Anne Margarita Dyrhol Riise

• Myhre, Anders Eivind; Meyer-Myklestad, Malin Holm; Gullaksen, Hanne Hestdal; Søgaard, Ole S.; Tolstrup, Martin & Salgado, Maria [Vis alle 51 forfattere av denne artikkelen] (2026). Long-term HIV-1 remission achieved through allogeneic haematopoietic stem cell transplant from a CCR5Δ32/Δ32 sibling donor. Nature Microbiology. 11, s. 1374–1386. doi: 10.1038/s41564-026-02304-8. Fulltekst i vitenarkiv Vis sammendrag

  Only few cases of human immunodeficiency virus (HIV) remission have been reported after allogeneic haematopoietic stem cell transplantation (HSCT), mostly involving stem cell donors with the homozygous CCR5Δ32 (CCR5Δ32/Δ32) mutation, which confers resistance to CCR5-tropic HIV-1. Here we report the case of a 63-year-old man in off-treatment HIV remission, 5 years after HSCT with a CCR5Δ32/Δ32 sibling donor for myelodysplastic syndrome. In-depth clinical characterization including virological and immunological analyses of peripheral blood, gut and bone marrow samples revealed that full donor chimerism was achieved. Antiretroviral therapy was discontinued after 24 months, and 48 months after HSCT, no intact HIV DNA was detected in blood or gut biopsies. Replication-competent virus and HIV-specific T cell responses were absent, and HIV antibody responses showed a gradual decline. Full donor chimerism in the gut, which is the primary viral reservoir, underscores the likelihood of a cure.

• Kildal, Anders Benjamin; Ueland, Thor; Mirlashari, Mohammad Reza; Nissen-Meyer, Lise Sofie; Granerud, Beathe Kiland & Riise, Anne Margarita Dyrhol [Vis alle 44 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv Vis sammendrag

  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 [Vis alle 18 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Tøndel, Camilla; Jenum, Synne; Tonby, Kristian; Christensen, Erik Egeland; Cox, Rebecca Jane & Onyango, Therese Bredholt [Vis alle 24 forfattere av denne artikkelen] (2026). SARS-CoV-2 T-cell vaccine VB10.2210 induces broad T-cell responses in a phase 1/2 open-label clinical trial. Vaccine. ISSN 0264-410X. 75. doi: 10.1016/j.vaccine.2026.128290. Fulltekst i vitenarkiv Vis sammendrag

  The repeated emergence of highly transmissive SARS-CoV-2 variants requires a broadly protective vaccine. We developed a T-cell vaccine VB10.2210 that targets SARS-CoV-2 viral antigens to antigen presenting cells comprising 96 validated immunogenic T-cell epitopes covering a global HLA diversity. We report results from a first in human open-label dose-escalation phase 1/2 clinical trial evaluating safety, reactogenicity and immunogenicity of VB10.2210. The study investigated three dose levels (0.3, 1.0 and 3.0 mg), delivered intramuscularly as DNA plasmid by jet injection (NCT05069623), in 34 healthy adults previously vaccinated with mRNA SARS-CoV-2 vaccines. The safety profile was favorable with no observed dose-limiting toxicity. The 3 mg dose elicited the most potent immune response with enhanced breadth and a CD8+ dominated T cell response. T cell responses towards spike protein and de novo responses to non-spike antigens were confirmed by ELISpot. Expansion of VB10.2210 specific T-cell clones was confirmed by TCR sequencing. Further studies are needed to evaluate the clinical benefit of DNA vaccines inducing broad virus specific T-cell immunity in preventing severe COVID-19 or as treatment of patients with persistent infection.

• Massonnaud, Clément R.; Peiffer-Smadja, Nathan; Poignard, Pascal; Jamard, Simon; Goehringer, François & Danion, François [Vis alle 85 forfattere av denne artikkelen] (2025). Efficacy, safety, pharmacokinetics, immunogenicity, and serum neutralizing activity of AZD7442 (tixagevimab-cilgavimab) in patients hospitalized with COVID-19: long-term results from the DisCoVeRy trial. Clinical Microbiology and Infection (CMI). ISSN 1198-743X. 32(4), s. 618–628. doi: 10.1016/j.cmi.2025.12.014. Fulltekst i vitenarkiv
• Sester, Martina; Altet-Gomez, Neus; Andersen, Åse Bengaard; Arias-Guillén, Miguel; Avsar, Korkut & Kran, Anne-Marte Bakken [Vis alle 44 forfattere av denne artikkelen] (2025). Diagnostic accuracy and predictive value of the QuantiFERON-TB gold plus assay for tuberculosis in immunocompromised individuals: a prospective TBnet study. The Lancet Regional Health - Europe. 57. doi: 10.1016/j.lanepe.2025.101416. Fulltekst i vitenarkiv
• Kirakosyan, O.; Reimann, M.; Andersen, A. B.; Bjarnason, A.; Bakos, A. & Riise, Anne Margarita Dyrhol [Vis alle 37 forfattere av denne artikkelen] (2025). Use of putative hepatoprotective agents as an adjunct to anti-TB treatment in Europe. International Journal of Tuberculosis and Lung Disease OPEN (IJTLD OPEN). 2(2), s. 101–106. doi: 10.5588/ijtldopen.24.0498. Fulltekst i vitenarkiv
• Kaarbø, Mari; Yang, Mingyi; Meyer-Myklestad, Malin Holm; Sundaram, Arvind; Sousa, Mirta & Sharma, Animesh [Vis alle 13 forfattere av denne artikkelen] (2025). Transcriptomic and proteomic profiling reveal immune and metabolic dysregulation in the colonic mucosa of people living with HIV with incomplete immune recovery. Frontiers in Immunology. 16. doi: 10.3389/fimmu.2025.1635523. Fulltekst i vitenarkiv Vis sammendrag

  Background People living with HIV are called immunological non-responders (INR) when their CD4+ T cell count is not restored to immunocompetent levels, despite successful viral suppression. INR have increased risk of progression to AIDS, non-AIDS related morbidity, and death. Impaired mucosal barrier function is a prevailing hypothesis for why INR among people with HIV (PWH) have persistently low CD4+ T cell counts. Objective To understand the molecular mechanisms behind incomplete immune recovery in INR, we analyzed gene regulation and protein expression in gut tissues from INR, immunological responders (IR) and healthy controls (HC). Methods The transcriptome was assessed by RNA-sequencing (RNA-seq) and the proteome was examined using shotgun proteomic mass spectrometry in mucosal biopsies from the sigmoid colon and terminal ileum. Results In INR compared to IR, we identified 3326 differentially expressed genes (DEGs) in the colon while no DEGs were observed in the ileum. Gene ontology (GO) analyses revealed that the DEGs in colon of INR, compared to IR, predominantly involved pathways related to immune response, metabolism, and cellular processes. Notably, GO analysis highlighted downregulation of genes associated with B cell-mediated immunity and adaptive responses in INR. Deconvolution analysis indicated that these transcriptomic changes were not solely due to shifts in immune cell composition. Proteomic analysis supported these findings, showing more differential protein composition between INR and IR in colon than ileum. These proteins are associated with the regulation of adaptive immune signaling and essential cellular processes, including cell signaling, tissue repair, and growth, all of which are characteristic features of inflammatory bowel disease (IBD). Conclusion Our findings suggest that incomplete immune recovery during anti-retroviral therapy in PWH is associated with specific dysregulations in the molecular environment of the sigmoid colon, which may share mechanisms with IBD. The identified macromolecules may serve as potential targets for adjuvant treatment to improve the prognosis for INR.

• Bodin, Johanna Eva; Tunheim, Gro; Kristoffersen, Anja Bråthen; Herstad, Tove Karin; Vianello, Eleonora & Haks, Mariëlle C. [Vis alle 17 forfattere av denne artikkelen] (2025). High-dimensional single-cell phenotyping unveils persistent differences in immune cell profiles between severe and moderate seasonal influenza. Frontiers in Immunology. 16, s. 1–20. doi: 10.3389/fimmu.2025.1576861. Fulltekst i vitenarkiv Vis sammendrag

  Background Influenza viruses with pandemic potential and possible burden of post-viral sequelae are a global concern. To prepare for future pandemics and the development of improved vaccines, it is vital to identify the immunological changes underlying influenza disease severity. Methods We combined unsupervised high-dimensional single-cell mass cytometry with gene expression analyses, plasma CXCL13 measurements, and antigen-specific immune cell assays to characterize the immune profiles of hospitalized patients with severe and moderate seasonal influenza disease during active infection and at 6-month follow-up. We used age-matched healthy donors as controls. Results Severe disease was associated with a distinct immune profile, including lower frequencies of ICOS + mucosal-associated invariant T (MAIT) cells, and CXCR5 + memory B and CD4 + CXCR5 + CD95 + ICOS + and CD8 + CXCR3 + CD95 + PD-1 + TIGIT + memory T cells, as well as lower CD4 gene expression. Higher frequencies of CD16 + CD161 + NK cells, CD169 + monocytes, CD123 +/− dendritic cells, and CD38 high plasma cells and high CXCL13 plasma levels were also associated with severe disease. Alterations in immune cell subpopulations persisted at convalescence for the severely ill patients only. Conclusions Our results indicated a reduction in regulatory MAIT cells and memory T and B cells and an increase in the inhibitory subpopulations of monocytes and NK cells in severe influenza that persisted at convalescence. These immune cell alterations were associated with higher age and the presence of several underlying conditions that may contribute to frailty. This study illustrates the power and sensitivity of high-dimensional single-cell analyses in identifying potential cellular biomarkers for disease severity after influenza infection.

• Granerud, Beathe Kiland; Kaarbø, Mari; Al-Baldawi, Huda; Heggelund, Lars; Tveita, Anders & Müller, Karl Erik [Vis alle 42 forfattere av denne artikkelen] (2025). Droplet Digital PCR or Real-Time PCR as a Method for Quantifying SARS-CoV-2 RNA in Plasma-Is There a Difference? Viruses. 17(6). doi: 10.3390/v17060772. Fulltekst i vitenarkiv Vis sammendrag

  The aim of this study is to ascertain whether qRT-PCR (reverse transcriptase real-time PCR) or RT-ddPCR (reverse transcriptase digital droplet PCR) is more effective for detecting SARS-CoV-2 RNA (severe acute respiratory syndrome coronavirus 2 RNA) in blood plasma from COVID-19 (coronavirus infectious disease-19) patients. The E-gene of SARS-CoV-2 RNA was quantified using both methods in 128 plasma samples from 70 hospitalized patients, followed by a statistical analysis to compare the sensitivity and concordance between the methods. Out of the 128 samples, 89 yielded consistent results irrespective of the method used, whereas 39 samples showed discrepancies between the two different methods. RT-ddPCR frequently registered higher viral quantities compared to qRT-PCR; however, the results did not demonstrate a clear superiority in sensitivity for RT-ddPCR. Although RT-ddPCR registered higher viral quantities, this study concludes that both methods provide comparable results for detecting SARS-CoV-2 E-gene RNA in plasma.

