Aleksander Rygh Holten

• Yoon, Chang Ho; Sjöholm, Daniel; Wickstrøm, Kristin; Danielsen, Anders Skyrud; Prebensen, Christian Haugland & Valik, John Karlsson [Show all 12 contributors for this article] (2026). Multicenter Validation of Clinical Sepsis Phenotypes. JAMA Network Open. 9(6). doi: 10.1001/jamanetworkopen.2026.16134. Full text in Research Archive
• Guttorm, Sander Johannes Thorbjørnsen; Gukasyan, Liana; Prebensen, Christian Haugland; Karlsson, Niclas G.; Holten, Aleksander Rygh & Kvale, Dag [Show all 9 contributors for this article] (2026). Metabolic and lipidomic stability in EDTA plasma from hospitalized patients: impact of refrigerated storage time and additional freeze—thaw cycle. Metabolomics. ISSN 1573-3882. 22(3). doi: 10.1007/s11306-026-02428-2. Full text in Research Archive
• Kildal, Anders Benjamin; Ueland, Thor; Mirlashari, Mohammad Reza; Nissen-Meyer, Lise Sofie; Granerud, Beathe Kiland & Riise, Anne Margarita Dyrhol [Show all 44 contributors for this article] (2026). Serial blood serum measurements of calprotectin and deoxyribonuclease in COVID-19 patients during hospitalization and recovery until one year: a prospective, multicenter, observational study. BMC Infectious Diseases. 26. doi: 10.1186/s12879-026-12939-x. Full text in Research Archive Show summary

  Objectives: To examine circulating calprotectin and deoxyribonuclease (DNase) serum levels during hospitalization in COVID-19 patients, their continuity post-discharge and dynamics in relation to disease severity. Methods: Serum levels were measured in samples collected from 252 COVID-19 patients during hospitalization (admission, days 3–5 and 7–10), at 3 months and after 1 year, and related to admission to intensive care unit (ICU) or high dependency unit (HDU), and 60-day total mortality. Results: During hospitalization, calprotectin and DNase levels were significantly elevated compared to healthy controls (HC). Calprotectin was increased in ICU/HDU patients compared to those at wards during hospitalization and in non-survivors compared to survivors during prolonged hospitalization. High calprotectin levels at admission were associated with male sex, PaO2/FiO2 ratio and national COVID-19 wave 2 and 3 compared to wave 1. High admission levels of both calprotectin and ferritin were associated with an approximately twofold higher odds ratio for ICU/HDU admission than either marker alone. DNase was lower at admission in non-survivors compared to survivors. Post-discharge, DNase but not calprotectin levels remained elevated extending to 1-year follow-up compared to HC. Conclusions: COVID‑19 non‑survivors showed persistently higher calprotectin levels during prolonged hospitalization, and elevated admission calprotectin was associated with later pandemic waves and poorer oxygenation. Incorporating calprotectin with ferritin improved prediction of ICU/HDU admission. DNase levels were lower at admission in non‑survivors, while overall DNase remained elevated from hospitalization through 1‑year follow‑up compared with HC, suggesting a possible role in long‑term COVID‑19–related immune alterations.

• Otterdal, Kari; Ueland, Thor; Holter, Jan Cato; Kaarbø, Mari; Schanke, Ylva & Granerud, Beathe Kiland [Show all 18 contributors for this article] (2026). Platelet-derived mediators in hospitalized COVID-19 patients and associations to respiratory failure, ICU admittance and 60-day mortality. Frontiers in Cardiovascular Medicine. 13. doi: 10.3389/fcvm.2026.1685861. Full text in Research Archive Show summary

  Background: Platelet activation is documented in COVID-19, but data on platelet-derived mediators are scarce. Objective: To examine the levels of various platelet-derived mediators in relation to adverse outcomes defined as the need for treatment at intensive care unit (ICU) and/or respiratory failure (RF) and 60-day total mortality in hospitalized COVID-19 patients. Methods: Plasma levels of RANTES/CCL5, PF4/CXCL4, ENA78/CXCL5, NAP-2/CXCL7, SDF-1/CXCL12, P-selectin, soluble CD40 ligand (sCD40L) and vascular endothelial cell growth factor A (VEGF-A) were measured in 245 hospitalized COVID-19 patients and in a subpopulation of the patients, also at three, six and 12 months after hospitalization. Results: Our main findings were: (i) High levels of P-selectin was associated with ICU/RF, while low levels of PF4/CXCL4, ENA-78/CXCL5 and NAP-2/CXCL7 were associated with 60-days mortality. (ii) Most of the mediators were normalized after hospitalization, but plasma levels of sCD40L, ENA-78/CXCL7 and VEGF-A were markedly elevated compared to healthy controls for up to 12 months after hospitalization. (iii) In vitro, inactivated SARS-CoV-2 induced a dose-dependent release of NAP-2, P-selectin, RANTES, sCD40L and VEGF-A from isolated platelets. Conclusion: Our findings underscore the role of platelet-derived inflammatory mediators in the pathogenesis of COVID-19, potentially involving direct effects of SARS-CoV-2. The study also points to a persistent platelet activation following hospitalization.

• Scheer, Christian S.; Giamarellos-Bourboulis, Evangelos J.; Ferrer, Ricard; Idelevich, Evgeny A.; Annane, Djillali & Artigas, Antonio [Show all 903 contributors for this article] (2025). Status of Sepsis Care in European Hospitals Results from an International Cross-Sectional Survey. American Journal of Respiratory and Critical Care Medicine. ISSN 1073-449X. 211(4), p. 587–599. doi: 10.1164/rccm.202406-1167OC. Full text in Research Archive
• Wickstrøm, Kristin; Holten, Aleksander Rygh; Prebensen, Christian Haugland; Luque, Alvaro Kohn; Vitelli, Valeria & Amundsen, Erik Koldberg (2025). Sysmex Cell Population Data for Diagnosing Infection in Patients With Suspected Sepsis in the Emergency Department. International Journal of Laboratory Hematology (IJLH). ISSN 1751-5521. 48(1), p. 71–80. doi: 10.1111/ijlh.70008. Full text in Research Archive Show summary

