunoassay. Cytokines were measured with multiplex technology. Results Combined C5 and CD14 inhibition significantly improved survival (p = 0.03). Nine piglets survived in the treatment group and four in the control group. The treatment group had significantly lower pulmonary artery pressure (p = 0.04) and ratio of pulmonary artery pressure to systemic artery pressure (p < 0.001). Plasma sC5b-9 levels were significantly lower in the treatment group (p < 0.001) and correlated significantly with mortality (p = 0.006). IL-8 and IL-10 were significantly (p < 0.05) lower in the treatment group. Conclusions Combined inhibition of C5 and CD14 significantly improved survival, hemodynamic parameters and inflammation in a blinded, randomized trial of porcine polymicrobial sepsis.

• Huber-Lang, Markus; Barratt-Due, Andreas; Pischke, Søren Erik; Sandanger, Øystein; Nilsson, Per & Nunn, Miles A. [Show all 10 contributors for this article] (2014). Double blockade of CD14 and complement C5 abolishes the cytokine storm and improves morbidity and survival in polymicrobial sepsis in mice. Journal of Immunology. ISSN 0022-1767. 192(11), p. 5324–5331. doi: 10.4049/jimmunol.1400341. Full text in Research Archive Show summary

  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.

• Egge, Kjetil Hagene; Thorgersen, Ebbe Billmann; Lindstad, Julie Katrine; Pharo, Anne Margrethe; Lambris, John D. & Barratt-Due, Andreas [Show all 7 contributors for this article] (2014). Post challenge inhibition of C3 and CD14 attenuates Escherichia coli-induced inflammation in human whole blood. Innate Immunity. ISSN 1753-4259. 20(1), p. 68–77. doi: 10.1177/1753425913482993. Full text in Research Archive
• Thorgersen, Ebbe Billmann; Pischke, Søren Erik; Barratt-Due, Andreas; Fure, Hilde; Lindstad, Julie Katrine & Pharo, Anne Margrethe [Show all 8 contributors for this article] (2013). Systemic CD14 inhibition attenuates organ inflammation in porcine escherichia coli sepsis. Infection and Immunity. ISSN 0019-9567. 81(9), p. 3173–3181. doi: 10.1128/IAI.00390-13. Full text in Research Archive
• Barratt-Due, Andreas; Sokolov, Andrey; Gustavsen, Alice; Hellerud, Bernt C; Egge, Kjetil Hagene & Pischke, Søren Erik [Show all 11 contributors for this article] (2013). Polyvalent immunoglobulin significantly attenuated the formation of IL-1 beta in Escherichia coli-induced sepsis in pigs. Immunobiology. ISSN 0171-2985. 218(5), p. 683–689. doi: 10.1016/j.imbio.2012.08.268. Full text in Research Archive
• Barratt-Due, Andreas; Thorgersen, Ebbe Billmann; Egge, Kjetil Hagene; Pischke, Søren Erik; Sokolov, Andrey & Hellerud, Bernt C [Show all 13 contributors for this article] (2013). Combined Inhibition of Complement (C5) and CD14 Markedly Attenuates Inflammation, Thrombogenicity, and Hemodynamic Changes in Porcine Sepsis. Journal of Immunology. ISSN 0022-1767. 191(2), p. 819–827. doi: 10.4049/jimmunol.1201909. Full text in Research Archive
• Lau, Corinna; Gunnarsen, Kristin Støen; Høydahl, Lene Støkken; Andersen, Jan Terje; Berntzen, Gøril & Pharo, Anne Margrethe [Show all 15 contributors for this article] (2013). Chimeric Anti-CD14 IGG2/4 Hybrid Antibodies for Therapeutic Intervention in Pig and Human Models of Inflammation. Journal of Immunology. ISSN 0022-1767. 191(9), p. 4769–4777. doi: 10.4049/jimmunol.1301653. Full text in Research Archive Show summary