• Viermyr, Hans-Kittil; Halvorsen, Bente; Sagen, Ellen Lund; Michelsen, Annika Elisabet; Barratt-Due, Andreas & Kåsine, Trine [Vis alle 73 forfattere av denne artikkelen] (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), s. 249–259. doi: 10.1111/joim.13820. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Viermyr, Hans-Kittil; Tonby, Kristian; Ponzi, Erica; Trouillet-Assant, Sophie; Poissy, Julien & Arribas, José R. [Vis alle 49 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Halvorsen, Bente; Viermyr, Hans-Kittil; Ueland, Thor; Sagen, Ellen Lund; Michelsen, Annika Elisabet & Bjerkeli, Vigdis [Vis alle 14 forfattere av denne artikkelen] (2024). IL-22 is increased in hospitalized patients with COVID-19 and associates with cardiac involvement. Journal of Infection. ISSN 0163-4453. 89(1). doi: 10.1016/j.jinf.2024.106176. Fulltekst i vitenarkiv
• Barratt-Due, Andreas; Pettersen, Kristin; Dahl, Tuva Børresdatter; Holter, Jan Cato; Grønli, Renathe Henriksen & Dyrhol-Riise, Anne Ma [Vis alle 20 forfattere av denne artikkelen] (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), s. 80–92. doi: 10.1111/joim.13783. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Alirezaylavasani, Amin; Skeie, Linda Gail; Egner, Ingrid Marie; Chopra, Adity; Dahl, Tuva Børresdatter & Prebensen, Christian Haugland [Vis alle 16 forfattere av denne artikkelen] (2024). Vaccine responses and hybrid immunity in people living with HIV after SARS-CoV-2 breakthrough infections. npj Vaccines. 9(1), s. 1–15. doi: 10.1038/s41541-024-00972-3. Fulltekst i vitenarkiv Vis sammendrag

  The COVID-19 pandemic posed a challenge for people living with HIV (PLWH), particularly immune non-responders (INR) with compromised CD4 T-cell reconstitution following antiretroviral therapy (CD4 count <350 cells per mm3). Their diminished vaccine responses raised concerns about their vulnerability to SARS-CoV-2 breakthrough infections (BTI). Our in-depth study here revealed chronic inflammation in PLWH and a limited anti-Spike IgG response after vaccination in INR. Nevertheless, the imprinting of Spike-specific B cells by vaccination significantly enhanced the humoral responses after BTI. Notably, the magnitude of cellular CD4 response in all PLWH was comparable to that in healthy donors (HD). However, the polyfunctionality and phenotype of Spike-specific CD8 T cells in INR differed from controls. The findings highlight the need for additional boosters with variant vaccines, and for monitoring ART adherence and the durability of both humoral and cellular anti-SARS-CoV-2 immunity in INR.

• Hoel, Hedda; Dahl, Tuva Børresdatter; Yang, Kuan; Skeie, Linda Gail; Michelsen, Annika Elisabet & Ueland, Thor [Vis alle 13 forfattere av denne artikkelen] (2024). Chronic HIV Infection Increases Monocyte NLRP3 Inflammasome-Dependent IL-1α and IL-1β Release. International Journal of Molecular Sciences. ISSN 1661-6596. 25(13). doi: 10.3390/ijms25137141. Fulltekst i vitenarkiv Vis sammendrag

  Antiretroviral treatment (ART) has converted HIV from a lethal disease to a chronic condition, yet co-morbidities persist. Incomplete immune recovery and chronic immune activation, especially in the gut mucosa, contribute to these complications. Inflammasomes, multi-protein complexes activated by innate immune receptors, appear to play a role in these inflammatory responses. In particular, preliminary data indicate the involvement of IFI16 and NLRP3 inflammasomes in chronic HIV infection. This study explores inflammasome function in monocytes from people with HIV (PWH); 22 ART-treated with suppressed viremia and 17 untreated PWH were compared to 33 HIV-negative donors. Monocytes were primed with LPS and inflammasomes activated with ATP in vitro. IFI16 and NLRP3 mRNA expression were examined in a subset of donors. IFI16 and NLRP3 expression in unstimulated monocytes correlated negatively with CD4 T cell counts in untreated PWH. For IFI16, there was also a positive correlation with viral load. Monocytes from untreated PWH exhibit increased release of IL-1α, IL-1β, and TNF compared to treated PWH and HIV-negative donors. However, circulating monocytes in PWH are not pre-primed for inflammasome activation in vivo. The findings suggest a link between IFI16, NLRP3, and HIV progression, emphasizing their potential role in comorbidities such as cardiovascular disease. The study provides insights into inflammasome regulation in HIV pathogenesis and its implications for therapeutic interventions.

• Murphy, Sarah Louise Mikalsen; Balzer, Nora Reka; Ranheim, Trine; Sagen, Ellen Lund; Huse, Camilla & Bjerkeli, Vigdis [Vis alle 19 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Mesinovic, Munib; Wong, Xin Ci; Rajahram, Giri Shan; Citarella, Barbara Wanjiru; Peariasamy, Kalaiarasu M. & Greve, Frank van Someren [Vis alle 1 671 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv
• Patrick-Brown, Thale Dawn; Barratt-Due, Andreas; Trøseid, Marius; Dyrhol-Riise, Anne Ma; Nezvalova-Henriksen, Katerina & Kåsine, Trine [Vis alle 8 forfattere av denne artikkelen] (2024). The effects of remdesivir on long-term symptoms in patients hospitalised for COVID-19: a pre-specified exploratory analysis. Communications Medicine. 4(231), s. 1–7. doi: 10.1038/s43856-024-00650-4. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Rodriguez, Noelia Alonso; Vianello, Eleonora; Veen, Suzanne van; Jenum, Synne; Tonby, Kristian & Riessen, Rosalie van [Vis alle 10 forfattere av denne artikkelen] (2024). Whole blood RNA signatures in tuberculosis patients receiving H56:IC31 vaccine as adjunctive therapy. Frontiers in Immunology. 15. doi: 10.3389/fimmu.2024.1350593. Fulltekst i vitenarkiv Vis sammendrag

  Introduction: Therapeutic vaccination in tuberculosis (TB) represents a Host Directed Therapy strategy which enhances immune responses in order to improve clinical outcomes and shorten TB treatment. Previously, we have shown that the subunit H56:IC31 vaccine induced both humoral and cellular immune responses when administered to TB patients adjunctive to standard TB treatment (TBCOX2 study, NCT02503839). Here we present the longitudinal whole blood gene expression patterns in H56:IC31 vaccinated TB patients compared to controls receiving standard TB treatment only. Methods: The H56:IC31 group (N=11) and Control group (N=7) underwent first-line TB treatment for 182 days. The H56:IC31 group received 5 micrograms of the H56:IC31 vaccine (Statens Serum Institut; SSI, Valneva Austria GmbH) intramuscularly at day 84 and day 140. Total RNA was extracted from whole blood samples collected in PAXgene tubes on days 0, 84, 98, 140, 154, 182 and 238. The expression level of 183 immune-related genes was measured by high-throughput microfluidic qPCR (Biomark HD system, Standard BioTools). Results: The targeted gene expression profiling unveiled the upregulation of modules such as interferon (IFN) signalling genes, pattern recognition receptors and small nucleotide guanosine triphosphate (GTP)-ases in the vaccinated group compared to controls two weeks after administration of the first H56:IC31 vaccine. Additionally, the longitudinal analysis of the Adolescent Cohort Study-Correlation of Risk (ACS-COR) signature showed a progressive downregulation in both study arms towards the end of TB treatment, in congruence with reported treatment responses and clinical improvements. Still, two months after the end of TB treatment, vaccinated patients, and especially those developing both cellular and humoral vaccine responses, showed a lower expression of the ACS-COR genes compared to controls. Discussion: Our data report gene expression patterns following H56:IC31 vaccination which might be interpreted as a lower risk of relapse in therapeutically vaccinated patients. Further studies are needed to conclude if these gene expression patterns could be used as prognostic biosignatures for therapeutic TB vaccine responses.

• Nissen-Meyer, Lise Sofie Haug; Macpherson, Magnhild Eide; Skeie, Linda Gail; Hvalryg, Marte; LLOHN, ABID HUSSAIN & Steinsvåg, Tine Torsvik [Vis alle 17 forfattere av denne artikkelen] (2023). Covid-19-pasienter behandlet med rekonvalesensplasma. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 143(11). doi: 10.4045/tidsskr.22.0577. Fulltekst i vitenarkiv Vis sammendrag

  BAKGRUNN I Norge er behandling med covid-19-rekonvalesensplasma gitt gjennom NORPLASMA-prosjektet. I begynnelsen ble behandlingen tilbudt kritisk syke pasienter etter individuell vurdering, men fra desember 2020 ble indikasjonen begrenset til kritisk syke pasienter med immunsvikt. Vi beskriver her kliniske karakteristika, komorbiditet og mortalitet hos pasienter som fikk rekonvalesensplasma i disse to periodene. MATERIALE OG METODE I perioden 22.4.2020–30.3.2022 ble 79 pasienter inkludert i observasjonsstudiene NORPLASMA MONITOR og Norwegian SARS-CoV-2-studien. Pasientene hadde mottatt totalt 193 enheter med rekonvalesensplasma ved 15 norske sykehus/sykehjem: 62 i Helse Sør-Øst, 8 i Helse Vest og 9 i Helse Midt-Norge. Opplysninger om immunstatus, komorbiditet og sykdomsforløp ble registrert fra pasientjournalen etter skriftlig samtykke. RESULTATER Av 79 pasienter med median alder 65 år (interkvartilbredde 51–73) som fikk behandling med rekonvalesensplasma, døde 31 (39 %) under sykehusoppholdet. 59 pasienter hadde immunsvikt, og blant disse døde 20 i sykehus, mot 11 av 20 antatt immunkompetente. Median antall komorbiditeter var 2 (interkvartilbredde 1–4). Pasientene fikk i median 2 plasmaenheter (min–maks 1–21). To av pasientene utviklet milde allergiske hudreaksjoner. FORTOLKNING Rekonvalesensplasma ble godt tolerert av pasienter med covid-19. Immunsviktpasienter hadde muligens effekt av behandlingen, med lavere dødelighet i denne gruppen enn blant antatt immunkompetente.

• Trøseid, Marius; Holter, Jan Cato; Holm, Kristian; Vestad, Beate; Sazonova, Taisiia & Granerud, Beathe Kiland [Vis alle 17 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Abdelhak, Ahmed; Barba, Lorenzo; Romoli, Michele; Benkert, Pascal; Conversi, Francesco & D’Anna, Lucio [Vis alle 38 forfattere av denne artikkelen] (2023). Prognostic performance of blood neurofilament light chain protein in hospitalized COVID-19 patients without major central nervous system manifestations: an individual participant data meta-analysis. Journal of Neurology. ISSN 0340-5354. doi: 10.1007/s00415-023-11768-1. Fulltekst i vitenarkiv
• Murphy, Sarah Louise Mikalsen; Halvorsen, Bente; Holter, Jan Cato; Huse, Camilla; Tveita, Anders & Trøseid, Marius [Vis alle 24 forfattere av denne artikkelen] (2023). Circulating markers of extracellular matrix remodelling in severe COVID-19 patients. Journal of Internal Medicine. ISSN 0954-6820. 294(6), s. 784–797. doi: 10.1111/joim.13725. Fulltekst i vitenarkiv Vis sammendrag

  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 [Vis alle 16 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Gunst, Jesper D.; Højen, Jesper F.; Pahus, Marie H.; Rosás-Umbert, Miriam; Stiksrud, Birgitte & McMahon, James H. [Vis alle 33 forfattere av denne artikkelen] (2023). Impact of a TLR9 agonist and broadly neutralizing antibodies on HIV-1 persistence: the randomized phase 2a TITAN trial. Nature Medicine. ISSN 1078-8956. 29(10), s. 2547–2558. doi: 10.1038/s41591-023-02547-6. Fulltekst i vitenarkiv Vis sammendrag

  Inducing antiretroviral therapy (ART)-free virological control is a critical step toward a human immunodeficiency virus type 1 (HIV-1) cure. In this phase 2a, placebo-controlled, double-blinded trial, 43 people (85% males) with HIV-1 on ART were randomized to (1) placebo/placebo, (2) lefitolimod (TLR9 agonist)/placebo, (3) placebo/broadly neutralizing anti-HIV-1 antibodies (bNAbs) or (4) lefitolimod/bNAb. ART interruption (ATI) started at week 3. Lefitolimod was administered once weekly for the first 8 weeks, and bNAbs were administered twice, 1 d before and 3 weeks after ATI. The primary endpoint was time to loss of virologic control after ATI. The median delay in time to loss of virologic control compared to the placebo/placebo group was 0.5 weeks (P = 0.49), 12.5 weeks (P = 0.003) and 9.5 weeks (P = 0.004) in the lefitolimod/placebo, placebo/bNAb and lefitolimod/bNAb groups, respectively. Among secondary endpoints, viral doubling time was slower for bNAb groups compared to non-bNAb groups, and the interventions were overall safe. We observed no added benefit of lefitolimod. Despite subtherapeutic plasma bNAb levels, 36% (4/11) in the placebo/bNAb group compared to 0% (0/10) in the placebo/placebo group maintained virologic control after the 25-week ATI. Although immunotherapy with lefitolimod did not lead to ART-free HIV-1 control, bNAbs may be important components in future HIV-1 curative strategies. ClinicalTrials.gov identifier: NCT03837756.

