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  • 1.
    Bosson, Jenny. A.
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Pourazar, Jamshid
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Sandström, Thomas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Connolly-Andersen, Anne-Marie
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Rankin, Gregory
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Langrish, J. P.
    Increased Soluble Thrombomodulin In Plasma Following Diesel Exhaust Exposure2015In: American Journal of Respiratory and Critical Care Medicine, ISSN 1073-449X, E-ISSN 1535-4970, Vol. 191, article id A3210Article in journal (Other academic)
  • 2.
    Connolly-Andersen, Anne-Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Sorkfeber ökar risken för stroke och hjärtinfarkt2014In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 111, no 6Article in journal (Other academic)
  • 3.
    Connolly-Andersen, Anne-Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Hammargren, Edvin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Whitaker, Heather
    Eliasson, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Holmgren, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Klingstrom, Jonas
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Increased Risk of Acute Myocardial Infarction and Stroke During Hemorrhagic Fever With Renal Syndrome A Self-Controlled Case Series Study2014In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 129, no 12, p. 1295-1302Article in journal (Refereed)
    Abstract [en]

    Background We recently observed that cardiovascular causes of death are common in patients with hemorrhagic fever with renal syndrome (HFRS), which is caused by hantaviruses. However, it is not known whether HFRS is a risk factor for the acute cardiovascular events of acute myocardial infarction (AMI) and stroke. Methods and Results Personal identification numbers from the Swedish HFRS patient database (1997-2012; n=6643) were cross-linked with the National Patient Register from 1987 to 2011. Using the self-controlled case series method, we calculated the incidence rate ratio of AMI/stroke in the 21 days after HFRS against 2 different control periods either excluding (analysis 1) or including (analysis 2) fatal AMI/stroke events. The incidence rate ratios for analyses 1 and 2 for all AMI events were 5.53 (95% confidence interval [CI], 2.6-11.8) and 6.02 (95% CI, 2.95-12.3) and for first AMI events were 3.53 (95% CI, 1.25-9.96) and 4.64 (95% CI, 1.83-11.77). The incidence rate ratios for analyses 1 and 2 for all stroke events were 12.93 (95% CI, 5.62-29.74) and 15.16 (95% CI, 7.21-31.87) and for first stroke events were 14.54 (95% CI, 5.87-36.04) and 17.09 (95% CI, 7.49-38.96). The majority of stroke events occurred in the first week after HFRS. Seasonal effects were not observed, and apart from 1 study, neither sex nor age interacted with the associations observed in this study. Conclusions There is a significantly increased risk for AMI and stroke in the immediate time period after HFRS. Therefore, HFRS patients should be carefully monitored during the acute phase of disease to ensure early recognition of symptoms of impending AMI or stroke.

  • 4.
    Connolly-Andersen, Anne-Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Rasmuson, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Öman, Mikael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Mesenteric Vein Thrombosis Following Platelet Transfusion in a Patient with Hemorrhagic Fever with Renal Syndrome: A Case Report2018In: TH open : companion journal to thrombosis and haemostasis, ISSN 2567-3459, Vol. 2, no 3, p. e261-e264Article in journal (Refereed)
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  • 5.
    Connolly-Andersen, Anne-Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Sundberg, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Baudin, Maria
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Larsson, Johanna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Dunne, Eimear
    Clinical Research Centre, Royal College of Surgeons in Ireland, Dublin .
    Kenny, Dermot
    Clinical Research Centre, Royal College of Surgeons in Ireland, Dublin .
    Lindahl, Tomas L.
    Department of Clinical and Experimental Medicine, Linköping University, Sweden.
    Ramström, Sofia
    Department of Clinical and Experimental Medicine, Linköping University, Sweden.
    Nilsson, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Increased Thrombopoiesis and Platelet Activation in Hantavirus-Infected Patients2015In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 212, no 7, p. 1061-1069Article in journal (Refereed)
    Abstract [en]

    Background. Thrombocytopenia is a common finding during viral hemorrhagic fever, which includes hemorrhagic fever with renal syndrome (HFRS). The 2 main causes for thrombocytopenia are impaired thrombopoiesis and/or increased peripheral destruction of platelets. In addition, there is an increased intravascular coagulation risk during HFRS, which could be due to platelet activation. Methods. Thrombopoiesis was determined by quantification of platelet counts, thrombopoietin, immature platelet fraction, and mean platelet volume during HFRS. The in vivo platelet activation was determined by quantification of soluble P-selectin (sP-selectin) and glycoprotein VI (sGPVI). The function of circulating platelets was determined by ex vivo stimulation followed by flow cytometry analysis of platelet surface-bound fibrinogen and P-selectin exposure. Intravascular coagulation during disease was determined by scoring for disseminated intravascular coagulation (DIC) and recording thromboembolic complications. Results. The levels of thrombopoietin, immature platelet fraction, and mean platelet volume all indicate increased thrombopoiesis during HFRS. Circulating platelets had reduced ex vivo function during disease compared to follow-up. Most interestingly, we observed significantly increased in vivo platelet activation in HFRS patients with intravascular coagulation (DIC and thromboembolic complications) as shown by sP-selectin and sGPVI levels. Conclusions. HFRS patients have increased thrombopoiesis and platelet activation, which contributes to intravascular coagulation.

  • 6.
    Connolly-Andersen, Anne-Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Thunberg, Therese
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Endothelial activation and repair during hantavirus infection: association with disease outcome2014In: Open forum infectious diseases, ISSN 2328-8957, Vol. 1, no 1, article id ofu027Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Endothelial activation and dysfunction play a central role in the pathogenesis of sepsis and viral hemorrhagic fevers. Hantaviral disease is a viral hemorrhagic fever and is characterized by capillary dysfunction, although the underlying mechanisms for hantaviral disease are not fully elucidated.

    METHODS: The temporal course of endothelial activation and repair were analyzed during Puumala hantavirus infection and associated with disease outcome and a marker for hypoxia, insulin-like growth factor binding protein 1 (IGFBP-1). The following endothelial activation markers were studied: endothelial glycocalyx degradation (syndecan-1) and leukocyte adhesion molecules (soluble vascular cellular adhesion molecule 1, intercellular adhesion molecule 1, and endothelial selectin). Cytokines associated with vascular repair were also analyzed (vascular endothelial growth factor, erythropoietin, angiopoietin, and stromal cell-derived factor 1).