  Objectives: Early diagnosis of suspected sepsis is crucial to improve patient survival. Cell population (CP) data, a set of leuco-cyte research parameters from hematology instruments, has a potential as markers for infection. The aim of this study was toinvestigate the diagnostic accuracy for infection of CP variables from Sysmex XN instruments in patients with suspected sepsisin the emergency department (ED). Methods: Adult patients with suspected sepsis in the ED were included. CP variables, C-reactive protein (CRP), and post hocassessments of infection were recorded. Logistic regression and machine learning methods were used to develop multivariablemodels, which were evaluated by area under the receiver operating curve (AUC) and calibration plots. Results: The development cohort and the validation cohort consisted of 600 and 656 patients, respectively. Univariate analysesrevealed that complexity in monocytes (MO-X); AUC of 0.78 (0.74, 0.82), reactivity intensity of neutrophils (NEUT-RI); 0.72 (0.67,0.76), and CRP 0.87 (0.84, 0.90) had the highest diagnostic accuracy for infection. A final multivariable model (the optimal model)using Multilayer perceptron (MLP), including MO-X, NEUT-RI, monocyte size (MO-Z), and neutrophil size (NE-FSC), had anAUC of 0.86 (0.85, 0.87) in the development cohort and 0.78 (0.74, 0.82) in the validation cohort with reasonable calibration.Including CRP in this model further improved accuracy and calibration. Conclusions: Sysmex CP variables may help diagnose infections in the ED. However, the lack of well-described calibration pro-cedures and quality assurance for non-IVD approved CP variables is an impediment to clinical implementation

• Aarskog, Nikolai Ravn; Bjørsrud, Hanna Othilie Lindvig; Holten, Aleksander Rygh; Watne, Leiv Otto; Neerland, Bjørn Erik & Rostrup, Morten (2025). Ventilatory response and delirium risk in hospitalised patients with acute hypoxia due to COVID-19. Scientific Reports. 15. doi: 10.1038/s41598-025-13016-0. Full text in Research Archive Show summary

  Mountaineers with a high ventilatory response to hypoxia experience greater cognitive impairment at high altitude, possibly because hyperventilation causes hypocapnia, cerebral vasoconstriction and ultimately cerebral ischaemia. We hypothesised that a high ventilatory response, and consequently a lower arterial partial pressure of carbon dioxide (PaCO2), could increase the risk of delirium in hospitalised patients with acute hypoxia. To test our hypothesis, we conducted a cohort study in which PaCO2 and arterial oxygen saturation were measured upon hospital admission in 126 patients with COVID-19. After adjusting for oxygen saturation, we found that a lower PaCO2 was associated with a higher risk of delirium during hospital admission (risk ratio 1.67 [95% confidence interval 1.09–2.54] per 1 kilopascal reduction, P = 0.017). The association remained statistically significant after adjusting for other well-established risk factors for delirium. This finding supports our hypothesis that a high hypoxic ventilatory response increases the risk of delirium in patients with acute hypoxia.

• Viermyr, Hans-Kittil; Tonby, Kristian; Ponzi, Erica; Trouillet-Assant, Sophie; Poissy, Julien & Arribas, José R. [Show all 49 contributors for this article] (2024). Safety of baricitinib in vaccinated patients with severe and critical COVID-19 sub study of the randomised Bari-SolidAct trial. EBioMedicine. 111. doi: 10.1016/j.ebiom.2024.105511. Full text in Research Archive Show summary

  Background The Bari-SolidAct randomized controlled trial compared baricitinib with placebo in patients with severe COVID-19. A post hoc analysis revealed a higher incidence of serious adverse events (SAEs) among SARS-CoV-2-vaccinated participants who had received baricitinib. This sub-study aimed to investigate whether vaccination influences the safety profile of baricitinib in patients with severe COVID-19. Methods Biobanked samples from 146 participants (55 vaccinated vs. 91 unvaccinated) were analysed longitudinally for inflammation markers, humoral responses, tissue viral loads, and plasma viral antigens on days 1, 3, and 8. High-dimensional analyses, including RNA sequencing and flow cytometry, were performed on available samples. Mediation analyses were used to assess relationships between SAEs, baseline-adjusted biomarkers, and treatment-vaccination status. Findings Vaccinated participants were older, more frequently hospitalized, had more comorbidities, and exhibited higher nasopharyngeal viral loads. Baricitinib treatment did not affect antibody responses or viral clearance, but reduced markers of T-cell and monocyte activation compared to placebo (sCD25, sCD14, sCD163, sTIM-3). Age, baseline levels of plasma viral antigen, and several inflammatory markers, as well as IL-2, IL-6, Neopterin, CXCL16, sCD14, and suPAR on day 8 were associated with the occurrence of SAEs. However, mediation analyses of markers linked to SAEs, baricitinib treatment, or vaccination status did not reveal statistically significant interactions between vaccination status and SAEs. Interpretation This sub-study did not identify any virus- or host-related biomarkers significantly associated with the interaction between SARS-CoV-2 vaccination status and the safety of baricitinib. However, caution should be exercised due to the moderate sample size.

• 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.

• Mesinovic, Munib; Wong, Xin Ci; Rajahram, Giri Shan; Citarella, Barbara Wanjiru; Peariasamy, Kalaiarasu M. & Greve, Frank van Someren [Show all 1,671 contributors for this article] (2024). At-admission prediction of mortality and pulmonary embolism in an international cohort of hospitalised patients with COVID-19 using statistical and machine learning methods. Scientific Reports. 14(1). doi: 10.1038/s41598-024-63212-7. Full text in Research Archive
• Christensen, Erik Egeland; Prebensen, Christian Haugland; Martinsen, Anders B.; Trydal, Elisabet; Hoff, Rune & Kvale, Dag [Show all 7 contributors for this article] (2023). Mortality and Sequential Organ Failure Assessment Score in Patients with Suspected Sepsis: The Impact of Acute and Preexisting Organ Failures and Infection Likelihood. Critical Care Explorations. 5(2), p. E0865–E0865. doi: 10.1097/CCE.0000000000000865. Full text in Research Archive Show summary

  IMPORTANCE: The Sequential Organ Failure Assessment (SOFA) was chosen in the definition of sepsis due to superior validity in predicting mortality. However, few studies have assessed the contributions of acute versus chronic organ failures to SOFA for mortality prediction. OBJECTIVES: The main objective in this study was to assess the relative importance of chronic and acute organ failures in mortality prediction in patients with suspected sepsis at hospital admission. We also evaluated how the presence of infection influenced the ability of SOFA to predict 30-day mortality. DESIGN, SETTING, AND PARTICIPANTS: Single-center prospective cohort study including 1,313 adult patients with suspected sepsis in rapid response teams in the emergency department. MAIN OUTCOMES AND MEASURES: The main outcome was 30-day mortality. We measured the maximum total SOFA score during admission (SOFATotal), whereas preexisting chronic organ failure SOFA (SOFAChronic) score was assessed by chart review, allowing calculation of the corresponding acute SOFA (SOFAAcute) score. Likelihood of infection was determined post hoc as “No infection” or “Infection.” RESULTS: SOFAAcute and SOFAChronic were both associated with 30-day mortality, adjusted for age and sex (adjusted odds ratios [AORs], 1.3; 95% CI, 1.3–14 and 1.3; 1.2–1.7), respectively. Presence of infection was associated with lower 30-day mortality (AOR, 0.4; 95% CI, 0.2–0.6), even when corrected for SOFA. In “No infection” patients, SOFAAcute was not associated with mortality (AOR, 1.1; 95% CI, 1.0–1.2), and in this subgroup, neither SOFAAcute greater than or equal to 2 (relative risk [RR], 1.1; 95% CI, 0.6–1.8) nor SOFATotal greater than or equal to 2 (RR, 3.6; 95% CI, 0.9–14.1) was associated with higher mortality. CONCLUSIONS AND RELEVANCE: Chronic and acute organ failures were equally associated with 30-day mortality in suspected sepsis. A substantial part of the total SOFA score was due to chronic organ failure, calling for caution when using total SOFA in defining sepsis and as an outcome in intervention studies. SOFA’s mortality prediction ability was highly dependent on actual presence of infection.

