Tuberculosis
Tuberculosis (TB) is a leading cause of death globally and is still a relevant disease in Norway.
We conduct studies on the TB biobank collected from the Department of Infectious Diseases, OUH, Ullevål, and are partners in national and international projects and clinical studies. We study the host's immune response in various stages of the disease and during treatment with the hypothesis that the immune system can be targeted by new host-directed treatments. We study diagnostic and prognostic biomarkers and gene signatures with various omnic technologies and immunological methods.
A TB MedInsight quality register has been established at our department. We also participate in clinical and epidemiological studies in the European TB network TBnet.
We have at OUH, Ullevål, in 2015-19 conducted a randomized clinical phase I/II trial of the therapeutic vaccine H56:IC31 (developed by Statens Serum Institutt, Denmark) and cyclo-oxygenase-2 inhibitors given to TB patients with active disease in addition to standard TB treatment (TBCOX2). Read more on U.S. Library of Medicine - ClinicalTrials ID: NCT02503839. The study was published in Nature Communications in 2021.
We find that the vaccine is safe and induces good T cell responses and has potential as a therapeutic vaccine that can be included in a personalized treatment strategy to strengthen the patient's immune system and reduce the length of TB treatment.
Current projects
SMA-TB - a novel Stratified Medicine Algorithm to predict treatment responses to host-directed therapy in TB patients
From 2019, we have been a partner in an EU Horizone 2020 project aiming to develop an algorithm to identify which TB patients can benefit from immune-directed personalized treatment. Read more on U.S. Library of Medicine - ClinicalTrials ID: NCT04575519.
In our part of the project, we will study immune profiles in TB patients included in clinical treatment studies in South Africa and Georgia by analyzing biobank with flow cytometry and various omnic techniques to find biomarkers for the effect of immune-directed treatment.
The principal investigator at OUH/UIO is Anne Ma Dyrhol-Riise. Read more about the SMA-TB study here.
Selected publications
- A Phase I/II randomized trial of H56:IC31 vaccination and adjunctive cyclooxygenase-2-inhibitor treatment in tuberculosis patients. Jenum S et al. Nat Commun. (2021), 12 (1), 6774, DOI 10.1038/s41467-021-27029-6.
- Utility of a three-gene transcriptomic signature in the diagnosis of tuberculosis in a low-endemic hospital setting. Chendi BH et al. Infect Dis (Lond). (2023) Jan;55(1):44-54. doi: 10.1080/23744235.2022.2129779.
- Elevated Levels of Anti-Inflammatory Eicosanoids and Monocyte Heterogeneity in Mycobacterium tuberculosis Infection and Disease. Nore KG et al. Front Immunol, 11, (2021), DOI 10.3389
- Monocytic myeloid-derived suppressor cells reflect tuberculosis severity and are influenced by cyclooxygenase-2 inhibitors. Jøntvedt Jørgensen M et al. J Leukoc Biol (2021), 110 (1), 177-186. DOI 10.1002/JLB.4A0720-409RR
- A Plasma 5-Marker Host Biosignature Identifies Tuberculosis in High and Low Endemic Countries. Chendi BH et al, Front Immunol (2021): 12, DOI 10.3389/fimmu.2021.608846.
- CCL1 and IL-2Ra differentiate Tuberculosis disease from latent infection Irrespective of HIV infection in low TB burden countries. Chendi BH el al, J Infect (2021), 83 (4), 433-443. DOI 10.1016/j.jinf.2021.07.036.
- Plasma LOX-Products and Monocyte Signaling Is Reduced by Adjunctive Cyclooxygenase-2 Inhibitor in a Phase I Clinical Trial of Tuberculosis Patients. Jøntvedt Jørgensen M el al, Front Cell Infect Microbiol. (2021): 11, 669623. DOI 10.3389/fcimb.2021.669623.
- Cyclooxygenase inhibitors impair CD4 T cell immunity and exacerbate Mycobacterium tuberculosis infection in aerosol-challenged mice. Mortensen R et al. Commun Biol. (2019) Aug 5;2:288. doi: 10.1038/s42003-019-0530-3.
- KLRG1-Expressing CD4 T Cells Are Reduced in Tuberculosis Patients Compared to Healthy Mycobacterium tuberculosis-Infected Subjects, but Increase With Treatment. Tonby K et al. J Infect Dis. 2019 Jun 5;220(1):174-176. doi: 10.1093/infdis/jiz056
HIV infection
HIV infection can be effectively treated with anti-retroviral therapy (ART), but some patients, so-called immunological non-responders (INR), still experience an inadequate rebuilding of the immune system and chronic immune activation and have poorer life prospects.