    RESULTS: Most of the markers we studied were highest during the earliest phase of hantaviral disease and associated with clinical and laboratory surrogate markers for disease outcome. In particular, the marker for glycocalyx degradation, syndecan-1, was significantly associated with levels of thrombocytes, albumin, IGFBP-1, decreased blood pressure, and disease severity.

    CONCLUSIONS: Hantaviral disease outcome was associated with endothelial dysfunction. Consequently, the endothelium warrants further investigation when designing future medical interventions.

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  • 7.
    Connolly-Andersen, Anne-Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Whitaker, Heather
    Klingstrom, Jonas
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Risk of venous thromboembolism following hemorrhagic fever with renal syndrome: a self-controlled case series study2018In: Clinical Infectious Diseases, ISSN 1058-4838, E-ISSN 1537-6591, Vol. 66, no 2, p. 268-273Article in journal (Refereed)
    Abstract [en]

    Background: Bleeding is associated with viral hemorrhagic fevers; however, thromboembolic complications have received less attention. Hemorrhagic fever with renal syndrome (HFRS) is a mild viral hemorrhagic fever caused by Puumala hantavirus. We previously identified HFRS as a risk factor for myocardial infarction and stroke, but the risk for venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is unknown.

    Methods: Personal identity numbers from the Swedish HFRS database were cross-linked with the National Patient register to obtain information on all causes for hospitalization during 1964 to 2013. The self-controlled case series method was used to calculate the incidence rate ratio (IRR) for first VTE, DVT, and PE during 1998 to 2013.

    Results: From 7244 HFRS patients, there were 146 with a first VTE of which 74 were DVT and 78 were PE, and 6 patients had both DVT and PE. The overall risk for a VTE was significantly higher during the first 2 weeks following HFRS onset, with an IRR of 64.3 (95% confidence interval [CI], 36.3-114). The corresponding risk for a DVT was 45.9 (95% CI, 18-117.1) and for PE, 76.8 (95% CI, 37.1-159). Sex interacted significantly with the association between HFRS and VTE, with females having a higher risk compared with males.

    Conclusions: A significantly increased risk for VTE was found in the time period following HFRS onset. It is important to keep this in mind and monitor HFRS patients, and possibly other viral hemorrhagic fever patients, for early symptoms of VTE.

  • 8.
    Connolly-Andersson, Anne-Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Ahlm, Kristin
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Forensic Medicine.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Klingström, Jonas
    Puumala virus infections associated with cardiovascular causes of death2013In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 19, no 1, p. 126-128Article in journal (Refereed)
    Abstract [en]

    We studied the causes of death of patients in Sweden with diagnoses of hemorrhagic fever with renal syndrome (HFRS) during 1997–2009. Cardiovascular disorders were a common cause of death during acute-phase HFRS and were the cause of death for >50% of those who died during the first year after HFRS.

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  • 9.
    Fonseca-Rodríguez, Osvaldo
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Connolly-Andersen, Anne-Marie
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Katsoularis, Ioannis
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Lindmark, Krister
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Farrington, Paddy
    School of Mathematics and Statistics, The Open University, Milton Keynes, United Kingdom.
    Avoiding bias in self-controlled case series studies of coronavirus disease 20192021In: Statistics in Medicine, ISSN 0277-6715, E-ISSN 1097-0258, Vol. 40, no 27, p. 6197-6208Article in journal (Refereed)
    Abstract [en]

    Many studies, including self-controlled case series (SCCS) studies, are being undertaken to quantify the risks of complications following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19). One such SCCS study, based on all COVID-19 cases arising in Sweden over an 8-month period, has shown that SARS-CoV-2 infection increases the risks of AMI and ischemic stroke. Some features of SARS-CoV-2 infection and COVID-19, present in this study and likely in others, complicate the analysis and may introduce bias. In the present paper we describe these features, and explore the biases they may generate. Motivated by data-based simulations, we propose methods to reduce or remove these biases.

  • 10.
    Fonseca-Rodríguez, Osvaldo
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Gustafsson, Per E
    Umeå University, Faculty of Medicine, Department of Epidemiology and Global Health.
    San Sebastian, Miguel
    Umeå University, Faculty of Medicine, Department of Epidemiology and Global Health.
    Connolly-Andersen, Anne-Marie
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Spatial clustering and contextual factors associated with hospitalisation and deaths due to COVID-19 in Sweden: A geospatial nationwide ecological study2021In: BMJ Global Health, E-ISSN 2059-7908, Vol. 6, no 7, article id e006247Article in journal (Refereed)
    Abstract [en]

    Introduction: In Sweden, thousands of hospitalisations and deaths due to COVID-19 were reported since the pandemic started. Considering the uneven spatial distribution of those severe outcomes at the municipality level, the objective of this study was, first, to identify high-risk areas for COVID-19 hospitalisations and deaths, and second, to determine the associated contextual factors with the uneven spatial distribution of both study outcomes in Sweden.

    Methods: The existences of spatial autocorrelation of the standardised incidence (hospitalisations) ratio and standardised mortality ratio were investigated using Global Moran's I test. Furthermore, we applied the retrospective Poisson spatial scan statistics to identify high-risk spatial clusters. The association between the contextual demographic and socioeconomic factors and the number of hospitalisations and deaths was estimated using a quasi-Poisson generalised additive regression model.

    Results: Ten high-risk spatial clusters of hospitalisations and six high-risk clusters of mortality were identified in Sweden from February 2020 to October 2020. The hospitalisations and deaths were associated with three contextual variables in a multivariate model: population density (inhabitants/km 2) and the proportion of immigrants (%) showed a positive association with both outcomes, while the proportion of the population aged 65+ years (%) showed a negative association.

    Conclusions: Our study identified high-risk spatial clusters for hospitalisations and deaths due to COVID-19 and the association of population density, the proportion of immigrants and the proportion of people aged 65+ years with those severe outcomes. Results indicate where public health measures must be reinforced to improve sustained and future disease control and optimise the distribution of resources.