• Nore, Kristin Grotle; Louet, Claire; Bugge, Marit; Gidon, Alexandre; Jørgensen, Marthe Jøntvedt & Jenum, Synne [Vis alle 9 forfattere av denne artikkelen] (2023). The Cyclooxygenase 2 Inhibitor Etoricoxib as Adjunctive Therapy in Tuberculosis Impairs Macrophage Control of Mycobacterial Growth. Journal of Infectious Diseases. ISSN 0022-1899. 229(3), s. 888–897. doi: 10.1093/infdis/jiad390. Fulltekst i vitenarkiv Vis sammendrag

  Background Current tuberculosis treatment regimens could be improved by adjunct host-directed therapies (HDT) targeting host responses. We investigated the antimycobacterial capacity of macrophages from patients with tuberculosis in a phase 1/2 randomized clinical trial (TBCOX2) of the cyclooxygenase-2 inhibitor etoricoxib. Methods Peripheral blood mononuclear cells from 15 patients with tuberculosis treated with adjunctive COX-2i and 18 controls (standard therapy) were collected on day 56 after treatment initiation. The ex vivo capacity of macrophages to control mycobacterial infection was assessed by challenge with Mycobacterium avium, using an in vitro culture model. Macrophage inflammatory responses were analyzed by gene expression signatures, and concentrations of cytokines were analyzed in supernatants by multiplex. Results Macrophages from patients receiving adjunctive COX-2i treatment had higher M. avium loads than controls after 6 days, suggesting an impaired capacity to control mycobacterial infection compared to macrophages from the control group. Macrophages from the COX-2i group had lower gene expression of TNF, IL-1B, CCL4, CXCL9, and CXCL10 and lowered production of cytokines IFN-β and S100A8/A9 than controls. Conclusions Our data suggest potential unfavorable effects with impaired macrophage capacity to control mycobacterial growth in patients with tuberculosis receiving COX-2i treatment. Larger clinical trials are required to analyze the safety of COX-2i as HDT in patients with tuberculosis. Clinical Trials Registration NCT02503839.

• Pan, Hongchao; Peto, Richard; Karim, Quarraisha Abdool; Alejandria, Marissa M.; Henao-Restrepo, Ana-Maria & Hernández-García, César [Vis alle 51 forfattere av denne artikkelen] (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), s. 1941–1953. doi: 10.1016/S0140-6736(22)00519-0. Fulltekst i vitenarkiv Vis sammendrag

  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).

• Chendi, Bih Hycenta; Jooste, Tracey; Scriba, Thomas Jens; Kidd, Martin; Mendelsohn, Simon & Tonby, Kristian [Vis alle 9 forfattere av denne artikkelen] (2022). Utility of a three-gene transcriptomic signature in the diagnosis of tuberculosis in a low-endemic hospital setting. Infectious Diseases. ISSN 2374-4235. doi: 10.1080/23744235.2022.2129779. Fulltekst i vitenarkiv Vis sammendrag

  Background Host transcriptomic blood signatures have demonstrated diagnostic potential for tuberculosis (TB), requiring further validation across different geographical settings. Discriminating TB from other diseases with similar clinical manifestations is crucial for the development of an accurate immunodiagnostic tool. In this exploratory cohort study, we evaluated the performance of potential blood-based transcriptomic signatures in distinguishing TB disease from non-TB lower respiratory tract infections in hospitalised patients in a TB low-endemic country. Method Quantitative real-time polymerase chain reaction qPCR) was used to evaluate 26 previously published genes in blood from 31 patients (14 TB and 17 lower respiratory tract infection cases) admitted to Oslo University Hospital in Norway. The diagnostic accuracies of differentially expressed genes were determined by receiver operating characteristic curves. Results A significant difference (p < .01) in the age distribution was observed between patients with TB (mean age, 40 ± 15 years) and lower respiratory tract infection (mean age 59 ± 12 years) . Following adjustment for age, ETV7, GBP1, GBP5, P2RY14 and BLK were significantly differentially expressed between patients with TB and those with LRI. A general discriminant analysis generated a three-gene signature (BAFT2, ETV7 and CD1C), which diagnosed TB with an area under the receiver operating characteristic curve (AUC) of 0.86 (95% CI, 0.69 − 1.00), sensitivity of 69.23% (95% CI, 38.57%−90.91%) and specificity of 94.12% (95% CI, 71.31%−99.85%). Conclusion The three-genes signature may have potential to improve diagnosis of TB in a hospitalised low-burden setting. However, the influence of confounding variables or covariates such as age requires further evaluation in larger studies.

• Ueland, Thor; Sørvoll, Ingvild Hausberg; Mørtberg, Trude Victoria; Dahl, Tuva Børresdatter; Lerum, Tøri Vigeland & Michelsen, Annika Elisabet [Vis alle 16 forfattere av denne artikkelen] (2022). Anti-PF4/polyanion antibodies in COVID-19 patients are associated with disease severity and pulmonary pathology. Platelets. ISSN 0953-7104. 33(4), s. 640–644. doi: 10.1080/09537104.2022.2042238. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Garcia-Gallo, Esteban; Merson, Laura; Kennon, Kalynn; Kelly, Sadie; Citarella, Barbara Wanjiru & Fryer, Daniel Vidali [Vis alle 1 775 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv Vis sammendrag

  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 [Vis alle 28 forfattere av denne artikkelen] (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), s. 2150–2160. doi: 10.1093/infdis/jiac313. Fulltekst i vitenarkiv Vis sammendrag

  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 [Vis alle 28 forfattere av denne artikkelen] (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), s. 816–828. doi: 10.1111/joim.13549. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Olsen, Maria Belland; Huse, Camilla; Sousa, Mirta; Murphy, Sarah Louise Mikalsen; Sarno, Antonio & Obermann, Tobias Sebastian [Vis alle 20 forfattere av denne artikkelen] (2022). DNA Repair Mechanisms are Activated in Circulating Lymphocytes of Hospitalized Covid-19 Patients. Journal of Inflammation Research. 15, s. 6629–6644. doi: 10.2147/JIR.S379331. Fulltekst i vitenarkiv Vis sammendrag

  Purpose: Reactive oxygen species (ROS) are an important part of the inflammatory response during infection but can also promote DNA damage. Due to the sustained inflammation in severe Covid-19, we hypothesized that hospitalized Covid-19 patients would be characterized by increased levels of oxidative DNA damage and dysregulation of the DNA repair machinery. Patients and Methods: Levels of the oxidative DNA lesion 8-oxoG and levels of base excision repair (BER) proteins were measured in peripheral blood mononuclear cells (PBMC) from patients (8-oxoG, n = 22; BER, n = 17) and healthy controls (n = 10) (Cohort 1). Gene expression related to DNA repair was investigated in two independent cohorts of hospitalized Covid-19 patients (Cohort 1; 15 patents and 5 controls, Cohort 2; 15 patients and 6 controls), and by publicly available datasets. Results: Patients and healthy controls showed comparable amounts of oxidative DNA damage as assessed by 8-oxoG while levels of several BER proteins were increased in Covid-19 patients, indicating enhanced DNA repair in acute Covid-19 disease. Furthermore, gene expression analysis demonstrated regulation of genes involved in BER and double strand break repair (DSBR) in PBMC of Covid-19 patients and expression level of several DSBR genes correlated with the degree of respiratory failure. Finally, by re-analyzing publicly available data, we found that the pathway Hallmark DNA repair was significantly more regulated in circulating immune cells during Covid-19 compared to influenza virus infection, bacterial pneumonia or acute respiratory infection due to seasonal coronavirus. Conclusion: Although beneficial by protecting against DNA damage, long-term activation of the DNA repair machinery could also contribute to persistent inflammation, potentially through mechanisms such as the induction of cellular senescence. However, further studies that also include measurements of additional markers of DNA damage are required to determine the role and precise molecular mechanisms for DNA repair in SARS-CoV-2 infection.

• Wæhre, Torgun; Tunheim, Gro; Bodin, Johanna Eva; Laake, Ida; Kvale, Dag & Kran, Anne-Marte Bakken [Vis alle 11 forfattere av denne artikkelen] (2022). Clinical characteristics and outcomes in hospitalized adult influenza patients: an observational study from Norway 2014-2018. Infectious Diseases. ISSN 2374-4235. 54(5), s. 367–377. doi: 10.1080/23744235.2021.2022196. Fulltekst i vitenarkiv Vis sammendrag

  Background Seasonal influenza causes substantial numbers of hospitalizations annually. We have characterized the clinical picture and treatment practice in hospitalized adult influenza patients and assessed whether clinical risk scores on admission or influenza type were associated with severe outcomes. Methods Clinical characteristics and risk scores on admission (CRB65, CRB, SIRS and quick Sequential Organ Failure Assessment [qSOFA]), treatment and severe outcomes (defined as: stay in intensive care unit (ICU), receiving oxygen supplementation or staying ≥5 days in hospital), were recorded in patients hospitalized with influenza at Oslo University Hospital, Norway, between 2014 and 2018. Results Among the 156 included patients, 52.6% had influenza A(H3N2), 32.6% influenza B and 12.8% influenza A(H1N1). Median age was 70 years and 59.6% of patients were ≥65 years. Nine (5.8%) of the patients were treated in ICU, 43.0% received oxygen and 47.4% stayed ≥5 days in hospital. Overall, 34.6% of the patients had a high CRB score on admission which was associated with stay in ICU and oxygen supplementation. Multivariate analyses identified age, and pneumonia (46.8%), but not influenza type, to be associated with severe outcomes. Antiviral treatment was given to 37.2% of the patients, while 77.6% received antibiotics. Only 25.5% of patients with influenza B received antiviral therapy. Conclusions The influenza patients were mostly elderly, and few patients were treated in ICU. A high CRB score was associated with severe outcomes with possible implications for patient monitoring. Less than 40% of the patients received antiviral therapy, whereas the majority were treated with antibiotics, indicating potential for optimising treatment strategies.

• Lekva, Tove; Ueland, Thor; Halvorsen, Bente; Murphy, Sarah Louise Mikalsen; Dyrhol-Riise, Anne Ma & Tveita, Anders Aune [Vis alle 14 forfattere av denne artikkelen] (2022). Markers of cellular senescence is associated with persistent pulmonary pathology after COVID-19 infection. Infectious Diseases. ISSN 2374-4235. 54(12), s. 918–923. doi: 10.1080/23744235.2022.2113135. Fulltekst i vitenarkiv Vis sammendrag

  Background The lungs are the organ most likely to sustain serious injury from coronavirus disease 2019 (COVID-19). However, the mechanisms for long-term complications are not clear. Patients with severe COVID-19 have shorter telomere lengths and higher levels of cellular senescence, and we hypothesized that circulating levels of the telomere-associated senescence markers chitotriosidase, β-galactosidase, cathelicidin antimicrobial peptide and stathmin 1 (STMN1) were elevated in hospitalized COVID-19 patients compared to controls and could be associated with pulmonary sequelae following hospitalization. Methods Ninety-seven hospitalized patients with COVID-19 who underwent assessment for pulmonary sequelae at three-month follow-up were included in the study. β-Galactosidase and chitotriosidase were analysed by fluorescence; stathmin 1 and cathelicidin antimicrobial peptide were analysed by enzyme immuno-assay in plasma samples from the acute phase and after three-months. In addition, the classical senescence markers cyclin-dependent kinase inhibitor 1A and 2A were analysed by enzyme immuno-assay in peripheral blood mononuclear cell lysate after three months. Results We found elevated plasma levels of the senescence markers chitotriosidase and stathmin 1 in patients three months after hospitalization with COVID-19, and these markers in addition to protein levels of cyclin-dependent kinase inhibitor 2A in cell lysate, were associated with pulmonary pathology. The elevated levels of these markers seem to reflect both age-dependent (chitotriosidase) and age-independent (stathmin 1, cyclin-dependent kinase inhibitor 2A) processes. Conclusions We suggest that accelerated ageing or senescence could be important for long-term pulmonary complications of COVID-19, and our findings may be relevant for future research exploring the pathophysiology and management of these patients.