• 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.

• Trøseid, Marius; Arribas, José R.; Assoumou, Lambert; Holten, Aleksander Rygh; Poissy, Julien & Terzić, Vida [Show all 56 contributors for this article] (2023). Efficacy and safety of baricitinib in hospitalized adults with severe or critical COVID‑19 (Bari‑SolidAct): a randomised, double‑blind, placebo‑controlled phase 3 trial. Critical Care. ISSN 1364-8535. 27(9), p. 1–15. doi: 10.1186/s13054-022-04205-8. Full text in Research Archive Show summary

  Background Baricitinib has shown efficacy in hospitalized patients with COVID-19, but no placebo-controlled trials have focused specifically on severe/critical COVID, including vaccinated participants. Methods Bari-SolidAct is a phase-3, multicentre, randomised, double-blind, placebo-controlled trial, enrolling participants from June 3, 2021 to March 7, 2022, stopped prematurely for external evidence. Patients with severe/critical COVID-19 were randomised to Baricitinib 4 mg once daily or placebo, added to standard of care. The primary endpoint was all-cause mortality within 60 days. Participants were remotely followed to day 90 for safety and patient related outcome measures. Results Two hundred ninety-nine patients were screened, 284 randomised, and 275 received study drug or placebo and were included in the modified intent-to-treat analyses (139 receiving baricitinib and 136 placebo). Median age was 60 (IQR 49–69) years, 77% were male and 35% had received at least one dose of SARS-CoV2 vaccine. There were 21 deaths at day 60 in each group, 15.1% in the baricitinib group and 15.4% in the placebo group (adjusted absolute difference and 95% CI − 0.1% [− 8·3 to 8·0]). In sensitivity analysis censoring observations after drug discontinuation or rescue therapy (tocilizumab/increased steroid dose), proportions of death were 5.8% versus 8.8% (− 3.2% [− 9.0 to 2.7]), respectively. There were 148 serious adverse events in 46 participants (33.1%) receiving baricitinib and 155 in 51 participants (37.5%) receiving placebo. In subgroup analyses, there was a potential interaction between vaccination status and treatment allocation on 60-day mortality. In a subsequent post hoc analysis there was a significant interaction between vaccination status and treatment allocation on the occurrence of serious adverse events, with more respiratory complications and severe infections in vaccinated participants treated with baricitinib. Vaccinated participants were on average 11 years older, with more comorbidities. Conclusion This clinical trial was prematurely stopped for external evidence and therefore underpowered to conclude on a potential survival benefit of baricitinib in severe/critical COVID-19. We observed a possible safety signal in vaccinated participants, who were older with more comorbidities. Although based on a post-hoc analysis, these findings warrant further investigation in other trials and real-world studies.

• Trøseid, Marius; Holter, Jan Cato; Holm, Kristian; Vestad, Beate; Sazonova, Taisiia & Granerud, Beathe Kiland [Show all 17 contributors for this article] (2023). Gut microbiota composition during hospitalization is associated with 60-day mortality after severe COVID-19. Critical Care. ISSN 1364-8535. 27(1). doi: 10.1186/s13054-023-04356-2. Full text in Research Archive Show summary

  Background Gut microbiota alterations have been reported in hospitalized COVID-19 patients, with reduced alpha diversity and altered microbiota composition related to respiratory failure. However, data regarding gut microbiota and mortality are scarce. Methods Rectal swabs for gut microbiota analyses were collected within 48 h after hospital admission (baseline; n = 123) and three-month post-admission (n = 50) in a subset of patients included in the Norwegian SARS-CoV2 cohort study. Samples were analysed by sequencing the 16S rRNA gene. Gut microbiota diversity and composition at baseline were assessed in relation to need for intensive care unit (ICU) admission during hospitalization. The primary objective was to investigate whether the ICU-related gut microbiota was associated with 60-day mortality. Results Gut microbiota diversity (Shannon index) at baseline was lower in COVID-19 patients requiring ICU admission during hospitalization than in those managed in general wards. A dysbiosis index representing a balance of enriched and reduced taxa in ICU compared with ward patients, including decreased abundance of butyrate-producing microbes and enrichment of a partly oral bacterial flora, was associated with need of ICU admission independent of antibiotic use, dexamethasone use, chronic pulmonary disease, PO2/FiO2 ratio, C-reactive protein, neutrophil counts or creatinine levels (adjusted p < 0.001). The ICU-related dysbiosis index at baseline correlated with systemic inflammation and was associated with 60-day mortality in univariate analyses (Hazard ratio 3.70 [2.00–8.6], p < 0.001), as well as after separate adjustment for covariates. At the three-month follow-up, the dysbiosis index remained elevated in ICU patients compared with ward patients (adjusted p = 0.007). Conclusions Although our data should be regarded as exploratory due to low number of clinical end points, they suggest that gut microbiota alterations during hospitalization could be related to poor prognosis after severe COVID-19. Larger studies of gut involvement during COVID-19 in relation to long-term clinical outcome are warranted.

• 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.

• 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).

• Garcia-Gallo, Esteban; Merson, Laura; Kennon, Kalynn; Kelly, Sadie; Citarella, Barbara Wanjiru & Fryer, Daniel Vidali [Show all 1,775 contributors for this article] (2022). ISARIC-COVID-19 dataset: A Prospective, Standardized, Global Dataset of Patients Hospitalized with COVID-19. Scientific Data. 9(1). doi: 10.1038/s41597-022-01534-9. Full text in Research Archive Show summary

  The International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) COVID-19 dataset is one of the largest international databases of prospectively collected clinical data on people hospitalized with COVID-19. This dataset was compiled during the COVID-19 pandemic by a network of hospitals that collect data using the ISARIC-World Health Organization Clinical Characterization Protocol and data tools. The database includes data from more than 705,000 patients, collected in more than 60 countries and 1,500 centres worldwide. Patient data are available from acute hospital admissions with COVID-19 and outpatient follow-ups. The data include signs and symptoms, pre-existing comorbidities, vital signs, chronic and acute treatments, complications, dates of hospitalization and discharge, mortality, viral strains, vaccination status, and other data. Here, we present the dataset characteristics, explain its architecture and how to gain access, and provide tools to facilitate its use.

• 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.