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  • 11.
    Gustafsson, Per E
    et al.
    Umeå University, Faculty of Medicine, Department of Epidemiology and Global Health.
    San Sebastian, Miguel
    Umeå University, Faculty of Medicine, Department of Epidemiology and Global Health.
    Fonseca Rodriguez, Osvaldo
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Connolly-Andersen, Anne-Marie
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Inequitable impact of infection: social gradients in severe COVID-19 outcomes among all confirmed SARS-CoV-2 cases during the first pandemic wave in Sweden.2022In: Journal of Epidemiology and Community Health, ISSN 0143-005X, E-ISSN 1470-2738, Vol. 76, no 3, p. 261-267Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The backdrop of the ubiquitous social inequalities has increasingly come into foreground in research on the COVID-19 pandemic, but the lack of high-quality population-based studies limits our understanding of the inequitable outcomes of the disease. The present study seeks to estimate social gradients in COVID-19 hospitalisations, intensive care admissions and death by education, income and country of birth, while taking into account disparities in comorbidities.

    METHODS: We used a register-based retrospective open cohort design enrolling all 74 659 confirmed SARS-CoV-2-positive cases aged >25 years in Sweden during the first wave of the pandemic (until 14 September 2020). Information was retrieved from multiple registers and linked by the unique Swedish personal identity number concerning COVID-19 case identification; COVID-19 hospitalisations, intensive care admissions and death; comorbidities as measured by the Charlson Comorbidity Index; and sociodemographic information. Social gradients were estimated by the Relative Index of Inequality (RII) using Cox regression.

    RESULTS: Adjusted analyses showed significant social gradients in COVID-19 hospitalisation, intensive care admission, across education, income and country of birth, which were unaffected by adjustment for comorbidities. Education and country of birth gradients were stronger for hospitalisation and intensive care admissions but small to non-existent for death. In contrast, income gradients were consistent across all three COVID-19 outcomes.

    CONCLUSION: Social gradients in severe COVID-19 outcomes are widespread in Sweden, but appear to be unrelated to pre-existing health disparities. Inequitable outcomes of SARS-CoV-2 infection may therefore be at least partially avoidable and could rely on equitable management of confirmed COVID-19 cases.

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  • 12. Hansson, Magnus
    et al.
    Gustafsson, Rasmus
    Jacquet, Chloé
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Chebaane, Nedia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Satchell, Simon
    Thunberg, Therese
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Fors Connolly, Anne-Marie
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Cystatin C and α-1-Microglobulin Predict Severe Acute Kidney Injury in Patients with Hemorrhagic Fever with Renal Syndrome2020In: Pathogens, E-ISSN 2076-0817, Vol. 9, no 8, article id 666Article in journal (Refereed)
    Abstract [en]

    Puumala orthohantavirus causes hemorrhagic fever with renal syndrome (HFRS) characterized by acute kidney injury (AKI), an abrupt decrease in renal function. Creatinine is routinely used to detect and quantify AKI; however, early AKI may not be reflected in increased creatinine levels. Therefore, kidney injury markers that can predict AKI are needed. The potential of the kidney injury markers urea, cystatin C, α1-microglobulin (A1M) and neutrophil gelatinase-associated lipocalin (NGAL) to detect early AKI during HFRS was studied by quantifying the levels of these markers in consecutively obtained plasma (P) and urine samples (U) for 44 HFRS patients. P-cystatin C and U-A1M levels were significantly increased during early HFRS compared to follow-up. In a receiver operating characteristic (ROC) curve analysis, P-cystatin C, U-A1M and P-urea predicted severe AKI with area under the curve 0.72, 0.73 and 0.71, respectively, whereas the traditional kidney injury biomarkers creatinine and U-albumin did not predict AKI. Nearly half of the HFRS patients (41%) fulfilled the criteria for shrunken pore syndrome, which was associated with the level of inflammation as measured by P-CRP. P-cystatin C and U-A1M are more sensitive and earlier markers compared to creatinine in predicting kidney injury during HFRS.

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  • 13.
    Jerndal, Hanna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Stegmayr, Bernd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Normark, J.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Norrland's University Hospital- Västerbotten County Council, Infectious Disease Clinic, Umeå, Sweden.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Norrland's University Hospital- Västerbotten County Council, Infectious Disease Clinic, Umeå, Sweden.
    Fors Connolly, Anne-Marie
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    WCN23-0624 acute kidney injury and covid-192023In: Kidney International Reports, Supplements, ISSN 2468-0249, Vol. 8, no 3, p. S438-S438, article id WCN23-0624Article in journal (Refereed)
    Abstract [en]

    Introduction: COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This emerging disease has become a public health emergency worldwide.

    Acute Kidney Injury (AKI) secondary to COVID-19 has been described in different studies, but information characterising patients with subsequent AKI is limited. The cause of kidney involvement in COVID-19 is thought to be multifactorial. Cardiovascular comorbidity and predisposing factors (e.g. sepsis and nephrotoxins) are considered as important contributors. The tubular damage has been linked to the cytopathic effects of kidney-resident cells and cytokine storm syndrome. To gain better understanding of the effect of COVID-19 on renal function, large clinical and register based studies have been requested.

    The objective of this study was to quantify the risk of acute kidney injury during and after covid-19.

    Methods: This was a Swedish prospective cohort study where Generalised Estimating Equation methods (GEE) was used to map the kinetics of kidney injury markers such as serum-creatinine (s-creatinine), cystatin and eGFR for the hospitalised patients in the cohort, comparing patients with moderate and severe COVID-19 during and after the acute infection. Furthermore, we will investigate if patients with kidney dysfunction during COVID-19 have more severe disease outcome compared with the whole cohort, adjusting for age, sex, and comorbidities. We will also compare start values of kidney injury markers with the latest values and count the percentage worsening among all disease severity groups.

    Cohort: Approximately 550 COVID-19 patients were recruited to the study following informed and signed consent at 2 Swedish University Hospitals. A case report form was filled in at pre-specified time points, and samples collected consecutively. A database was then created containing dates and information regarding symptoms, laboratory samples, complications, and disease severity (e.g., need of oxygen, intensive care, mechanical ventilation, death).

    Results: There was a significant increase in s-creatinine among hospitalised and intensive care unit patients (n=126) during the acute phase of COVID-19 (day 0-6 post disease onset) when compared to the follow up samples after 90 days from disease onset. There was also a decrease in s-creatinine in day 11-21 and 31-70 among hospitalised and intensive care unit COVID-19 patients when compared to the same follow up samples. This analysis was adjusted for age and sex. See figure 1.

    Conclusions: Our preliminary results show that s-creatinine was increased during the first days of COVID-19 followed by decreased levels compared to baseline.