• Bouziotis, Jason; Arvanitakis, Marianna; Preiser, Jean-Charles; Abbas, Ali; Abdukahil, Sheryl Ann & Abdulkadir, Nurul Najmee [Vis alle 50 forfattere av denne artikkelen] (2022). Association of body mass index with COVID-19 related in-hospital death. Clinical Nutrition. ISSN 0261-5614. 41(12), s. 2924–2926. doi: 10.1016/j.clnu.2022.01.017. Fulltekst i vitenarkiv Vis sammendrag

  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 [Vis alle 51 forfattere av denne artikkelen] (2022). Detailed stratified GWAS analysis for severe COVID-19 in four European populations. Human Molecular Genetics. ISSN 0964-6906. 31(23), s. 3945–3966. doi: 10.1093/hmg/ddac158. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Vestad, Beate; Ueland, Thor; Lerum, Tøri Vigeland; Dahl, Tuva Børresdatter; Holm, Kristian & Barratt-Due, Andreas [Vis alle 37 forfattere av denne artikkelen] (2022). Respiratory dysfunction three months after severe COVID-19 is associated with gut microbiota alterations. Journal of Internal Medicine. ISSN 0954-6820. 291(6), s. 801–812. doi: 10.1111/joim.13458. Fulltekst i vitenarkiv Vis sammendrag

  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)

• Christensen, Erik Egeland; Binde, Christina; Leegaard, Marianne; Tonby, Kristian; Dyrhol-Riise, Anne Ma & Kvale, Dag [Vis alle 8 forfattere av denne artikkelen] (2022). DIAGNOSTIC ACCURACY and ADDED VALUE of INFECTION BIOMARKERS in PATIENTS with POSSIBLE SEPSIS in the EMERGENCY DEPARTMENT. Shock. ISSN 1073-2322. 58(4), s. 251–259. doi: 10.1097/SHK.0000000000001981. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Meyer-Myklestad, Malin Holm; Medhus, Asle Wilhelm; Stiksrud, Birgitte; Lorvik, Kristina Berg; Seljeflot, Ingebjørg & Hansen, Simen Hyll [Vis alle 13 forfattere av denne artikkelen] (2022). Probiotics to HIV-infected immunological nonresponders: Altered mucosal immunity and microbial diversity restricted to ileum. Journal of Acquired Immune Deficiency Syndromes. ISSN 1525-4135. 89(1), s. 77–86. doi: 10.1097/QAI.0000000000002817. Fulltekst i vitenarkiv
• Cho, Sung-Min; White, Nicole; Premraj, Lavienraj; Battaglini, Denise; Fanning, Jonathon & Suen, Jacky [Vis alle 50 forfattere av denne artikkelen] (2022). Neurological manifestations of COVID-19 in adults and children. Brain. ISSN 0006-8950. doi: 10.1093/brain/awac332. Fulltekst i vitenarkiv
• Baruch, Joaquin; Rojek, Amanda; Kartsonaki, Christiana; Vijayaraghavan, Bharath Kumar Tirupakuzhi; Gonçalves, Bronner P. & Pritchard, Mark G. [Vis alle 50 forfattere av denne artikkelen] (2022). Symptom-based case definitions for COVID-19: Time and geographical variations for detection at hospital admission among 260,000 patients. Influenza and Other Respiratory Viruses. ISSN 1750-2640. 16(6), s. 1040–1050. doi: 10.1111/irv.13039. Fulltekst i vitenarkiv
• Gonçalves, Bronner P.; Hall, Matthew; Jassat, Waasila; Balan, Valeria; Murthy, Srinivas & Kartsonaki, Christiana [Vis alle 50 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv
• Reyes, Luis Felipe; Murthy, Srinivas; Garcia-Gallo, Esteban; Merson, Laura; Ibáñez-Prada, Elsa D. & Rello, Jordi [Vis alle 51 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv
• Wainstein, Marina; MacDonald, Samual; Fryer, Daniel; Young, Kyle; Balan, Valeria & Begum, Husna [Vis alle 50 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv
• Hammer, Quirin; Dunst, Josefine; Christ, Wanda; Picarazzi, Francesca; Wendorff, Mareike & Momayyezi, Pouria [Vis alle 51 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Gohli, Jostein; Brantsæter, Arne Broch; Bøifot, Kari Oline; Grub, Carola; Granerud, Beathe Kiland & Holter, Jan Cato [Vis alle 9 forfattere av denne artikkelen] (2022). SARS-CoV-2 in the Air Surrounding Patients during Nebulizer Therapy. Canadian Journal of Infectious Diseases and Medical Microbiology. ISSN 1712-9532. 2022. doi: 10.1155/2022/9297974. Fulltekst i vitenarkiv Vis sammendrag

  Nebulizer therapy is commonly used for patients with obstructive pulmonary disease or acute pulmonary infections with signs of obstruction. It is considered a “potential aerosol-generating procedure,” and the risk of disease transmission to health care workers is uncertain. The aim of this pilot study was to assess whether nebulizer therapy in hospitalized COVID-19 patients is associated with increased dispersion of SARS-CoV-2. Air samples collected prior to and during nebulizer therapy were analyzed by RT-PCR and cell culture. Total aerosol particle concentrations were also quantified. Of 13 patients, seven had quantifiable virus in oropharynx samples, and only two had RT-PCR positive air samples. For both these patients, air samples collected during nebulizer therapy had higher SARS-CoV-2 RNA concentrations compared to control air samples. Also, for particle sizes 0.3–5 µm, particle concentrations were significantly higher during nebulizer therapy than in controls. We were unable to cultivate virus from any of the RT-PCR positive air samples, and it is therefore unknown if the detected virus were replication-competent; however, the significant increase in smaller particles, which can remain airborne for extended periods of time, and increased viral RNA concentrations during treatment may indicate that nebulizer therapy is associated with increased risk of SARS-CoV-2 transmission.

• Lorvik, Kristina Berg; Meyer-Myklestad, Malin Holm; Kushekhar, Kushi; Handeland, Charlotte Andrea; Medhus, Asle Wilhelm & Lund-Iversen, Marius [Vis alle 11 forfattere av denne artikkelen] (2021). Enhanced Gut-Homing Dynamics and Pronounced Exhaustion of Mucosal and Blood CD4⁺ T Cells in HIV-Infected Immunological Non-Responders. Frontiers in Immunology. 12, s. 1–12. doi: 10.3389/fimmu.2021.744155. Fulltekst i vitenarkiv Vis sammendrag

  Immunological non-responders (INR), a subgroup of people living with HIV (PLHIV) who fail to restore CD4 + T cell numbers upon effective antiretroviral treatment, have impaired gut mucosal barrier function and an inferior clinical prognosis compared with immunological responders (IR). The contribution of gut-homing and exhaustion of mucosal T cells to the INR phenotype was previously unknown. Flow cytometry analysis of mononuclear cells from peripheral blood and ileal and colonic lamina propria showed that INR had higher fractions of gut-homing CD4 + T cells in blood compared with IR. In addition, gut-homing cells were more likely to display signs of exhaustion in INR. The increased CD4 + T cell exhaustion in INR was ubiquitous and not restricted to subpopulations defined by activation, differentiation or regulatory T cell markers. In INR, colon CD4 + T cell exhaustion correlated negatively with the fraction of CD4 + T cells in the same compartment, this was not apparent in the ileum. The fraction of exhausted mucosal CD4 + T cells correlated with I-FABP and REG3α, markers of enterocyte damage. We conclude that alterations of gut-homing and exhaustion of T cells may contribute to impaired gut immune and barrier functions associated with immunological non-response in PLHIV.

• Niemi, Mari E.K.; Karjalainen, Juha; Liao, Rachel G.; Neale, Benjamin M.; Daly, Mark & Ganna, Andrea [Vis alle 84 forfattere av denne artikkelen] (2021). Mapping the human genetic architecture of COVID-19. Nature. ISSN 0028-0836. 600(7889), s. 472–477. doi: 10.1038/s41586-021-03767-x. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Chendi, Bih Hycenta; Snyders, Candice I.; Tonby, Kristian; Jenum, Synne; Kidd, Martin & Walzl, Gerhard [Vis alle 8 forfattere av denne artikkelen] (2021). A Plasma 5-Marker Host Biosignature Identifies Tuberculosis in High and Low Endemic Countries. Frontiers in Immunology. 12, s. 1–13. doi: 10.3389/fimmu.2021.608846. Fulltekst i vitenarkiv Vis sammendrag

  Background: Several host inflammatory markers have been proposed as biomarkers for diagnosis and treatment response in Tuberculosis (TB), but few studies compare their utility in different demographic, ethnic, and TB endemic settings. Methods: Fifty-four host biomarkers were evaluated in plasma samples obtained from presumed TB cases recruited at the Oslo University Hospital in Norway, and a health center in Cape Town, South Africa. Based on clinical and laboratory assessments, participants were classified as having TB or other respiratory diseases (ORD). The concentrations of biomarkers were analyzed using the Luminex multiplex platform. Results: Out of 185 study participants from both study sites, 107 (58%) had TB, and 78 (42%) ORD. Multiple host markers showed diagnostic potential in both the Norwegian and South African cohorts, with I-309 as the most accurate single marker irrespective of geographical setting. Although study site-specific biosignatures had high accuracy for TB, a site-independent 5-marker biosignature (G-CSF, C3b/iC3b, procalcitonin, IP-10, PDGF-BB) was identified diagnosing TB with a sensitivity of 72.7% (95% CI, 49.8–82.3) and specificity of 90.5% (95% CI, 69.6–98.8) irrespective of geographical site. Conclusion: A 5-marker host plasma biosignature has diagnostic potential for TB disease irrespective of TB setting and should be further explored in larger cohorts.

• Lerum, Tøri Vigeland; Maltzahn, Niklas; Aukrust, Pål; Trøseid, Marius; Nezvalova-Henriksen, Katerina & Kåsine, Trine [Vis alle 27 forfattere av denne artikkelen] (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, s. 1–12. doi: 10.1038/s41598-021-02547-x. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Kåsine, Trine; Riise, Anne Margarita Dyrhol; Barratt-Due, Andreas; Kildal, Anders Benjamin; Olsen, Inge Christoffer & Nezvalova-Henriksen, Katerina [Vis alle 39 forfattere av denne artikkelen] (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), s. 241–243. doi: 10.1111/joim.13377. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Jenum, Synne; Tonby, Kristian; Rueegg, Corina Silvia; Ruhwald, Morten; Kristiansen, Max Per & Bang, Peter [Vis alle 14 forfattere av denne artikkelen] (2021). A Phase I/II randomized trial of H56:IC31 vaccination and adjunctive cyclooxygenase-2-inhibitor treatment in tuberculosis patients. Nature Communications. 12. doi: 10.1038/s41467-021-27029-6. Fulltekst i vitenarkiv Vis sammendrag

  Host-directed-therapy strategies are warranted to fight tuberculosis. Here we assess the safety and immunogenicity of adjunctive vaccination with the H56:IC31 candidate and cyclooxygenase-2-inhibitor treatment (etoricoxib) in pulmonary and extra-pulmonary tuberculosis patients in a randomized open-label phase I/II clinical trial (TBCOX2, NCT02503839). A total of 222 patients were screened, 51 enrolled and randomized; 13 in the etoricoxib-group, 14 in the H56:IC31-group, 12 in the etoricoxib+H56:IC31-group and 12 controls. Three Serious Adverse Events were reported in the etoricoxib-groups; two urticarial rash and one possible disease progression, no Serious Adverse Events were vaccine related. H56:IC31 induces robust expansion of antigen-specific T-cells analyzed by fluorospot and flow cytometry, and higher proportion of seroconversions. Etoricoxib reduced H56:IC31-induced T-cell responses. Here, we show the first clinical data that H56:IC31 vaccination is safe and immunogenic in tuberculosis patients, supporting further studies of H56:IC31 as a host-directed-therapy strategy. Although etoricoxib appears safe, our data do not support therapy with adjunctive cyclooxygenase-2-inhibitors.