Our group focus on studies of immunopathogenesis and immunological biomarkers that can identify INR. We analyze prospectively collected biobank from people living with HIV (PLW) at the department's outpatient clinic in collaboration with national and international partners. We have previously conducted several clinical phase I/II intervention studies with therapeutic HIV vaccines which have resulted in several PhD degrees.
We have established a HIV MedInsight quality register. We provide data to international multi-centre databases and large European HIV cohort studies.
The group is a member of Nordic HIV Cure, a Nordic consortium with joint projects. In 2020, the group took the initiative to establish the research network Oslo HIV Research Network to strengthen interdisciplinary research on HIV infection.
Current projects
OUSHIVProbiot2 - Improving prognosis in HIV infection and Gut control of HIV infection
We work from the hypothesis that intestinal leakage and microbial translocation can explain why some patients are INR.
We have conducted a clinical phase II intervention trial focusing on intestinal immunology and the role of microbiota in HIV infection. Find more on the study on U.S. Library of Medicine - ClinicalTrials ID: NCT02640625.
Here, INR patients received probiotics over eight weeks in addition to antiviral treatment to clarify whether probiotics can function as adjunctive treatment in INR patients with a dysfunctional intestinal mucosa. Mucosal biopsies were obtained from the colon before and after the treatment and follow-up studies are planned.
The study is financed by South-Eastern Norway Regional Health Authority. The principal investigator is Dag Henrik Reikvam.
Selected publications
- Probiotics to HIV-Infected Immunological Nonresponders: Altered Mucosal Immunity and Microbial Diversity Restricted to Ileum. Meyer-Myklestad MH et al. J Acquir Immune Defic Syndr. 2022 Jan 1;89(1):77-86. doi: 10.1097/QAI.0000000000002817.
- Probiotics to manage inflammation in HIV infection, Reikvam DH et al. Curr Opin Infect Dis, 2020: 33 (1), 34-43.
- Enhanced Gut-Homing Dynamics and Pronounced Exhaustion of Mucosal and Blood CD4+ T Cells in HIV-Infected Immunological Non-Responders. Lorvik KB et al. Front Immunol 2021, 12, 744155. DOI 10.3389/fimmu.2021.744155.
- Human Immunodeficiency Virus-Infected Immunological Nonresponders Have Colon-Restricted Gut Mucosal Immune Dysfunction. Meyer-Myklestad MH et al. J Infect Dis. 2022 Feb 15;225(4):661-674. doi: 10.1093/infdis/jiaa714
- Activated dendritic cells and monocytes in HIV immunological nonresponders: HIV-induced interferon-inducible protein-10 correlates with low future CD4+ recovery. Stiksrud B et al. AIDS. 2019 Jun 1;33(7):1117-1129. doi: 10.1097/QAD.0000000000002173.
- Immune activation and HIV-specific T cell responses are modulated by a cyclooxygenase-2 inhibitor in untreated HIV-infected individuals: An exploratory clinical trial. Prebensen C et al. PLoS One. 2017 May 2;12(5):e0176527. doi: 10.1371/journal.pone.0176527.
- Plasma IP-10 Is Increased in Immunological NonResponders and Associated With Activated Regulatory T Cells and Persisting Low CD4 Counts. Stiksrud B et al, J Acquir Immune Defic Syndr. 2016 Oct 1;73(2):138-48. doi: 10.1097/QAI.0000000000001080.
- Reduced Levels of D-dimer and Changes in Gut Microbiota Composition After Probiotic Intervention in HIV-Infected Individuals on Stable ART. Stiksrud B et al.J Acquir Immune Defic Syndr. 2015 Dec 1;70(4):329-37. doi: 10.1097/QAI.0000000000000784.
Hepatitis B
Hepatitis B virus (HBV) infection causes a chronic immune reaction in the liver and the liver cells act as a virus reservoir. Most infected people cannot be cured of HBV, but the disease is controlled through anti-viral treatment (nucleoside analogues, Nuc). It is still unclear whether treatment can be stopped or must be lifelong, as in the case for HIV infection.
Our aim is to use the knowledge we have acquired through research on HIV and TB immunology to study the immune mechanisms of HBV and biomarkers for disease stages and the effect of treatment.