    The higher levels of s-creatinine day 0-6 of COVID-19 could be an effect of the acute infection, but it could also be caused by other factors such as dehydration or medication. The lower levels of s-creatinine might be caused by dietary changes or loss of muscle mass due to immobilisation during hospitalisation. Knowledge about fluctuations in s-creatinine in COVID-19 patients may be of use for treating physicians.

  • 14.
    Katsoularis, Ioannis
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Fonseca Rodriguez, Osvaldo
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Farrington, Paddy
    School of Mathematics and Statistics, The Open University, Milton Keynes, United Kingdom.
    Lindmark, Krister
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Connolly-Andersen, Anne-Marie
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    COVID-19 and myocardial infarction – Authors' reply2021In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 398, no 10315, p. 1964-1964Article in journal (Other academic)
  • 15.
    Katsoularis, Ioannis
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Fonseca Rodriguez, Osvaldo
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Jerndal, Hanna
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Kalucza, Sebastian
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Lindmark, Krister
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Fors Connolly, Anne-Marie
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Risk of atrial tachycardias after covid-19: nationwide self-controlled cases series and matched cohort study2023In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 44, no Suppl. 2, article id ehad655.449Article in journal (Refereed)
    Abstract [en]

    Background: COVID-19 is a multiorgan disease. We previously identified COVID-19 as a risk factor for myocardial infarction, stroke (1), venous thromboembolism and bleeding (2). Less evidence exists on the risk of arrhythmias after COVID-19. Previous studies included mainly hospitalized patients with severe COVID-19, and there are no nationwide studies published.

    Purpose: The aim of this study was to estimate the risk of atrial tachycardias (atrial fibrillation and atrial flutter) following COVID-19, including all individuals tested positive for SARS-CoV-2 in Sweden, regardless of disease severity.

    Method: COVID-19 has been a notifiable disease in Sweden. All individuals in Sweden who were tested positive for SARS-CoV-2 between February 1, 2020 and May 25, 2021 were included in the study. We identified four control individuals for each COVID-19 individual matched on age, sex, and county of residence. Using Personal Identification Numbers, we cross-linked data from national registries: COVID-19 registry; Inpatient and Outpatient Registry; Cause of Death Registry; Prescribed Pharmaceutical Registry and Intensive Care Registry. Outcomes are cardiovascular events, defined using ICD-10 diagnosis codes for atrial fibrillation and atrial flutter in the registries. We performed a ‘’first-ever event’’ analysis, i.e., we excluded individuals with events before the study period. The self-controlled case series (SCCS) method was used to determine the incidence rate ratio (IRR) of a first atrial tachycardia during the risk periods 1-7, 8-14, 15-30, 31-60, 61-90, and 91-180 days after COVID-19. In the matched cohort study (MCS), Poisson regression was performed to calculate the risk ratio (RR) of a first arrhythmia event in the risk period 1-30 days following COVID-19, after adjusting for the effect of confounders, such as cardiac disease, treatment with antiarrhythmics, comorbidities and vaccination status.

    Results: 1 057 174 cases and 4 074 844 controls were included in the study. In the SCCS, the risk of first atrial tachycardia was significantly increased up to 60 days following COVID-19. Specifically, during days 1-7 and 8-14 post-COVID-19 the IRRs were approximately 12 and 10 respectively. Similarly, in the MCS the RR for the first atrial tachycardia during day 1-30 post-COVID-19 was approximately 11. The risks were higher in patients with more severe COVID-19; and during the first pandemic wave compared to the second and third wave.

    Conclusions: This study suggests that COVID-19 is a risk factor for atrial tachycardias, based on information obtained on all people who tested positive for SARS-CoV-2 in Sweden, regardless of disease severity. These results could impact recommendations on diagnostic and prophylactic strategies against atrial tachycardias after COVID-19. The importance of preventive strategies, such as risk factor control; vaccination to prevent severe COVID-19; and early review of high-risk individuals after COVID-19, is indicated.

  • 16.
    Katsoularis, Ioannis
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Fonseca-Rodríguez, Osvaldo
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Farrington, Paddy
    School of Mathematics and Statistics, The Open University, Milton Keynes, UK.
    Jerndal, Hanna
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Häggström Lundevaller, Erling
    Umeå School of Business, Economics and Statistics, Umeå University, Umeå, Sweden.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
    Lindmark, Krister
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Fors Connolly, Anne-Marie
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Risks of deep vein thrombosis, pulmonary embolism, and bleeding after covid-19: nationwide self-controlled cases series and matched cohort study2022In: The BMJ, E-ISSN 1756-1833, Vol. 377, article id e069590Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To quantify the risk of deep vein thrombosis, pulmonary embolism, and bleeding after covid-19.

    DESIGN: Self-controlled case series and matched cohort study.

    SETTING: National registries in Sweden.

    PARTICIPANTS: 1 057 174 people who tested positive for SARS-CoV-2 between 1 February 2020 and 25 May 2021 in Sweden, matched on age, sex, and county of residence to 4 076 342 control participants.

    MAIN OUTCOMES MEASURES: Self-controlled case series and conditional Poisson regression were used to determine the incidence rate ratio and risk ratio with corresponding 95% confidence intervals for a first deep vein thrombosis, pulmonary embolism, or bleeding event. In the self-controlled case series, the incidence rate ratios for first time outcomes after covid-19 were determined using set time intervals and the spline model. The risk ratios for first time and all events were determined during days 1-30 after covid-19 or index date using the matched cohort study, and adjusting for potential confounders (comorbidities, cancer, surgery, long term anticoagulation treatment, previous venous thromboembolism, or previous bleeding event).

    RESULTS: Compared with the control period, incidence rate ratios were significantly increased 70 days after covid-19 for deep vein thrombosis, 110 days for pulmonary embolism, and 60 days for bleeding. In particular, incidence rate ratios for a first pulmonary embolism were 36.17 (95% confidence interval 31.55 to 41.47) during the first week after covid-19 and 46.40 (40.61 to 53.02) during the second week. Incidence rate ratios during days 1-30 after covid-19 were 5.90 (5.12 to 6.80) for deep vein thrombosis, 31.59 (27.99 to 35.63) for pulmonary embolism, and 2.48 (2.30 to 2.68) for bleeding. Similarly, the risk ratios during days 1-30 after covid-19 were 4.98 (4.96 to 5.01) for deep vein thrombosis, 33.05 (32.8 to 33.3) for pulmonary embolism, and 1.88 (1.71 to 2.07) for bleeding, after adjusting for the effect of potential confounders. The rate ratios were highest in patients with critical covid-19 and highest during the first pandemic wave in Sweden compared with the second and third waves. In the same period, the absolute risk among patients with covid-19 was 0.039% (401 events) for deep vein thrombosis, 0.17% (1761 events) for pulmonary embolism, and 0.101% (1002 events) for bleeding.