• Bouziotis, Jason; Arvanitakis, Marianna; Preiser, Jean-Charles; Abbas, Ali; Abdukahil, Sheryl Ann & Abdulkadir, Nurul Najmee [Show all 50 contributors for this article] (2022). Association of body mass index with COVID-19 related in-hospital death. Clinical Nutrition. ISSN 0261-5614. 41(12), p. 2924–2926. doi: 10.1016/j.clnu.2022.01.017. Full text in Research Archive Show summary

  Background: Patients with extreme body mass indices (BMI) could have an increased risk of death while hospitalized for COVID-19.<p> <p>Methods: The database of the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) was used to assess the time to in-hospital death with competing-risks regression by sex and between the categories of BMI. <p>Results: Data from 12,137 patients (age 60.0 ± 16.2 years, 59% males, BMI 29.4 ± 6.9 kg/m² ) of 48 countries were available. By univariate analysis, underweight patients had a higher risk of mortality than the other patients (sub-hazard ratio (SHR) 1.75 [1.44e2.14]). Mortality was lower in normal (SHR 0.69 [0.58e0.85]), overweight (SHR 0.53 [0.43e0.65]) and obese (SHR 0.55 [0.44e0.67]) than in underweight patients. Multivariable analysis (adjusted for age, chronic pulmonary disease, malignant neoplasia, type 2 diabetes) confirmed that in-hospital mortality of underweight patients was higher than overweight patients (females: SHR 0.63 [0.45e0.88] and males: 0.69 [0.51e0.94]). <p>Conclusion: Even though these findings do not imply changes in the medical care of hospitalized patients, they support the use of BMI category for the stratification of patients enrolled in interventional studies where mortality is recorded as an outcome.

• Degenhardt, Frauke; Ellinghaus, David; Juzenas, Simonas; Lerga-Jaso, Jon; Wendorff, Mareike & Maya-Miles, Douglas [Show all 51 contributors for this article] (2022). Detailed stratified GWAS analysis for severe COVID-19 in four European populations. Human Molecular Genetics. ISSN 0964-6906. 31(23), p. 3945–3966. doi: 10.1093/hmg/ddac158. Full text in Research Archive Show summary

  Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended genome-wide association meta-analysis of a well-characterized cohort of 3255 COVID-19 patients with respiratory failure and 12 488 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a ∼0.9-Mb inversion polymorphism that creates two highly differentiated haplotypes and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative including non-Caucasian individuals, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung.

• Christensen, Erik Egeland; Binde, Christina; Leegaard, Marianne; Tonby, Kristian; Dyrhol-Riise, Anne Ma & Kvale, Dag [Show all 8 contributors for this article] (2022). DIAGNOSTIC ACCURACY and ADDED VALUE of INFECTION BIOMARKERS in PATIENTS with POSSIBLE SEPSIS in the EMERGENCY DEPARTMENT. Shock. ISSN 1073-2322. 58(4), p. 251–259. doi: 10.1097/SHK.0000000000001981. Full text in Research Archive Show summary

  Background: Biomarkers for early recognition of infection are warranted. The hypothesis of this study was that calprotectin, C-reactive protein (CRP), IL-6 and procalcitonin (PCT), alone or in combination, provide clinically useful information to the clinicians for early identification of infection in patients with possible sepsis in the emergency department (ED). Biomarker dynamics in the first week of hospitalization were explored. Methods: Adult patients in rapid response teams in the ED were included in a prospective observational study (n = 391). Patients who received antibiotics after biomarker availability were excluded. The ED clinician (EDC) decision whether to start antibiotics was registered. Calprotectin, CRP, IL-6, and PCT were analyzed in blood samples drawn within 15 min after ED arrival and in a subgroup for 1 week. Infection likelihood was evaluated post hoc. Results: In identifying patients with infection, CRP (area under the receiver operating characteristic curve [AUC], 0.913) and IL-6 (AUC, 0.895) were superior to calprotectin (AUC, 0.777) and PCT (AUC, 0.838). The best regression model predicting infections included EDC, CRP, and IL-6. Using optimal cutoff values, CRP and IL-6 in combination reached 95% positive and 90% negative predictive values for infection. The EDC undertreated or overtreated 65 of 391 patients (17%), and CRP and IL-6 optimal cutoff values could correct this in 32 of 65 patients (49%). Longitudinal samples revealed that IL-6 peaked in the ED, whereas CRP and PCT peaked later. Conclusion: C-reactive protein and IL-6 were superior to calprotectin and PCT for recognizing infection in patients with possible sepsis in the ED. Combining these two biomarkers with different dynamics improved recognition of infection and could aid clinical management in rapid response teams in the ED.

• Cho, Sung-Min; White, Nicole; Premraj, Lavienraj; Battaglini, Denise; Fanning, Jonathon & Suen, Jacky [Show all 50 contributors for this article] (2022). Neurological manifestations of COVID-19 in adults and children. Brain. ISSN 0006-8950. doi: 10.1093/brain/awac332. Full text in Research Archive
• Gonçalves, Bronner P.; Hall, Matthew; Jassat, Waasila; Balan, Valeria; Murthy, Srinivas & Kartsonaki, Christiana [Show all 50 contributors for this article] (2022). An international observational study to assess the impact of the Omicron variant emergence on the clinical epidemiology of COVID-19 in hospitalised patients. eLIFE. 11. doi: 10.7554/eLife.80556. Full text in Research Archive
• Reyes, Luis Felipe; Murthy, Srinivas; Garcia-Gallo, Esteban; Merson, Laura; Ibáñez-Prada, Elsa D. & Rello, Jordi [Show all 51 contributors for this article] (2022). Respiratory support in patients with severe COVID-19 in the International Severe Acute Respiratory and Emerging Infection (ISARIC) COVID-19 study: a prospective, multinational, observational study. Critical Care. ISSN 1364-8535. 26(1). doi: 10.1186/s13054-022-04155-1. Full text in Research Archive
• Wainstein, Marina; MacDonald, Samual; Fryer, Daniel; Young, Kyle; Balan, Valeria & Begum, Husna [Show all 50 contributors for this article] (2022). Use of an extended KDIGO definition to diagnose acute kidney injury in patients with COVID-19: A multinational study using the ISARIC–WHO clinical characterisation protocol. PLoS Medicine. ISSN 1549-1277. 19(4). doi: 10.1371/journal.pmed.1003969. Full text in Research Archive
• Hammer, Quirin; Dunst, Josefine; Christ, Wanda; Picarazzi, Francesca; Wendorff, Mareike & Momayyezi, Pouria [Show all 51 contributors for this article] (2022). SARS-CoV-2 Nsp13 encodes for an HLA-E-stabilizing peptide that abrogates inhibition of NKG2A-expressing NK cells. Cell reports. 38(10). doi: 10.1016/j.celrep.2022.110503. Full text in Research Archive Show summary

  Natural killer (NK) cells are innate immune cells that contribute to host defense against virus infections. NK cells respond to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro and are activated in patients with acute coronavirus disease 2019 (COVID-19). However, by which mechanisms NK cells detect SARS-CoV-2-infected cells remains largely unknown. Here, we show that the Non-structural protein 13 of SARS-CoV-2 encodes for a peptide that is presented by human leukocyte antigen E (HLA-E). In contrast with self-peptides, the viral peptide prevents binding of HLA-E to the inhibitory receptor NKG2A, thereby rendering target cells susceptible to NK cell attack. In line with these observations, NKG2A-expressing NK cells are particularly activated in patients with COVID-19 and proficiently limit SARS-CoV-2 replication in infected lung epithelial cells in vitro. Thus, these data suggest that a viral peptide presented by HLA-E abrogates inhibition of NKG2A+ NK cells, resulting in missing self-recognition.