• Christensen, Erik; Jørgensen, Marthe Jøntvedt; Nore, Kristin Grotle; Dahl, Tuva Børresdatter; Yang, Kuan & Ranheim, Trine [Vis alle 16 forfattere av denne artikkelen] (2021). Critical COVID-19 is associated with distinct leukocyte phenotypes and transcriptome patterns. Journal of Internal Medicine. ISSN 0954-6820. s. 1–16. doi: 10.1111/joim.13310. Fulltekst i vitenarkiv Vis sammendrag

  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 [Vis alle 50 forfattere av denne artikkelen] (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, s. 889–905. doi: 10.1007/s15010-021-01599-5. Fulltekst i vitenarkiv Vis sammendrag

  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 [Vis alle 50 forfattere av denne artikkelen] (2021). Ten months of temporal variation in the clinical journey of hospitalised patients with COVID-19: An observational cohort. eLIFE. 10:e70970, s. 1–30. doi: 10.7554/eLife.70970. Fulltekst i vitenarkiv Vis sammendrag

  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 [Vis alle 50 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv Vis sammendrag

  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 [Vis alle 10 forfattere av denne artikkelen] (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), s. 186–230. doi: 10.1016/j.jinf.2021.01.017. Fulltekst i vitenarkiv
• Aamodt, Anne Hege; Høgestøl, Einar August; Popperud, Trine Haug; Holter, Jan Cato; Dyrhol-Riise, Anne Ma & Tonby, Kristian [Vis alle 15 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Chendi, Bih Hycenta; Tveiten, Hallgeir; Snyders, Candice I.; Tonby, Kristian; Jenum, Synne & Nielsen, Susanne D. [Vis alle 10 forfattere av denne artikkelen] (2021). CCL1 and IL-2Ra differentiate Tuberculosis disease from latent infection Irrespective of HIV infection in low TB burden countries. Journal of Infection. ISSN 0163-4453. s. 1–11. doi: 10.1016/j.jinf.2021.07.036. Fulltekst i vitenarkiv Vis sammendrag

  Objectives: To evaluate the performance of selected host immunological biomarkers in differentiating tuberculosis (TB) disease from latent TB infection (LTBI) in HIV uninfected and infected individuals enrolled in TB low-burden countries. Design: Participants with TB disease (N = 85) and LTBI (N = 150) were recruited from prospective cohorts at hospitals in Norway and Denmark. Plasma concentrations of 54 host markers were assessed by Luminex multiplex immunoassays. Using receiver operator characteristic curves and general discriminant analysis, we determined the abilities of individual and combined biomarkers to discriminate between TB disease and LTBI including when patients were stratified according to HIV infection status. Results: Regardless of the groups compared, CCL1 and IL-2Ra were the most accurate single biomarkers in differentiating TB disease from LTBI. Regardless of HIV status, a 4-marker signature (CCL1+RANTES+CRP+MIP-1α) derived from a training set (n = 155) differentiated TB disease from LTBI in the test set (n = 67) with a sensitivity of 56.0% (95% CI, 34.9–75.6) and a specificity of 85.7% (95% CI, 71.5–94.6). A 5-marker signature derived from the HIV uninfected group (CCL1+RANTES+MIP-1α+procalcitonin+IP-10) performed in HIV-infected individuals with a sensitivity of 75.0% and a specificity of 96.7% after leave-one-out cross validation. A 2-marker signature (CCL1+TNF-α) identified in HIV-infected persons performed in HIV-uninfected with a sensitivity and specificity of 66.7% and 100% respectively in the test set. Conclusions: Plasma CCL1 and IL-2Ra have potential as biomarkers for differentiating TB disease from LTBI in low TB burden settings unaffected by HIV infection. Combinations between these and other biomarkers in bio-signatures for global use warrant further exploration.

• Jørgensen, Marthe Jøntvedt; Nore, Kristin Grotle; Aass, Hans Christian Dalsbotten; Layre, Emilie; Nigou, Jérôme & Mortensen, Rasmus [Vis alle 11 forfattere av denne artikkelen] (2021). Plasma LOX-Products and Monocyte Signaling Is Reduced by Adjunctive Cyclooxygenase-2 Inhibitor in a Phase I Clinical Trial of Tuberculosis Patients. Frontiers in Cellular and Infection Microbiology. 11, s. 1–13. doi: 10.3389/fcimb.2021.669623. Fulltekst i vitenarkiv Vis sammendrag

  Introduction Eicosanoids and intracellular signaling pathways are potential targets for host-directed therapy (HDT) in tuberculosis (TB). We have explored the effect of cyclooxygenase 2 inhibitor (COX-2i) treatment on eicosanoid levels and signaling pathways in monocytes. Methods Peripheral blood mononuclear cells isolated from TB patients included in a randomized phase I clinical trial of standard TB treatment with (n=21) or without (n=18) adjunctive COX-2i (etoricoxib) were analyzed at baseline, day 14 and day 56. Plasma eicosanoids were analyzed by ELISA and liquid chromatography-mass spectrometry (LC-MS), plasma cytokines by multiplex, and monocyte signaling by phospho-flow with a defined set of phospho-specific antibodies. Results Lipoxygenase (LOX)-derived products (LXA4 and 12-HETE) and pro-inflammatory cytokines were associated with TB disease severity and were reduced during TB therapy, possibly accelerated by adjunctive COX-2i. Phosphorylation of p38 MAPK, NFkB, Erk1/2, and Akt in monocytes as well as plasma levels of MIG/CXCL9 and procalcitonin were reduced in the COX-2i group compared to controls. Conclusion COX-2i may reduce excess inflammation in TB via the LOX-pathway in addition to modulation of phosphorylation patterns in monocytes. Immunomodulatory effects of adjunctive COX-2i in TB should be further investigated before recommended for use as a HDT strategy.

• Sigfrid, Louise; Cevik, Muge; Jesudason, Edwin; Lim, Wei Shen; Rello, Jordi & Amuasi, John [Vis alle 37 forfattere av denne artikkelen] (2021). What is the recovery rate and risk of long-term consequences following a diagnosis of COVID-19? A harmonised, global longitudinal observational study protocol. BMJ Open. 11:e043887(3), s. 1–8. doi: 10.1136/bmjopen-2020-043887. Fulltekst i vitenarkiv Vis sammendrag

  Introduction Very little is known about possible clinical sequelae that may persist after resolution of acute COVID-19. A recent longitudinal cohort from Italy including 143 patients followed up after hospitalisation with COVID-19 reported that 87% had at least one ongoing symptom at 60-day follow-up. Early indications suggest that patients with COVID-19 may need even more psychological support than typical intensive care unit patients. The assessment of risk factors for longer term consequences requires a longitudinal study linked to data on pre-existing conditions and care received during the acute phase of illness. The primary aim of this study is to characterise physical and psychosocial sequelae in patients post-COVID-19 hospital discharge. Methods and analysis This is an international open-access prospective, observational multisite study. This protocol is linked with the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) and the WHO’s Clinical Characterisation Protocol, which includes patients with suspected or confirmed COVID-19 during hospitalisation. This protocol will follow-up a subset of patients with confirmed COVID-19 using standardised surveys to measure longer term physical and psychosocial sequelae. The data will be linked with the acute phase data. Statistical analyses will be undertaken to characterise groups most likely to be affected by sequelae of COVID-19. The open-access follow-up survey can be used as a data collection tool by other follow-up studies, to facilitate data harmonisation and to identify subsets of patients for further in-depth follow-up. The outcomes of this study will inform strategies to prevent long-term consequences; inform clinical management, interventional studies, rehabilitation and public health management to reduce overall morbidity; and improve long-term outcomes of COVID-19. Ethics and dissemination The protocol and survey are open access to enable low-resourced sites to join the study to facilitate global standardised, longitudinal data collection. Ethical approval has been given by sites in Colombia, Ghana, Italy, Norway, Russia, the UK and South Africa. New sites are welcome to join this collaborative study at any time. Sites interested in adopting the protocol as it is or in an adapted version are responsible for ensuring that local sponsorship and ethical approvals in place as appropriate. The tools are available on the ISARIC website (www.isaric.org). Protocol registration number osf.io/c5rw3/ Protocol version 3 August 2020 EuroQol ID 37035.

• Barratt-Due, Andreas; Olsen, Inge Christoffer; Nezvalova-Henriksen, Katerina; Kåsine, Trine; Lund-Johansen, Fridtjof & Hoel, Hedda Benedicte [Vis alle 43 forfattere av denne artikkelen] (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), s. 1261–1269. doi: 10.7326/M21-0653. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Jørgensen, Marthe Jøntvedt; Jenum, Synne; Tonby, Kristian; Mortensen, Rasmus; Walzl, Gerhard & Plessis, Nelita Du [Vis alle 7 forfattere av denne artikkelen] (2020). Monocytic myeloid-derived suppressor cells reflect tuberculosis severity and are influenced by cyclooxygenase-2 inhibitors. Journal of Leukocyte Biology. ISSN 0741-5400. doi: 10.1002/JLB.4A0720-409RR. Fulltekst i vitenarkiv Vis sammendrag

  Myeloid‐derived suppressor cells (MDSCs) increase in tuberculosis (TB) and may be targets for host‐directed therapy (HDT). In this study, we use flow cytometry to analyze the effects of cyclooxygenase‐2 inhibitors (COX‐2i) on monocytic (M)‐MDSCs in blood from TB patients attending a clinical trial of COX‐2i. The effects of COX‐2i on M‐MDSCs and mycobacterial uptake were also studied by an in vitro mycobacterial infection model. We found that M‐MDSC frequencies correlated with TB disease severity. Reduced M‐MDSC (P = 0.05) and IDO (P = 0.03) expression was observed in the COX‐2i group. We show that peripheral blood‐derived M‐MDSCs successfully internalized Mycobacterium bovis and that in vitro mycobacterial infection increased COX‐2 (P = 0.002), PD‐L1 (P = 0.01), and Arginase‐1 (P = 0.002) expression in M‐MDSCs. Soluble IL‐1β, IL‐10, and S100A9 were reduced in COX‐2i‐treated M‐MDSCs cultures (P < 0.05). We show novel data that COX‐2i had limited effect in vivo but reduced M‐MDSC cytokine production in vitro. The relevance of COX‐2i in a HDT strategy needs to be further explored.

• Hoel, Hedda Benedicte; Heggelund, Lars; Reikvam, Dag Henrik; Stiksrud, Birgitte; Ueland, Thor & Michelsen, Annika [Vis alle 15 forfattere av denne artikkelen] (2020). Elevated markers of gut leakage and inflammasome activation in COVID-19 patients with cardiac involvement. Journal of Internal Medicine. ISSN 0954-6820. 289(4). doi: 10.1111/joim.13178. Fulltekst i vitenarkiv Vis sammendrag

  Background A high proportion of COVID‐19 patients have cardiac involvement, even those without known cardiac disease. Downregulation of angiotensin converting enzyme 2 (ACE2), a receptor for SARS‐CoV‐2 and the renin‐angiotensin system, as well as inflammatory mechanisms have been suggested to play a role. ACE2 is abundant in the gut and associated with gut microbiota composition. We hypothesized that gut leakage of microbial products, and subsequent inflammasome activation could contribute to cardiac involvement in COVID‐19 patients. Methods Plasma levels of a gut leakage marker (LPS‐binding protein, LBP), a marker of enterocyte damage (intestinal fatty acid binding protein, IFABP), a gut homing marker (CCL25, ligand for chemokine receptor CCR9) and markers of inflammasome activation (IL‐1β, IL‐18 and their regulatory proteins) were measured at three time points (day 1, 3–5 and 7–10) in 39 hospitalized COVID‐19 patients and related to cardiac involvement. Results Compared to controls, COVID‐19 patients had elevated plasma levels of LBP and CCL25 but not IFABP, suggesting impaired gut barrier function and accentuated gut homing of T cells without excessive enterocyte damage. Levels of LBP were twice as high at baseline in patients with elevated cardiac markers compared with those without and remained elevated during hospitalization. Also, markers of inflammasome activation were moderately elevated in patients with cardiac involvement. LBP was associated with higher NT‐pro‐BNP levels, whereas IL‐18, IL‐18BP and IL‐1Ra were associated with higher troponin levels. Conclusion Patients with cardiac involvement had elevated markers of gut leakage and inflammasome activation, suggestive of a potential gut‐heart axis in COVID‐19.