    CONCLUSIONS: The findings of this study suggest that covid-19 is a risk factor for deep vein thrombosis, pulmonary embolism, and bleeding. These results could impact recommendations on diagnostic and prophylactic strategies against venous thromboembolism after covid-19.

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  • 17.
    Katsoularis, Ioannis
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Fonseca-Rodríguez, Osvaldo
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Farrington, Paddy
    Lindmark, Krister
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Connolly-Andersen, Anne-Marie
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Risk of acute myocardial infarction and ischaemic stroke following COVID-19 in Sweden: a self-controlled case series and matched cohort study2021In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 398, no 10300, p. 599-607Article in journal (Refereed)
    Abstract [en]

    Background: COVID-19 is a complex disease targeting many organs. Previous studies highlight COVID-19 as a probable risk factor for acute cardiovascular complications. We aimed to quantify the risk of acute myocardial infarction and ischaemic stroke associated with COVID-19 by analysing all COVID-19 cases in Sweden.

    Methods: This self-controlled case series (SCCS) and matched cohort study was done in Sweden. The personal identification numbers of all patients with COVID-19 in Sweden from Feb 1 to Sept 14, 2020, were identified and cross-linked with national inpatient, outpatient, cancer, and cause of death registers. The controls were matched on age, sex, and county of residence in Sweden. International Classification of Diseases codes for acute myocardial infarction or ischaemic stroke were identified in causes of hospital admission for all patients with COVID-19 in the SCCS and all patients with COVID-19 and the matched control individuals in the matched cohort study. The SCCS method was used to calculate the incidence rate ratio (IRR) for first acute myocardial infarction or ischaemic stroke following COVID-19 compared with a control period. The matched cohort study was used to determine the increased risk that COVID-19 confers compared with the background population of increased acute myocardial infarction or ischaemic stroke in the first 2 weeks following COVID-19.

    Findings: 86 742 patients with COVID-19 were included in the SCCS study, and 348 481 matched control individuals were also included in the matched cohort study. When day of exposure was excluded from the risk period in the SCCS, the IRR for acute myocardial infarction was 2·89 (95% CI 1·51–5·55) for the first week, 2·53 (1·29–4·94) for the second week, and 1·60 (0·84–3·04) in weeks 3 and 4 following COVID-19. When day of exposure was included in the risk period, IRR was 8·44 (5·45–13·08) for the first week, 2·56 (1·31–5·01) for the second week, and 1·62 (0·85–3·09) for weeks 3 and 4 following COVID-19. The corresponding IRRs for ischaemic stroke when day of exposure was excluded from the risk period were 2·97 (1·71–5·15) in the first week, 2·80 (1·60–4·88) in the second week, and 2·10 (1·33–3·32) in weeks 3 and 4 following COVID-19; when day of exposure was included in the risk period, the IRRs were 6·18 (4·06–9·42) for the first week, 2·85 (1·64–4·97) for the second week, and 2·14 (1·36–3·38) for weeks 3 and 4 following COVID-19. In the matched cohort analysis excluding day 0, the odds ratio (OR) for acute myocardial infarction was 3·41 (1·58–7·36) and for stroke was 3·63 (1·69–7·80) in the 2 weeks following COVID-19. When day 0 was included in the matched cohort study, the OR for acute myocardial infarction was 6·61 (3·56–12·20) and for ischaemic stroke was 6·74 (3·71–12·20) in the 2 weeks following COVID-19.

    Interpretation: Our findings suggest that COVID-19 is a risk factor for acute myocardial infarction and ischaemic stroke. This indicates that acute myocardial infarction and ischaemic stroke represent a part of the clinical picture of COVID-19, and highlights the need for vaccination against COVID-19. 

  • 18.
    Katsoularis, Ioannis
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Jerndal, Hanna
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Kalucza, Sebastian
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Lindmark, Krister
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Department of Clinical Sciences, Karolinska Institutet, Stockholm, Sweden.
    Fonseca Rodriguez, Osvaldo
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Fors Connolly, Anne-Marie
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Risk of arrhythmias following COVID-19: nationwide self-controlled case series and matched cohort study2023In: European Heart Journal Open, E-ISSN 2752-4191, Vol. 3, no 6, article id oead120Article in journal (Refereed)
    Abstract [en]

    Aims: COVID-19 increases the risk of cardiovascular disease, especially thrombotic complications. There is less knowledge on the risk of arrhythmias after COVID-19. In this study, we aimed to quantify the risk of arrhythmias following COVID-19.

    Methods and Results: This study was based on national register data on all individuals in Sweden who tested positive for SARS-CoV-2 between 1 February 2020 and 25 May 2021. The outcome was incident cardiac arrhythmias, defined as international classification of diseases (10th revision) codes in the registers as follows: atrial arrhythmias; paroxysmal supraventricular tachycardias; bradyarrhythmias; and ventricular arrhythmias. A self-controlled case series study and a matched cohort study, using conditional Poisson regression, were performed to determine the incidence rate ratio and risk ratio, respectively, for an arrhythmia event following COVID-19.A total of 1 057 174 exposed (COVID-19) individuals were included in the study as well as 4 074 844 matched unexposed individuals. The incidence rate ratio of atrial tachycardias, paroxysmal supraventricular tachycardias, and bradyarrhythmias was significantly increased up to 60, 180, and 14 days after COVID-19, respectively. In the matched cohort study, the risk ratio during Days 1–30 following COVID-19/index date was 12.28 (10.79–13.96), 5.26 (3.74–7.42), and 3.36 (2.42–4.68), respectively, for the three outcomes. The risks were generally higher in older individuals, in unvaccinated individuals, and in individuals with more severe COVID-19. The risk of ventricular arrhythmias was not increased.