Current projects
Nuc-Stop - the Norwegian Nucleoside Analogue Stop Study
Clinical multicenter trial (11 centers in Norway, Sweden, Denmark and Ethiopia) from 2018 to investigate whether stopping Nuc treatment in selected people with chronic HBV can trigger an immune reaction that leads to the loss of circulating virus and thus a functional cure. Further details on the study on U.S. Library of Medicine - ClinicalTrials ID: NCT03681132.
Recruitment has been completed and the patients are followed for three years. Biobank will, in collaboration with partners at the Karolinska Institute in Stockholm, be analyzed with flow cytometry and various omnic techniques to identify markers and mechanisms that can predict a clinically favorable outcome in patients who have stopped Nuc treatment.
The project leader is Asgeir Johannessen, Hospital in Vestfold and UiO. The principal investigator at OUH/UiO is Dag Henrik Reikvam.The study is funded by South-Eastern Norway Regional Health Authority and the Research Council of Norway.
Selected publications
- Hepatitis delta infection among persons living with HIV in Europe. Béguelin C et al, EuroSIDA and SHCS. Liver Int. 2023 Jan 10. doi: 10.1111/liv.15519.
- Systematic review and individual-patient-data meta-analysis of non-invasive fibrosis markers for chronic hepatitis B in Africa. Johannessen A et al, Nat Commun. 2023 Jan 3;14(1):45. doi: 10.1038/s41467-022-35729-w.
Sepsis
Sepsis is a common and dangerous condition characterized by an inappropriate immune response to an acute infection, which damages the body's own tissues and causes organ failure and death if the patient does not receive prompt and effective treatment. It is therefore important to identify which patients may benefit from drugs that may dampen the harmful immune response.
Our focus is to study immunopathogenesis and prognostic biomarkers (multi-omnics) in sepsis. Many of the studies are based on the OUH Sepsis quality register and the sepsis biobank "SIRS". We have also carried out the study CalSep for the company Gentian AS, where we have investigated the role of calprotectin in sepsis. The research takes place in close collaboration with the OUH departments Emergency Medicine, Medical Biochemistry and Microbiology.
Current projects
SEPSOMICS - Multi-omics to identify sepsis endotypes in the emergency department - laying the groundwork for personalized therapy
Sepsis patients from OUH, Ullevål, are included in the study where multi-omics analyzes of biobank will be carried out in order to better classify the sepsis patients into subgroups (endotypes). The long-term goal is for sepsis patients to receive customized specific treatment targeting the immune response.
The study is financed by South-Eastern Norway Regional Health Authority from 2022. The principal investigator is Dag Kvale.
NOR-GECCO - Norwegian study of Genetic variation in Escherichia Coli and Clinical Outcome
Retrospective national multicenter cohort study studying the significance of genetic variants of the bacterium E. coli on the severity of sepsis by linking sequencing data from 3000 bacterial strains from the blood to the patients clinical data.
The study is in close collaboration with NORM in Tromsø. The principal investigator is Aleksander Rygh Holten.
Sepsis biomarkers for improvement and personalized treatment
Observational study in which data from the sepsis quality register is linked to exciting laboratory data to study the role of biochemical and haematological markers in the early diagnosis and subgrouping of sepsis.
Project managers are Erik Amundsen (Department of Biochemistry) and Aleksander Rygh Holten in collaboration.
Selected publications
- Mortality and Sequential Organ Failure Assessment Score in Patients With Suspected Sepsis: The Impact of Acute and Preexisting Organ Failures and Infection Likelihood. Christensen, E. E., et al. Crit Care Explor. 2023 5(2): e0865. doi: 10.1097/CCE.0000000000000865
- DIAGNOSTIC ACCURACY AND ADDED VALUE OF INFECTION BIOMARKERS IN PATIENTS WITH POSSIBLE SEPSIS IN THE EMERGENCY DEPARTMENT. Christensen EE et al. Shock. 2022 Oct 1;58(4):251-259. doi: 10.1097/SHK.0000000000001981.
- Prognostic Value of Nucleated RBCs for Patients With Suspected Sepsis in the Emergency Department: A Single-Center Prospective Cohort Study. Amundsen EK et al, Crit Care Explor. 2021 Jul 16;3(7):e0490. doi: 10.1097/CCE.0000000000000490.
- Strukturert mottak av sepsispasienter og oppstart av antibiotika. Trydal et al. Tidsskrift for den Norske laegeforening : tidsskrift for praktisk medicin, 2019, 139.
Covid-19
Coronavirus disease 2019 (Covid-19) is caused by the virus SARS-CoV-2. Our research on Covid-19 started immediately when the pandemic started in the spring of 2020. We have participated in a number of projects to better understand this disease and how best to treat it.
