Corona-undersøkelsen i Trøndelag CUT-COVID-19

The Covid-19 pandemic is caused by the virus named SARS-CoV2. The Covid-19 virus is a corona virus closely related to SARS, the virus that caused an epidemic in 2002-2003. Covid-19 disease severity varies from mild symptoms in 80% of the cases to severe disease in 15% of the cases. The final 5% of the patients become hospitalized with the need for intensive care treatment, especially needing help to breathe. The majority of patients who become severely ill from Covid-19 are older or have an underlying disease. However, young and otherwise healthy people can also develop severe symptoms or die from Covid-19. How sick a patient becomes during an infection is influenced by many factors. In some patients, the immune system is able to fend off infections, while others struggle or fail to do so. The cause might be genetic - small alterations in our genes can have a great effect on how our cells perform certain functions. Life-style related factors, often called modifiable factors, also play a role. For instance, we know what smoking, alcohol use and diet affects or susceptibility to infections. Clinical factors, such as other diseases or medications, can also affect the risk of infection or how well the immune system can defend against infections. In the CUT COVID study (Coronaundersøkelsen I Trøndelag), we collected clinical information and a detailed biobank in patients hospitalized with COVID 19 I Central Norway. All hospitalized COVID 19 patients were invited to informed consent to have their information and biological material collected and stored for research. An important aim for the study was to enable international collaboration were mechanisms and risk factors for disease severity could be studied. The study had two parts: adult patient and pediatric patients. Adults: Clinical information and biological material, including genetic data and immunologic cells were collected. Through participation in the global network of researchers from 19 countries we investigate the role of human genetics in SARS-COV-2 infection and COVID-19 severity (the COVID-19 Host Genetics Initiative). Through this work the CUT COVID project has participated in some of the important mechanisms in severe COVID 19 disease that identify targets for new drugs. This network gained knowledge and published for each year of the pandemic and beyond (3 Nature papers: 2021, 2022, 2023) every time more comprehensive analyses of genes related to disease severity. Through these analyses the important parts of the human gene involved in the biological pathways to disease severity in COVID 19 were mapped. We also participated in the international consortium GenOMICC (Genetics of Mortality in Critical Care) study, comparing genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms (Nature, July 2022). This work provided support of causal roles for myeloid cell adhesion molecules and the coagulation factors, all potentially novel therapeutic targets. In Central Norway we saw through the pandemic a more limited number of intensive care COVID 19 patients than anticipated. We included 180 adult patients in the study from March 2020-March 2022. As the initiatives mentioned only selected some of our participants for genetic analyses, we have in 2023 extracted DNA from all participants and are setting up a comparison of genetic risk factors comparing to healthy controls in the HUNT study. This will be published in 2024 along with detailed characteristics of the adult patients. Briefly, the adult CUT COVID population had mean age of 61.5 years (22-93 years), 75% of them reported comorbidities. The most prevalent comorbidities were: type 2 diabetes (20%), cardiac diseases (23%), hypertension (32%), chronic lung disease (18%). 11% had cancer (4% hematologic cancers and 7 % solid cancers). 32% had a history of any serious medical condition in the past (including 6.5% myocardial infarction, 8.4% cancer and 4.5% stroke). Only one pregnant woman was included. The mean duration of hospitalization was 10.4 days. In total, 30 required admission to the intensive care unit (ICU) and 7 patients died during their hospitalization (4.6 %). Among the 30 admitted to ICU, 17 patients required non-invasive ventilation (NIV) and 13 required intubation, with 7 given both NIV and ventilator support during their admission to ICU. Children: We have established a clinical database (1500 patients 0-18 years of age) with biobank (300 patients) in children hospitalized with viral respiratory tract infections were COVID 19 will be compared to other more well-known viruses such as influenza, RSV and MPV. According to the consent given by the participants, long-term chronic disease and infection risk will be followed by using the Norwegian population-based registries like NPR and KUHR. Clinical follow-up with emphasis on lung function and fatigue of COVID 19 affected children is planned and ethically approved.

. The CUT-Covid cohort was included in the global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity, the COVID-19 Host Genetics Initiative. After the second update in the consortia In the second up-date; we performed a meta-analysis of up to 219,692 cases and over 3?million controls, identifying in total 51 distinct genome-wide significant loci. The large number of candidate genes at the identified loci helped us to map three major biological pathways that are involved in susceptibility and severity of Covid-19. We also participated in the international consortium GenOMICC (Genetics of Mortality in Critical Care) study, studying genomes from individuals who are critically ill with those of population controls we were able to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. All these findings are being further investigated around the globe for discovering preventable and therapeutic measures. These papers are in total referred nearly 400 times (see Google Scholar). A very comprehensive biobank for 187 patients and GWAS results are now available for collaborative and own research, and follow-up is linked to national registries and the HUNT population. The CUT COVID -19 study has several societal impacts: The clinical burden of COVID-19 and therefore the data on adults in our region were lower than we anticipated. Many countries and centers could early demonstrate clinical patterns and risk factors in larger cohorts. We can on behalf of people and society in our region see from the data we have collected that patterns were similar as comparable settings and treatments and outcomes are also in line other Norwegian data and comparable High Income countries. The possibility to link clinical and biological specimens to long-term outcomes has potential for important societal impacts, especially considering the emphasis on pediatric cases were long-term consequences may be yet to be apparent. Pandemic preparedness: The very rapid study organization that covered an entire Norwegian hospital region, including 7 hospital sites and 3 different hospital organization. Lessons were learned in terms of organizational structures on all levels, from hospital directors through different research departments with biobank setup and clinical departments. A clinical research set-up was set up throughout these settings and built on existing and new structures. The rapid collaboration though national and international consortia was fundamental for pandemic related scientific impact. To have existing infrastructures like biobank facilities and clinical research units in all hospitals is very important to enable us to handle the next pandemic of unknown etiology!

The Covid-19 pandemic is caused by the virus named SARS-CoV2, a corona virus closely related to SARS. The spectrum of disease severity of Covid-19 is wide, ranging from mild symptoms in 80% of the cases, to severe illness with hospitalization in 15% of the cases. The final 5% need intensive care, typically including help to breathe. There is currently no vaccine and no treatment targeting SARS-CoV2. Treatment mainly consist of helping the patient coping with the infection and the immune response. There are important knowledge gaps in our understanding of SARS-CoV2 pathogenesis. The majority of patients that need intensive care are older or have underlying diseases. However, we do not know why some people are at higher risk of Covid-19 infection, serious complications or death. Furthermore, the host and pathogen factors that determines the severity and outcome of the infection are not understood for SARS-CoV2. With this project, we aim to adress these questions. We will establish a database consisting of all hospitalized Covid-19 patients in all ages in Mid-Norway. Furthermore, we will establish a biobank including all these patients. These efforts will make it possible to discover genetic, modifiable, microbiological, clinical and phenotypical factors that can predict disease severity and poor outcome. By including children and adults in the same clinical database and biobank, we will be able to address why children seem to be protected from developing severe disease compared to adults. Many patients will have participated in the population based HUNT and Trøndelagsundersøkelsen (>180 000) from 1984-2019, adding significant value to the proposed study. We expect this research project to result in new knowledge of Covid-19 disease that will aid clinicians in determining risk of disease and poor outcome for individual patients. Furthermore, we expect our results to be relevant in the short term (months) treatment of Covid-19 patients in Norway and globally.