    1 057 174 exposed (COVID-19) individuals were included in the study as well as 4 074 844 matched unexposed individuals. The incidence rate ratio of atrial tachycardias, paroxysmal supraventricular tachycardias and bradyarrhythmias was significantly increased up to 60, 180 and 14 days after COVID-19, respectively. In the matched cohort study, the risk ratio during day 1-30 following COVID-19/index date was 12.28 (10.79-13.96), 5.26 (3.74-7.42) and 3.36 (2.42-4.68), respectively for the three outcomes. The risks were generally higher in older individuals, unvaccinated individuals and in individuals with more severe COVID-19. The risk of ventricular arrhythmias was not increased.

    Conclusion: There is an increased risk of cardiac arrhythmias following COVID-19, and particularly increased in elderly vulnerable individuals, as well as in individuals with severe COVID-19.

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  • 19.
    Katsoularis, Ioannis
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Jerndal, Hanna
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Kalucza, Sebastian
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Lindmark, Krister
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Fonseca Rodriguez, Osvaldo
    Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR). Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Department of Epidemiology and Global Health.
    Fors Connolly, Anne-Marie
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Risks of arrhythmias after covid-19: nationwide self-controlled cases series and matched cohort studyManuscript (preprint) (Other academic)
  • 20.
    Ollila, Hanna M
    et al.
    Institute for Molecular Medicine, FIMM, University of Helsinki, Helsinki, Finland; Massachusetts General Hospital Center for Genomic Medicine, Boston, Massachusetts, USA; Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA; Broad Institute, Cambridge, Massachusetts, USA.
    Fonseca Rodriguez, Osvaldo
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Caspersen, Ida Henriette
    Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway.
    Kalucza, Sebastian
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Normark, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Trogstad, Lill
    Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway.
    Magnus, Per Minor
    Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway.
    Rod, Naja Hulvej
    Department of Public Health, University of Copenhagen, Copenhagen, Denmark.
    Ganna, Andrea
    Institute for Molecular Medicine, FIMM, University of Helsinki, Helsinki, Finland; Broad Institute, Cambridge, Massachusetts, USA.
    Eriksson, Marie
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Fors Connolly, Anne-Marie
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    How do clinicians use post-COVID syndrome diagnosis? Analysis of clinical features in a Swedish COVID-19 cohort with 18 months’ follow-up: a national observational cohort and matched cohort study2024In: BMJ Public Health, E-ISSN 2753-4294, Vol. 2, no 1, article id e000336Article in journal (Refereed)
    Abstract [en]

    Introduction: SARS-CoV-2 infection causes acute COVID-19 and may result in post-COVID syndrome (PCS). We aimed to investigate how clinicians diagnose PCS and identify associated clinical and demographic characteristics.

    Methods: We analysed multiregistry data of all SARS-CoV-2 test-positive individuals in Sweden (n=1 057 174) between 1 February 2020 and 25 May 2021. We described clinical characteristics that prompt PCS diagnosis in outpatient and inpatient settings. In total, there were 6389 individuals with a hospital inpatient or outpatient diagnosis for PCS. To understand symptomatology, we examined individuals diagnosed with PCS at least 3 months after COVID-19 onset (n=6389) and assessed factors associated with PCS diagnosis.

    Results: Mechanical ventilation correlated with PCS (OR 114.7, 95% CI 105.1 to 125.3) compared with no outpatient/inpatient contact during initial COVID-19. Dyspnoea (13.4%), malaise/fatigue (8%) and abnormal pulmonary diagnostic imaging findings (4.3%) were the most common features linked to PCS. We compared clinical features of PCS with matched controls (COVID-19 negative, n=23 795) and COVID-19 severity-matched patients (COVID-19 positive, n=25 556). Hypertension associated with PCS cohort (26.61%) than in COVID-19-negative (OR 17.16, 95% CI 15.23 to 19.3) and COVID-19-positive (OR 9.25, 95% CI 8.41 to 10.16) controls, although most individuals received this diagnosis before COVID-19. Dyspnoea was the second most common feature in the PCS cohort (17.2%), and new to the majority compared with COVID-19-negative (OR 54.16, 95% CI 42.86 to 68.45) and COVID-19-positive (OR 18.7, 95% CI 16.21 to 21.57) controls.

    Conclusions: Our findings highlight factors Swedish physicians associate with PCS.

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  • 21.
    Rankin, Gregory
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Byström, Julia Wigren
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Gustafsson, Rasmus
    Hansson, Magnus
    Thunberg, Therese
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Connolly, Anne-Marie Fors
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    MMP9 Associates with Endothelial Glycocalyx Degradation During Haemorrhagic Fever with Renal Syndrome2019In: Journal of Vascular Research, ISSN 1018-1172, E-ISSN 1423-0135, Vol. 56, p. 35-35Article in journal (Other academic)
    Abstract [en]

    Introduction: Haemorrhagic fever with renal syndrome (HFRS) is characterized by fever, hypotension, vascular leakage, thrombocytopenia and renal failure. HFRS in Sweden is caused by the Puumala hantavirus and is spread by viral-infested droppings from bank voles. The health care system has little to offer these patients since there is no antiviral treatment and as of yet there is no vaccine prophylaxis available. We previously showed that a marker of endothelial glycocalyx degradation (Syndecan-1) was associated with disease severity and disseminated intravascular coagulation during HFRS (Connolly-Andersen et al., 2014, Open Forum Infect Dis.).

    Methods: We analysed the levels of other endothelial glycocalyx degradation markers (heparan sulfate, soluble thrombomodulin, albumin), a potential “sheddase”: Matrix Metalloproinase 9 (MMP9) and neutrophil activation/tissue damage (neutrophil gelatinase-associated lipocalin, NGAL) in patient plasma from 44 HFRS patients collected consecutively following disease onset. We used the generalized estimating equation to analyse the association between endothelial glycocalyx degradation, MMP9 levels, neutrophil activation/tissue damage and HFRS disease outcome (need for oxygen, transfusion with blood components, need for intensive care unit (ICU) treatment and renal damage).

    Results: 44 HFRS patients were included in this study (29 females (66%)); need for oxygen: 11 (25%); transfusion with blood components: 3 (7%) and stay at ICU: 2 (5%)). The levels of MMP9 were significantly associated with all markers of endothelial glycocalyx degradation. Neutrophil activation/tissue damage (NGAL) was also significantly associated with MMP9 and endothelial glycocalyx degradation markers (apart from albumin (p = 0.053). In addition degradation of endothelial glycocalyx associated with HFRS disease outcome.