Current projects
International clinical trials
During 2020-21, we recruited patients into three international clinical treatment trials of severe Covid-19 (NOR-Solidarity, Discovery and Bari-SolidAct). We have contributed to develop EU-Response, a European study platform where 16 countries participate for the rapid initiation of clinical studies in the event of new pandemics. From 2022, we participates in the AXL-SolidAct trial, which tests Bemcentinib in hospitalized patients with moderate Covid-19.
Local principal investigators of clinical trials: Kristian Tonby, Aleksander Rygh Holten and Anne Ma Dyrhol-Riise.
Biobanks
In the observational cohort "Norwegian SARS-CoV-2 study" in collaboration with the department of Microbiology OUH (project leader Jan Cato Holter), we have throughout much of the pandemic recorded prospective clinical data and collected a longitudinal biobank from hospitalized patients with COVID-19. The study has produced a number of publications that have contributed to a better understanding of COVID-19. The project is part of the international WHO/ISARIC COVID-19 network.
We continue to carry out biobank analyzes from all these studies in collaboration with national and international partners. The Department of Infectious Diseases in collaboration with other departments at OUH, has also established a Covid-19 quality register with clinical data from patients admitted to hospital in the period 2020-2021. We have also carried out a survey of the risk of SARS-CoV-2 infection among healthcare personnel.
Vaccine candidates
On behalf of the Norwegian company Nykode Therapeutics, in 2021-22 we led a phase 1/2, dose-escalating clinical multicenter study of two SARS-CoV-2 DNA plasmid vaccine candidates, VB10.2129 (C1) and VB10.2210 (C2). The vaccines were tested for safety and capacity to produce an immune response in healthy study participants.
The principal investigator is Anne Ma Dyrhol-Riise. Read more about the study on the project pages for Nykode Therapeutics and on U.S. Library of Medicine - ClinicalTrials ID: NCT05069623.
Selected publications
- Efficacy and safety of baricitinib in hospitalized adults with severe or critical COVID-19 (Bari-SolidAct): a randomised, double-blind, placebo-controlled phase 3 trial. Trøseid M et al, SolidAct study group. Crit Care. 2023 Jan 10;27(1):9. doi: 10.1186/s13054-022-04205-8.
- Remdesivir modifies interferon response in hospitalized COVID-19 patients. Murphy SL et al. J Infect. 2022 Nov;85(5):573-607. doi: 10.1016/j.jinf.2022.07.021.
- Markers of cellular senescence is associated with persistent pulmonary pathology after COVID-19 infection. Lekva T. et al. Infect Dis (Lond). 2022 Dec;54(12):918-923. doi: 10.1080/23744235.2022.2113135.
- High Circulating Levels of the Homeostatic Chemokines CCL19 and CCL21 Predict Mortality and Disease Severity in COVID-19. Tveita A et al, NOR-SOLIDARITY Consortium and the Norwegian SARS-CoV-2 Study Group Investigators. J Infect Dis. 2022 Dec 13;226(12):2150-2160. doi: 10.1093/infdis/jiac313.
- Respiratory dysfunction three months after severe COVID-19 is associated with gut microbiota alterations. Vestad B et al NOR-Solidarity study group. J Intern Med. 2022 Jun;291(6):801-812. doi: 10.1111/joim.13458.
- Remdesivir and three other drugs for hospitalised patients with COVID-19: final results of the WHO Solidarity randomised trial and updated meta-analyses. Lancet 2022, 399(10339):1941-1953
- Evaluation of the Effects of Remdesivir and Hydroxychloroquine on Viral Clearance in COVID-19: A Randomized Trial. Barratt-Due A et al. Ann Intern Med (2021); 174 (9), 1261-1269. DOI 10.7326/M21-0653.
- Critical COVID-19 is associated with distinct leukocyte phenotypes and transcriptome patterns. Christensen EE et al. J Intern Med (2021); 290 (3), 677-692. DOI 10.1111/joim.13310
- Increased interleukin-6 and macrophage chemoattractant protein-1 are associated with respiratory failure in COVID-19. Jøntvedt Jørgensen M et al. Sci Rep. (2021), 10 (1), 21697. DOI 10.1038/s41598-020-78710-7.
- Predicting severe COVID-19 in the Emergency Department. Holten AR et al. Resusc Plus. 2020 Dec;4:100042. doi: 10.1016/j.resplu.2020.100042.