  CD14 is a key recognition molecule of innate immune responses, interacting with several TLRs. TLR signaling cross-talks extensively with the complement system, and combined CD14 and complement inhibition has been proved effective in attenuating inflammatory responses. Pig models of human diseases have emerged as valuable tools to study therapeutic intervention, but suitable neutralizing Abs are rare. Undesired Fc-mediated functions, such as platelet activation and IL-8 release induced by the porcine CD14-specific clone Mil2, limit further studies. Therefore, an inert human IgG2/IgG4 hybrid C region was chosen for an rMil2. As revealed in ex vivo and in vivo pig experiments, rMil2 inhibited the CD14-mediated proinflammatory cytokine response similar to the original clone, but lacked the undesired Fc-effects, and inflammation was attenuated further by simultaneous complement inhibition. Moreover, rMil2 bound porcine FcRn, a regulator of t1/2 and biodistribution. Thus, rMil2, particularly combined with complement inhibitors, should be well suited for in vivo studies using porcine models of diseases, such as sepsis and ischemia-reperfusion injury. Similarly, the recombinant anti-human CD14 IgG2/4 Ab, r18D11, was generated with greatly reduced Fc-mediated effects and preserved inhibitory function ex vivo. Such Abs might be drug candidates for the treatment of innate immunity-mediated human diseases.

• Barratt-Due, Andreas; Pischke, Søren Erik; Brekke, Ole Lars; Thorgersen, Ebbe Billmann; Nielsen, Erik Waage & Espevik, Terje [Show all 8 contributors for this article] (2012). Bride and groom in systemic inflammation - The bells ring for complement and Toll in cooperation. Immunobiology. ISSN 0171-2985. 217(11), p. 1047–1056. doi: 10.1016/j.imbio.2012.07.019. Full text in Research Archive
• Barratt-Due, Andreas; Johansen, Harald Thidemann; Sokolov, Andrey; Thorgersen, Ebbe Billmann; Hellerud, Bernt C & Reubsaet, Leon [Show all 13 contributors for this article] (2011). The Role of Bradykinin and the Effect of the Bradykinin Receptor Antagonist Icatibant in Porcine Sepsis. Shock. ISSN 1073-2322. 36(5), p. 517–523. doi: 10.1097/SHK.0b013e3182336a34. Full text in Research Archive