    Conclusion: Degradation of the endothelial glycocalyx could be a potential mechanism of HFRS pathogenesis, and potentially MMP9 could contribute to degradation of the endothelial glycocalyx

  • 22. Schmedes, Clare M.
    et al.
    Grover, Steven P.
    Hisada, Yohei M.
    Goeijenbier, Marco
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Nilsson, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Thunberg, Therese
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Mackman, Nigel
    Connolly-Andersen, Anne-Marie
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Circulating extracellular vesicle tissue factor activity during orthohantavirus infection is associated with intravascular coagulation2020In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 222, no 8, p. 1392-1399Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Puumala (PUUV) orthohantavirus causes hemorrhagic fever with renal syndrome (HFRS). HFRS patients have an activated coagulation system with increased risk of disseminated intravascular coagulation (DIC) and venous thromboembolism (VTE). The aim of the study was to determine if circulating extracellular vesicle tissue factor (EVTF) activity levels associates with DIC and VTE (grouped as intravascular coagulation) in HFRS patients.

    METHODS: Longitudinal samples were collected from 88 HFRS patients. Patients were stratified into groups of those with intravascular coagulation (n=27) and those who did not (n=61). We measured levels of circulating EVTF activity, fibrinogen, activated partial prothrombin time, prothrombin time international normalized ratio, D-dimer, tissue plasminogen activator (tPA), plasminogen activator inhibitor 1 (PAI-1) and platelets.

    RESULTS: Plasma EVTF activity was transiently increased during HFRS. Levels of EVTF activity significantly associated with plasma tPA and PAI-1, suggesting endothelial cells as a potential source. Patients with intravascular coagulation had significantly higher peak EVTF activity levels compared to those who did not. The peak EVTF activity value predicting intravascular coagulation was 0.51 ng/L with 63% sensitivity and 61% specificity with AUC 0.63 (95% CI 0.51 - 0.76), p-value 0.046.

    CONCLUSIONS: Increased circulating EVTF activity during HFRS is associated with intravascular coagulation.

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  • 23.
    Sund, Malin
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Department of Surgery, Univerisity of Helsinki and Helsinki University Hospital, Helsinki, Finland.
    Fonseca-Rodríguez, Osvaldo
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Urology, University of Gothenburg, Gothenburg, Sweden.
    Welen, Karin
    Department of Urology, University of Gothenburg, Gothenburg, Sweden.
    Fors Connolly, Anne-Marie
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Association between pharmaceutical modulation of oestrogen in postmenopausal women in Sweden and death due to COVID-19: a cohort study2022In: BMJ Open, E-ISSN 2044-6055, Vol. 12, no 2, article id e053032Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Determine whether augmentation of oestrogen in postmenopausal women decreases the risk of death following COVID-19.

    DESIGN: Nationwide registry-based study in Sweden based on registries from the Swedish Public Health Agency (all individuals who tested positive for SARS-CoV-2); Statistics Sweden (socioeconomical variables) and the National Board of Health and Welfare (causes of death).

    PARTICIPANTS: Postmenopausal women between 50 and 80 years of age with verified COVID-19.

    INTERVENTIONS: Pharmaceutical modulation of oestrogen as defined by (1) women with previously diagnosed breast cancer and receiving endocrine therapy (decreased systemic oestrogen levels); (2) women receiving hormone replacement therapy (increased systemic oestrogen levels) and (3) a control group not fulfilling requirements for group 1 or 2 (postmenopausal oestrogen levels). Adjustments were made for potential confounders such as age, annual disposable income (richest group as the reference category), highest level of education (primary, secondary and tertiary (reference)) and the weighted Charlson Comorbidity Index (wCCI). PRIMARY OUTCOME MEASURE: Death following COVID-19.

    RESULTS: From a nationwide cohort consisting of 49 853 women diagnosed with COVID-19 between 4 February and 14 September 2020 in Sweden, 16 693 were between 50 and 80 years of age. We included 14 685 women in the study with 11 923 (81%) in the control group, 227 (2%) women in group 1 and 2535 (17%) women in group 2. The unadjusted ORs for death following COVID-19 were 2.35 (95% CI 1.51 to 3.65) for group 1 and 0.45 (0.34 to 0.6) for group 2. Only the adjusted OR for death remained significant for group 2 with OR 0.47 (0.34 to 0.63). Absolute risk of death was 4.6% for the control group vs 10.1% and 2.1%, for the decreased and increased oestrogen groups, respectively. The risk of death due to COVID-19 was significantly associated with: age, OR 1.15 (1.14 to 1.17); annual income, poorest 2.79 (1.96 to 3.97), poor 2.43 (91.71 to 3.46) and middle 1.64 (1.11 to 2.41); and education (primary 1.4 (1.07 to 1.81)) and wCCI 1.13 (1.1 to 1.16).

    CONCLUSIONS: Oestrogen supplementation in postmenopausal women is associated with a decreased risk of dying from COVID-19 in this nationwide cohort study. These findings are limited by the retrospective and non-randomised design. Further randomised intervention trials are warranted.

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  • 24. Tatsumi, Kohei
    et al.
    Hisada, Yohei
    Fors Connolly, Anne-Marie
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Buranda, Tione
    Mackman, Nigel
    Patients with severe orthohantavirus cardiopulmonary syndrome due to Sin Nombre Virus infection have increased circulating extracellular vesicle tissue factor and an activated coagulation system2019In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 179, p. 31-33Article in journal (Refereed)
  • 25.
    Waltraud, Schrottmaier
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Institute of Vascular Biology and Thrombosis Research, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
    Schmuckenschlager, Anna
    Institute of Vascular Biology and Thrombosis Research, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
    Thunberg, Therese
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Wigren, Julia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Fors Connolly, Anne-Marie
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Assinger, Alice
    Institute of Vascular Biology and Thrombosis Research, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Forsell, Mattias N. E.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Direct and indirect effects of Puumala hantavirus on platelet function2024In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 233, p. 41-54Article in journal (Refereed)
    Abstract [en]