• Mustafa, Tehmina; Wergeland, Ida; Baba, Kamaldeen; Pathak, Sharad; Hoosen, Anwar A. & Riise, Anne Margarita Dyrhol (2020). Mycobacterial antigens in pleural fluid mononuclear cells to diagnose pleural tuberculosis in HIV co-infected patients. BMC Infectious Diseases. 20:459, s. 1–13. doi: 10.1186/s12879-020-05165-6. Fulltekst i vitenarkiv Vis sammendrag

  Background Extra pulmonary manifestation of tuberculosis (TB) accounts for approximately one-half of TB cases in HIV-infected individuals with pleural TB as the second most common location. Even though mycobacteria are cleared, mycobacterial antigens may persist in infected tissues, causing sustained inflammation and chronicity of the disease. The aim of this study was to explore various mycobacterial antigens in pleural effusions, the impact of HIV infection and CD4+ T-cell depletion on the presence of antigens, and the diagnostic potential of antigens for improved and rapid diagnosis of pleural TB. Methods Pleural fluid specimens were collected from patients presenting with clinically suspected pleural TB, and processed routinely for culture, cytology, and adenosine deaminase activity analysis. HIV status and CD4+ T-cell counts were recorded. Pleural fluid mononuclear cells (PFMC) were isolated, and cell smears were stained with acid-fast staining and immunocytochemistry for various mycobacterial antigens. Real-time and nested-PCR were performed. Patients were categorized as pleural TB or non-TB cases using a composite reference standard. Performance of the mycobacterial antigens as diagnostic test was assessed. Results A total of 41 patients were enrolled, of which 32 were classified as pleural TB and 9 as non-TB. Thirteen patients had culture confirmed pleural TB, 26 (81%) were HIV-TB co-infected, and 64% had < 100 CD4+ T-cells/microL. Both secreted and cell-wall mycobacterial antigens were detected in PFMC. Lipoarabinomannan (LAM) was the most frequently detected antigen. There was no direct correlation between positive culture and antigens. Cases with low CD4+ T-cell counts had higher bacterial and antigen burden. By combining detection of secreted antigen or LAM, the sensitivity and specificity to diagnose pleural TB was 56 and 78%, respectively, as compared to 41 and 100% for culture, 53 and 89% for nested PCR, and 6 and 100% for real-time PCR. Conclusion Mycobacterial antigens were detectable in PFMC from tuberculous pleural effusions, even in cases where viable mycobacteria or bacterial DNA were not always detected. Thus, a combination of secreted antigen and LAM detection by immunocytochemistry may be a complement to acid-fast staining and contribute to rapid and accurate diagnosis of pleural TB.

• Hoel, Ida Marie; Sviland, Lisbeth; Syre, Heidi; Dyrhol-Riise, Anne Ma; Skarstein, Ingerid & Jebsen, Peter Wilhelm [Vis alle 9 forfattere av denne artikkelen] (2020). Diagnosis of extrapulmonary tuberculosis using the MPT64 antigen detection test in a high-income low tuberculosis prevalence setting. BMC Infectious Diseases. 20, s. 1–11. doi: 10.1186/s12879-020-4852-z. Fulltekst i vitenarkiv Vis sammendrag

  Background Extrapulmonary tuberculosis (EPTB) poses diagnostic challenges due to the paucibacillary nature of the disease. The immunochemistry-based MPT64 antigen detection test (MPT64 test) has shown promising results for diagnosing EPTB in previous studies performed in low-resource settings, with higher sensitivity than microscopy and culture. The aim of this study was to investigate the performance of the MPT64 test in a routine clinical setting in a high-income low TB prevalence country. Methods Extrapulmonary samples sent for TB diagnostics to microbiology and pathology laboratories at three regional tertiary care hospitals in Norway in a one-year period were included and subjected to the MPT64 test in parallel to the routine TB diagnostic tests. Results Samples from 288 patients were included and categorised as confirmed TB cases (n = 26), clinically diagnosed TB cases (n = 5), non-TB cases (n = 243) and uncategorised (n = 14), using a composite reference standard (CRS). In formalin-fixed biopsies, the sensitivity (95% CI) of the MPT64 test, microscopy, PCR-based tests pooled, and culture was 37% (16–62), 20% (4–48), 37% (16–62) and 50% (23–77), respectively, against the CRS. The MPT64 test showed a good positive predictive value (88%) and an excellent specificity (99, 95% CI 92–100) in formalin-fixed biopsies. In fine-needle aspirates, pus and fluid samples, the test performance was lower. Conclusions The MPT64 test was implementable in pathology laboratories as part of routine diagnostics, and although the sensitivity of the MPT64 test was not better than culture in this setting, the test supplements other rapid diagnostic methods, including microscopy and PCR-based tests, and can contribute to strengthen the diagnosis of EPTB in formalin-fixed biopsies in the absence of culture confirmation.

• Meyer-Myklestad, Malin Holm; Medhus, Asle Wilhelm; Lorvik, Kristina Berg; Seljeflot, Ingebjørg; Hansen, Simen Hyll & Holm, Kristian [Vis alle 13 forfattere av denne artikkelen] (2020). HIV-infected immunological non-responders have colon-restricted gut mucosal immune dysfunction. Journal of Infectious Diseases. ISSN 0022-1899. doi: 10.1093/infdis/jiaa714. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Background Human immunodeficiency virus (HIV)–infected immunological nonresponders (INRs) fail to reconstitute their CD4+ T-cell pool after initiation of antiretroviral therapy, and their prognosis is inferior to that of immunological responders (IRs). A prevailing hypothesis is that the INR phenotype is caused by a persistently disrupted mucosal barrier, but assessments of gut mucosal immunology in different anatomical compartments are scarce. Methods We investigated circulating markers of mucosal dysfunction, immune activation, mucosal Th17 and Th22 cells, and mucosa-adherent microbiota signatures in gut mucosal specimens from sigmoid colon and terminal ileum of 19 INRs and 20 IRs in addition to 20 HIV-negative individuals. Results INRs had higher blood levels of the enterocyte damage marker intestinal fatty acid–binding protein than IRs. In gut mucosal biopsies, INRs had lower fractions of CD4+ T cells, higher fractions of interleukin 22, and a tendency to higher fractions of interleukin 17–producing CD4+ T cells. These findings were all restricted to the colon and correlated to circulating markers of enterocyte damage. There were no observed differences in gut microbial composition between INRs and IRs. Conclusions Restricted to the colon, enterocyte damage and mucosal immune dysfunction play a role for insufficient immune reconstitution in HIV infection independent of the gut microbiota.

• Nore, Kristin Grotle; Jørgensen, Marthe Jøntvedt; Dyrhol-Riise, Anne Ma; Jenum, Synne & Tonby, Kristian (2020). Elevated Levels of Anti-Inflammatory Eicosanoids and Monocyte Heterogeneity in Mycobacterium tuberculosis Infection and Disease. Frontiers in Immunology. 11. doi: 10.3389/fimmu.2020.579849. Fulltekst i vitenarkiv Vis sammendrag

  Eicosanoids modulate both innate and adaptive immune responses in Mycobacterium tuberculosis (Mtb) infection and have been suggested as possible Host Directed Therapy (HDT) targets, but more knowledge of eicosanoid dynamics in Mtb infection is required. We investigated the levels and ratios of eicosanoid mediators and their cellular sources, monocyte subsets and CD4 T cells in Tuberculosis (TB) patients with various clinical states of Mtb infection. Patients consenting to prospective enrolment in a TB quality registry and biorepository, 16 with pulmonary TB (before and at-end-of treatment), 14 with extrapulmonary TB and 17 latently infected (LTBI) were included. Plasma levels of Prostaglandin E2 (PGE2), Lipoxin A4 (LXA4), and Leukotriene B4 (LTB4) were measured by enzyme-linked immunosorbent assay. Monocyte subsets and CD4 T cells and their expression of Cyclooxygenase-2 (COX-2), Prostaglandin receptor EP2 (EP2), and 5-Lipoxygenase (5-LOX) were analyzed by flow cytometry with and without Purified Protein Derivate (PPD)-stimulation. Pulmonary TB patients had elevated levels of the anti-inflammatory mediator LXA4 at diagnosis compared to LTBI (p < 0.01), while levels of PGE2 and LTB4 showed no difference between clinical states of Mtb infection. LTB4 was the only mediator to be reduced upon treatment (p < 0.05), along with the ratio LTB4/LXA4 (p < 0.01). Pulmonary TB patients had higher levels of total monocytes at diagnosis compared to end-of-treatment and LTBI (both p < 0.05), and a relative increase in the classical monocyte subset. All monocyte subsets had low basal expression of COX-2 and 5-LOX, which were markedly increased upon PPD stimulation. By contrast, the expression of EP2 was reduced upon stimulation. CD4 T cells expressed low basal COX-2 activity that increased modestly upon stimulation, whereas their basal expression of 5-LOX was considerable. In conclusion, the level of eicosanoids in plasma seem to vary between clinical states of Mtb infection. Mediators in the eicosanoid system are present in monocytes and CD4 T cells. The expression of eicosanoids in monocytes are responsive to mycobacterial stimulation independent of Mtb disease state, but subsets are heterogeneous with regard to eicosanoid-mediator expression. Further exploration of eicosanoid mediators as targets for HDT in TB are warranted.

• Jørgensen, Marthe Jøntvedt; Holter, Jan Cato; Christensen, Erik; Schjalm, Camilla; Tonby, Kristian & Pischke, Soeren [Vis alle 22 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv Vis sammendrag

  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 [Vis alle 26 forfattere av denne artikkelen] (2020). Elevated plasma sTIM-3 levels in patients with severe COVID-19. Journal of Allergy and Clinical Immunology. ISSN 0091-6749. 147(1), s. 92–98. doi: 10.1016/j.jaci.2020.09.007. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Holter, Jan Cato; Pischke, Soeren; Boer, Eline de; Lind, Andreas; Jenum, Synne & Holten, Aleksander Rygh [Vis alle 32 forfattere av denne artikkelen] (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), s. 25018–25025. doi: 10.1073/pnas.2010540117. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Stiksrud, Birgitte; Aass, Hans Christian Dalsbotten; Lorvik, Kristina Berg; Ueland, Thor; Trøseid, Marius & Dyrhol-Riise, Anne Ma (2019). Activated dendritic cells and monocytes in HIV immunological nonresponders: HIV-induced interferon-inducible protein-10 correlates with low future CD4+ recovery. AIDS (London). ISSN 0269-9370. 33(7), s. 1117–1129. doi: 10.1097/QAD.0000000000002173. Fulltekst i vitenarkiv Vis sammendrag

  Objective: To explore monocyte and dendritic cell immune responses, and their association with future CD4+ gain in treated HIV patients with suboptimal CD4+ recovery. Design: A cross-sectional study of HIV-infected, virally suppressed individuals on antiretroviral therapy for at least 24 months; 41 immunological nonresponders (INRs) (CD4+ cell count <400 cells/μl) and 26 immunological responders (CD4+ cell count >600 cells/μl). Ten HIV-infected antiretroviral therapy-naive and 10 HIV-negative healthy persons served as controls. CD4+ cell counts were registered after median 2.4 and 4.7 years. Methods: Monocyte, dendritic-cell and T-cell activation and regulatory T cells (Tregs) were analyzed by flow cytometry. In INR and immunological responder subgroups matched on age and nadir CD4+ cell count, upregulation of interferon-inducible protein-10 (IP-10) and indoleamine 2,3-dioxygenase in monocytes and dendritic cells and cytokines in cell supernatants were measured in vitro in peripheral blood mononuclear cells stimulated with aldrithiol-2-inactivated HIV-1. Results: The INR group displayed higher spontaneous activation of both monocytes (HLA-DR+) and myeloid and plasmacytoid dendritic cells (HLA-DR+, CD83+ and CD86+) compared with immunological responders, and this was associated with increased T-cell activation (CD38+HLA-DR+), an effector memory T-cell phenotype and activated Tregs. The IP-10 response in monocytes after in-vitro HIV stimulation was negatively associated with prospective CD4+ gain. IP-10, indoleamine 2,3-dioxygenase and cytokines levels were comparable between the groups, but inversely correlated with activated Tregs in INRs. Conclusion: HIV-infected individuals with suboptimal immune recovery demonstrated more activated monocytes and in particular dendritic cells, compared with patients with acceptable CD4+ gain. A high level of HIV-specific IP-10 expression in monocytes may be predictive of future CD4+ recovery.