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• Dahl, Tuva Børresdatter; Aftab, Friha; Prebensen, Christian Haugland; Berdal, Jan-Erik; Ueland, Thor & Barratt-Due, Andreas [Show all 15 contributors for this article] (2025). Imidazole propionate is increased in severe COVID-19 and correlates with cardiac involvement. Journal of Infection. ISSN 0163-4453. 90(6). doi: 10.1016/j.jinf.2025.106494. Full text in Research Archive
• Lindahl, Jørn Petter Hanto; Dörje, Christina; Kro, Grete Anette Birkeland; Grzyb, Krzyztof; Hugenschmidt, Harald & Hov, Johannes Espolin Roksund [Show all 8 contributors for this article] (2025). Case Report: Donor-derived herpes simplex virus type 1 hepatitis in a kidney transplant recipient with fatal outcome. doi: 10.3389/frtra.2025.1591855. Full text in Research Archive
• Anthon, Carl Thomas; Pène, Frédéric; Perner, Anders; Azoulay, Elie; Puxty, Kathryn & Louw, Andry Van De [Show all 121 contributors for this article] (2023). Correction: Thrombocytopenia and platelet transfusions in ICU patients: an international inception cohort study (PLOT-ICU) (Intensive Care Medicine, (2023), 49, 11, (1327-1338), 10.1007/s00134-023-07225-2). Intensive Care Medicine. ISSN 0342-4642. doi: 10.1007/s00134-023-07291-6. Full text in Research Archive
• Laake, Jon Henrik; Aslam, Tayyba Naz; Barratt-Due, Andreas; Löwhagen, Bjørn; Pischke, Soeren & Tønnessen, Tor Inge [Show all 8 contributors for this article] (2023). ARDS eller akutt lungesviktsyndrom? Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 143(10). doi: 10.4045/tidsskr.23.0402. Full text in Research Archive
• Tran, Trung; Vaage, Eline Benno; Mehta, Adi; Chopra, Adity; Tietze, Lisa & Kolderup, Heidi Anette [Show all 40 contributors for this article] (2023). Author Correction: Titers of antibodies against ancestral SARS-CoV-2 correlate with levels of neutralizing antibodies to multiple variants (npj Vaccines, (2022), 7, 1, (174), 10.1038/s41541-022-00586-7). npj Vaccines. 8(1). doi: 10.1038/s41541-023-00600-6. Full text in Research Archive
• Gregersen, Ida; Ueland, Thor; Holter, Jan Cato; Olsen, Maria Belland; Michelsen, Annika Elisabet & Murphy, Sarah L [Show all 22 contributors for this article] (2022). CXCL16 associates with adverse outcome and cardiac involvement in hospitalized patients with Covid-19. Journal of Infection. ISSN 0163-4453. 85(6), p. 735–738. doi: 10.1016/j.jinf.2022.09.029. Full text in Research Archive
• Anthon, Carl Thomas; Pène, Frédéric; Perner, Anders; Azoulay, Elie; Puxty, Kathryn & Louw, Andry Van De [Show all 19 contributors for this article] (2022). Platelet transfusions and thrombocytopenia in intensive care units: Protocol for an international inception cohort study (PLOT-ICU). Acta Anaesthesiologica Scandinavica. ISSN 0001-5172. 66(9), p. 1146–1155. doi: 10.1111/aas.14124. Full text in Research Archive
• Murphy, Sarah Louise Mikalsen; Halvorsen, Bente; Barratt-Due, Andreas; Dyrhol-Riise, Anne Ma; Aukrust, Pål & Trøseid, Marius [Show all 7 contributors for this article] (2022). Remdesivir modifies interferon response in hospitalized COVID-19 patients. Journal of Infection. ISSN 0163-4453. 85(5), p. 573–607. doi: 10.1016/j.jinf.2022.07.021. Full text in Research Archive
• Trøseid, Marius; Hites, Maya; Barratt-Due, Andreas; Ader, Florence & Yazdanpanah, Yazdan (2021). Assessing the evidence on remdesivir. The Lancet Infectious Diseases. ISSN 1473-3099. 21(12), p. 1630–1631. doi: 10.1016/S1473-3099(21)00695-2. Full text in Research Archive
• Pascal, Furaha Nzanzu Blaise; Malisawa, Agnes; Barratt-Due, Andreas; Namboya, Felix & Pollach, Gregor (2021). Correction to: General anaesthesia related mortality in a limited resource settings region: a retrospective study in two teaching hospitals of Butembo (BMC Anesthesiology, (2021), 21, 1, (60), 10.1186/s12871-021-01280-2). BMC Anesthesiology. 21(1). doi: 10.1186/s12871-021-01297-7. Full text in Research Archive
