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| 2. |
- Connolly-Andersen, Anne-Marie, et al.
(författare)
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Endothelial activation and repair during hantavirus infection : association with disease outcome
- 2014
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Ingår i: Open forum infectious diseases. - : Oxford University Press (OUP). - 2328-8957. ; 1:1
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Tidskriftsartikel (refereegranskat)abstract
- 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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| 3. |
- Connolly-Andersen, Anne-Marie, et al.
(författare)
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Increased Risk of Acute Myocardial Infarction and Stroke During Hemorrhagic Fever With Renal Syndrome A Self-Controlled Case Series Study
- 2014
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Ingår i: Circulation. - 0009-7322 .- 1524-4539. ; 129:12, s. 1295-1302
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 4. |
- Connolly-Andersen, Anne-Marie, et al.
(författare)
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Increased Thrombopoiesis and Platelet Activation in Hantavirus-Infected Patients
- 2015
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Ingår i: Journal of Infectious Diseases. - : Oxford University Press. - 0022-1899 .- 1537-6613. ; 212:7, s. 1061-1069
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 5. |
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| 6. |
- Connolly-Andersen, Anne-Marie
(författare)
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Pathogenesis of an emerging pathogen : Crimean-Congo hemorrhagic fever virus
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Epithelial cells represent the first barrier to viral infection and the site of viral entry and release is often intimately connected with viral spread and pathogenesis. The plasma membrane of epithelial cells is polarized into an apical and basolateral domain separated by tight junctions (TJs). TJs also regulate paracellular permeability and can cause leakage upon deregulation. The key players underlying VHF pathogenesis are believed to be endothelial cells (ECs) and immune cells. Generally ECs can be targeted either directly by viral infection and/or indirectly by soluble mediators released from infected immune cells leading to the observed hemorrhage and vascular permeability. The main aims of this thesis were to study the direct and indirect effect of viral replication on epithelial and immune cells as a possible contribution to CCHF molecular pathogenesis. By studying the site of entry and release in polarized epithelial cells, we showed the entry and release of CCHFV to be preferentially basolateral. We studied the transepithelial electrical resistance (TER) over infected epithelial cells, and showed that CCHFV replication has no direct effect on epithelial permeability. Furthermore, we observed no effect of CCHFV on the localization of the TJ proteins occludin and ZO-1 in epithelial cells. Interestingly, CCHFV directly activates ECs upon infection as shown by upregulation of intercellular adhesion molecule 1 (ICAM-1), release of IL-6 and IL- 8 and most importantly increased adhesion of leukocytes. The finding that the increased vascular permeability and hemorrhage is most likely not caused by CCHFV induced TJ disassembly suggests that other cells are likely to be, at least partly, involved in pathogenesis and we therefore focused on the contribution of immune cells to pathogenesis. We showed that only monocyte-derived dendritic cells (moDCs) could be productively infected by CCHFV and that infection was followed by the release of tumor necrosis factor (TNF), IL-6 and IL-10. Interestingly, conditioned media from CCHFV-infected moDCs activated ECs as indicated by enhanced intercellular adhesion molecule 1 (ICAM-1) expression. This effect was shown to be dependent on TNF. The work presented in this thesis provides an insight into the direct and indirect interplay between epithelial cells and immune cells and provides data that could be used for further studies into the underlying mechanisms of CCHF pathogenesis. Importantly understanding the mechanisms behind CCHF pathogenesis is most likely needed for the future development of specific treatments and/or vaccines against CCHFV.
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| 7. |
- Connolly-Andersen, Anne-Marie, et al.
(författare)
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Risk of venous thromboembolism following hemorrhagic fever with renal syndrome : a self-controlled case series study
- 2018
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Ingår i: Clinical Infectious Diseases. - : Oxford University Press. - 1058-4838 .- 1537-6591. ; 66:2, s. 268-273
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 8. |
- Connolly-Andersen, Anne-Marie, et al.