• Niemi, Mari E.K.; Karjalainen, Juha; Liao, Rachel G.; Neale, Benjamin M.; Daly, Mark & Ganna, Andrea [Show all 84 contributors for this article] (2021). Mapping the human genetic architecture of COVID-19. Nature. ISSN 0028-0836. 600(7889), p. 472–477. doi: 10.1038/s41586-021-03767-x. Full text in Research Archive Show summary

  The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3,4,5,6,7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

• Aarskog, Nikolai Ravn; Aass, Hans Christian Dalsbotten; Holter, Jan Cato; Rostrup, Morten & Holten, Aleksander Rygh (2021). Interleukin-6 in Critical Coronavirus Disease 2019, a Driver of Lung Inflammation of Systemic Origin? Critical Care Explorations. 3(10). doi: 10.1097/cce.0000000000000542. Full text in Research Archive Show summary

  OBJECTIVES: To examine whether interleukin-6 in critical coronavirus disease 2019 is higher in arterial than in central venous blood, as a sign of predominantly local pulmonal rather than systemic interleukin-6 production. DESIGN: Prospective cohort pilot study with repeated weekly measurements of interleukin-6 in arterial and central venous blood. Respiratory function, assessed with Pao2/Fio2 ratio, was measured at the time of blood sampling. SETTING: ICU at a university hospital. SUBJECTS: Nine adult patients with critical coronavirus disease 2019, actively treated and receiving mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: No difference between arterial and central venous interleukin-6 was found. There was a significant negative relationship between interleukin-6 concentration and P/F ratio in both arterial (p = 0.04) and central venous (p = 0.03) blood. CONCLUSIONS: The absence of an arteriovenous interleukin-6 difference implies that interleukin-6 in critical coronavirus disease 2019 is mainly produced outside the lungs as part of a systemic inflammatory response syndrome and act as a driver of local inflammation and damage in the lungs.

• 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.

• Christensen, Erik; Jørgensen, Marthe Jøntvedt; Nore, Kristin Grotle; Dahl, Tuva Børresdatter; Yang, Kuan & Ranheim, Trine [Show all 16 contributors for this article] (2021). Critical COVID-19 is associated with distinct leukocyte phenotypes and transcriptome patterns. Journal of Internal Medicine. ISSN 0954-6820. p. 1–16. doi: 10.1111/joim.13310. Full text in Research Archive Show summary

  Background Prognostic markers for disease severity and identification of therapeutic targets in COVID-19 are urgently needed. We have studied innate and adaptive immunity on protein and transcriptomic level in COVID-19 patients with different disease severity at admission and longitudinally during hospitalization. Methods Peripheral blood mononuclear cells (PBMCs) were collected at three time points from 31 patients included in the Norwegian SARS-CoV-2 cohort study and analysed by flow cytometry and RNA sequencing. Patients were grouped as either mild/moderate (n = 14), severe (n = 11) or critical (n = 6) disease in accordance with WHO guidelines and compared with patients with SARS-CoV-2-negative bacterial sepsis (n = 5) and healthy controls (n = 10). Results COVID-19 severity was characterized by decreased interleukin 7 receptor alpha chain (CD127) expression in naïve CD4 and CD8 T cells. Activation (CD25 and HLA-DR) and exhaustion (PD-1) markers on T cells were increased compared with controls, but comparable between COVID-19 severity groups. Non-classical monocytes and monocytic HLA-DR expression decreased whereas monocytic PD-L1 and CD142 expression increased with COVID-19 severity. RNA sequencing exhibited increased plasma B-cell activity in critical COVID-19 and yet predominantly reduced transcripts related to immune response pathways compared with milder disease. Conclusion Critical COVID-19 seems to be characterized by an immune profile of activated and exhausted T cells and monocytes. This immune phenotype may influence the capacity to mount an efficient T-cell immune response. Plasma B-cell activity and calprotectin were higher in critical COVID-19 while most transcripts related to immune functions were reduced, in particular affecting B cells. The potential of these cells as therapeutic targets in COVID-19 should be further explored.

• Abdukahil, Sheryl Ann; Abe, Ryuzo; Abel, Laurent; Absil, Lara; Acker, Andrew & Adachi, Shingo [Show all 50 contributors for this article] (2021). COVID‐19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study. Infection. ISSN 0300-8126. 49, p. 889–905. doi: 10.1007/s15010-021-01599-5. Full text in Research Archive Show summary

  Background The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men.

• Abdukahil, Sheryl Ann; Abe, Ryuzo; Abel, Laurent; Absil, Lara; Acharya, Subhash & Acker, Andrew [Show all 50 contributors for this article] (2021). Ten months of temporal variation in the clinical journey of hospitalised patients with COVID-19: An observational cohort. eLIFE. 10:e70970, p. 1–30. doi: 10.7554/eLife.70970. Full text in Research Archive Show summary

  Background: There is potentially considerable variation in the nature and duration of the care provided to hospitalised patients during an infectious disease epidemic or pandemic. Improvements in care and clinician confidence may shorten the time spent as an inpatient, or the need for admission to an intensive care unit (ICU) or high dependency unit (HDU). On the other hand, limited resources at times of high demand may lead to rationing. Nevertheless, these variables may be used as static proxies for disease severity, as outcome measures for trials, and to inform planning and logistics. Methods: We investigate these time trends in an extremely large international cohort of 142,540 patients hospitalised with COVID-19. Investigated are: time from symptom onset to hospital admission, probability of ICU/HDU admission, time from hospital admission to ICU/HDU admission, hospital case fatality ratio (hCFR) and total length of hospital stay. Results: Time from onset to admission showed a rapid decline during the first months of the pandemic followed by peaks during August/September and December 2020. ICU/HDU admission was more frequent from June to August. The hCFR was lowest from June to August. Raw numbers for overall hospital stay showed little variation, but there is clear decline in time to discharge for ICU/HDU survivors. Conclusions: Our results establish that variables of these kinds have limitations when used as outcome measures in a rapidly evolving situation. Funding: This work was supported by the UK Foreign, Commonwealth and Development Office and Wellcome [215091/Z/18/Z] and the Bill & Melinda Gates Foundation [OPP1209135]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