• Mortensen, Rasmus; Clemmensen, Helena Strand; Woodworth, Joshua S.; Therkelsen, Marie Louise; Mustafa, Tehmina & Tonby, Kristian [Vis alle 10 forfattere av denne artikkelen] (2019). Cyclooxygenase inhibitors impair CD4 T cell immunity and exacerbate Mycobacterium tuberculosis infection in aerosol-challenged mice. Communications Biology. 2:288, s. 1–10. doi: 10.1038/s42003-019-0530-3. Fulltekst i vitenarkiv Vis sammendrag

  Tuberculosis, caused by infection with Mycobacterium tuberculosis (Mtb), kills over 1.6 million people each year despite availability of antibiotics. The increase in drug resistant Mtb strains is a major public health emergency and host-directed therapy as adjunct to antibiotic treatment has gained increased interest. Cyclooxygenase inhibitors (COXi) are frequently used drugs to alleviate tuberculosis related symptoms. Mouse studies of acute intravenous Mtb infection have suggested a potential benefit of COXi for host-directed therapy. Here we show that COXi treatment (ibuprofen and celecoxib) is detrimental to Mtb control in different mouse models of respiratory infection. This effect links to impairments of the Type-1 helper (Th1) T-cell response as CD4 T-cells in COXi-treated animals have significantly decreased Th1 differentiation, reduced IFNγ expression and decreased protective capacity upon adoptive transfer. If confirmed in clinical trials, these findings could have major impact on global health and question the use of COXi for host-directed therapy.

• Jørstad, Melissa Davidsen; Dyrhol-Riise, Anne Ma; Assmus, Jörg; Marijani, Msafiri; Sviland, Lisbeth & Mustafa, Tehmina (2019). Evaluation of treatment response in extrapulmonary tuberculosis in a low-resource setting. BMC Infectious Diseases. 19:426, s. 1–9. doi: 10.1186/s12879-019-4034-z. Fulltekst i vitenarkiv Vis sammendrag

  Background Diagnosing extrapulmonary tuberculosis (EPTB) is challenging and many patients are initiated on empirical anti-TB treatment without a laboratory confirmed diagnosis. Monitoring treatment response is thus important to ensure correct diagnosis and proper disease management. The definition of satisfactory response to treatment in EPTB remains unclear. The objectives of this study were to describe the clinical presentation of EPTB and the effect of treatment on clinical parameters. Further, to assess if simple clinical parameters, without laboratory data, could evaluate treatment response. Methods Prospective cohort study of presumptive EPTB patients at Mnazi Mmoja Hospital, Zanzibar. By using a composite reference standard, patients were categorized as TB or non-TB cases. The TB patients were followed during anti-TB treatment. Results There were 64 TB and 62 non-TB cases. The frequency of symptoms at baseline were comparable in TB and non-TB patients, with lymphadenitis and pleuritis as the most common manifestations. Among TB cases, there was a trend towards regression of lymphadenopathy after 2 months, and at treatment completion 24/28 (86%) cases showed full regression. Weight gain ≥5% was reported in 36/49 (73%) of the TB patients at 2 months and in 38/46 (83%) at treatment completion. After 2 months of treatment, a combination of clinical parameters; improvement of symptoms (50/50), ≥5% weight gain (36/49) and regression of physical signs (45/49) correlated with the treatment response. Conclusions An algorithm including only simple clinical parameters could be used as an easy tool to assess treatment responses in low-resource settings. However, this needs to be tested on a larger sample size.

• Hoel, Ida Marie; Jørstad, Melissa Davidsen; Marijani, Msafiri; Ruhwald, Morten; Mustafa, Tehmina & Dyrhol-Riise, Anne Ma (2019). IP-10 dried blood spots assay monitoring treatment efficacy in extrapulmonary tuberculosis in a low-resource setting. Scientific Reports. 9:3871, s. 1–9. doi: 10.1038/s41598-019-40458-0. Fulltekst i vitenarkiv Vis sammendrag

  Treatment efficacy is difficult to evaluate in extrapulmonary tuberculosis (EPTB) patients. Interferon-γ inducible protein (IP-)10 has been suggested as a biomarker for response to treatment. We have investigated if IP-10 from dried plasma spots (DPS) or dried blood spots (DBS) can be used in treatment monitoring of EPTB patients in a low-resource setting of Zanzibar. IP-10 levels in plasma, DPS and DBS samples collected before, during (2 months) and after TB treatment of 36 EPTB patients (6 culture and/or Xpert MTB/RIF positive and 30 clinically diagnosed) and 8 pulmonary tuberculosis (PTB) patients, were quantified by an enzyme-linked immunosorbent assay. There was a high positive correlation between IP-10 measured in plasma and DPS and DBS, respectively. We found a significant decline in IP-10 levels from baseline to end of treatment in plasma, DPS and DBS, both in EPTB and PTB patients. The declines were observed already after 2 months in HIV negative patients. In conclusion, the DPS/DBS IP-10 assay allows for easy and manageable monitoring in low-resource settings and our findings suggest that IP-10 may serve as a biomarker for treatment efficacy in EPTB patients, albeit further studies in cohorts of patients with treatment failure and relapse are needed.

• Schepisi, Monica Sane; Navarra, Assunta; Gómez, Maria de las Nieves Altet; Dudnyk, Andrii; Dyrhol-Riise, Anne Ma & Esteban, Jaime [Vis alle 22 forfattere av denne artikkelen] (2019). Burden and characteristics of the comorbidity tuberculosis - diabetes in Europe: TBnet prevalence survey and case-control study. Open Forum Infectious Diseases. 6(1), s. 1–8. doi: 10.1093/ofid/ofy337. Fulltekst i vitenarkiv Vis sammendrag

  Background: The growing burden of diabetes mellitus (DM) is posing a threat to global tuberculosis (TB) control. DM triples the risk of developing TB, modifies the presenting features of pulmonary TB, and worsens TB treatment outcomes. We aimed to analyze the prevalence of DM among TB patients and to describe the characteristics and clinical presentation of TB-DM patients in Europe. Methods: We performed a cross-sectional survey on the prevalence of DM among consecutively diagnosed adult TB patients in 11 European TB referral centers located in France, Germany, Greece, Italy, Russia, Slovakia, Spain, and the United Kingdom over the period 2007–2015. We also selected DM-TB cases and TB only controls with a 1:3 ratio to perform a case-control analysis, including patients selected from the countries mentioned above plus Norway and Ukraine. Results: Among 3143 TB enrolled patients, DM prevalence overall was 10.7% and ranged from 4.4% in Greece to 28.5% in the United Kingdom. Patients’ median ages ranged from 36 to 49 years, and all centers had >60% males; the proportion of foreign-born patients varied widely across sites. In the case-control study, DM was independently associated with older age and, among older patients, with being foreign-born. Among patients with pulmonary involvement, cavities on chest imaging were more frequently observed among those with DM. Conclusions: Diabetes mellitus represents a challenge for TB control in Europe, especially in foreign-born and in elderly patients. Specific screening strategies should be evaluated.

• Schein, Yvette Louise; Madebo, Tesfaye; Andersen, Hilde Elise; Arnesen, Trude Margrete; Dyrhol-Riise, Anne Ma & Tveiten, Hallgeir [Vis alle 8 forfattere av denne artikkelen] (2018). Treatment completion for latent tuberculosis infection in Norway: a prospective cohort study. BMC Infectious Diseases. 18. doi: 10.1186/s12879-018-3468-z. Fulltekst i vitenarkiv Vis sammendrag

  Background: Successful treatment of latent tuberculosis infection (LTBI) is essential to reduce tuberculosis (TB) incidence rates in low-burden countries. This study measures treatment completion and determinants of non-completion of LTBI treatment in Norway in 2016. Methods: This prospective cohort study included all individuals notified with LTBI treatment to the Norwegian Surveillance System for Infectious Diseases (MSIS) in 2016. We obtained data from MSIS and from a standardized form that was sent to health care providers at the time of patient notification to MSIS. We determined completion rates. Pearson’s chi squared test was used to study associations between pairs of categorical variables and separate crude and multivariable logistic regression models were used to identify factors associated with treatment completion and adverse drug effects. Results: We obtained information on treatment completion from 719 of the 726 individuals notified for LTBI treatment in 2016. Overall, 91% completed treatment. Treatment completion was highest in the foreign-born group [foreign-born, n = 562 (92%) vs Norwegian-born, n = 115 (85%), p = 0.007]. Treatment completion did not differ significantly between prescribed regimens (p = 0.124). Adverse events were the most common reason for incomplete treatment. We found no significant differences in adverse events when comparing weekly rifapentine (3RPH) with three months daily isoniazid and rifampicin (3RH). However, there were significantly fewer adverse events with 3RPH compared to other regimens (p = 0.037). Age over 35 years was significantly associated with adverse events irrespective of regimen (p = 0.024), whereas immunosuppression was not significantly associated with adverse events after adjusting for other variables (p = 0.306). Treatment under direct observation had a significant effect on treatment completion for foreign-born (multivariate Wald p-value = 0.017), but not for Norwegian-born (multivariate Wald p-value = 0.408) individuals. Conclusions: We report a very high treatment completion rate, especially among individuals from countries with high TB incidence. The follow-up from tuberculosis-coordinators and the frequent use of directly observed treatment probably contributes to this. Few severe adverse events were reported, even with increased age and in individuals that are more susceptible. While these results are promising, issues of cost-effectiveness and targeting treatment to individuals at highest risk of TB are important components of public health impact.

• Jørstad, Melissa Davidsen; Marijani, Msafiri; Dyrhol-Riise, Anne Ma; Sviland, Lisbeth & Mustafa, Tehmina (2018). MPT64 antigen detection test improves routine diagnosis of extrapulmonary tuberculosis in a low-resource setting: A study from the tertiary care hospital in Zanzibar. PLOS ONE. 13:e0196723(5), s. 1–15. doi: 10.1371/journal.pone.0196723. Fulltekst i vitenarkiv Vis sammendrag

  Background: Extrapulmonary tuberculosis (EPTB) is a diagnostic challenge. An immunochemistry-based MPT64 antigen detection test (MPT64 test) has reported higher sensitivity in the diagnosis of EPTB compared with conventional methods. The objective of this study was to implement and evaluate the MPT64 test in routine diagnostics in a low-resource setting. Methods: Patients with presumptive EPTB were prospectively enrolled at Mnazi Mmoja Hospital, Zanzibar, and followed to the end of treatment. Specimens collected were subjected to routine diagnostics, GeneXpert® MTB/RIF assay and the MPT64 test. The performance of the MPT64 test was assessed using a composite reference standard, defining the patients as tuberculosis (TB) cases or non-TB cases. Results: Patients (n = 132) were classified as confirmed TB (n = 12), probable TB (n = 34), possible TB (n = 18), non-TB (n = 62) and uncategorized (n = 6) cases. Overall, in comparison to the composite reference standard for diagnosis, the sensitivity, specificity, positive predictive value, negative predictive value and accuracy of the MPT64 test was 69%, 95%, 94%, 75% and 82%, respectively. The MPT64 test performance was best in TB lymphadenitis cases (n = 67, sensitivity 79%, specificity 97%) and in paediatric TB (n = 41, sensitivity 100%, specificity 96%). Conclusions: We show that the MPT64 test can be implemented in routine diagnostics in a low-resource setting and improves the diagnosis of EPTB, especially in TB lymphadenitis and in children.

