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Trial Lecture – time and place
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Adjudication committee
- First opponent: Senior Consultant Kristoffer Strålin, Karolinska Institute, Sweden
- Second opponent: Professor Jan Kristian Damås, Norwegian University of Science and Technology, Trondheim
- Third member and chair of the evaluation committee: Associate Professor Elisabeth Toverud Landaas, University of Oslo
Chair of the Defence
Professor II Marius Trøseid, University of Oslo
Principal Supervisor
Researcher Aleksander Rygh Holten, University of Oslo
Summary
Sepsis is a highly lethal syndrome of organ failure, infection and dysregulated immune responses. Despite extensive research, the treatment of sepsis has remained largely unchanged for decades. The lack of scientific progress in the field has been attributed to the enormous heterogenicity of sepsis patients: a given therapeutic approach may benefit certain sepsis patients, but harm others. A major challenge is identifying sepsis patients and what differentiates them.
In this thesis, we aim to approach some of the challenges in defining organ failures in sepsis and identifying infection early, and we compare immune cell phenotypes in sepsis caused by SARS-CoV-2 and other pathogens.
There is no gold standard test for sepsis and the diagnosis depends on definitions and clinical criteria that describe the syndrome. Sepsis was re-defined in 2016 as “a life-threatening organ dysfunction caused by a dysregulated host response to infection”. This is however not readily identifiable in the clinic, and clinical criteria were established after testing and validation in large cohorts, assessing the ability of organ failure scoring systems to predict death among patients with suspected infections. An acute increase in .Sequential organ failure assessment. (SOFA) score of 2 or more was chosen to diagnose sepsis. These studies could not, however, separate acute and chronic organ failures, with potential implications for the operationalization of the sepsis diagnosis. In paper I, we found that a significant proportion of the SOFA score was present before the acute illness (chronic organ failures). This implies a significant risk of over-diagnosing chronically ill patients with sepsis. Furthermore, we found that taking only acute organ failure into account when calculating SOFA compromises the score’s ability to predict death, which is problematic when mortality prediction was the reason for selecting SOFA in the first place.
Studies of infection biomarkers in patients with possible sepsis in the emergency department have shown highly variable results and no biomarkers are currently recommended for diagnosing infection in this patient group. In paper II, we investigated how well the biomarkers calprotectin, c-reactive protein, interleukin 6 and procalcitonin detected infection in potentially septic patients. Interleukin 6 and c-reactive protein were the two best biomarkers, and could potentially improve and in many cases correct the emergency department physician's decision on whether or not to start antibiotic treatment. Interestingly, interleukin 6 and c-reactive protein were frequently discordant, and may thus complement each other in the detection of infection.
In paper III, we explored phenotypes and gene expression in mononuclear peripheral immune cells in patients with sepsis and various severities of Covid-19. We found that leukocyte phenotypes were associated with Covid-19 severity: T cell IL-7 receptor expression was lower in critically ill Covid-19 patients. In the same patient group, we found lower HLA-DR and higher PD-L1 expression in monocytes and lower frequencies of non-classical monocytes than in less critically ill Covid-19 patients. This suggests a central role of monocytes in the development of critical Covid-19. Furthermore, the patterns of PD-L1 and IL-7 receptor expression may explain mechanisms of lymphopenia in these patients, and may constitute therapeutic targets in Covid-19-associated lymphopenia.
SARS-CoV-2 can, like many bacteria and other viruses, cause sepsis, but whether the causative microbe explains the heterogenicity seen in sepsis patients remains unknown. We therefore compared the characteristics of immune cells in intensive care unit (ICU) patients with sepsis caused by SARS-CoV-2 and bacteria, and found a more homogenous immune cell compartment in the former group. This may help to explain why a number of immunotherapies have been shown to improve survival in patients with severe Covid-19, but not in patients with sepsis caused by other microbes.
Additional information
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