• Reyes, Luis Felipe; Murthy, Srinivas; Garcia-Gallo, Esteban; Irvine, Mike; Merson, Laura & Martin-Loeches, Ignacio [Show all 50 contributors for this article] (2021). Clinical characteristics, risk factors and outcomes in patients with severe COVID-19 registered in the ISARIC WHO clinical characterisation protocol: a prospective, multinational, multicentre, observational study. European Respiratory Journal Open Research (ERJ Open Research). 8(1). doi: 10.1183/23120541.00552-2021. Full text in Research Archive Show summary

  Due to the large number of patients with severe coronavirus disease 2019 (COVID-19), many were treated outside the traditional walls of the intensive care unit (ICU), and in many cases, by personnel who were not trained in critical care. The clinical characteristics and the relative impact of caring for severe COVID-19 patients outside the ICU is unknown. This was a multinational, multicentre, prospective cohort study embedded in the International Severe Acute Respiratory and Emerging Infection Consortium World Health Organization COVID-19 platform. Severe COVID-19 patients were identified as those admitted to an ICU and/or those treated with one of the following treatments: invasive or noninvasive mechanical ventilation, high-flow nasal cannula, inotropes or vasopressors. A logistic generalised additive model was used to compare clinical outcomes among patients admitted or not to the ICU. A total of 40 440 patients from 43 countries and six continents were included in this analysis. Severe COVID-19 patients were frequently male (62.9%), older adults (median (interquartile range (IQR), 67 (55–78) years), and with at least one comorbidity (63.2%). The overall median (IQR) length of hospital stay was 10 (5–19) days and was longer in patients admitted to an ICU than in those who were cared for outside the ICU (12 (6–23) days versus 8 (4–15) days, p<0.0001). The 28-day fatality ratio was lower in ICU-admitted patients (30.7% (5797 out of 18 831) versus 39.0% (7532 out of 19 295), p<0.0001). Patients admitted to an ICU had a significantly lower probability of death than those who were not (adjusted OR 0.70, 95% CI 0.65–0.75; p<0.0001). Patients with severe COVID-19 admitted to an ICU had significantly lower 28-day fatality ratio than those cared for outside an ICU.

• Ueland, Thor; Dyrhol-Riise, Anne Ma; Woll, Bjørn Martin; Holten, Aleksander Rygh; Pettersen, Frank O. & Lind, Andreas [Show all 10 contributors for this article] (2021). Increased inflammatory markers reflecting fibrogenesis are independently associated with cardiac involvement in hospitalized COVID-19 patients. Journal of Infection. ISSN 0163-4453. 82(5), p. 186–230. doi: 10.1016/j.jinf.2021.01.017. Full text in Research Archive
• Wickstrøm, Kristin Elisabeth; Vitelli, Valeria; Carr, Ewan; Holten, Aleksander R.; Bendayan, Rebecca & Reiner, Andrew Henry [Show all 15 contributors for this article] (2021). Regional performance variation in external validation of four prediction models for severity of COVID-19 at hospital admission: An observational multi-centre cohort study. PLOS ONE. 16(8), p. 1–13. doi: 10.1371/journal.pone.0255748. Full text in Research Archive Show summary

  Background: Prediction models should be externally validated to assess their performance before implementation. Several prediction models for coronavirus disease-19 (COVID-19) have been published. This observational cohort study aimed to validate published models of severity for hospitalized patients with COVID-19 using clinical and laboratory predictors. Methods: Prediction models fitting relevant inclusion criteria were chosen for validation. The outcome was either mortality or a composite outcome of mortality and ICU admission (severe disease). 1295 patients admitted with symptoms of COVID-19 at Kings Cross Hospital (KCH) in London, United Kingdom, and 307 patients at Oslo University Hospital (OUH) in Oslo, Norway were included. The performance of the models was assessed in terms of discrimination and calibration. Results: We identified two models for prediction of mortality (referred to as Xie and Zhang1) and two models for prediction of severe disease (Allenbach and Zhang2). The performance of the models was variable. For prediction of mortality Xie had good discrimination at OUH with an area under the receiver-operating characteristic (AUROC) 0.87 [95% confidence interval (CI) 0.79–0.95] and acceptable discrimination at KCH, AUROC 0.79 [0.76–0.82]. In prediction of severe disease, Allenbach had acceptable discrimination (OUH AUROC 0.81 [0.74–0.88] and KCH AUROC 0.72 [0.68–0.75]). The Zhang models had moderate to poor discrimination. Initial calibration was poor for all models but improved with recalibration. Conclusions: The performance of the four prediction models was variable. The Xie model had the best discrimination for mortality, while the Allenbach model had acceptable results for prediction of severe disease.

• Amundsen, Erik Koldberg; Binde, Christina; Christensen, Erik Egeland; Klingenberg, Olav Inge; Kvale, Dag & Holten, Aleksander Rygh (2021). Prognostic Value of Nucleated RBCs for Patients With Suspected Sepsis in the Emergency Department: A Single-Center Prospective Cohort Study. Critical Care Explorations. 3(7), p. 1–9. doi: 10.1097/CCE.0000000000000490. Full text in Research Archive Show summary

  Objectives: Increase of nucleated RBCs in peripheral blood has been shown to be predictive of mortality in ICU patients. The aim of this study was to explore the prognostic value of nucleated RBCs in the first blood sample taken at admission to the emergency department from patients with suspected sepsis. Design: Single-center prospective cohort study. Setting: Emergency department. Patients: One-thousand two-hundred thirty-one consecutive adult patients with suspected sepsis were included in a prospective quality register-based co-hort study. Inclusion criteria were as follows: patients received in rapid response team with blood cultures taken and immediate antibiotics given in the emergency department. Intervention: Not applicable. Measurement and main results: Nucleated RBCs, Sequential Organ Failure Assessment score, Quick Sequential Organ Failure Assessment, Charlson Comorbidity Index, and commonly used laboratory tests measured in the emergency department were compared with 30-day mortality. Nvaucleated RBC counts were divided into five groups, called “Nucleated RBC score,” according to nucleated RBC count levels and analyzed with logistic regression together with the Sequential Organ Failure Assessment score and Charlson Comorbidity Index. Of the 262 patients with nucleated RBCs equal to or higher than the detection limit (0.01 × 109/L), 26% died within 30 days, compared with 12% of the 969 patients with nucleated RBCs below the detection limit (p < 0.0001). Mortality was significantly higher for each increase in Nucleated RBC score, except from score 2 to 3, and was 62% in the highest group. In multivariate logistic regression, odds ratios for 30-day mortality were as follows: Nucleated RBC score: 1.33 (95% CI, 1.13–1.56), Sequential Organ Failure Assessment score: 1.32 (1.29–1.56), and Charlson Comorbidity Index: 1.17 (1.09–1.25). Conclusions: Most patients with suspected sepsis in emergency department had undetectable nucleated RBCs at admission to the emergency department. However, increased nucleated RBCs significantly predicted 30-day mortality. Nucleated RBCs may provide additional prognostic information to Sequential Organ Failure Assessment score and other laboratory tests.