    Thrombocytopenia is a cardinal symptom of hantavirus-induced diseases including Puumala virus (PUUV)-induced hemorrhagic fever with renal syndrome (HFRS), which is associated with impaired platelet function, bleeding manifestations and augmented thrombotic risk. However, the underlying mechanisms causing thrombocytopenia and platelet hypo-responsiveness are unknown. Thus, we investigated the direct and indirect impact of PUUV on platelet production, function and degradation. Analysis of PUUV-HFRS patient blood revealed that platelet hypo-responsiveness in PUUV infection was cell-intrinsic and accompanied by reduced platelet-leukocyte aggregates (PLAs) and upregulation of monocyte tissue factor (TF), whereas platelet vasodilator-stimulated phosphoprotein (VASP) phosphorylation was comparable to healthy controls. Plasma CXCL4 levels followed platelet count dynamics throughout disease course. PUUV activated both neutrophils and monocytes in vitro, but platelet desialylation, degranulation and GPIIb/IIIa activation as well as PLA formation and endothelial adhesion under flow remained unaltered in the presence of PUUV. Further, MEG-01 megakaryocytes infected with PUUV displayed unaltered polyploidization, expression of surface receptors and platelet production. However, infection of endothelial cells with PUUV significantly increased platelet sequestration. Our data thus demonstrate that although platelet production, activation or degradation are not directly modulated, PUUV indirectly fosters thrombocytopenia by sequestration of platelets to infected endothelium. Upregulation of immunothrombotic processes in PUUV-HFRS may further contribute to platelet dysfunction and consumption. Given the pathophysiologic similarities of hantavirus infections, our findings thus provide important insights into the mechanisms underlying thrombocytopenia and highlight immune-mediated coagulopathy as potential therapeutic target.

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  • 26.
    Welen, Karin
    et al.
    Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Rosendal, Ebba
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Freyhult, Eva
    Department of Medical Sciences, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Fors Connolly, Anne-Marie
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). The Laboratory for Molecular Infection Medicine Sweden, Umeå, Sweden.
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). The Laboratory for Molecular Infection Medicine Sweden, Umeå, Sweden.
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Re: Chen Dong, Sung-Lang Chen, and Wen-Wei Sung's Letter to the Editor re: Karin Welén, Ebba Rosendal, Magnus Gisslén, et al. A Phase 2 Trial of the Effect of Antiandrogen Therapy on COVID-19 Outcome: No Evidence of Benefit, Supported by Epidemiology and In Vitro Data. Eur Urol. 2022;81:285–93.2022In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 81, no 5, p. e124-e125Article in journal (Other academic)
  • 27.
    Welén, Karin
    et al.
    Institute of Clinical Sciences, Department of Urology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Rosendal, Ebba
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Freyhult, Eva
    Department of Cell and Molecular Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Oh, William K.
    Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, NY, New York, United States.
    Gisslén, Magnus
    Institute of Biomedicine, Department of Infectious Diseases, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Fors Connolly, Anne-Marie
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Institute of Clinical Sciences, Department of Urology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Reply to Carlos G. Wambier and Gerard J. Nau's Letter to the Editor re: Karin Welén, Ebba Rosendal, Magnus Gisslén, et al. A Phase 2 Trial of the Effect of Antiandrogen Therapy on COVID-19 Outcome: No Evidence of Benefit, Supported by Epidemiology and In Vitro Data. Eur Urol. 2022;81:285–93. Positive Effects of Enzalutamide for Hospitalized COVID-19 Patients: Still No Positive Effect of Enzalutamide for Hospitalized COVID-19 Patients2022In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 81, no 6, p. e143-e144Article in journal (Other academic)
  • 28. Welén, Karin
    et al.
    Rosendal, Ebba
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Gisslén, Magnus
    Lenman, Annasara
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Freyhult, Eva
    Fonseca Rodriguez, Osvaldo
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Bremell, Daniel
    Stranne, Johan
    Östholm Balkhed, Åse
    Niward, Katarina
    Repo, Johanna
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Robinsson, David
    Henningsson, Anna J.
    Styrke, Johan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Angelin, Martin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Lindquist, Elisabeth
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Allard, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Becker, Miriam
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Rudolfsson, Stina H.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Buckland, Robert
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Thellenberg Carlsson, Camilla
    Bjartell, Anders
    Nilsson, Anna C.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Fors Connolly, Anne-Marie
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    A Phase 2 Trial of the Effect of Antiandrogen Therapy on COVID-19 Outcome: No Evidence of Benefit, Supported by Epidemiology and In Vitro Data2022In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 81, no 3, p. 285-293Article in journal (Refereed)
    Abstract [en]

    Background: Men are more severely affected by COVID-19. Testosterone may influence SARS-CoV-2 infection and the immune response.

    Objective: To clinically, epidemiologically, and experimentally evaluate the effect of antiandrogens on SARS-CoV-2 infection.

    Designs, settings, and participants: A randomized phase 2 clinical trial (COVIDENZA) enrolled 42 hospitalized COVID-19 patients before safety evaluation. We also conducted a population-based retrospective study of 7894 SARS-CoV-2–positive prostate cancer patients and an experimental study using an air-liquid interface three-dimensional culture model of primary lung cells.

    Intervention: In COVIDENZA, patients were randomized 2:1 to 5 d of enzalutamide or standard of care.

    Outcome measurements: The primary outcomes in COVIDENZA were the time to mechanical ventilation or discharge from hospital. The population-based study investigated risk of hospitalization, intensive care, and death from COVID-19 after androgen inhibition.

    Results and limitations: Enzalutamide-treated patients required longer hospitalization (hazard ratio [HR] for discharge from hospital 0.43, 95% confidence interval [CI] 0.20–0.93) and the trial was terminated early. In the epidemiological study, no preventive effects were observed. The frail population of patients treated with androgen deprivation therapy (ADT) in combination with abiraterone acetate or enzalutamide had a higher risk of dying from COVID-19 (HR 2.51, 95% CI 1.52–4.16). In vitro data showed no effect of enzalutamide on virus replication. The epidemiological study has limitations that include residual confounders.

    Conclusions: The results do not support a therapeutic effect of enzalutamide or preventive effects of bicalutamide or ADT in COVID-19. Thus, these antiandrogens should not be used for hospitalized COVID-19 patients or as prevention for COVID-19. Further research on these therapeutics in this setting are not warranted.

    Patient summary: We studied whether inhibition of testosterone could diminish COVID-19 symptoms. We found no evidence of an effect in a clinical study or in epidemiological or experimental investigations. We conclude that androgen inhibition should not be used for prevention or treatment of COVID-19.

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