• Laake, Jon Henrik; Aasmundstad, Tor Aksel; Kåsine, Trine; Pischke, Soeren & Barratt-Due, Andreas (2020). Covid-19: Evidens-, eminens-, eller erfaringsbasert behandling? Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 140(12), p. 1–2. doi: 10.4045/tidsskr.20.0649. Full text in Research Archive
• Azoulay, Elie; Bauer, Philippe R.; Mariotte, Eric; Russell, Lene; Knoebl, Paul & Martin-Loeches, Ignacio [Show all 20 contributors for this article] (2020). Correction to: Expert statement on the ICU management of patients with thrombotic thrombocytopenic purpura (Intensive Care Medicine, (2019), 45, 11, (1518-1539), 10.1007/s00134-019-05736-5). Intensive Care Medicine. ISSN 0342-4642. 46(3), p. 570–571. doi: 10.1007/s00134-019-05904-7. Full text in Research Archive
• Buanes, Eirik Alnes; Barratt-Due, Andreas; Leistad, Lillian & Konstante, Rita (2018). Viktig å skilje intermediærpasientar frå intensivpasientar. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. Full text in Research Archive
• Laffey, John G.; Bellani, Giacomo; Pham, Tài; Fan, Eddy; Madotto, Fabiana & Bajwa, Ednan K. [Show all 30 contributors for this article] (2018). Correction to: Potentially modifiable factors contributing to outcome from acute respiratory distress syndrome: the LUNG SAFE study (Intensive Care Medicine, (2016), 42, 12, (1865-1876), 10.1007/s00134-016-4571-5). Intensive Care Medicine. ISSN 0342-4642. 44(1), p. 157–165. doi: 10.1007/s00134-017-4981-z. Full text in Research Archive
• Egge, Kjetil Hagene; Thorgersen, Ebbe Billmann; Lindstad, Julie Katrine; Pharo, Anne Margrethe; Lambris, J.D. & Barratt-Due, Andreas [Show all 7 contributors for this article] (2013). Combined inhibition of C3 and CD14 attenuates the inflammatory reaction significantly more as compared to single inhibition. Molecular Immunology. ISSN 0161-5890. 56(3), p. 304–305. doi: 10.1016/j.molimm.2013.05.182. Full text in Research Archive
• Egge, Kjetil Hagene; Thorgersen, Ebbe Billmann; Lindstad, Julie Katrine; Pharo, Anne Margrethe; Bongoni, AK & Rieben, R [Show all 8 contributors for this article] (2013). Combined inhibition of C5 and CD14 attenuates organ inflammation in porcine Escherichia coli sepsis. Molecular Immunology. ISSN 0161-5890. 56(3), p. 246–246. doi: 10.1016/j.molimm.2013.05.027. Full text in Research Archive
• Mollnes, Tom Eirik; Barratt-Due, Andreas; Pischke, Søren Erik; Sandanger, Inger; Nilsson, Per & Lambris, J [Show all 10 contributors for this article] (2013). Double-blockade of CD14 and complement component C5 abolish the inflammatory storm and improve survival in mouse polymicrobial sepsis. Molecular Immunology. ISSN 0161-5890. 56(3), p. 294–294. doi: 10.1016/j.molimm.2013.05.153. Full text in Research Archive
• Thorgersen, Ebbe Billmann; Pischke, Søren Erik; Barratt-Due, Andreas; Fure, Hilde; Lindstad, Julie Katrine & Pharo, Anne Margrethe [Show all 8 contributors for this article] (2012). Systemic CD14-inhibition attenuates local inflammatory responses organ-dependently in porcine Escherichia coli-sepsis. Immunobiology. ISSN 0171-2985. 217(11), p. 1206–1206. doi: 10.1016/j.imbio.2012.08.222. Full text in Research Archive
• Mollnes, Tom Eirik; Barratt-Due, Andreas; Pischke, Søren Erik; Sandanger, Øystein; Nunn, Miles A. & Espevik, Terje [Show all 8 contributors for this article] (2012). The systemic inflammatory reaction in polymicrobial sepsis induced by murine cecal ligation and puncture is equally dependent on C5 and CD14. Immunobiology. ISSN 0171-2985. 217(11), p. 1129–1129. doi: 10.1016/j.imbio.2012.08.002. Full text in Research Archive
• Egge, Kjetil Hagene; Thorgersen, Ebbe Billmann; Lindstad, Julie Katrine; Pharo, Anne Margrethe; Barratt-Due, Andreas & Mollnes, Tom Eirik (2012). An ex vivo posttreatment model of sepsis: Effect on inflammation by adding complement- and CD14-inhibitors after E. coli to human whole blood. Immunobiology. ISSN 0171-2985. 217(11), p. 1137–1138. doi: 10.1016/j.imbio.2012.08.026. Full text in Research Archive

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