• 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.

• Carr, Ewan; Bendayan, Rebecca; Bean, Daniel; Stammers, Matt; Wang, Wenjuan & Zhang, Huayu [Show all 48 contributors for this article] (2021). Evaluation and improvement of the National Early Warning Score (NEWS2) for COVID-19: a multi-hospital study. BMC Medicine. 19(23), p. 1–16. doi: 10.1186/s12916-020-01893-3. Full text in Research Archive Show summary

  Background The National Early Warning Score (NEWS2) is currently recommended in the UK for the risk stratification of COVID-19 patients, but little is known about its ability to detect severe cases. We aimed to evaluate NEWS2 for the prediction of severe COVID-19 outcome and identify and validate a set of blood and physiological parameters routinely collected at hospital admission to improve upon the use of NEWS2 alone for medium-term risk stratification. Methods Training cohorts comprised 1276 patients admitted to King’s College Hospital National Health Service (NHS) Foundation Trust with COVID-19 disease from 1 March to 30 April 2020. External validation cohorts included 6237 patients from five UK NHS Trusts (Guy’s and St Thomas’ Hospitals, University Hospitals Southampton, University Hospitals Bristol and Weston NHS Foundation Trust, University College London Hospitals, University Hospitals Birmingham), one hospital in Norway (Oslo University Hospital), and two hospitals in Wuhan, China (Wuhan Sixth Hospital and Taikang Tongji Hospital). The outcome was severe COVID-19 disease (transfer to intensive care unit (ICU) or death) at 14 days after hospital admission. Age, physiological measures, blood biomarkers, sex, ethnicity, and comorbidities (hypertension, diabetes, cardiovascular, respiratory and kidney diseases) measured at hospital admission were considered in the models. Results A baseline model of ‘NEWS2 + age’ had poor-to-moderate discrimination for severe COVID-19 infection at 14 days (area under receiver operating characteristic curve (AUC) in training cohort = 0.700, 95% confidence interval (CI) 0.680, 0.722; Brier score = 0.192, 95% CI 0.186, 0.197). A supplemented model adding eight routinely collected blood and physiological parameters (supplemental oxygen flow rate, urea, age, oxygen saturation, C-reactive protein, estimated glomerular filtration rate, neutrophil count, neutrophil/lymphocyte ratio) improved discrimination (AUC = 0.735; 95% CI 0.715, 0.757), and these improvements were replicated across seven UK and non-UK sites. However, there was evidence of miscalibration with the model tending to underestimate risks in most sites. Conclusions NEWS2 score had poor-to-moderate discrimination for medium-term COVID-19 outcome which raises questions about its use as a screening tool at hospital admission. Risk stratification was improved by including readily available blood and physiological parameters measured at hospital admission, but there was evidence of miscalibration in external sites. This highlights the need for a better understanding of the use of early warning scores for COVID.

• Gundem, Trine; Olasveengen, Theresa M.; Hovda, Knut Erik; Gaustad, Knut; Schøndorf, Christina Luise & Rostrup, Morten [Show all 11 contributors for this article] (2020). Ventilasjonsstotte for hypoksemiske intensivpasienter med covid-19. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 140(11), p. 1–10. doi: 10.4045/tidsskr.20.0445. Full text in Research Archive Show summary

  BAKGRUNN Covid-19-pneumoni kan gi alvorlig hypoksemisk respirasjonssvikt som krever intensivmedisinsk behandling. Vi ønsket å beskrive covid-19-intensivpasienter som ble behandlet med og uten invasiv ventilasjonsstøtte. MATERIALE OG METODE Materialet er hentet fra lokalt kvalitetsregister og består av data om pasienter med covid-19 innlagt på intensivavdelingen ved Oslo universitetssykehus, Ullevål i perioden 5.3–28.5.2020. Pasientene ble kategorisert i tre grupper basert på respirasjonssviktbehandlingen (oksygen alene, tillegg av ikke-invasiv ventilasjonsstøtte (NIV) og intubasjon/respirator) og beskrevet med deskriptiv statistikk. RESULTATER Av 165 innlagte covid-19-pasienter ble 26 (16 %) behandlet ved vår intensivavdeling. Fire av disse hadde behandlingsbegrensninger og ble ekskludert. De 22 pasientene inkludert i denne studien hadde gjennomsnittsalder 56 år (spredning 25–78 år), 17 (77 %) var menn. Elleve pasienter fikk respiratorbehandling, syv oksygen på maske og fire tillegg av ikke-invasiv ventilasjonsstøtte. I respiratorgruppen var to døde per 28.5.2020, resten var skrevet ut av intensivavdelingen i live, hvorav én fortsatt lå på sengepost. Alle pasienter behandlet med oksygen og ikke-invasiv ventilasjonsstøtte var i live og utskrevet fra sykehus. FORTOLKNING Mange pasienter med covid-19-respirasjonssvikt og behov for intensivbehandling kan klare seg med økt oksygentilbud og ikke-invasiv ventilasjonsstøtte, men behov for intubasjon må fortløpende vurderes. Over 90 % av aktivt behandlede intensivpasienter overlevde.

• Jørgensen, Marthe Jøntvedt; Holter, Jan Cato; Christensen, Erik; Schjalm, Camilla; Tonby, Kristian & Pischke, Soeren [Show all 22 contributors for this article] (2020). Increased interleukin-6 and macrophage chemoattractant protein-1 are associated with respiratory failure in COVID-19. Scientific Reports. 10. doi: 10.1038/s41598-020-78710-7. Full text in Research Archive Show summary

  In SARS-CoV-2 infection there is an urgent need to identify patients that will progress to severe COVID-19 and may benefit from targeted treatment. In this study we analyzed plasma cytokines in COVID-19 patients and investigated their association with respiratory failure (RF) and treatment in Intensive Care Unit (ICU). Hospitalized patients (n = 34) with confirmed COVID-19 were recruited into a prospective cohort study. Clinical data and blood samples were collected at inclusion and after 2–5 and 7–10 days. RF was defined as PaO2/FiO2 ratio (P/F) < 40 kPa. Plasma cytokines were analyzed by a Human Cytokine 27-plex assay. COVID-19 patients with RF and/or treated in ICU showed overall increased systemic cytokine levels. Plasma IL-6, IL-8, G-CSF, MCP-1, MIP-1α levels were negatively correlated with P/F, whereas combinations of IL-6, IP-10, IL-1ra and MCP-1 showed the best association with RF in ROC analysis (AUC 0.79–0.80, p < 0.05). During hospitalization the decline was most significant for IP-10 (p < 0.001). Elevated levels of pro-inflammatory cytokines were present in patients with severe COVID-19. IL-6 and MCP-1 were inversely correlated with P/F with the largest AUC in ROC analyses and should be further explored as biomarkers to identify patients at risk for severe RF and as targets for improved treatment strategies.