• Mekonnen, Meseret Habtamu; Abebe, Markos; Aseffa, Abraham; Dyrhol-Riise, Anne Ma; Spurkland, Anne & Abrahamsen, Greger (2018). In vitro analysis of antigen induced T cell-monocyte conjugates by imaging flow cytometry. Journal of Immunological Methods (JIM). ISSN 0022-1759. 460, s. 93–100. doi: 10.1016/j.jim.2018.06.014. Fulltekst i vitenarkiv Vis sammendrag

  There is a lack of suitable correlates of immune protection against Mycobacterium tuberculosis (Mtb) infection. T cells and monocytes play key roles in host immunity against Mtb. Thus, a method that allows assessing their interaction would contribute to the understanding of immune regulation in tuberculosis (TB). We have established imaging flow cytometer (IFC) based in vitro assay for the analysis of early events in T cell-monocyte interaction, upstream of cytokine production and T cell proliferation. This was achieved through short term stimulation of peripheral blood mononuclear cells (PBMC) from healthy Norwegian blood donors with Mycobacterium bovis Bacille Calmette-Guérin (BCG). In our assay, we examined the kinetics of BCG uptake by monocytes using fluorescently labeled BCG and T cell-monocyte interaction based on synapse formation (CD3/TCR polarization). Our results showed that BCG stimulation induced a gradual increase in the proportion of conjugated T cells displaying NF-κB translocation to the nucleus in a time dependent manner, with the highest frequency observed at 6 h. We subsequently tested PBMC from a small cohort of active TB patients (n = 7) and observed a similar BCG induced NF-κB translocation in T cells conjugated with monocytes. The method allowed for simultaneous evaluation of T cell-monocyte conjugates and T cell activation as measured by NF-κB translocation, following short-term challenge of human PBMC with BCG. Whether this novel approach could serve as a diagnostic or prognostic marker needs to be investigated using a wide array of Mtb specific antigens in a larger cohort of patients with different TB infection status.

• Orlien, Stian Magnus Staurung; Ismael, Nejib Yusuf; Ahmed, Tekabe Abdosh; Berhe, Nega; Lauritzen, Trine & Roald, Borghild [Vis alle 12 forfattere av denne artikkelen] (2018). Unexplained chronic liver disease in Ethiopia: a cross-sectional study. BMC Gastroenterology. 18(1). doi: 10.1186/s12876-018-0755-5. Fulltekst i vitenarkiv Vis sammendrag

  Background: Hepatitis B virus (HBV) infection is assumed to be the major cause of chronic liver disease (CLD) in sub-Saharan Africa. The contribution of other aetiological causes of CLD is less well documented and hence opportunities to modulate other potential risk factors are being lost. The aims of this study were to explore the aetiological spectrum of CLD in eastern Ethiopia and to identify plausible underlying risk factors for its development. Methods: A cross-sectional study was undertaken between April 2015 and April 2016 in two public hospitals in Harar, eastern Ethiopia. The study population comprised of consenting adults with clinical and radiological evidence of chronic liver disease. The baseline evaluation included: (i) a semi-structured interview designed to obtain information about the ingestion of alcohol, herbal medicines and local recreational drugs such as khat (Catha edulis); (ii) clinical examination; (iii) extensive laboratory testing; and, (iv) abdominal ultrasonography. Results: One-hundred-and-fifty patients with CLD (men 72.0%; median age 30 [interquartile range 25–40] years) were included. CLD was attributed to chronic HBV infection in 55 (36.7%) individuals; other aetiological agents were identified in a further 12 (8.0%). No aetiological factors were identified in the remaining 83 (55.3%) patients. The overall prevalence of daily khat use was 78.0%, while alcohol abuse, defined as > 20 g/day in women and > 30 g/day in men, was rare (2.0%). Histological features of toxic liver injury were observed in a subset of patients with unexplained liver injury who underwent liver biopsy. Conclusion: The aetiology of CLD in eastern Ethiopia is largely unexplained. The widespread use of khat in the region, together with histopathological findings indicating toxic liver injury, suggests an association which warrants further investigation.

Se alle arbeider i NVA

• Dahl, Tuva Børresdatter; Aftab, Friha; Prebensen, Christian Haugland; Berdal, Jan-Erik; Ueland, Thor & Barratt-Due, Andreas [Vis alle 15 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv
• Hites, Maya; Lapique, Eva Larranaga; Massonnaud, Clément R.; Belhadi, Drifa; Jamard, Simon & Goehringer, François [Vis alle 86 forfattere av denne artikkelen] (2024). Tixagevimab-cilgavimab (AZD7442) for the treatment of patients hospitalized with COVID-19 (DisCoVeRy): A phase 3, randomized, double-blind, placebo-controlled trial. Journal of Infection. ISSN 0163-4453. 88(3). doi: 10.1016/j.jinf.2024.106120. Fulltekst i vitenarkiv
• Mortensen, Rasmus; Clemmensen, Helena Strand; Woodworth, Joshua S.; Therkelsen, Marie Louise; Mustafa, Tehmina & Tonby, Kristian [Vis alle 10 forfattere av denne artikkelen] (2024). Erratum: Author Correction: Cyclooxygenase inhibitors impair CD4 T cell immunity and exacerbate Mycobacterium tuberculosis infection in aerosol-challenged mice (Communications biology (2019) 2 (288)). Communications Biology. 7(1), s. 662–662. doi: 10.1038/s42003-024-06260-z. Fulltekst i vitenarkiv
• Mohn, Kristin Greve-Isdahl; Bredholt, Geir; Onyango, Therese Bredholt; Brokstad, Karl Albert; Zhou, Fan & Holter, Jan Cato [Vis alle 9 forfattere av denne artikkelen] (2023). SARS-CoV-2 infection induces long-lived B and T-cell responses up to 15 months post-infection, irrespective of disease severity. Journal of Infection. ISSN 0163-4453. 87(4), s. 346–349. doi: 10.1016/j.jinf.2023.05.023. Fulltekst i vitenarkiv
• Quiles-Jiménez, Ana M T; Sousa, Mirta; Huse, Camilla; Dyrhol-Riise, Anne Ma; Holter, Jan Cato & Christensen, Erik Egeland [Vis alle 12 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv
• Ueland, Thor; Äikäs, Lauri A.O.; Dahl, Tuva Børresdatter; Gregersen, Ida; Olsen, Maria Belland & Michelsen, Annika Elisabet [Vis alle 20 forfattere av denne artikkelen] (2023). Low-density lipoprotein particles carrying proinflammatory proteins with altered aggregation pattern detected in COVID-19 patients 3 months after hospitalization. Journal of Infection. ISSN 0163-4453. 86(5), s. 489–492. doi: 10.1016/j.jinf.2023.02.024. Fulltekst i vitenarkiv
• Gregersen, Ida; Ueland, Thor; Holter, Jan Cato; Olsen, Maria Belland; Michelsen, Annika Elisabet & Murphy, Sarah L [Vis alle 22 forfattere av denne artikkelen] (2022). CXCL16 associates with adverse outcome and cardiac involvement in hospitalized patients with Covid-19. Journal of Infection. ISSN 0163-4453. 85(6), s. 735–738. doi: 10.1016/j.jinf.2022.09.029. Fulltekst i vitenarkiv
• Murphy, Sarah Louise Mikalsen; Halvorsen, Bente; Barratt-Due, Andreas; Dyrhol-Riise, Anne Ma; Aukrust, Pål & Trøseid, Marius [Vis alle 7 forfattere av denne artikkelen] (2022). Remdesivir modifies interferon response in hospitalized COVID-19 patients. Journal of Infection. ISSN 0163-4453. 85(5), s. 573–607. doi: 10.1016/j.jinf.2022.07.021. Fulltekst i vitenarkiv
• Ueland, Thor; Holter, Jan Cato; Holten, Aleksander Rygh; Muller, Karl Erik; Lind, A. & Bekken, Gry Klouman [Vis alle 10 forfattere av denne artikkelen] (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), s. e41–e43. doi: 10.1016/j.jinf.2020.06.061. Fulltekst i vitenarkiv
• 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. s. 1–2. doi: 10.1111/apm.13108. Fulltekst i vitenarkiv Vis sammendrag

  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).

• Tonby, Kristian; Mortensen, Rasmus; Ruhwald, Morten; Dyrhol-Riise, Anne Ma & Jenum, Synne (2019). KLRG1-expressing CD4 T cells are reduced in tuberculosis patients compared to healthy mycobacterium tuberculosis-infected subjects, but increase with treatment. Journal of Infectious Diseases. ISSN 0022-1899. 220(1), s. 174–176. doi: 10.1093/infdis/jiz056. Fulltekst i vitenarkiv
• Jørgensen, Marthe Jøntvedt; Jenum, Synne; Tonby, Kristian; Ruhwald, Morten; DuPlessis, Nelita & Dyrhol-Riise, Anne Ma (2019). Host directed therapy - the in vivo and in vitro effects of Cyclooxygenase-2 inhibitors on myeloid derived suppressor cells in active tuberculosis. Fulltekst i vitenarkiv
• Dyrhol-Riise, Anne Ma (2019). TBCOX2 study. Fulltekst i vitenarkiv
• Jørgensen, Marthe Jøntvedt; Jenum, Synne; Tonby, Kristian; Ruhwald, Morten; DuPlessis, Nelita & Dyrhol-Riise, Anne Ma (2019). Host directed therapy - the in vivo and in vitro effects of Cyclooxygenase-2 inhibitors on myeloid derived suppressor cells in active tuberculosis. Fulltekst i vitenarkiv
• Nore, Kristin Grotle; Jørgensen, Marthe Jøntvedt; Jenum, Synne; Dyrhol-Riise, Anne Ma & Tonby, Kristian (2019). Eicosanoid balance in tuberculosis - dynamics of lipid mediators in monocytes during infection. Fulltekst i vitenarkiv
• Meyer-Myklestad, Malin Holm; Kummen, Martin; Stiksrud, Birgitte; Holm, Kristian; Dyrhol-Riise, Anne Ma & Kvale, Dag [Vis alle 11 forfattere av denne artikkelen] (2019). ALTERED GUT IMMUNITY IN IMMUNOLOGICAL NONRESPONDERS PARTLY RESTORED BY PROBIOTICS. Fulltekst i vitenarkiv
• Lorvik, Kristina Berg; Meyer-Myklestad, Malin Holm; Medhus, Asle Wilhelm; Kvale, Dag; Dyrhol-Riise, Anne Ma & Reikvam, Dag Henrik [Vis alle 7 forfattere av denne artikkelen] (2019). Increased expression of gut and blood CD4+ T cells in people living with HIV and insufficient response to antiviral therapy. Fulltekst i vitenarkiv
• Dyrhol-Riise, Anne Ma (2018). Abstrakt: Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) exacerbates TB infection after aerosol challenge in mice – implications for host-directed therapy Mortensen R, Clemmensen HS, Woodworth J, Therkelsen ML, Tonby K, Jenum S, Tasken K, Ruhwald M, Agger EM, Dyrhol-Riise AM, Andersen P. Fulltekst i vitenarkiv

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