(författare)
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Sorkfeber ökar risken för stroke och hjärtinfarkt
- 2014
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Ingår i: Läkartidningen. - : Sveriges läkarförbund. - 0023-7205 .- 1652-7518. ; 111:6
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 9. |
- Fonseca-Rodríguez, Osvaldo, et al.
(författare)
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Avoiding bias in self-controlled case series studies of coronavirus disease 2019
- 2021
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Ingår i: Statistics in Medicine. - : John Wiley & Sons. - 0277-6715 .- 1097-0258. ; 40:27, s. 6197-6208
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 10. |
- Fonseca-Rodríguez, Osvaldo, et al.
(författare)
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Spatial clustering and contextual factors associated with hospitalisation and deaths due to COVID-19 in Sweden : A geospatial nationwide ecological study
- 2021
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Ingår i: BMJ Global Health. - : BMJ Publishing Group Ltd. - 2059-7908. ; 6:7
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Tidskriftsartikel (refereegranskat)abstract
- 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.
(författare)
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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.
- 2022
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Ingår i: Journal of Epidemiology and Community Health. - : BMJ Publishing Group Ltd. - 0143-005X .- 1470-2738. ; 76:3, s. 261-267
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Tidskriftsartikel (refereegranskat)abstract
- 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. |
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| 13. |
- Katsoularis, Ioannis, et al.
(författare)
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Risk of acute myocardial infarction and ischaemic stroke following COVID-19 in Sweden : a self-controlled case series and matched cohort study
- 2021
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Ingår i: The Lancet. - : Elsevier. - 0140-6736 .- 1474-547X. ; 398:10300, s. 599-607
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 14. |
- Moll, Guido, et al.
(författare)
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Are Therapeutic Human Mesenchymal Stromal Cells Compatible with Human Blood?
- 2012
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Ingår i: Stem Cells. - : Oxford University Press (OUP). - 1066-5099 .- 1549-4918. ; 30:7, s. 1565-1574
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Tidskriftsartikel (refereegranskat)abstract
- Multipotent mesenchymal stromal cells (MSCs) are tested in numerous clinical trials. Questions have been raised concerning fate and function of these therapeutic cells after systemic infusion. We therefore asked whether culture-expanded human MSCs elicit an innate immune attack, termed instant blood-mediated inflammatory reaction (IBMIR), which has previously been shown to compromise the survival and function of systemically infused islet cells and hepatocytes. We found that MSCs expressed hemostatic regulators similar to those produced by endothelial cells but displayed higher amounts of prothrombotic tissue/stromal factors on their surface, which triggered the IBMIR after blood exposure, as characterized by formation of blood activation markers. This process was dependent on the cell dose, the choice of MSC donor, and particularly the cell-passage number. Short-term expanded MSCs triggered only weak blood responses in vitro, whereas extended culture and coculture with activated lymphocytes increased their prothrombotic properties. After systemic infusion to patients, we found increased formation of blood activation markers, but no formation of hyperfibrinolysis marker D-dimer or acute-phase reactants with the currently applied dose of 1.0-3.0 x 10(6) cells per kilogram. Culture-expanded MSCs trigger the IBMIR in vitro and in vivo. Induction of IBMIR is dose-dependent and increases after prolonged ex vivo expansion. Currently applied doses of low-passage clinical-grade MSCs elicit only minor systemic effects, but higher cell doses and particularly higher passage cells should be handled with care. This deleterious reaction can compromise the survival, engraftment, and function of these therapeutic cells.
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| 15. |
- Schmedes, Clare M., et al.
(författare)
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Circulating extracellular vesicle tissue factor activity during orthohantavirus infection is associated with intravascular coagulation
- 2020
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Ingår i: Journal of Infectious Diseases. - : Oxford University Press. - 0022-1899 .- 1537-6613. ; 222:8, s. 1392-1399
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Tidskriftsartikel (refereegranskat)abstract
- 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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