• 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.

• Holten, Aleksander Rygh; Nore, Kristin Grotle; Tveiten, Caroline Emilie Van Woensel Ko; Olasveengen, Theresa M. & Tonby, Kristian (2020). Predicting severe COVID-19 in the Emergency Department. Resuscitation Plus. 4. doi: 10.1016/j.resplu.2020.100042. 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.

• Trydal, Elisabet; Martinsen, Anders B.; Beisland, Frode; Jacobsen, Dag & Holten, Aleksander Rygh (2019). Strukturert mottak av sepsispasienter og oppstart av antibiotika. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 139(9), p. 811–816. doi: 10.4045/tidsskr.18.0216. Full text in Research Archive Show summary

  BAKGRUNN Akuttmottaket ved Oslo universitetssykehus, Ullevål, innførte i 2017 en egen prosedyre for mottak av pasienter med mistenkt sepsis. Et strukturert sepsismottak skulle utløses hos disse pasientene, spesielt hvis minst to av tre kriterier i skåringsverktøyet Quick Sequential Organ Failure Assessment (qSOFA) var oppfylt. Vi ønsket å undersøke om tiltaket var hensiktsmessig for å oppfylle nasjonale anbefalinger om oppstart av antibiotika innen én time ved behandling av sepsis. MATERIALE OG METODE Voksne pasienter med mistenkt sepsis som ble tatt imot i strukturerte teammottak i perioden 15.5.–15.11.2017 ble inkludert. Det ble gjort en retrospektiv vurdering av om de inkluderte faktisk hadde hatt sepsis eller ikke. RESULTATER Det ble gitt antibiotika mot mistenkt sepsis i 216 strukturerte pasientmottak (172 sepsismottak og 44 medisinske teammottak). 175 (81 %) av pasientene fikk antibiotika innen den første timen i akuttmottaket. Mediantid fra ankomst til antibiotika ble igangsatt var 35 minutter. Bruk av qSOFA-skår alene fanget opp 80 (71 %) av de 112 pasientene som i ettertid ble klassifisert til å ha sepsis. FORTOLKNING Etter innføring av strukturert mottak av pasienter med mistenkt sepsis ble antibiotikabehandling i stor grad gitt innen én time.

• Holten, Aleksander Talgøy; Danbolt, Niels Christian; Keiko, S & Gundersen, Vidar (2008). Low-affinity excitatory amino acid uptake in hippocampal astrocytes: A possible role of Na+/dicarboxylate cotransporters. Glia. ISSN 0894-1491. 56, p. 990–997. doi: 10.1002/glia.20672. Full text in Research Archive
• Holten, Aleksander Talgøy; Morland, Cecilie; Nordengen, Kaja & Gundersen, Vidar (2008). Vesicular Release of L- and D-Aspartate from Hippocampal Nerve Terminals: Immunogold Evidence. Open Neuroscience Journal. 2, p. 51–58. doi: 10.2174/1874082000802010051. Full text in Research Archive
• Holten, Aleksander Talgøy & Gundersen, Vidar (2008). Glutamine as a precursor for transmitter glutamate, aspartate and GABA in the cerebellum: a role for phosphate-activated glutaminase. Journal of Neurochemistry. ISSN 0022-3042. 104. doi: 10.1111/j.1471-4159.2007.05065.x. Full text in Research Archive
• Gundersen, Vidar; Holten, Aleksander Talgøy & Storm-Mathisen, Jon (2004). GABAergic synapses in hippocampus exocytose aspartate on to NMDA receptors: quantitative immunogold evidence for co-transmission. Molecular and Cellular Neuroscience. ISSN 1044-7431. 26(1), p. 156–165. Full text in Research Archive

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• Holten, Aleksander Rygh; Bjerkhaug, Andreas Wigmostad; Maharjan, Urusha; Rykkvin, Rikard; Hagen, Thijs & Fevang, Børre [Show all 12 contributors for this article] (2025). A case of fatal hemorrhagic fever associated with tick-borne encephalitis virus infection. doi: 10.1016/j.ijid.2025.107989. 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
• Quiles-Jiménez, Ana M T; Sousa, Mirta; Huse, Camilla; Dyrhol-Riise, Anne Ma; Holter, Jan Cato & Christensen, Erik Egeland [Show all 12 contributors for this article] (2023). Severely ill COVID-19 patients have altered circulating levels of proteins controlling the epitranscriptome. Journal of Infection. ISSN 0163-4453. doi: 10.1016/j.jinf.2023.03.002. Full text in Research Archive
• Holten, Aleksander Rygh & Skrede, Steinar (2023). Tidlig antibiotikabehandling til de rett pasientene. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 143(2). doi: 10.4045/tidsskr.22.0702. 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
• Gundem, Trine; Olasveengen, Theresa M.; Schøndorf, Christina Luise; Hovda, Knut Erik; Rostrup, Morten & Frøyshov, Sten [Show all 11 contributors for this article] (2020). T.M. Gundem og medarbeidere svarer. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 140(12), p. 1–2. doi: 10.4045/tidsskr.20.0650. Full text in Research Archive
• Ueland, Thor; Holter, Jan Cato; Holten, Aleksander Rygh; Muller, Karl Erik; Lind, A. & Bekken, Gry Klouman [Show all 10 contributors for this article] (2020). Distinct and early increase in circulating MMP-9 in COVID-19 patients with respiratory failure: MMP-9 and respiratory failure in COVID-19. Journal of Infection. ISSN 0163-4453. 81(3), p. e41–e43. doi: 10.1016/j.jinf.2020.06.061. Full text in Research Archive
• Kolberg, Espen Skarstein; Wickstrøm, Kristin; Tonby, Kristian; Dyrhol-Riise, Anne Ma; Holten, Aleksander Rygh & Amundsen, Erik Koldberg (2020). Serum ACE as a prognostic biomarker in COVID-19: A Case series. APMIS - Journal of Pathologiy, Microbiology and Immunology. ISSN 0903-4641. p. 1–2. doi: 10.1111/apm.13108. Full text in Research Archive Show summary

  We have earlier proposed that serum ACE (s‐ACE) could be used as a biomarker for severity in COVID‐19 due to an assumed inverse relationship between ACE and ACE2. High s‐ACE could indicate lower ACE2 activity and therefore more widespread and severe SARS‐CoV2 infection, owing to virally mediated downregulation of ACE2 (1). Dysregulation of the Renin‐Angiotensin‐Aldosterone system (RAAS) are found in comorbidities known as risk factors for increased morbidity and mortality, such as hypertension and cardiovascular disease (2).

• Holten, Aleksander Talgøy (2013). Dobbel pylorus. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 133(6), p. 645–645. doi: 10.4045/tidsskr.13.0033. Full text in Research Archive

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